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Teipel S, Akmatov M, Michalowsky B, Riedel-Heller S, Bohlken J, Holstiege J. Timing of risk factors, prodromal features, and comorbidities of dementia from a large health claims case-control study. Alzheimers Res Ther 2025; 17:22. [PMID: 39819557 PMCID: PMC11736938 DOI: 10.1186/s13195-024-01662-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 12/20/2024] [Indexed: 01/19/2025]
Abstract
BACKGROUND Many risk factors for dementia have been identified, but the timing of risk is less well understood. Here, we analyzed risk factors in a case-control study covering 10 years before an incident dementia diagnosis. METHODS We designed a case-control study using insurance claims of outpatient consultations of patients with German statutory health insurance between January 1, 2012, and December 31, 2022. We included patients with an incident diagnosis of dementia and controls without a diagnosis of dementia matched 1:2 for age, sex, region, and earliest year of outpatient encounter. We selected exposures based on previous systematic reviews, case-control and cohort studies reporting on risk factors, comorbidities, and prodromal features of dementia. We calculated the prevalence of risk factors in cases and controls and odds ratios for each year before the index date, along with Bonferroni-corrected confidence intervals, using conditional logistic regression. RESULTS We identified a total of 1,686,759 patients with incident dementia (mean (SD) age, 82.15 (6.90) years; 61.70% female) and 3,373,518 matched controls (mean (SD) age, 82.15 (6.90) years; 61.70% female). Study participants were followed up for a mean (SD) of 6.6 (2.3) years. Of the 63 risk factors and prodromal features examined, 56 were associated with an increased risk of dementia in all years during the 10th and the 1st year before the index date. These included established risk factors, such as depression, hypertension, hearing impairment, nicotine and alcohol abuse, obesity, hypercholesterolaemia, traumatic brain injury, and diabetes. The greatest risk, with odds ratios greater than 2.5, was conferred by delirium, memory impairment, mental retardation, personality and behavioral disorders, sensory disorders, schizophrenia, and psychosis. Cancer was associated with a reduced risk of dementia. CONCLUSIONS This large case-control study confirmed established risk factors of dementia. In addition, the study identified non-specific diagnoses that showed a steep increase in risk close to the index date, such as psychosis, conduct disorder, and other sensory disorders. Consideration of these diagnoses, which may represent prodromal features rather than risk factors for dementia, may help to identify people with dementia in routine care.
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Affiliation(s)
- Stefan Teipel
- German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald, Gehlsheimer Str. 20, Rostock, 18147, Germany.
- Department of Psychosomatic Medicine, University Medicine Rostock, Gehlsheimer Str. 20, Rostock, 18147, Germany.
| | - Manas Akmatov
- Department of Epidemiology and Healthcare Atlas, Central Research Institute of Ambulatory Health Care in Germany, Berlin, Germany
| | - Bernhard Michalowsky
- German Center for Neurodegenerative Diseases (DZNE), Rostock/Greifswald, Greifswald, Germany
| | - Steffi Riedel-Heller
- Institute of Social Medicine, Occupational Health and Public Health, Faculty of Medicine, University of Leipzig, Leipzig, Germany
| | - Jens Bohlken
- Institute of Social Medicine, Occupational Health and Public Health, Faculty of Medicine, University of Leipzig, Leipzig, Germany
| | - Jakob Holstiege
- Department of Epidemiology and Healthcare Atlas, Central Research Institute of Ambulatory Health Care in Germany, Berlin, Germany
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Giraldo-Berrio D, Mendivil-Perez M, Velez-Pardo C, Jimenez-Del-Rio M. Rotenone Induces a Neuropathological Phenotype in Cholinergic-like Neurons Resembling Parkinson's Disease Dementia (PDD). Neurotox Res 2024; 42:28. [PMID: 38842585 PMCID: PMC11156752 DOI: 10.1007/s12640-024-00705-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 04/12/2024] [Accepted: 05/01/2024] [Indexed: 06/07/2024]
Abstract
Parkinson's disease with dementia (PDD) is a neurological disorder that clinically and neuropathologically overlaps with Parkinson's disease (PD) and Alzheimer's disease (AD). Although it is assumed that alpha-synuclein ( α -Syn), amyloid beta (A β ), and the protein Tau might synergistically induce cholinergic neuronal degeneration, presently the pathological mechanism of PDD remains unclear. Therefore, it is essential to delve into the cellular and molecular aspects of this neurological entity to identify potential targets for prevention and treatment strategies. Cholinergic-like neurons (ChLNs) were exposed to rotenone (ROT, 10 μ M) for 24 h. ROT provokes loss of Δ Ψ m , generation of reactive oxygen species (ROS), phosphorylation of leucine-rich repeated kinase 2 (LRRK2 at Ser935) concomitantly with phosphorylation of α -synuclein ( α -Syn, Ser129), induces accumulation of intracellular A β (iA β ), oxidized DJ-1 (Cys106), as well as phosphorylation of TAU (Ser202/Thr205), increases the phosphorylation of c-JUN (Ser63/Ser73), and increases expression of proapoptotic proteins TP53, PUMA, and cleaved caspase 3 (CC3) in ChLNs. These neuropathological features resemble those reproduced in presenilin 1 (PSEN1) E280A ChLNs. Interestingly, anti-oxidant and anti-amyloid cannabidiol (CBD), JNK inhibitor SP600125 (SP), TP53 inhibitor pifithrin- α (PFT), and LRRK2 kinase inhibitor PF-06447475 (PF475) significantly diminish ROT-induced oxidative stress (OS), proteinaceous, and cell death markers in ChLNs compared to naïve ChLNs. In conclusion, ROT induces p- α -Syn, iA β , p-Tau, and cell death in ChLNs, recapitulating the neuropathology findings in PDD. Our report provides an excellent in vitro model to test for potential therapeutic strategies against PDD. Our data suggest that ROT induces a neuropathologic phenotype in ChLNs similar to that caused by the mutation PSEN1 E280A.
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Affiliation(s)
- Daniela Giraldo-Berrio
- Neuroscience Research Group, Medical Research Institute, Faculty of Medicine, University of Antioquia (UdeA), Calle 70 No. 52-21, and Calle 62 # 52-59, Building 1, Room 412, Medellin, Antioquia, Colombia
| | - Miguel Mendivil-Perez
- Neuroscience Research Group, Medical Research Institute, Faculty of Medicine, University of Antioquia (UdeA), Calle 70 No. 52-21, and Calle 62 # 52-59, Building 1, Room 412, Medellin, Antioquia, Colombia
| | - Carlos Velez-Pardo
- Neuroscience Research Group, Medical Research Institute, Faculty of Medicine, University of Antioquia (UdeA), Calle 70 No. 52-21, and Calle 62 # 52-59, Building 1, Room 412, Medellin, Antioquia, Colombia.
| | - Marlene Jimenez-Del-Rio
- Neuroscience Research Group, Medical Research Institute, Faculty of Medicine, University of Antioquia (UdeA), Calle 70 No. 52-21, and Calle 62 # 52-59, Building 1, Room 412, Medellin, Antioquia, Colombia.
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Degirmenci Y, Angelopoulou E, Georgakopoulou VE, Bougea A. Cognitive Impairment in Parkinson's Disease: An Updated Overview Focusing on Emerging Pharmaceutical Treatment Approaches. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1756. [PMID: 37893474 PMCID: PMC10608778 DOI: 10.3390/medicina59101756] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/17/2023] [Accepted: 09/29/2023] [Indexed: 10/29/2023]
Abstract
Cognitive impairment in patients with Parkinson's disease (PD) is one of the commonest and most disabling non-motor manifestations during the course of the disease. The clinical spectrum of PD-related cognitive impairment includes subjective cognitive decline (SCD), mild cognitive impairment (MCI) and PD dementia (PDD). As the disease progresses, cognitive decline creates a significant burden for the family members and/or caregivers of patients with PD, and has a great impact on quality of life. Current pharmacological treatments have demonstrated partial efficacy and failed to halt disease progression, and novel, effective, and safe therapeutic strategies are required. Accumulating preclinical and clinical evidence shows that several agents may provide beneficial effects on patients with PD and cognitive impairment, including ceftriaxone, ambroxol, intranasal insulin, nilotinib, atomoxetine, mevidalen, blarcamesine, prasinezumab, SYN120, ENT-01, NYX-458, GRF6021, fosgonimeton, INT-777, Neuropeptide S, silibinin, osmotin, cordycepin, huperzine A, fibroblast growth factor 21, Poloxamer 188, ginsenoside Rb1, thioredoxin-1, tangeretin, istradefylline and Eugenia uniflora. Potential underlying mechanisms include the inhibition of a-synuclein aggregation, the improvement of mitochondrial function, the regulation of synaptic plasticity, an impact on the gut-brain axis, the modulation of neuroinflammation and the upregulation of neurotrophic factors, as well as cholinergic, dopaminergic, serotoninergic and norepinephrine neurotransmission. In this updated overview, we aim to cover the clinical aspects of the spectrum of PD-related cognitive impairment and discuss recent evidence on emerging treatment approaches that are under investigation at a preclinical and clinical level. Finally, we aim to provide additional insights and propose new ideas for investigation that may be feasible and effective for the spectrum of PD-related cognitive impairment.
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Affiliation(s)
- Yildiz Degirmenci
- Department of Neurology, School of Medicine, Istanbul Health and Technology University, 34093 Istanbul, Turkey;
- Parkinson’s Disease and Movement Disorders Unit, Neurology Clinic, Sisli Kolan International Hospital, 34384 Istanbul, Turkey
| | - Efthalia Angelopoulou
- 1st Department of Neurology, Medical School, National and Kapodistrian University of Athens, Eginition Hospital, 11528 Athens, Greece;
| | | | - Anastasia Bougea
- 1st Department of Neurology, Medical School, National and Kapodistrian University of Athens, Eginition Hospital, 11528 Athens, Greece;
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Skylar-Scott IA, Sha SJ. Lewy Body Dementia: An Overview of Promising Therapeutics. Curr Neurol Neurosci Rep 2023; 23:581-592. [PMID: 37572228 DOI: 10.1007/s11910-023-01292-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/30/2023] [Indexed: 08/14/2023]
Abstract
PURPOSE OF REVIEW Lewy body dementia (LBD) encompasses dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). This article will emphasize potential disease-modifying therapies as well as investigative symptomatic treatments for non-motor symptoms including cognitive impairment and psychosis that can present a tremendous burden to patients with LBD and their caregivers. RECENT FINDINGS We review 11 prospective disease-modifying therapies (DMT) including four with phase 2 data (neflamapimod, nilotinib, bosutinib, and E2027); four with some limited data in symptomatic populations including phase 1, open-label, registry, or cohort data (vodabatinib, ambroxol, clenbuterol, and terazosin); and three with phase 1 data in healthy populations (Anle138b, fosgonimeton, and CT1812). We also appraise four symptomatic therapies for cognitive impairment, but due to safety and efficacy concerns, only NYX-458 remains under active investigation. Of symptomatic therapies for psychosis recently investigated, pimavanserin shows promise in LBD, but studies of nelotanserin have been suspended. Although the discovery of novel symptomatic and disease-modifying therapeutics remains a significant challenge, recently published and upcoming trials signify promising strides toward that aim.
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Affiliation(s)
- Irina A Skylar-Scott
- Memory Disorders Division, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 213 Quarry Road, Palo Alto, CA, 94305, USA.
| | - Sharon J Sha
- Memory Disorders Division, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 213 Quarry Road, Palo Alto, CA, 94305, USA
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Zhao W, Cheng B, Zhu T, Cui Y, Shen Y, Fu X, Li M, Feng Y, Zhang S. Effects of white matter hyperintensity on cognitive function in PD patients: a meta-analysis. Front Neurol 2023; 14:1203311. [PMID: 37621858 PMCID: PMC10445042 DOI: 10.3389/fneur.2023.1203311] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 07/27/2023] [Indexed: 08/26/2023] Open
Abstract
Background Parkinson's disease (PD) is often accompanied by cognitive dysfunction, which imposes a heavy burden on patients, their families, and society. Early identification and intervention are particularly important, but reliable biomarkers for identifying PD-related cognitive impairment at an early stage are currently lacking. Although numerous clinical studies have investigated the association between brain white matter hyperintensity (WMH) and cognitive decline, the findings regarding the relationships between WMH and cognitive dysfunction in PD patients have been inconsistent. Therefore, this study aims to conduct a meta-analysis of the effect of WMH on PD cognitive function. Methods This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines. We systematically searched relevant literature from databases such as PubMed, Web of Science, EMBASE, CNKI, and CBM. The retrieval time was limited to database records created up until December 31, 2022. Additionally, we manually retrieved references for full-text reading. Statistical data analysis was performed using RevMan 5.3 and Stata 15.0 software. Results This study encompassed 23 individual studies and involved 2,429 patients with PD. The group of PD with mild cognitive impairment (PD-MCI) exhibited a significantly higher overall level of WMH than the group of PD with normal cognitive function (PD-NC) (SMD = 0.37, 95% CI: 0.21-0.52, p < 0.01). This finding was consistent across subgroup analyses based on different ethnicities (Asian or Caucasian), WMH assessment methods (visual rating scale or volumetry), and age matching. In addition to the overall differences in WMH load between the PD-MCI and PD-NC groups, the study found that specific brain regions, including periventricular white matter hyperintensity (PVH) and deep white matter hyperintensity (DWMH), had significantly higher WMH load in the PD-MCI group compared to the PD-NC group. The study also conducted a meta-analysis of WMH load data for PD with dementia (PDD) and PD without dementia (PDND), revealing that the overall WMH load in the PDD group was significantly higher than that in the PDND group (SMD = 0.98, 95% CI: 0.56-1.41, p < 0.01). This finding was consistent across subgroup analyses based on different ethnicities and age matching. Moreover, regarding specific brain regions (PVH or DWMH), the study found that the PDD group had significantly higher WMH load than the PDND group (p < 0.01). Conclusion WMH was associated with PD cognitive dysfunction. The early appearance of WMH may indicate PD with MCI.
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Affiliation(s)
- Wenhao Zhao
- Department of Neurology, Affiliated Hospital of Medical College, North Sichuan Medical College, Nanchong, China
| | - Bo Cheng
- Department of Neurology, Affiliated Hospital of Medical College, North Sichuan Medical College, Nanchong, China
| | - Tao Zhu
- Department of Preventive Medicine, North Sichuan Medical College, Nanchong, China
| | - Yingjuan Cui
- Department of Nursing, Affiliated Hospital of Medical College, North Sichuan Medical College, Nanchong, China
| | - Yao Shen
- Department of Neurology, Affiliated Hospital of Medical College, North Sichuan Medical College, Nanchong, China
| | - Xudong Fu
- Department of Neurology, Affiliated Hospital of Medical College, North Sichuan Medical College, Nanchong, China
| | - Maogeng Li
- Department of Neurology, Affiliated Hospital of Medical College, North Sichuan Medical College, Nanchong, China
| | - Yuliang Feng
- Department of Neurology, Affiliated Hospital of Medical College, North Sichuan Medical College, Nanchong, China
| | - Shushan Zhang
- Department of Neurology, Affiliated Hospital of Medical College, North Sichuan Medical College, Nanchong, China
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McFall GP, Bohn L, Gee M, Drouin SM, Fah H, Han W, Li L, Camicioli R, Dixon RA. Identifying key multi-modal predictors of incipient dementia in Parkinson's disease: a machine learning analysis and Tree SHAP interpretation. Front Aging Neurosci 2023; 15:1124232. [PMID: 37455938 PMCID: PMC10347530 DOI: 10.3389/fnagi.2023.1124232] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 06/13/2023] [Indexed: 07/18/2023] Open
Abstract
Background Persons with Parkinson's disease (PD) differentially progress to cognitive impairment and dementia. With a 3-year longitudinal sample of initially non-demented PD patients measured on multiple dementia risk factors, we demonstrate that machine learning classifier algorithms can be combined with explainable artificial intelligence methods to identify and interpret leading predictors that discriminate those who later converted to dementia from those who did not. Method Participants were 48 well-characterized PD patients (Mbaseline age = 71.6; SD = 4.8; 44% female). We tested 38 multi-modal predictors from 10 domains (e.g., motor, cognitive) in a computationally competitive context to identify those that best discriminated two unobserved baseline groups, PD No Dementia (PDND), and PD Incipient Dementia (PDID). We used Random Forest (RF) classifier models for the discrimination goal and Tree SHapley Additive exPlanation (Tree SHAP) values for deep interpretation. Results An excellent RF model discriminated baseline PDID from PDND (AUC = 0.84; normalized Matthews Correlation Coefficient = 0.76). Tree SHAP showed that ten leading predictors of PDID accounted for 62.5% of the model, as well as their relative importance, direction, and magnitude (risk threshold). These predictors represented the motor (e.g., poorer gait), cognitive (e.g., slower Trail A), molecular (up-regulated metabolite panel), demographic (age), imaging (ventricular volume), and lifestyle (activities of daily living) domains. Conclusion Our data-driven protocol integrated RF classifier models and Tree SHAP applications to selectively identify and interpret early dementia risk factors in a well-characterized sample of initially non-demented persons with PD. Results indicate that leading dementia predictors derive from multiple complementary risk domains.
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Affiliation(s)
- G. Peggy McFall
- Department of Psychology, University of Alberta, Edmonton, AB, Canada
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
| | - Linzy Bohn
- Department of Psychology, University of Alberta, Edmonton, AB, Canada
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
| | - Myrlene Gee
- Department of Medicine (Neurology), University of Alberta, Edmonton, AB, Canada
| | - Shannon M. Drouin
- Department of Psychology, University of Alberta, Edmonton, AB, Canada
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
| | - Harrison Fah
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
- Department of Computing Science, University of Alberta, Edmonton, AB, Canada
| | - Wei Han
- Department of Chemistry, University of Alberta, Edmonton, AB, Canada
| | - Liang Li
- Department of Chemistry, University of Alberta, Edmonton, AB, Canada
| | - Richard Camicioli
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
- Department of Medicine (Neurology), University of Alberta, Edmonton, AB, Canada
| | - Roger A. Dixon
- Department of Psychology, University of Alberta, Edmonton, AB, Canada
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
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Dubey S, Das S, Ghosh R, Dubey MJ, Chakraborty AP, Roy D, Das G, Dutta A, Santra A, Sengupta S, Benito-León J. The Effects of SARS-CoV-2 Infection on the Cognitive Functioning of Patients with Pre-Existing Dementia. J Alzheimers Dis Rep 2023; 7:119-128. [PMID: 36891252 PMCID: PMC9986710 DOI: 10.3233/adr-220090] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 01/03/2023] [Indexed: 02/05/2023] Open
Abstract
Background Cognitive postscripts of COVID-19, codenamed as 'cognitive COVID' or 'brain fog,' characterized by multidomain cognitive impairments, are now being reckoned as the most devastating sequelae of COVID-19. However, the impact on the already demented brain has not been studied. Objective We aimed to assess the cognitive functioning and neuroimaging following SARS-CoV-2 infection in patients with pre-existing dementia. Methods Fourteen COVID-19 survivors with pre-existing dementia (four with Alzheimer's disease, five with vascular dementia, three with Parkinson's disease dementia, and two with the behavioral variant of frontotemporal dementia) were recruited. All these patients had detailed cognitive and neuroimaging evaluations within three months before suffering from COVID-19 and one year later. Results Of the 14 patients, ten required hospitalization. All developed or increased white matter hyperintensities that mimicked multiple sclerosis and small vessel disease. There was a significant increase in fatigue (p = 0.001) and depression (p = 0.016) scores following COVID-19. The mean Frontal Assessment Battery (p < 0.001) and Addenbrooke's Cognitive Examination (p = 0.001) scores also significantly worsened. Conclusion The rapid progression of dementia, the addition of further impairments/deterioration of cognitive abilities, and the increase or new appearance of white matter lesion burden suggest that previously compromised brains have little defense to withstand a new insult (i.e., 'second hit' like infection/dysregulated immune response, and inflammation). 'Brain fog' is an ambiguous terminology without specific attribution to the spectrum of post-COVID-19 cognitive sequelae. We propose a new codename, i.e. 'FADE-IN MEMORY' (i.e., Fatigue, decreased Fluency, Attention deficit, Depression, Executive dysfunction, slowed INformation processing speed, and subcortical MEMORY impairment).
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Affiliation(s)
- Souvik Dubey
- Department of Neuromedicine, Bangur Institute of
Neurosciences (BIN), Kolkata, West Bengal, India
| | - Shambaditya Das
- Department of Neuromedicine, Bangur Institute of
Neurosciences (BIN), Kolkata, West Bengal, India
| | - Ritwik Ghosh
- Department of General Medicine, Burdwan Medical College, and
Hospital, Burdwan, West Bengal, India
| | - Mahua Jana Dubey
- Department of Psychiatry, Berhampur Mental
Hospital, Berhampur, West Bengal, India
| | - Arka Prava Chakraborty
- Department of Neuromedicine, Bangur Institute of
Neurosciences (BIN), Kolkata, West Bengal, India
| | - Dipayan Roy
- Department of Biochemistry, All India Institute of Medical
Sciences (AIIMS), Patna, Bihar, India
- Indian Institute of Technology (IIT), Madras,
Tamil Nadu, India
- School of Sciences, Indira Gandhi National Open
University, New Delhi, India
| | - Gautam Das
- Department of Neuromedicine, Bangur Institute of
Neurosciences (BIN), Kolkata, West Bengal, India
| | - Ajitava Dutta
- Department of Neuromedicine, Bangur Institute of
Neurosciences (BIN), Kolkata, West Bengal, India
| | - Arindam Santra
- Department of Neuromedicine, Bangur Institute of
Neurosciences (BIN), Kolkata, West Bengal, India
| | - Samya Sengupta
- Department of General Medicine, Apollo Gleneagles
Hospital, Kolkata, West Bengal, India
| | - Julián Benito-León
- Department of Neurology, University Hospital “12 de
Octubre”, Madrid, Spain
- Centro de Investigación Biomódica en Red Sobre
Enfermedades Neurodegenerativas (CIBERNED), Madrid,
Spain
- Department of Medicine, Complutense University,
Madrid, Spain
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Bayram E, Holden SK, Fullard M, Armstrong MJ. Race and Ethnicity in Lewy Body Dementia: A Narrative Review. J Alzheimers Dis 2023; 94:861-878. [PMID: 37355902 PMCID: PMC10448838 DOI: 10.3233/jad-230207] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/26/2023]
Abstract
Lewy body dementia is the third most common and costliest type of dementia. It is an umbrella term for dementia with Lewy bodies and Parkinson's disease dementia, both of which place a substantial burden on the person and society. Recent findings outline ethnoracial differences in dementia risk. Delayed and misdiagnosis across ethnoracial groups contribute to higher levels of burden. In this context, we aimed to summarize current knowledge, gaps, and unmet needs relating to race and ethnicity in Lewy body dementia. In this narrative review, we provide an overview of studies on Lewy body dementia focusing on differences across ethnoracial groups and outline several recommendations for future studies. The majority of the findings comparing different ethnoracial groups were from North American sites. There were no differences in clinical prevalence and progression across ethnoracial groups. Compared to people identifying as non-Hispanic White, co-pathologies were more common and clinical diagnostic accuracy was lower for people identifying as Black. Co-morbidities (e.g., diabetes, hypertension) were more common and medication use rates (e.g., antidepressants, antiparkinsonian agents) were lower for people identifying as Black or Hispanic compared to people identifying as White. More than 90% of clinical trial participants identified as non-Hispanic White. Despite increasing efforts to overcome disparities in Alzheimer's disease and related dementias, inclusion of individuals from minoritized communities in Lewy body dementia studies continues to be limited and the findings are inconclusive. Representation of diverse populations is crucial to improve the diagnostic and therapeutic efforts in Lewy body dementia.
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Affiliation(s)
- Ece Bayram
- Parkinson and Other Movement Disorders Center, Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
| | - Samantha K Holden
- Department of Neurology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Michelle Fullard
- Department of Neurology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Melissa J Armstrong
- Department of Neurology, University of Florida College of Medicine, Gainesville, FL, USA
- Fixel Institute for Neurological Diseases, Gainesville, FL, USA
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Wang Z, Zheng Y, Cai H, Yang C, Li S, Lv H, Feng T, Yu Z. Aβ1-42-containing platelet-derived extracellular vesicle is associated with cognitive decline in Parkinson's disease. Front Aging Neurosci 2023; 15:1170663. [PMID: 37122378 PMCID: PMC10140302 DOI: 10.3389/fnagi.2023.1170663] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 03/27/2023] [Indexed: 05/02/2023] Open
Abstract
Background Cortical amyloid deposition is a common observation in Parkinson's disease dementia (PDD) patients. Aβ1-42 is linked to a more rapid progression of dementia. Platelets, which degranulate upon activation, are a primary source of Aβ. It has been repeatedly reported that peripheral extracellular vesicles (EVs) can partially reach the central nervous system. Thus, we speculate that activated platelet-derived Aβ1-42-containing EVs (PEV-Aβ1-42) play a crucial role in the cognitive decline of PD patients. Methods The study included 189 participants: 66 with non-dementia PD, 73 with PDD, and 50 healthy controls. All participants underwent blood collection and clinical assessments. Twenty PD patients underwent re-examination and repeated blood collection 14 months later. A nano-scale flow cytometry assay was used to detect PEVs and PEV-Aβ1-42 using fluorescence-labeled CD62P and Aβ1-42 antibodies. Results Parkinson's disease dementia patients had higher PEV-Aβ1-42 concentrations than healthy controls (p = 0.028). The ratio of PEV-Aβ1-42 to PEV was significantly higher in PDD patients compared to those in non-dementia PD and healthy controls (p PD-ND < 0.001, p HC = 0.041). The PEV-Aβ1-42/PEV ratio appears to influence the odds of developing dementia (OR = 1.76, p < 0.001). The change in the PEV-Aβ1-42/PEV ratio was also correlated with cognitive decline over 14 months (r = -0.447, p < 0.05). Conclusion The plasma PEV-Aβ1-42/PEV ratio may serve as a diagnostic and prognostic biomarker for PDD patients.
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Affiliation(s)
- Ziyu Wang
- Center for Movement Disorders, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Yuanchu Zheng
- Center for Movement Disorders, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Huihui Cai
- Center for Movement Disorders, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Chen Yang
- Center for Movement Disorders, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Siming Li
- Center for Movement Disorders, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Hong Lv
- Clinical Diagnosis Department of Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- *Correspondence: Zhenwei Yu, ; Tao Feng, , ; Hong Lv,
| | - Tao Feng
- Center for Movement Disorders, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- *Correspondence: Zhenwei Yu, ; Tao Feng, , ; Hong Lv,
| | - Zhenwei Yu
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
- *Correspondence: Zhenwei Yu, ; Tao Feng, , ; Hong Lv,
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Byeon H. Can the prediction model using regression with optimal scale improve the power to predict the Parkinson's dementia? World J Psychiatry 2022; 12:1031-1043. [PMID: 36158303 PMCID: PMC9476836 DOI: 10.5498/wjp.v12.i8.1031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 06/15/2022] [Accepted: 07/11/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Efficiently detecting Parkinson's disease (PD) with dementia (PDD) as soon as possible is an important issue in geriatric medicine.
AIM To develop a model for predicting PDD based on various neuropsychological tests using data from a nationwide survey conducted by the Korean Centers for Disease Control and Prevention and to present baseline data for the early detection of PDD.
METHODS This study comprised 289 patients who were 60 years or older with PD [110 with PDD and 179 Parkinson's Disease-Mild Cognitive Impairment (PD-MCI)]. Regre-ssion with optimal scaling (ROS) was used to identify independent relationships between the neuropsychological test results and PDD.
RESULTS In the ROS analysis, Korean version of mini mental state ex-amination (MMSE) (KOREAN version of MMSE) (b = -0.52, SE = 0.16) and Hoehn and Yahr staging (b = 0.44, SE = 0.19) were significantly effective models for distinguishing PDD from PD-MCI (P < 0.05), even after adjusting for all of the Parkinson's motor symptom and neuropsychological test results. The optimal number of categories (scaling factors) for KOREAN version of MMSE and Hoehn and Yahr Scale was 10 and 7, respectively.
CONCLUSION The results of this study suggest that among the various neuropsychological tests conducted, the optimal classification scores for KOREAN version of MMSE and Hoehn and Yahr Scale could be utilized as an effective screening test for the early discrimination of PDD from PD-MCI.
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Affiliation(s)
- Haewon Byeon
- Department of Medical Big Data, Inje University, Gimhae 50834, South Korea
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11
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Salwierz P, Davenport C, Sumra V, Iulita MF, Ferretti MT, Tartaglia MC. Sex and gender differences in dementia. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2022; 164:179-233. [PMID: 36038204 DOI: 10.1016/bs.irn.2022.07.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
The dementia landscape has undergone a striking paradigm shift. The advances in understanding of neurodegeneration and proteinopathies has changed our approach to patients with cognitive impairment. Firstly, it has recently been shown that the various proteinopathies that are the cause of the dementia begin to build up long before the appearance of any obvious symptoms. This has cemented the idea that there is an urgency in diagnosis as it occurs very late in the pathophysiology of these diseases. Secondly, that accurate diagnosis is required to deliver targeted therapies, that is precision medicine. With this latter point, the realization that various factors of a person need to be considered as they may impact the presentation and progression of disease has risen to the forefront. Two of these factors aside from race and age are biological sex and gender (social construct), as both can have tremendous impact on manifestation of disease. This chapter will cover what is known and remains to be known on the interaction of sex and gender with some of the major causes of dementia.
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Affiliation(s)
- Patrick Salwierz
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada
| | - Carly Davenport
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada
| | - Vishaal Sumra
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada
| | - M Florencia Iulita
- Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; Center of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain; Women's Brain Project, Guntershausen, Switzerland
| | | | - Maria Carmela Tartaglia
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada; Memory Clinic, Krembil Brain Institute, University Health Network, Toronto, ON, Canada.
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12
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Kwon KY, Park S, Kim RO, Lee EJ, Lee M. Associations of cognitive dysfunction with motor and non-motor symptoms in patients with de novo Parkinson's disease. Sci Rep 2022; 12:11461. [PMID: 35794147 PMCID: PMC9259652 DOI: 10.1038/s41598-022-15630-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 06/27/2022] [Indexed: 11/24/2022] Open
Abstract
The risk factors of mild cognitive impairment (MCI) in patients with de novo Parkinson’s disease (PD) remain unclear. Therefore, the objective of this study was to compare motor and non-motor symptoms between de novo patients with PD with and without MCI. Moreover, detailed relationships between each cognitive deficit and other clinical characteristics in de novo patients with PD were investigated. Consecutive patients with de novo PD were retrospectively enrolled in this study. Motor symptoms were assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS) part-III and the Hoehn and Yahr (HY) stage. Non-motor symptoms including depression, anxiety, fatigue, and autonomic dysfunction were measured using representative questionnaires. Motor symptoms, depression, and dysautonomia were associated with MCI in de novo patients with PD. Compared with the non-MCI group with PD, the MCI group with PD had higher scores of UPDRS-III, HY stage, depression, and dysautonomia, but not fatigue or anxiety. Both UPDRS-III and HY stage were significantly linked to all cognitive deficits except attention. Logistic regression analysis showed that depression was associated with memory, visuospatial, and executive impairment, and dysautonomia was related to visuospatial and executive impairment. The results of this study suggest that cognitive impairment in PD might have a different relationship pattern to the motor and some non-motor symptoms.
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Affiliation(s)
- Kyum-Yil Kwon
- Department of Neurology, Soonchunhyang University Seoul Hospital, Soonchunhyang University School of Medicine, 59 Daesagwan-ro, Yongsan-gu, Seoul, 04401, Republic of Korea.
| | - Suyeon Park
- Department of Biostatistics, Soonchunhyang University Seoul Hospital, Soonchunhyang University School of Medicine, Seoul, Republic of Korea.,Department of Applied Statistics, Chung-Ang University, Seoul, Republic of Korea
| | - Rae On Kim
- Department of Neurology, Soonchunhyang University Seoul Hospital, Soonchunhyang University School of Medicine, 59 Daesagwan-ro, Yongsan-gu, Seoul, 04401, Republic of Korea
| | - Eun Ji Lee
- Department of Neurology, Soonchunhyang University Seoul Hospital, Soonchunhyang University School of Medicine, 59 Daesagwan-ro, Yongsan-gu, Seoul, 04401, Republic of Korea
| | - Mina Lee
- Department of Neurology, Soonchunhyang University Seoul Hospital, Soonchunhyang University School of Medicine, 59 Daesagwan-ro, Yongsan-gu, Seoul, 04401, Republic of Korea
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13
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D'Antonio F, Boccia M, Di Vita A, Suppa A, Fabbrini A, Canevelli M, Caramia F, Fiorelli M, Guariglia C, Ferracuti S, de Lena C, Aarsland D, Ffytche D. Visual hallucinations in Lewy body disease: pathophysiological insights from phenomenology. J Neurol 2022; 269:3636-3652. [PMID: 35099586 PMCID: PMC9217885 DOI: 10.1007/s00415-022-10983-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 01/16/2022] [Accepted: 01/19/2022] [Indexed: 11/13/2022]
Abstract
Visual hallucinations (VH) in Lewy body disease (LBD) have a heterogenous phenomenology classified into minor phenomena (MVH) and complex hallucinations (CVH). Mechanisms underpinning VH and their temporal aspects are largely unknown. According to the hodotopic model, we investigated whether changes in distinct cognitive domains and neural networks in the hallucination trait underpin temporal aspects of MVH and CVH in the hallucination state. 35 LBD patients with VH underwent a complete neuropsychological evaluation and resting-state fMRI. North-East-Visual-Hallucinations-Interview was used to assess their typical VH content, duration, and frequency. We found that MVH was not associated with cognitive impairment, while CVH was associated with impairments in visuoperceptual processes, attention and visual abstract reasoning. In seed-to-seed functional connectivity (FC) analysis we identified functional couplings associated with MVH and CVH temporal severity (duration x frequency), duration and frequency. MVH severity was negatively associated with FC between early visual areas (EVA) and ventral-visual-stream regions, and negatively associated with FC between brainstem and EVA, which may be linked to LBD brainstem neuropathology. CVH duration was positively associated with FC between ventral-visual stream and salience network (SN). CVH frequency was negatively associated with FC between DMN and SN. Functional alterations in distinct visual and attentional networks and their dynamic interaction in trait LBD hallucinators are linked to both the phenomenology of state content and its temporal characteristics. Within a network, VH frequency and duration may be linked to different types of functional alterations: increased connectivity leading to sustained activity prolonging VH (duration) and decreased connectivity increasing dysregulated, spontaneous activity (frequency). These findings support the hodotopic hypothesis of VH and may reflect a link between VH phenomenology, LBD neuropathological progression and the involvement of specific neurotransmitter systems.
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Affiliation(s)
- Fabrizia D'Antonio
- Department of Human Neuroscience, "Sapienza" University of Rome, Viale dell'Università, 30 00165, Rome, Italy.
| | - Maddalena Boccia
- Department of Psychology, Sapienza University of Rome, Rome, Italy
- Cognitive and Motor Rehabilitation Unit, IRCSS Fondazione Santa Lucia, Rome, Italy
| | - Antonella Di Vita
- Department of Human Neuroscience, "Sapienza" University of Rome, Viale dell'Università, 30 00165, Rome, Italy
| | - Antonio Suppa
- Department of Human Neuroscience, "Sapienza" University of Rome, Viale dell'Università, 30 00165, Rome, Italy
- IRCCS Neuromed Institute, Pozzilli, IS, Italy
| | | | - Marco Canevelli
- Department of Human Neuroscience, "Sapienza" University of Rome, Viale dell'Università, 30 00165, Rome, Italy
| | - Francesca Caramia
- Department of Human Neuroscience, "Sapienza" University of Rome, Viale dell'Università, 30 00165, Rome, Italy
| | - Marco Fiorelli
- Department of Human Neuroscience, "Sapienza" University of Rome, Viale dell'Università, 30 00165, Rome, Italy
| | - Cecilia Guariglia
- Department of Psychology, Sapienza University of Rome, Rome, Italy
- Cognitive and Motor Rehabilitation Unit, IRCSS Fondazione Santa Lucia, Rome, Italy
| | - Stefano Ferracuti
- Department of Human Neuroscience, "Sapienza" University of Rome, Viale dell'Università, 30 00165, Rome, Italy
| | | | - Dag Aarsland
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Dominic Ffytche
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
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14
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Chung SJ, Kim YJ, Jung JH, Lee HS, Ye BS, Sohn YH, Jeong Y, Lee PH. Association Between White Matter Connectivity and Early Dementia in Patients With Parkinson Disease. Neurology 2022; 98:e1846-e1856. [PMID: 35190467 DOI: 10.1212/wnl.0000000000200152] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 01/18/2022] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVES Several clinical and neuroimaging biomarkers have been proposed to identify individuals with Parkinson's disease (PD) who are at risk for ongoing cognitive decline. This study aimed to explore whether white matter (WM) connectivity disruption is associated with dementia conversion in patients with newly diagnosed PD with mild cognitive impairment (PD-MCI). METHODS Seventy-five patients with drug-naïve PD-MCI who underwent serial cognitive assessments during the follow-up period (>5 years) were enrolled for the neuroimaging analyses. The patients were classified into either the PD with dementia (PDD) high-risk group (PDD-H, n = 38) or low-risk group (PDD-L, n = 37), depending on whether they converted to dementia within 5 years of PD diagnosis. We conducted degree-based statistic analyses based on a graph-theoretical concept to identify the subnetworks whose WM connectivity was disrupted in the PDD-H group compared with the PDD-L group. RESULTS The PDD-H group showed poorer cognitive performance on frontal/executive, visual memory/visuospatial, and attention/working memory/language function than the PDD-L group at baseline assessment. The PDD-H group exhibited more severely disrupted WM connectivity in both frontal and posterior cortical regions with eight hub nodes in the degree-based statistic analysis. The strength of structural connectivity within the identified subnetworks was correlated with the composite scores of frontal/executive function domain (γ = 0.393) and the risk score of PDD conversion within 5 years (γ = -0.480). CONCLUSIONS This study demonstrated that disrupted WM connectivity in frontal and posterior cortical regions, which correlated with frontal/executive dysfunction, is associated with early dementia conversion in PD-MCI.
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Affiliation(s)
- Seok Jong Chung
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea.,Department of Neurology, Yongin Severance Hospital, Yonsei University Health System, Yongin, South Korea
| | - Yae Ji Kim
- Program of Brain and Cognitive Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.,KI for Health Science and Technology, Korea Advanced Institute of Science and Technology, Daejeon, South Korea
| | - Jin Ho Jung
- Department of Neurology, Inje University Busan Paik Hospital, Busan, South Korea.,Dementia and Neurodegenerative Disease Research Center, Inje University, Busan, South Korea
| | - Hye Sun Lee
- Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, South Korea
| | - Byoung Seok Ye
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
| | - Young H Sohn
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
| | - Yong Jeong
- Program of Brain and Cognitive Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.,KI for Health Science and Technology, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.,Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea
| | - Phil Hyu Lee
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea; .,Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea
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15
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Chang Z, Xie F, Li H, Yuan F, Zeng L, Shi L, Zhu S, Lu X, Wei X, Wang Q. Retinal Nerve Fiber Layer Thickness and Associations With Cognitive Impairment in Parkinson’s Disease. Front Aging Neurosci 2022; 14:832768. [PMID: 35222000 PMCID: PMC8867012 DOI: 10.3389/fnagi.2022.832768] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 01/20/2022] [Indexed: 01/18/2023] Open
Abstract
ObjectiveThis study intended to investigate whether retinal nerve fiber layer (RNFL) thickness could become a potential marker in patients with Parkinson’s disease with cognitive impairment (PD-CI).MethodsFifty-seven PD patients and 45 age-matched healthy controls (HCs) were recruited in our cross-sectional study and completed optical coherence tomography (OCT) evaluations. PD with normal cognition (PD-NC) and cognitive impairment (PD-CI) patients were divided following the 2015 Movement Disorder Society criteria. RNFL thickness was quantified in subfields of the 3.0-mm circle surrounding the optic disk; while a battery of neuropsychiatric assessments was conducted to estimate the Parkinsonism severity. General linear models and one-way ANOVA were adopted to assess RNFL thickness between subgroups with different cognitive statuses; logistic regression analyses were applied to determine the relation between RNFL and PD-CI cases.ResultsCompared with HCs, more thinning of the RNFL was observed in the inferior and temporal sectors in PD patients, especially in the PD-CI group. Inferior RNFL thickness was reduced in PD-CI compared with PD-NC patients. Logistic regression analysis found that inferior RNFL thickness was independently associated with PD-CI cases (odds ratio = 0.923, p = 0.014). Receiver operating characteristic analysis showed that the RNFL-involved combined model provided a high accuracy in screening cognitive deficiency in PD cases (area under the curve = 0.85, p < 0.001).ConclusionReduced RNFL thickness especially in the inferior sector is independently associated with PD-CI patients. Our study present new perspectives into verifying possible indicators for neuropathological processes or disease severity in Parkinsonians with cognitive dysfunction.
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Affiliation(s)
- Zihan Chang
- Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Fen Xie
- Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Hualing Li
- Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Feilan Yuan
- Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Lina Zeng
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Lin Shi
- Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Shuzhen Zhu
- Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaohe Lu
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- *Correspondence: Xiaohe Lu,
| | - Xiaobo Wei
- Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Xiaobo Wei,
| | - Qing Wang
- Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Qing Wang, ;
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16
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Cervantes González A, Belbin O. Fluid markers of synapse degeneration in synucleinopathies. J Neural Transm (Vienna) 2022; 129:187-206. [PMID: 35147800 DOI: 10.1007/s00702-022-02467-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 01/20/2022] [Indexed: 01/06/2023]
Abstract
The abnormal accumulation of α-synuclein in the brain is a common feature of Parkinson's disease (PD), PD dementia (PDD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), and synucleinopathies that present with overlapping but distinct clinical symptoms that include motor and cognitive deficits. Synapse degeneration is the crucial neuropathological event in these synucleinopathies and the neuropathological correlate of connectome dysfunction. The cognitive and motor deficits resulting from the connectome dysfunction are currently measured by scalar systems that are limited in their sensitivity and largely subjective. Ideally, a marker of synapse degeneration would correlate with measures of cognitive or motor impairment, and could therefore be used as a more objective, surrogate biomarker of the core clinical features of these diseases. Furthermore, an objective surrogate biomarker that can detect and monitor the progression of synapse degeneration would improve patient management and clinical trial design, and could provide a measure of therapeutic response. Here, we review the published findings relating to candidate biomarkers of synapse degeneration in PD, PDD, DLB, and MSA patient-derived biofluids and discuss the findings in the context of the mechanisms associated with α-synuclein-mediated synapse degeneration. Understanding these mechanisms is essential not only for discovery of biomarkers, but also to improve our understanding of the earliest changes in disease pathogenesis of synucleinopathies.
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Affiliation(s)
- Alba Cervantes González
- Neurology Department, Biomedical Research Institute Sant Pau (IIB Sant Pau) and Sant Pau Memory Unit, Hospital de la Santa Creu i Sant Pau, 08025, Barcelona, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28031, Madrid, Spain
| | - Olivia Belbin
- Neurology Department, Biomedical Research Institute Sant Pau (IIB Sant Pau) and Sant Pau Memory Unit, Hospital de la Santa Creu i Sant Pau, 08025, Barcelona, Spain.
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28031, Madrid, Spain.
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17
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Lubomski M, Davis RL, Sue CM. Cognitive Influences in Parkinson's Disease Patients and Their Caregivers: Perspectives From an Australian Cohort. Front Neurol 2021; 12:673816. [PMID: 34867699 PMCID: PMC8634644 DOI: 10.3389/fneur.2021.673816] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 10/11/2021] [Indexed: 01/01/2023] Open
Abstract
Objectives: Cognitive impairment impacts negatively on Parkinson's disease (PD) patient and caregiver quality of life (QoL). We examined cognitive impairment in PD patients and their caregivers to determine if caregiver cognition affected their PD relative. Methods: Validated cognition and clinical outcome measures were assessed in 103 PD patients and 81 caregivers. Results: PD patients showed more cognitive impairment than their carers, with 48.6% having possible Mild Cognitive Impairment (MCI) and 16.5% having PD dementia. Increasing age, male gender, lower education level, various non-motor symptoms and certain therapies, associated with poorer cognition in PD. Eighteen and a half percent of caregivers were found to have MCI, in association with a lower physical and mental QoL. This reflected in lower QoL and mood for the respective PD patients. Conclusion: Impaired cognition and QoL in caregivers was associated with decreased QoL and mood for respective PD patients, suggesting MCI in caregivers is an important consideration for the management of PD.
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Affiliation(s)
- Michal Lubomski
- Department of Neurology, Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, NSW, Australia.,Department of Neurogenetics, Kolling Institute, Faculty of Medicine and Health, University of Sydney, Northern Sydney Local Health District, St Leonards, NSW, Australia.,School of Medicine, The University of Notre Dame Australia, Sydney, NSW, Australia
| | - Ryan L Davis
- Department of Neurogenetics, Kolling Institute, Faculty of Medicine and Health, University of Sydney, Northern Sydney Local Health District, St Leonards, NSW, Australia
| | - Carolyn M Sue
- Department of Neurology, Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, NSW, Australia.,Department of Neurogenetics, Kolling Institute, Faculty of Medicine and Health, University of Sydney, Northern Sydney Local Health District, St Leonards, NSW, Australia
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18
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Altmann CF, Trubelja K, Emmans D, Jost WH. Time-course of decline in different cognitive domains in Parkinson's disease: a retrospective study. J Neural Transm (Vienna) 2021; 129:1179-1187. [PMID: 34817687 DOI: 10.1007/s00702-021-02441-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 11/04/2021] [Indexed: 11/25/2022]
Abstract
Cognitive impairment and dementia are common non-motor symptoms in Parkinson's disease (PD). To elucidate the potentially typical progression of cognitive decline in PD and its variation, we retrospectively surveyed neuropsychological data obtained at the Parkinson-Klinik Ortenau, Germany in the years 1996-2015. Many of the patients in the surveyed period were repeatedly admitted to our clinic and we were thus able to compile neuropsychological re-test data for 252 patients obtained at varying time intervals. Neuropsychological testing was conducted with the NAI (Nürnberger Alters-Inventar). This battery provides sub-tests that examine cognitive processing speed, executive function, working memory, and verbal/visual memory functions. The re-test time span varied across patients from below 1 year up to about 12 years. Most patients were seen twice, but some patients were tested up to eight times. The steepest rates of cognitive decline were observed for the NAI sub-tests Trail-Making, Maze Test, and Stroop-Word Reading/Color Naming. Intermediate rates of decline were found for Digit Span, Word List-Immediate Recall, and Picture Test. Stroop Test-Interference, Word List-Delayed Recognition, and Figure Test exhibited the slowest decline rates. We did not observe a significant effect of age at diagnosis or gender on the rate of decline. In sum, this study retrospectively evaluated cognitive decline in a sample of patients with PD. Our data suggest a broad cognitive decline that particularly affects the cognitive capacities for processing speed, executive functions, and immediate memory functions.
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Affiliation(s)
| | - Kristian Trubelja
- Department of Neurology, Rhön Klinikum, 97616, Bad Neustadt an der Saale, Germany
| | - David Emmans
- Parkinson-Klinik Ortenau, Kreuzbergstr. 12-16, 77709, Wolfach, Germany
| | - Wolfgang H Jost
- Parkinson-Klinik Ortenau, Kreuzbergstr. 12-16, 77709, Wolfach, Germany
- Department of Neurology, University of Saarland, Homburg/Saar, Germany
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19
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Xu DD, Li GQ, Wu ZS, Liu XQ, Yang XX, Wang JH. Bioinformatics analysis and identification of genes and molecular pathways involved in Parkinson's disease in patients with mutations in the glucocerebrosidase gene. Neuroreport 2021; 32:918-924. [PMID: 34132705 PMCID: PMC8253507 DOI: 10.1097/wnr.0000000000001685] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 02/09/2021] [Indexed: 11/25/2022]
Abstract
Glucocerebrosidase (GBA) mutations occur frequently in Parkinson's disease (PD) patients. This study aims to identify potential crucial genes and pathways associated with GBA mutations in patients with PD and to further analyze new molecular mechanisms related to the occurrence of gene mutations from the perspective of bioinformatics. Gene expression profiles of datasets GSE53424 and GSE99142 were acquired from the Gene Expression Ominibus database. Differentially expressed genes (DEGs) were detected, using the 'limma' package in R, comparing IDI-PD 1 (idiopathic PD patients) and GBA-PD 1 [PD patients with heterozygous GBA mutations (GBA N370S)] group samples. The functions of top modules were assessed using the DAVID, whereas gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed. Protein-protein interaction networks were assembled with Cytoscape software and separated into subnetworks using the Molecular Complex Detection Algorithm. Data from GSE53424 and GSE99142 were also extracted to verify our findings. There were 283 DEGs identified in PD patients heterozygous for GBA mutations. Module analysis revealed that GBA mutations in PD patients were associated with significant pathways, including Calcium signaling pathway, Rap1 signaling pathway and Cytokine-cytokine receptor interaction. Hub genes of the two modules were corticotropin-releasing hormone (CRH) and Melatonin receptor 1B (MTNR1B). The expression of CRH was downregulated, whereas that of MTNR1B was upregulated in PD patients with GBA mutations. The expression of CRH and MTNR1B has diagnostic value for PD patients with heterozygous GBA mutations. Novel DEGs and pathways identified herein might provide new insights into the underlying molecular mechanisms of heterozygous GBA mutations in PD patients.
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Affiliation(s)
- Dan-Dan Xu
- Department of Neurology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, Fujian 362000, China
| | - Guo-Qian Li
- Department of Neurology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, Fujian 362000, China
| | - Zhi-Sheng Wu
- Department of Neurology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, Fujian 362000, China
| | - Xiao-Qiang Liu
- Department of Neurology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, Fujian 362000, China
| | - Xiao-Xia Yang
- Department of Neurology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, Fujian 362000, China
| | - Jie-Hua Wang
- Department of Neurology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, Fujian 362000, China
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20
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Zhang J, Li Y, Gao Y, Hu J, Huang B, Rong S, Chen J, Zhang Y, Wang L, Feng S, Wang L, Nie K. An SBM-based machine learning model for identifying mild cognitive impairment in patients with Parkinson's disease. J Neurol Sci 2020; 418:117077. [PMID: 32798842 DOI: 10.1016/j.jns.2020.117077] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 07/28/2020] [Accepted: 07/30/2020] [Indexed: 11/29/2022]
Abstract
OBJECTIVE To identify Parkinson's disease with mild cognitive impairment (PD-MCI) through surface-based morphometry (SBM) based machine learning model. METHODS 93 patients with parkinson's disease (35 PD with normal cognition, 58 PD-MCI) were examined, obtaining 276 SBM variables per subject. 20 healthy control subjects were used as the reference. After extracting features with statistically significance, support vector machine (SVM) model with grid search method was applied to identify patients with PD-MCI. Accuracy, matthews correlation coefficient (MCC), receiver operating characteristic curve (ROC), precision-recall curve (PR), AUC-ROC, AUC-PR and leave-one-out cross validation (LOOCV) strategy were employed for model evaluation. RESULTS PD-MCI is characterized by widespread structural abnormality. SVM model with SBM features achieved an accuracy of 80.00% and area under the ROC of 0.86 for identifying PD-MCI. MCC, AUC-PR, and LOOCV classification accuracy were 0.56, 0.89, and 78.08%, respectively. CONCLUSION Automatic identification of PD-MCI could be realized by SBM-based machine learning model.
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Affiliation(s)
- Jiahui Zhang
- Department of Neurology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangdong Neuroscience Institute, No. 106 Zhongshan Er Road, Guangzhou 510080, China
| | - You Li
- Department of Neurology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangdong Neuroscience Institute, No. 106 Zhongshan Er Road, Guangzhou 510080, China
| | - Yuyuan Gao
- Department of Neurology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangdong Neuroscience Institute, No. 106 Zhongshan Er Road, Guangzhou 510080, China
| | - Jinlong Hu
- School of Computer Science & Engineering, Guangzhou Higher Education Mega Centre South China University of Technology, No.381 Wushan Road, Guangzhou, China
| | - Biao Huang
- Department of Radiology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, No. 106 Zhongshan Er Road, Guangzhou 510080, China
| | - Siming Rong
- Department of Neurology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangdong Neuroscience Institute, No. 106 Zhongshan Er Road, Guangzhou 510080, China
| | - Jianing Chen
- Department of Neurology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangdong Neuroscience Institute, No. 106 Zhongshan Er Road, Guangzhou 510080, China
| | - Yuhu Zhang
- Department of Neurology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangdong Neuroscience Institute, No. 106 Zhongshan Er Road, Guangzhou 510080, China
| | - Limin Wang
- Department of Neurology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangdong Neuroscience Institute, No. 106 Zhongshan Er Road, Guangzhou 510080, China
| | - Shujun Feng
- Department of Neurology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangdong Neuroscience Institute, No. 106 Zhongshan Er Road, Guangzhou 510080, China
| | - Lijuan Wang
- Department of Neurology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangdong Neuroscience Institute, No. 106 Zhongshan Er Road, Guangzhou 510080, China.
| | - Kun Nie
- Department of Neurology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangdong Neuroscience Institute, No. 106 Zhongshan Er Road, Guangzhou 510080, China.
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A Customized Next-Generation Sequencing-Based Panel to Identify Novel Genetic Variants in Dementing Disorders: A Pilot Study. Neural Plast 2020. [PMID: 32908482 DOI: 10.1155/2020/8078103.] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Purpose The advancements in the next-generation sequencing (NGS) techniques have allowed for rapid, efficient, and cost-time-effective genetic variant detection. However, in both clinical practice and research setting, sequencing is still often limited to the use of gene panels clinically targeted on the genes underlying the disease of interest. Methods We performed a neurogenetic study through an ad hoc NGS-based custom sequencing gene panel in order to screen 16 genes in 8 patients with different types of degenerative cognitive disorders (Alzheimer's disease, mild cognitive impairment, frontotemporal dementia, and dementia associated with Parkinson's disease). The study protocol was based on previous evidence showing a high sensitivity and specificity of the technique even when the panel is limited to some hotspot exons. Results We found variants of the TREM2 and APP genes in three patients; these have been previously identified as pathogenic or likely pathogenic and, therefore, considered "disease causing." In the remaining subjects, the pathogenicity was evaluated according to the guidelines of the American College of Medical Genetics (ACMG). In one patient, the p.R205W variant in the CHMP2B gene was found to be likely pathogenic of the disease. A variant in the CSF1R and SERPINI1 genes found in two patients was classified as benign, whereas the other two (in the GRN and APP genes) were classified as likely pathogenic according to the ACMG. Conclusions Notwithstanding the preliminary value of this study, some rare genetic variants with a probable disease association were detected. Although future application of NGS-based sensors and further replication of these experimental data are needed, this approach seems to offer promising translational perspectives in the diagnosis and management of a wide range of neurodegenerative disorders.
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Kozak VV, Chaturvedi M, Gschwandtner U, Hatz F, Meyer A, Roth V, Fuhr P. EEG Slowing and Axial Motor Impairment Are Independent Predictors of Cognitive Worsening in a Three-Year Cohort of Patients With Parkinson's Disease. Front Aging Neurosci 2020; 12:171. [PMID: 32625079 PMCID: PMC7314977 DOI: 10.3389/fnagi.2020.00171] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 05/15/2020] [Indexed: 11/23/2022] Open
Abstract
Objective: We aimed to determine whether the combination of two parameters: (a) score of axial impairment and limb rigidity (SAILR) with (b) EEG global relative median power in the frequency range theta 4–8 Hz (GRMPT) predicted cognitive outcome in patients with Parkinson's disease (PD) better than each of these measures alone. Methods: 47 non-demented patients with PD were examined and re-examined after 3 years. At both time-points, the patients underwent a comprehensive neuropsychological and neurological assessment and EEG in eyes-closed resting-state condition. The results of cognitive tests were normalized and individually summarized to obtain a “global cognitive score” (GCS). Change of GCS was used to represent cognitive changes over time. GRMPT and SAILR was used for further analysis. Linear regression models were calculated. Results: GRMPT and SAILR independently predicted cognitive change. Combination of GRMPT and SAILR improved the significance of the regression model as compared to using each of these measures alone. GRMPT and SAILR only slightly correlate between each other. Conclusion: The combination of axial signs and rigidity with quantitative EEG improves early identification of patients with PD prone to severe cognitive decline. GRMPT and SAILR seem to reflect different disease mechanisms. Significance Combination of EEG and axial motor impairment assessment may be a valuable marker in the cognitive prognosis of PD.
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Affiliation(s)
- Vitalii V Kozak
- Neurology and Neurophysiology, University Hospital of Basel, Basel, Switzerland
| | - Menorca Chaturvedi
- Neurology and Neurophysiology, University Hospital of Basel, Basel, Switzerland.,Mathematics and Computer Science, University of Basel, Basel, Switzerland
| | - Ute Gschwandtner
- Neurology and Neurophysiology, University Hospital of Basel, Basel, Switzerland
| | - Florian Hatz
- Neurology and Neurophysiology, University Hospital of Basel, Basel, Switzerland
| | - Antonia Meyer
- Neurology and Neurophysiology, University Hospital of Basel, Basel, Switzerland
| | - Volker Roth
- Mathematics and Computer Science, University of Basel, Basel, Switzerland
| | - Peter Fuhr
- Neurology and Neurophysiology, University Hospital of Basel, Basel, Switzerland
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Evaluation of Cognitive Function in Relation to Progression of Parkinson Disease. Am J Phys Med Rehabil 2020; 99:626-629. [PMID: 31972613 DOI: 10.1097/phm.0000000000001385] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE Cognitive impairments are among the nonmotor symptoms in patients with Parkinson disease. Understanding the cognitive impairments in patients with Parkinson disease may be critical for developing effective rehabilitation interventions. The aims of this study were to assess cognitive function in patients with Parkinson disease using the Wechsler Adult Intelligence Scale Third Edition, and the Wechsler Memory Scale Revised and to investigate how cognitive impairments relate to progression of disease in patients with Parkinson disease according to the Hoehn and Yahr stages. DESIGN Seventy-eight patients with Parkinson disease participated in the present study. Our study consisted of patients in the following Hoehn and Yahr groups: 1 (no disability, n = 11), 2 (mild, n = 34), 3 (moderate, n = 26), and 4 and 5 (severe, n = 7). Cognitive function was assessed using the Wechsler Adult Intelligence Scale Third Edition, and the Wechsler Memory Scale Revised. RESULTS The verbal memory was significantly higher in group 1 (106.4 ± 12.0) than in the other groups (2: 90.5 ± 14.0, 3: 89.9 ± 16.9, 4 and 5: 89.6 ± 11.4). Visual memory and delayed recall were similar to the results seen with verbal memory; however, the differences between groups were not statistically significant. The full-scale IQ was not significantly different (1: 107.3 ± 8.1, 2: 96.9 ± 18.2, 3: 96.7 ± 14.8, 4 and 5: 91.7 ± 9.5). CONCLUSIONS These results suggest that a comprehensive assessment focused on memory impairments is important for applying the appropriate interventions in patients with early-stage Parkinson disease.
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Zhang Y, Chen J, Xu C, Feng J, Li J. Effects of glucocerebrosidase gene polymorphisms and mutations on the risk of Parkinson's disease dementia: A meta-analysis. Neurosci Lett 2020; 714:134544. [PMID: 31672490 DOI: 10.1016/j.neulet.2019.134544] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 10/02/2019] [Accepted: 10/09/2019] [Indexed: 12/01/2022]
Abstract
OBJECTIVE Exploring the impact of glucocerebrosidase gene (GBA) polymorphisms and mutations on the pathogenesis of Parkinson's disease dementia (PDD) plays an important role in the diagnosis and treatment of this disease. This meta-analysis aimed to investigate the effects of GBA polymorphisms and mutations on the risk of PDD and to identify the relationship between GBA genotype and PDD. METHODS A computer-based search was performed to retrieve publications from PubMed, Cochrane library, Embase, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, and Wanfang databases using the search terms "glucocerebrosidase", "Parkinson's disease", and "dementia". After rigorous screening, cohort studies were included for meta-analysis. RESULTS The risk of PDD in GBA variant carriers was 1.94 times that in non-carriers (hazard ratio [HR], 1.94; 95% confidence interval [CI], 1.53-2.46). The risk of PDD in GBA polymorphism carriers was 1.87 times that in non-carriers (HR, 1.87; 95% CI, 1.18-2.98). The risk of PDD in GBA mutation carriers was 3.64 times that in non-carriers (HR, 3.64; 95% CI, 2.74-4.83). The risk of PDD in p.L444P variant carriers (HR, 4.81; 95% CI, 3.37-6.86) was significantly higher than that in p.N370S variant carriers (HR, 1.95; 95% CI, 1.29-1.94). CONCLUSION GBA polymorphisms and mutations are potential risk factors for PDD.
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Affiliation(s)
- Yingyu Zhang
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Jiajun Chen
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Chuan Xu
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Jingqi Feng
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Jia Li
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China.
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25
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Lanza G, Calì F, Vinci M, Cosentino FII, Tripodi M, Spada RS, Cantone M, Bella R, Mattina T, Ferri R. A Customized Next-Generation Sequencing-Based Panel to Identify Novel Genetic Variants in Dementing Disorders: A Pilot Study. Neural Plast 2020; 2020:8078103. [PMID: 32908482 PMCID: PMC7450320 DOI: 10.1155/2020/8078103] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 06/13/2020] [Accepted: 07/13/2020] [Indexed: 02/07/2023] Open
Abstract
PURPOSE The advancements in the next-generation sequencing (NGS) techniques have allowed for rapid, efficient, and cost-time-effective genetic variant detection. However, in both clinical practice and research setting, sequencing is still often limited to the use of gene panels clinically targeted on the genes underlying the disease of interest. METHODS We performed a neurogenetic study through an ad hoc NGS-based custom sequencing gene panel in order to screen 16 genes in 8 patients with different types of degenerative cognitive disorders (Alzheimer's disease, mild cognitive impairment, frontotemporal dementia, and dementia associated with Parkinson's disease). The study protocol was based on previous evidence showing a high sensitivity and specificity of the technique even when the panel is limited to some hotspot exons. RESULTS We found variants of the TREM2 and APP genes in three patients; these have been previously identified as pathogenic or likely pathogenic and, therefore, considered "disease causing." In the remaining subjects, the pathogenicity was evaluated according to the guidelines of the American College of Medical Genetics (ACMG). In one patient, the p.R205W variant in the CHMP2B gene was found to be likely pathogenic of the disease. A variant in the CSF1R and SERPINI1 genes found in two patients was classified as benign, whereas the other two (in the GRN and APP genes) were classified as likely pathogenic according to the ACMG. CONCLUSIONS Notwithstanding the preliminary value of this study, some rare genetic variants with a probable disease association were detected. Although future application of NGS-based sensors and further replication of these experimental data are needed, this approach seems to offer promising translational perspectives in the diagnosis and management of a wide range of neurodegenerative disorders.
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Affiliation(s)
- Giuseppe Lanza
- 1Department of Surgery and Medical-Surgical Specialties, University of Catania, Catania, Italy
- 2Oasi Research Institute–IRCCS, Troina, Italy
| | | | | | | | | | | | - Mariagiovanna Cantone
- 3Department of Neurology, Sant'Elia Hospital, ASP Caltanissetta, Caltanissetta, Italy
| | - Rita Bella
- 4Department of Medical and Surgical Sciences and Advanced Technologies, University of Catania, Catania, Italy
| | - Teresa Mattina
- 5Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
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Brás IC, Xylaki M, Outeiro TF. Mechanisms of alpha-synuclein toxicity: An update and outlook. PROGRESS IN BRAIN RESEARCH 2019; 252:91-129. [PMID: 32247376 DOI: 10.1016/bs.pbr.2019.10.005] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Alpha-synuclein (aSyn) was identified as the main component of inclusions that define synucleinopathies more than 20 years ago. Since then, aSyn has been extensively studied in an attempt to unravel its roles in both physiology and pathology. Today, studying the mechanisms of aSyn toxicity remains in the limelight, leading to the identification of novel pathways involved in pathogenesis. In this chapter, we address the molecular mechanisms involved in synucleinopathies, from aSyn misfolding and aggregation to the various cellular effects and pathologies associated. In particular, we review our current understanding of the mechanisms involved in the spreading of aSyn between different cells, from the periphery to the brain, and back. Finally, we also review recent studies on the contribution of inflammation and the gut microbiota to pathology in synucleinopathies. Despite significant advances in our understanding of the molecular mechanisms involved, we still lack an integrated understanding of the pathways leading to neurodegeneration in PD and other synucleinopathies, compromising our ability to develop novel therapeutic strategies.
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Affiliation(s)
- Inês Caldeira Brás
- Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany
| | - Mary Xylaki
- Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany
| | - Tiago Fleming Outeiro
- Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany; Max Planck Institute for Experimental Medicine, Göttingen, Germany; Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.
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Amyloid beta in nasal secretions may be a potential biomarker of Alzheimer's disease. Sci Rep 2019; 9:4966. [PMID: 30899050 PMCID: PMC6428828 DOI: 10.1038/s41598-019-41429-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 03/08/2019] [Indexed: 12/31/2022] Open
Abstract
We investigated the level of amyloid beta (Aβ) in nasal secretions of patients with Alzheimer’s disease dementia (ADD) using interdigitated microelectrode (IME) biosensors and determined the predictive value of Aβ in nasal secretions for ADD diagnosis. Nasal secretions were obtained from 35 patients with ADD, 18 with cognitive decline associated with other neurological disorders (OND), and 26 cognitively unimpaired (CU) participants. Capacitance changes in IMEs were measured by capturing total Aβ (ΔCtAβ). After 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid (EPPS) was injected, additional capacitance changes due to the smaller molecular weight Aβ oligomers disassembled from the higher molecular weight oligomeric Aβ were determined (ΔCoAβ). By dividing two values, the capacitance ratio (ΔCoAβ/ΔCtAβ) was determined and then normalized to the capacitance change index (CCI). The CCI was higher in the ADD group than in the OND (p = 0.040) and CU groups (p = 0.007). The accuracy of the CCI was fair in separating into the ADD and CU groups (area under the receiver operating characteristic curve = 0.718, 95% confidence interval = 0.591–0.845). These results demonstrate that the level of Aβ in nasal secretions increases in ADD and the detection of Aβ in nasal secretions using IME biosensors may be possible in predicting ADD.
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28
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Tampi RR, Young JJ, Tampi D. Behavioral symptomatology and psychopharmacology of Lewy body dementia. HANDBOOK OF CLINICAL NEUROLOGY 2019; 165:59-70. [PMID: 31727230 DOI: 10.1016/b978-0-444-64012-3.00005-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Lewy body dementia (LBD) is an umbrella term for major neurocognitive disorders caused by Lewy body pathology. Parkinson's disease dementia (PDD) and Dementia with Lewy bodies (DLB) are the two main syndromes in LBD. LBDs typically present with cognitive impairment, cholinergic deficiency, neuropsychiatric symptoms such as visual hallucinations and paranoid delusions, as well as parkinsonian symptoms. Due to the urgency in diagnosing LBD early in the disease course to provide the most optimal management of these syndromes, it is important that clinicians elicit the most clinically significant symptoms during patient encounters. The focus of this chapter is to discuss current LBD classification systems and assessments, neuropathology of LBDs, behavioral symptomatology, contemporary management options, and possible future targets of treatment. PubMed was searched to obtain reviews and studies that pertain to classification, behavioral symptomatology, neurobiology, neuroimaging, and treatment of LBDs. Articles were chosen with a predilection to more recent clinical trials and systematic reviews or meta-analyses. Updates to diagnostic criteria have increased clinical diagnostic sensitivity and specificity. Current therapeutic modalities are limited as there is no current disease-modifying drug available. Cholinesterase inhibitors have been reported to be effective in decreasing neuropsychiatric and cognitive symptoms. Neuroleptics should be avoided unless clinically indicated. There is a paucity of studies investigating treatment options for mood symptoms. Current novel targets of treatment focus on decreasing α-synuclein burden. LBDs are a group of dementia syndromes that affect a significant portion of the elderly population. Early diagnosis and treatment is necessary to improve patient quality of life with current treatment options more focused on alleviating severe symptomatology rather than modifying disease pathology.
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Affiliation(s)
- Rajesh R Tampi
- Department of Psychiatry & Behavioral Sciences, Cleveland Clinic Akron General, Akron, OH, United States; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, United States.
| | - Juan Joseph Young
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States
| | - Deena Tampi
- Diamond Healthcare, Richmond, VA, United States
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Auricular Vagus Nerve Stimulation Exerts Antiinflammatory Effects and Immune Regulatory Function in a 6-OHDA Model of Parkinson’s Disease. Neurochem Res 2018; 43:2155-2164. [DOI: 10.1007/s11064-018-2639-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 08/03/2018] [Accepted: 09/16/2018] [Indexed: 01/26/2023]
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30
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Li DTH, Hui ES, Chan Q, Yao N, Chua SE, McAlonan GM, Pang SYY, Ho SL, Mak HKF. Quantitative susceptibility mapping as an indicator of subcortical and limbic iron abnormality in Parkinson's disease with dementia. Neuroimage Clin 2018; 20:365-373. [PMID: 30128274 PMCID: PMC6096006 DOI: 10.1016/j.nicl.2018.07.028] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 07/23/2018] [Accepted: 07/26/2018] [Indexed: 01/19/2023]
Abstract
Late stage Parkinson's disease (PD) patients were commonly observed with other non-motor comorbidities such as dementia and psychosis. While abnormal iron level in the substantia nigra was clinically accepted as a biomarker of PD, it was also suggested that the increased iron deposition could impair other brain regions and induce non-motor symptoms. A new Magnetic Resonance Imaging (MRI) called Quantitative Susceptibility Mapping (QSM) has been found to measure iron concentration in the grey matter reliably. In this study, we investigated iron level of different subcortical and limbic structures of Parkinson's disease (PD) patients with and without dementia by QSM. QSM and volumetric analysis by MRI were performed in 10 PD dementia (PDD) patients (73 ± 6 years), 31 PD patients (63 ± 8 years) and 27 healthy controls (62 ± 7 years). No significant differences were observed in the L-Dopa equivalent dosage for the two PD groups (p = 0.125). Putative iron content was evaluated in different subcortical and limbic structures of the three groups, as well as its relationship with cognitive performance. One-way ANCOVA with FDR adjustment at level of 0.05, adjusted for age and gender, showed significant group differences for left and right hippocampus (p = 0.015 & 0.032, respectively, BH-corrected for multiple ROIs) and right thalamus (p = 0.032, BH-corrected). Post-hoc test with Bonferroni's correction suggested higher magnetic susceptibility in PDD patients than healthy controls in the left and right hippocampus (p = 0.001 & 0.047, respectively, Bonferroni's corrected), while PD patients had higher magnetic susceptibility than the healthy controls in right hippocampus and right thalamus (p = 0.006 & 0.005, respectively, Bonferroni's corrected). PDD patients also had higher susceptibility than the non-demented PD patients in left hippocampus (p = 0.046, Bonferroni's corrected). The magnetic susceptibilities of the left and right hippocampus were negatively correlated with the Mini-Mental State Examination score (r = -0.329 & -0.386, respectively; p < 0.05). This study provides support for iron accumulation in limbic structures of PDD and PD patients and its correlation with cognitive performance, however, its putative involvement in development of non-motor cognitive dysfunction in PD pathogenesis remains to be elucidated.
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Affiliation(s)
- Darrell T H Li
- Department of Diagnostic Radiology, The University of Hong Kong, Hong Kong
| | - Edward S Hui
- Department of Diagnostic Radiology, The University of Hong Kong, Hong Kong
| | | | - N Yao
- Department of Psychiatry, Yale University, New Haven, CT, United States,; Department of Psychiatry, The University of Hong Kong, Hong Kong
| | - S E Chua
- Department of Psychiatry, The University of Hong Kong, Hong Kong,; Raffles Counselling Centre, Raffles Hospital, Singapore
| | - Gráinne M McAlonan
- Department of Psychiatry, The University of Hong Kong, Hong Kong,; Department of Forensic and Neurodevelopmental Science, King's College London, London, United Kingdom,; South London and Maudsley NHS Foundation Trust, United Kingdom
| | - Shirley Y Y Pang
- Division of Neurology, Department of Medicine, The University of Hong Kong, Hong Kong
| | - S L Ho
- Division of Neurology, Department of Medicine, The University of Hong Kong, Hong Kong
| | - Henry K F Mak
- Department of Diagnostic Radiology, The University of Hong Kong, Hong Kong,; State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong,; Alzheimer's Disease Research Network, The University of Hong Kong, Hong Kong.
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31
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Dawson BK, Fereshtehnejad SM, Anang JBM, Nomura T, Rios-Romenets S, Nakashima K, Gagnon JF, Postuma RB. Office-Based Screening for Dementia in Parkinson Disease: The Montreal Parkinson Risk of Dementia Scale in 4 Longitudinal Cohorts. JAMA Neurol 2018; 75:704-710. [PMID: 29582054 PMCID: PMC5885166 DOI: 10.1001/jamaneurol.2018.0254] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 12/18/2017] [Indexed: 01/05/2023]
Abstract
Importance Parkinson disease dementia dramatically increases mortality rates, patient expenditures, hospitalization risk, and caregiver burden. Currently, predicting Parkinson disease dementia risk is difficult, particularly in an office-based setting, without extensive biomarker testing. Objective To appraise the predictive validity of the Montreal Parkinson Risk of Dementia Scale, an office-based screening tool consisting of 8 items that are simply assessed. Design, Setting, and Participants This multicenter study (Montreal, Canada; Tottori, Japan; and Parkinson Progression Markers Initiative sites) used 4 diverse Parkinson disease cohorts with a prospective 4.4-year follow-up. A total of 717 patients with Parkinson disease were recruited between May 2005 and June 2016. Of these, 607 were dementia-free at baseline and followed-up for 1 year or more and so were included. The association of individual baseline scale variables with eventual dementia risk was calculated. Participants were then randomly split into cohorts to investigate weighting and determine the scale's optimal cutoff point. Receiver operating characteristic curves were calculated and correlations with selected biomarkers were investigated. Main Outcomes and Measures Dementia, as defined by Movement Disorder Society level I criteria. Results Of the 607 patients (mean [SD] age, 63.4 [10.1]; 376 men [62%]), 70 (11.5%) converted to dementia. All 8 items of the Montreal Parkinson Risk of Dementia Scale independently predicted dementia development at the 5% significance level. The annual conversion rate to dementia in the high-risk group (score, >5) was 14.9% compared with 5.8% in the intermediate group (score, 4-5) and 0.6% in the low-risk group (score, 0-3). The weighting procedure conferred no significant advantage. Overall predictive validity by the area under the receiver operating characteristic curve was 0.877 (95% CI, 0.829-0.924) across all cohorts. A cutoff of 4 or greater yielded a sensitivity of 77.1% (95% CI, 65.6-86.3) and a specificity of 87.2% (95% CI, 84.1-89.9), with a positive predictive value (as of 4.4 years) of 43.90% (95% CI, 37.76-50.24) and a negative predictive value of 96.70% (95% CI, 95.01-97.85). Positive and negative likelihood ratios were 5.94 (95% CI, 4.08-8.65) and 0.26 (95% CI, 0.17-0.40), respectively. Scale results correlated with markers of Alzheimer pathology and neuropsychological test results. Conclusions and Relevance Despite its simplicity, the Montreal Parkinson Risk of Dementia Scale demonstrated predictive validity equal or greater to previously described algorithms using biomarker assessments. Future studies using head-to-head comparisons or refinement of weighting would be of interest.
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Affiliation(s)
- Benjamin K. Dawson
- Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
- Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Seyed-Mohammad Fereshtehnejad
- Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
- Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
| | - Julius B. M. Anang
- Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
| | - Takashi Nomura
- Division of Neurology, Department of Brain and Neurosciences, Tottori University, Tottori, Japan
| | - Silvia Rios-Romenets
- Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
| | - Kenji Nakashima
- Division of Neurology, Department of Brain and Neurosciences, Tottori University, Tottori, Japan
| | - Jean-François Gagnon
- Centre d’Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Coeur de Montréal, Montréal, Quebec, Canada
- Department of Psychology, Université du Québec à Montréal, Montreal, Quebec, Canada
| | - Ronald B. Postuma
- Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
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Sforza M, Assogna F, Rinaldi D, Sette G, Tagliente S, Pontieri FE. Orthostatic hypotension acutely impairs executive functions in Parkinson’s disease. Neurol Sci 2018; 39:1459-1462. [DOI: 10.1007/s10072-018-3394-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 03/26/2018] [Indexed: 11/28/2022]
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Vlagsma TT, Duits AA, Dijkstra HT, van Laar T, Spikman JM. Effectiveness of ReSET; a strategic executive treatment for executive dysfunctioning in patients with Parkinson's disease. Neuropsychol Rehabil 2018; 30:67-84. [PMID: 29566588 DOI: 10.1080/09602011.2018.1452761] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
In this multicentre randomised controlled trial (RCT), 43 patients with Parkinson's disease (PD) were randomly allocated to either the experimental condition receiving cognitive rehabilitation including strategy training (ReSET; Strategic Executive Treatment, n = 24) or to the control condition receiving computerised repetitive practice training for attention (Cogniplus, n = 16). We expected that strategy training (ReSET) would be more effective than cognitive training (Cogniplus) in improving patients' everyday life executive functioning. Neuropsychological assessment was administered at baseline, at 2 weeks and 3-5 months post-treatment. Primary outcome measure was the Role Resumption List (RRL). Secondary outcome measures were treatment goal attainment (TGA), Dysexecutive Questionnaire (DEX), Parkinson's Disease Questionnaire (PDQ-39), Zarit Burden Interview (ZBI) and neuropsychological tests. No effects of treatment were found on the primary outcome measure and on neuropsychological tests, except for one test of attention. At 2 weeks and 3-5 months post-treatment, PD patients in both the ReSET and Cogniplus group reported a significant improvement in everyday life executive functioning, as measured with TGA and the DEX-self, with an advantage for ReSET only shortly after treatment. Given these results and that PD patients were able to adhere to these treatments despite their motor symptoms and fatigue (i.e., the drop-out rate was small), we conclude that both strategy training and cognitive training for impairments in EF might be beneficial and feasible for PD patients.
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Affiliation(s)
- Thialda T Vlagsma
- Department of Clinical & Developmental Neuropsychology, University of Groningen, Groningen, The Netherlands
| | - Annelien A Duits
- Department of Psychiatry and Psychology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Hilde T Dijkstra
- Department of Medical psychology, Medical Center Nij Smellinghe, Drachten, The Netherlands
| | - Teus van Laar
- Department of Neurology, University Medical Center Groningen, Groningen, The Netherlands
| | - Jacoba M Spikman
- Department of Clinical & Developmental Neuropsychology, University of Groningen, Groningen, The Netherlands.,Department of Neurology, University Medical Center Groningen, Groningen, The Netherlands
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Abstract
A neurodegenerative disorder displaying an altered α-synuclein (αS) in the brain tissue is called α-synucleinopathy (αS-pathy) and incorporates clinical entities such as Parkinson disease (PD), PD with dementia, dementia with Lewy bodies, and multiple-system atrophy. Neuroradiologic techniques visualizing αS pathology in the brain or assays of αS in the cerebrospinal fluid or blood are probably available and will be implemented in the near future but currently the definite diagnosis of αS-pathy relies on a postmortem examination of the brain. Since the 1980s immunohistochemical technique based on the use of antibodies directed to proteins of interest has become a method of choice for neuropathologic diagnosis. Furthermore, since the 1990s it has been acknowledged that progressions of most neurodegenerative pathologies follow a certain predictable time-related neuroanatomic distribution. Currently, for Lewy body disease, two staging techniques are commonly used: McKeith and Braak staging. Thus, the neuropathologic diagnosis of a αS-pathy is based on detection of altered αS in the tissue and registration of the neuroanatomic distribution of this alteration in the brain. The clinicopathologic correlation is not absolute due to the quite frequent observation of incidental and concomitant αS pathology.
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Affiliation(s)
- Irina Alafuzoff
- Department of Immunology, Genetics and Pathology, Uppsala University, Department of Pathology, Uppsala University Hospital and Rudbeck Laboratory, Uppsala, Sweden.
| | - Päivi Hartikainen
- Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland and Department of Neurology, Kuopio University Hospital, Kuopio, Finland
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Abstract
Previous studies of patients with brain damage have suggested a close relationship between aphasia and movement disorders. Neurodegenerative extrapyramidal syndromes associated with cognitive impairment provide an interesting model for studying the neural substrates of cognitive and motor symptoms. In this review, we focused on studies investigating language production abilities in patients with Parkinson's disease (PD), Corticobasal Syndrome (CBS) and Progressive Supranuclear Palsy (PSP). According to some reports, these patients exhibit a reduction in performance in both action and object naming or verb production compared to healthy individuals. Furthermore, a disproportional impairment of action naming compared to object naming was systematically observed in patients with these disorders. The study of these clinical conditions offers the unique opportunity to examine the close link between linguistic features and motor characteristics of action. This particular pattern of language impairment may contribute to the debate on embodiment theory and on the involvement of the basal ganglia in language and in integrating language and movement. From a translational perspective, we suggest that language ability assessments are useful in the clinical work-up, along with neuropsychological and motor evaluations. Specific protocols should be developed in the near future to better characterize language deficits and to permit an early cognitive diagnosis. Moreover, the link between language deficits and motor impairment opens a new issue for treatment approaches. Treatment of one of these two symptoms may ameliorate the other, and treating both may produce a greater improvement in patients' global clinical conditions.
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Redden W, Bheemisetty S. Lewy Body Spectrum Disorders: from Dementia with Lewy Bodies to Parkinson’s Disease Dementia. CURRENT GERIATRICS REPORTS 2016. [DOI: 10.1007/s13670-016-0190-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Silva Adaya D, Aguirre-Cruz L, Guevara J, Ortiz-Islas E. Nanobiomaterials' applications in neurodegenerative diseases. J Biomater Appl 2016; 31:953-984. [PMID: 28178902 DOI: 10.1177/0885328216659032] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The blood-brain barrier is the interface between the blood and brain, impeding the passage of most circulating cells and molecules, protecting the latter from foreign substances, and maintaining central nervous system homeostasis. However, its restrictive nature constitutes an obstacle, preventing therapeutic drugs from entering the brain. Usually, a large systemic dose is required to achieve pharmacological therapeutic levels in the brain, leading to adverse effects in the body. As a consequence, various strategies are being developed to enhance the amount and concentration of therapeutic compounds in the brain. One such tool is nanotechnology, in which nanostructures that are 1-100 nm are designed to deliver drugs to the brain. In this review, we examine many nanotechnology-based approaches to the treatment of neurodegenerative diseases. The review begins with a brief history of nanotechnology, followed by a discussion of its definition, the properties of most reported nanomaterials, their biocompatibility, the mechanisms of cell-material interactions, and the current status of nanotechnology in treating Alzheimer's, Parkinson's diseases, and amyotrophic lateral sclerosis. Of all strategies to deliver drug to the brain that are used in nanotechnology, drug release systems are the most frequently reported.
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Affiliation(s)
- Daniela Silva Adaya
- 1 Experimental Laboratory for Neurodegenerative Diseases, National Institute of Neurology and Neurosurgery, Manuel Velasco Suárez, México City, Mexico
| | - Lucinda Aguirre-Cruz
- 2 Laboratory of Neuroimmunoendocrinology, National Institute of Neurology and Neurosurgery, Manuel Velasco Suárez, México City, Mexico
| | - Jorge Guevara
- 3 Biochemistry Department, Faculty of Medicine, National Autonomous University of Mexico, Mèxico City, Mexico
| | - Emma Ortiz-Islas
- 4 Nanotechnology Laboratory, National Institute of Neurology and Neurosurgery, México City, Manuel Velasco Suárez, Mexico
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Seritan AL, Kim K, Benjamin I, Seritan I, Hagerman RJ. Risk Factors for Cognitive Impairment in Fragile X-Associated Tremor/Ataxia Syndrome. J Geriatr Psychiatry Neurol 2016; 29:328-337. [PMID: 27647792 PMCID: PMC5357600 DOI: 10.1177/0891988716666379] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disease with motor, psychiatric, and cognitive manifestations that occurs in carriers of the fragile X mental retardation 1 ( FMR1) gene premutations. This was a retrospective chart review of 196 individuals (127 men and 69 women) with FXTAS. Forty-six (23%) participants were cognitively impaired, of whom 19 (10%) had dementia. Risk factors for dementia were examined (CGG repeat size; alcohol, benzodiazepine, and opioid use; diabetes; hyperlipidemia; hypertension; hypothyroidism; obesity; sleep apnea; surgeries with general anesthesia; depression; family history of dementia). Thirteen individuals with FXTAS and dementia were then compared to 13 cognitively intact individuals matched on age, gender, and FXTAS stage. CGG repeat size was significantly higher (mean = 98.5, standard deviation [SD] = 22.2) in the dementia group, compared to the cognitively intact group (mean = 81.6, SD = 11.5; P = .0256). These results show that CGG repeat size is a risk factor for FXTAS dementia.
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Affiliation(s)
- Andreea L. Seritan
- Department of Psychiatry, University of California, San Francisco, San Francisco, California
| | - Kyoungmi Kim
- Department of Public Health Sciences, Division of Biostatistics, University of California, Davis, Davis California,Medical Investigation of Neurodevelopmental Disorders (M.I.N.D.) Institute, Sacramento, California
| | | | - Ioana Seritan
- University of California, Berkeley, Berkeley, California
| | - Randi J. Hagerman
- Medical Investigation of Neurodevelopmental Disorders (M.I.N.D.) Institute, Sacramento, California,Department of Pediatrics, University of California, Davis Medical Center, Sacramento, California
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Erskine D, Khundakar AA. Stereological approaches to dementia research using human brain tissue. J Chem Neuroanat 2016; 76:73-81. [PMID: 26777894 DOI: 10.1016/j.jchemneu.2016.01.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Accepted: 01/12/2016] [Indexed: 01/01/2023]
Abstract
The relationship between the clinical features of dementia disorders and the resultant changes in underlying neuropathological mechanisms has long been of interest to researchers working in the field of neurodegenerative disorders. The majority of neuropathological research in dementia has utilized semi-quantitative analysis of protein inclusions, which have defined the hallmark histological features of the conditions. However, the advent of three-dimensional stereological techniques has enabled unbiased and fully quantitative assessment of brain tissue. The present review focuses on studies that have used these techniques to elucidate important relationships between neuropathological changes and clinical features and, in doing so, revealed important mechanistic insights into the pathophysiology of dementia disorders.
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Affiliation(s)
- D Erskine
- Institute of Neuroscience and Newcastle University Institute for Ageing, Newcastle University, United Kingdom
| | - A A Khundakar
- Institute of Neuroscience and Newcastle University Institute for Ageing, Newcastle University, United Kingdom.
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