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Weijs RWJ, Shkredova DA, Brekelmans ACM, Thijssen DHJ, Claassen JAHR. Longitudinal changes in cerebral blood flow and their relation with cognitive decline in patients with dementia: Current knowledge and future directions. Alzheimers Dement 2023; 19:532-548. [PMID: 35485906 DOI: 10.1002/alz.12666] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 02/24/2022] [Accepted: 02/28/2022] [Indexed: 01/15/2023]
Abstract
The pathophysiology underlying cognitive decline is multifactorial, with increasing literature suggesting a role for cerebrovascular health. Cerebral blood flow (CBF) is an important element of cerebrovascular health, which raises questions regarding the relation between CBF and cognitive decline. Cross-sectional studies demonstrate lower CBF in patients with cognitive decline compared to healthy age-matched peers. Remarkably, longitudinal studies do not support a link between CBF reductions and cognitive decline. These studies, however, are often limited by small sample sizes and may therefore be underpowered to detect small effect sizes. Therefore, through a systematic review and meta-analysis of longitudinal studies, we examined whether longitudinal changes in global CBF are related to cognitive decline in subjects with Alzheimer's disease, and qualitatively described findings on regional CBF. Considering the growing impact of dementia and the lack of treatment options, it is important to understand the role of CBF as a prognostic biomarker and/or treatment target in dementia.
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Affiliation(s)
- Ralf W J Weijs
- Department of Physiology, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Daria A Shkredova
- Department of Physiology, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.,Centre for Heart, Lung, and Vascular Health, School of Health and Exercise Sciences, University of British Columbia Okanagan, Kelowna, British Columbia, Canada
| | - Anna C M Brekelmans
- Department of Physiology, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Dick H J Thijssen
- Department of Physiology, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.,Research Institute for Sport and Exercise Science, Liverpool John Moores University, Liverpool, UK
| | - Jurgen A H R Claassen
- Department of Geriatrics, Radboud UMC Alzheimer's Center, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands
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Tyler SEB, Tyler LDK. Therapeutic roles of plants for 15 hypothesised causal bases of Alzheimer's disease. NATURAL PRODUCTS AND BIOPROSPECTING 2022; 12:34. [PMID: 35996065 PMCID: PMC9395556 DOI: 10.1007/s13659-022-00354-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 06/15/2022] [Indexed: 05/26/2023]
Abstract
Alzheimer's disease (AD) is progressive and ultimately fatal, with current drugs failing to reverse and cure it. This study aimed to find plant species which may provide therapeutic bioactivities targeted to causal agents proposed to be driving AD. A novel toolkit methodology was employed, whereby clinical symptoms were translated into categories recognized in ethnomedicine. These categories were applied to find plant species with therapeutic effects, mined from ethnomedical surveys. Survey locations were mapped to assess how this data is at risk. Bioactivities were found of therapeutic relevance to 15 hypothesised causal bases for AD. 107 species with an ethnological report of memory improvement demonstrated therapeutic activity for all these 15 causal bases. The majority of the surveys were found to reside within biodiversity hotspots (centres of high biodiversity under threat), with loss of traditional knowledge the most common threat. Our findings suggest that the documented plants provide a large resource of AD therapeutic potential. In demonstrating bioactivities targeted to these causal bases, such plants may have the capacity to reduce or reverse AD, with promise as drug leads to target multiple AD hallmarks. However, there is a need to preserve ethnomedical knowledge, and the habitats on which this knowledge depends.
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Affiliation(s)
| | - Luke D K Tyler
- School of Natural Sciences, Bangor University, Gwynedd, UK
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3
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Chronic hypoperfusion due to intracranial large artery stenosis is not associated with cerebral β-amyloid deposition and brain atrophy. Chin Med J (Engl) 2022; 135:591-597. [PMID: 34985014 PMCID: PMC8920433 DOI: 10.1097/cm9.0000000000001918] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Background: Insufficient cerebral perfusion is suggested to play a role in the development of Alzheimer disease (AD). However, there is a lack of direct evidence indicating whether hypoperfusion causes or aggravates AD pathology. We investigated the effect of chronic cerebral hypoperfusion on AD-related pathology in humans. Methods: We enrolled a group of cognitively normal patients (median age: 64 years) with unilateral chronic cerebral hypoperfusion. Regions of interest with the most pronounced hypoperfusion changes were chosen in the hypoperfused region and were then mirrored in the contralateral hemisphere to create a control region with normal perfusion. 11C-Pittsburgh compound-positron emission tomography standard uptake ratios and brain atrophy indices were calculated from the computed tomography images of each patient. Results: The median age of the 10 participants, consisting of 4 males and 6 females, was 64 years (47–76 years). We found that there were no differences in standard uptake ratios of the cortex (volume of interest [VOI]: P = 0.721, region of interest [ROI]: P = 0.241) and grey/white ratio (VOI: P = 0.333, ROI: P = 0.445) and brain atrophy indices (Bicaudate, Bifrontal, Evans, Cella, Cella media, and Ventricular index, P > 0.05) between the hypoperfused regions and contralateral normally perfused regions in patients with unilateral chronic cerebral hypoperfusion. Conclusion: Our findings suggest that chronic hypoperfusion due to large vessel stenosis may not directly induce cerebral β-amyloid deposition and neurodegeneration in humans.
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Wang X, Yang X, Han F, Gao L, Zhou Y. Propofol improves brain injury induced by chronic cerebral hypoperfusion in rats. Food Sci Nutr 2021; 9:2801-2809. [PMID: 34136148 PMCID: PMC8194753 DOI: 10.1002/fsn3.1915] [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: 08/19/2020] [Accepted: 08/23/2020] [Indexed: 12/12/2022] Open
Abstract
To study effect of propofol on cognitive dysfunction and brain injury in a rat model of chronic cerebral hypoperfusion. The bilateral carotid artery ligation (bilateral common carotid artery occlusion and BCCAO) to establish rat model of chronic cerebral hypoperfusion and randomly assigned to 4 groups (n = 10): sham-operation group treated with saline model group, propofol treatment model group, normal saline treatment, propofol treatment in the sham-operation group; continuous intraperitoneal injection of propofol and saline for 12 weeks. Morris water maze was used to evaluate the learning and memory ability of rats. Determination of central cholinergic and oxidative stress in brain tissue by spectrophotometry. Detection of inflammatory response in brain tissue by immunohistochemistry and ELISA method. Detection of neuronal loss in brain tissue by Nissl and TUNEL staining. Compared with the saline-treated model group, propofol in model group significantly increased the rat brain tissue SOD activity (p < .01) and GPX activity (p < .01), decreased the MDA levels (p < .01) and protein carbonyl compound levels (p < .01). The propofol treatment of model group rats hippocampal GFAP-immunoreactive satellite glial cells (p < .01) and immune Iba1-positive microglia cells (p < .01) area percent compared to saline-treated model group decreased significantly. The number of normal propofol treatment of model group rats hippocampus neuron than in physiological saline treatment model group rats was significantly increased (p < .01). Propofol can improve chronic cerebral hypoperfusion in rats induced by cognitive dysfunction and brain damage.
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Affiliation(s)
- Xiaodong Wang
- Department of AnesthesiologyPeking University Hospital of StomatologyBeijingChina
| | - Xudong Yang
- Department of AnesthesiologyPeking University Hospital of StomatologyBeijingChina
| | - Fang Han
- Department of AnesthesiologyPeking University Hospital of StomatologyBeijingChina
| | - Ling Gao
- Department of AnesthesiologyPeking University Hospital of StomatologyBeijingChina
| | - Yi Zhou
- Department of AnesthesiologyPeking University Hospital of StomatologyBeijingChina
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Loeffler DA. Modifiable, Non-Modifiable, and Clinical Factors Associated with Progression of Alzheimer's Disease. J Alzheimers Dis 2021; 80:1-27. [PMID: 33459643 DOI: 10.3233/jad-201182] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
There is an extensive literature relating to factors associated with the development of Alzheimer's disease (AD), but less is known about factors which may contribute to its progression. This review examined the literature with regard to 15 factors which were suggested by PubMed search to be positively associated with the cognitive and/or neuropathological progression of AD. The factors were grouped as potentially modifiable (vascular risk factors, comorbidities, malnutrition, educational level, inflammation, and oxidative stress), non-modifiable (age at clinical onset, family history of dementia, gender, Apolipoprotein E ɛ4, genetic variants, and altered gene regulation), and clinical (baseline cognitive level, neuropsychiatric symptoms, and extrapyramidal signs). Although conflicting results were found for the majority of factors, a positive association was found in nearly all studies which investigated the relationship of six factors to AD progression: malnutrition, genetic variants, altered gene regulation, baseline cognitive level, neuropsychiatric symptoms, and extrapyramidal signs. Whether these or other factors which have been suggested to be associated with AD progression actually influence the rate of decline of AD patients is unclear. Therapeutic approaches which include addressing of modifiable factors associated with AD progression should be considered.
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Affiliation(s)
- David A Loeffler
- Beaumont Research Institute, Department of Neurology, Beaumont Health, Royal Oak, MI, USA
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de Oliveira FF, de Almeida SS, Chen ES, Smith MC, Naffah-Mazzacoratti MDG, Bertolucci PHF. Lifetime Risk Factors for Functional and Cognitive Outcomes in Patients with Alzheimer's Disease. J Alzheimers Dis 2019; 65:1283-1299. [PMID: 30149448 DOI: 10.3233/jad-180303] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Lifetime risk factors for cognitive and functional decline in Alzheimer's disease (AD) are not fully understood, and were prospectively evaluated in patients with low mean schooling from São Paulo, Brazil. Consecutive outpatients with late-onset AD were assessed for APOE haplotypes and the following potential baseline predictors: gender, schooling, age at dementia onset, lifetime urban living and sanitary conditions, occupational complexity, cognitive and physical activities, cerebrovascular risk factors (obesity, lifetime alcohol use and smoking, length of arterial hypertension, diabetes mellitus, and a dyslipidemic profile), use of a pacemaker, creatinine clearance, body mass index, waist circumference, head traumas with unconsciousness, treated systemic bacterial infections, amount of surgical procedures under general anesthesia, and family history of AD. Participants were followed from October 2010 to May 2017 for baseline risk factor associations with time since dementia onset for Clinical Dementia Rating and Mini-Mental State Examination score changes. For 227 patients (154 women, 119 APOE ε 4 carriers), later AD onset (mean 73.60±6.4 years-old, earlier for APOE ε 4/ε 4 carriers, p < 0.001) was the only variable hastening all endpoints, baseline creatinine clearance and lifetime alcohol use were hazardous for earlier cognitive and functional endpoints, women had earlier cognitive endpoints only, and schooling had a cumulative protective effect over later cognitive endpoints, particularly for carriers of APOE ε 4. Exclusively for carriers of APOE ε 4, head traumas with unconsciousness were hazardous for earlier cognitive endpoints, while lifetime sanitary conditions were protective regarding later cognitive endpoints. Functional and cognitive outcomes in AD represent probable interactions between effects of brain reserve and cerebral perfusion over neurodegeneration.
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Affiliation(s)
- Fabricio Ferreira de Oliveira
- Department of Neurology and Neurosurgery, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil
| | - Sandro Soares de Almeida
- Department of Biophysics, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil
| | - Elizabeth Suchi Chen
- Department of Morphology and Genetics, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil
| | - Marilia Cardoso Smith
- Department of Morphology and Genetics, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil
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de la Torre J. The Vascular Hypothesis of Alzheimer's Disease: A Key to Preclinical Prediction of Dementia Using Neuroimaging. J Alzheimers Dis 2019; 63:35-52. [PMID: 29614675 DOI: 10.3233/jad-180004] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The vascular hypothesis of Alzheimer's disease (VHAD) was proposed 24 years ago from observations made in our laboratory using aging rats subjected to chronic brain hypoperfusion. In recent years, VHAD has become a mother-lode to numerous neuroimaging studies targeting cerebral hemodynamic changes, particularly brain hypoperfusion in elderly patients at risk of developing Alzheimer's disease (AD). There is a growing consensus among neuroradiologists that brain hypoperfusion is likely involved in the pathogenesis of AD and that disturbed cerebral blood flow (CBF) can serve as a key biomarker for predicting conversion of mild cognitive impairment to AD. The use of cerebral hypoperfusion as a preclinical predictor of AD is becoming decisive in stratifying low and high risk patients that may develop cognitive decline and for assessing the effectiveness of therapeutic interventions. There is currently an international research drive from neuroimaging groups to seek new perspectives that can broaden our understanding of AD and improve lifestyle. Diverse neuroimaging methods are currently being used to monitor normal and dyscognitive brain activity. Some techniques are very powerful and can detect, diagnose, quantify, prognose, and predict cognitive decline before AD onset, even from a healthy cognitive state. Multimodal imaging offers new insights in the treatment and prevention of cognitive decline during advanced aging and better understanding of the functional and structural organization of the human brain. This review discusses the impact the VHAD and CBF are having on the neuroimaging technology that can usher practical strategies to help prevent AD.
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Affiliation(s)
- Jack de la Torre
- Department of Psychology, University of Texas, Austin, Austin, TX, USA
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rCBF and cognitive impairment changes assessed by SPECT and ADAS-cog in late-onset Alzheimer's disease after 18 months of treatment with the cholinesterase inhibitors donepezil or galantamine. Brain Imaging Behav 2019; 13:75-86. [PMID: 29247294 DOI: 10.1007/s11682-017-9803-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Late-onset Alzheimer's disease (AD) differs substantially from early-onset AD. In this cross sectional study we investigated brain perfusion changes after 18 months of treatment with cholinesterase inhibitors (ChEIs) donepezil or galantamine. Twenty-five drug-naïve late-onset AD patients were recruited from outpatient clinics. We examined brain perfusion using single photon emission computed tomography (SPECT) and used three-dimensional stereotactic surface projection (3D-SSP) and the stereotactic extraction estimation method (SEE) level 3 to analyze classified gyrus level segments. We assessed cognitive function using the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) grouped into three subgroup domains, language, memory, and praxis. In the follow-up data, some regions were further hypoperfused, reflecting worsening of the disease, while other regions showed alleviated hypoperfusion, potentially related to the ChEIs treatment. Regional cerebral blood flow (rCBF) decreased in the parietal cortex and increased in the frontal and the limbic cortices. Increased hypoperfusion significantly correlated with ADAS-cog scores changes were seen in the superior parietal lobule, inferior parietal lobule, angular gyrus, and supramarginal gyrus of the parietal cortex. Alleviated hypoperfusion significantly related to recovery of ADAS-cog scores were seen in the rectal and paracentral lobule of the frontal cortex, and the anterior cingulate of the limbic cortex. These regions showed significant relationships with total ADAS-cog and language, memory and praxis subscales scores. The current longitudinal study indicates prominent rCBF changes and their relationships with changes in ADAS-cog scores in late-onset AD patients.
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Vascular risk factors and the relationships between cognitive impairment and hypoperfusion in late-onset Alzheimer's disease. Acta Neuropsychiatr 2018; 30:350-358. [PMID: 30132427 DOI: 10.1017/neu.2018.17] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
OBJECTIVE Our recent single-photon emission computed tomography (SPECT) study of patients with late-onset Alzheimer's disease (AD) revealed that regional cerebral blood flow (rCBF) was reduced in the frontal, temporal, and limbic lobes, and to a lesser degree in the parietal and occipital lobes. Moreover, these patients' scores on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) were significantly correlated with rCBF in some gyri of the frontal, parietal, and limbic lobes. Our present study aimed to understand how vascular factors and metabolic disease influenced the relationship between rCBF and ADAS-cog scores. METHODS We divided late-onset AD patients into two groups according to their Hachinski Ischemic Score (HIS), low vascular risk patients had values of ≤4 (n=25) and high vascular risk patients had scores ≥5 (n=15). We examined rCBF using brain perfusion SPECT data. RESULTS The degrees and patterns of reduced rCBF were largely similar between late-onset AD patients in both groups, regardless of HIS values. Cognitive function was significantly associated with rCBF among late-onset AD patients with low vascular risk (HIS≤4), but not among those with high vascular risk (HIS≥5). Furthermore, metabolic diseases, such as hypertension and diabetes mellitus, disrupted the relationships between hypoperfusion and cognitive impairments in late-onset AD patients. CONCLUSION Factors other than hypoperfusion, such as hypertension and diabetes mellitus, could be involved in the cognitive dysfunction of late-onset AD patients with high vascular risk.
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Ishimaru K, Nakajima T, Namiki Y, Ryotokuji K. Influences of Pinpoint Plantar Long-Wavelength Infrared Light Irradiation (Stress-Free Therapy) on Chorioretinal Hemodynamics, Atherosclerosis Factors, and Vascular Endothelial Growth Factor. Integr Med Res 2018; 7:103-107. [PMID: 29629297 PMCID: PMC5884040 DOI: 10.1016/j.imr.2017.12.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Revised: 11/24/2017] [Accepted: 12/14/2017] [Indexed: 11/29/2022] Open
Abstract
Background We previously reported that pinpoint plantar long-wavelength infrared light irradiation (stress-free therapy; SFT) is useful for alleviating insulin resistance and improving intracranial blood flow in patients with type 2 diabetes mellitus. This study was undertaken to evaluate the influences of SFT on chorioretinal hemodynamics (retinal artery and vein blood flows) as well as atherosclerosis-related factors (TG, LDL-C) and VEGF in patients with dyslipidemia. Methods Four patients with dyslipidemia received 15-minute irradiation with a stress-free apparatus (far-infrared wavelength, 30 mW). Using laser speckle flowgraphy, associations of chorioretinal blood flow with peripheral atherosclerosis-inducing factors/VEGF levels before and after irradiation were analyzed. Results Chorioretinal blood flow increased, while TG/LDL-C levels decreased, after irradiation. VEGF tended to rise in cases with pre-irradiation baseline levels at the lower limit but tended to decrease in cases in which baseline levels had exceeded the normal range. Conclusion SFT was suggested to enhance chorioretinal circulation and to normalize VEGF, thereby possibly contributing to amelioration of atherosclerosis-inducing factors. Abnormalities in chorioretinal hemodynamics are known to be highly involved in the pathophysiology of diabetic retinopathy and age-related macular degeneration, and anti-VEGF antibody has been used for treating these conditions. The necessity of risk management, involving chorioretinal blood flow, has been pointed out when dealing with central retinal vein occlusion, diabetes mellitus, ischemic cerebral/cardiac disease, dementia and so on. SFT is therefore a potential complementary medical strategy which can be expected to contribute to normalization of chorioretinal blood flow and atherosclerosis-inducing factors/VEGF levels, and thereby to the prevention of lifestyle-related chronic diseases.
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Affiliation(s)
- Keisou Ishimaru
- Corresponding author at: Faculty of Health Sciences, Ryotokuji University, Urayasu, Japan.
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Wang F, Feng J, Yang Y, Liu J, Liu M, Wang Z, Pei H, Wei Y, Li H. The Chinese herbal formula Fuzheng Quxie Decoction attenuates cognitive impairment and protects cerebrovascular function in SAMP8 mice. Neuropsychiatr Dis Treat 2018; 14:3037-3051. [PMID: 30519025 PMCID: PMC6233692 DOI: 10.2147/ndt.s175484] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
PURPOSE This study was designed to explore the underlying mechanism of action for a Fuzheng Quxie Decoction (FQD) in Alzheimer's disease (AD), to validate its neuroprotective effects, and to provide experimental support for its predicted mechanism of action. METHODS An integrative approach to network pharmacology was performed to predict the mechanism of action for treatment of AD with FQD. The predicted mechanism was validated in SAMP8 mice. RESULTS With predicted putative FQD targets and a collection of AD-related genes, 245 possible regulatory targets of FQD were identified for the treatment of AD. Pathway-enrichment analysis for the possible regulatory targets indicated that vascular endothelial growth factor (VEGF) and VEGF-receptor signaling were pivotal in the treatment of AD with FQD. In vivo experiments confirmed the neuroprotective effect and the predicted mechanism of action for treatment of AD with FQD. CONCLUSION This study contributes to an understanding of the neuroprotective effect of FQD and its potential mechanism of action for the treatment of AD.
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Affiliation(s)
- Feixue Wang
- Department of Geriatrics, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China, ;
| | - Jianchao Feng
- Intensive Care Unit, Heze Hospital of Traditional Chinese Medicine, Heze, Shandong, China
| | - Yang Yang
- Department of Geriatrics, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China, ;
| | - Jiangang Liu
- Department of Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Meixia Liu
- Department of Geriatrics, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China, ;
| | - Zhiyong Wang
- Department of Geriatrics, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China, ;
| | - Hui Pei
- Department of Geriatrics, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China, ;
| | - Yun Wei
- Department of Geriatrics, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China, ;
| | - Hao Li
- Department of Geriatrics, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China, ;
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Relationships between cognitive impairment on ADAS-cog and regional cerebral blood flow using SPECT in late-onset Alzheimer's disease. J Neural Transm (Vienna) 2017; 124:1109-1121. [PMID: 28509077 DOI: 10.1007/s00702-017-1734-7] [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: 02/25/2017] [Accepted: 05/08/2017] [Indexed: 10/19/2022]
Abstract
The aim of this study was to examine brain hypoperfusion and its relationship with cognitive dysfunction in late-onset Alzheimer's disease (AD). Forty patients with late-onset AD and not receiving acetylcholinesterase inhibitors were recruited from outpatient clinics. We examined cognitive function using the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and brain perfusion using single-photon emission computed tomography, and analyzed classified gyrus level segments with three-dimensional stereotactic surface projection and the stereotactic extraction estimation method level 3. ADAS-cog subscales were grouped into three domains: language, memory, and praxis. Patients with late-onset AD showed an apparent reduction in regional cerebral blood flow (rCBF) with a z score >1.5 in the frontal, temporal, and limbic lobes, with lesser reduction in the parietal and occipital lobes. Although hypoperfusion in the orbital, rectal, and subcallosal gyri of the frontal lobe was prominent, rCBF in the inferior frontal gyrus of the frontal lobe was significantly correlated with ADAS-cog total and language and praxis subscale scores. The parahippocampal gyrus of the limbic lobe was also significantly correlated with the ADAS-cog total, language, and praxis subscale scores. Additionally, the cingulate of the limbic lobe was significantly related with ADAS-cog memory. In spite of lesser hypoperfusion, the posterior cingulate gyrus of the limbic lobe was significantly related with ADAS-cog total, language, and memory subscale scores. Further, each subdivision of ADAS-cog was found to be related with various brain regions.
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André-Petersson L, Thorsson O, Siennicki-Lantz A. Cognitive abnormalities and cerebral perfusion defects in a community-dwelling cohort of elderly men with MMSE within the normal range. AGING NEUROPSYCHOLOGY AND COGNITION 2017; 25:200-212. [PMID: 28068866 DOI: 10.1080/13825585.2016.1277970] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
OBJECTIVES Mini Mental State Examination's (MMSE's) sensitivity in its upper level is questioned, hence we investigated cognitive abnormalities and defects in regional cerebral blood flow (rCBF) in elderly with MMSE scores ≥24. METHODS One hundred and four men at age 81 with MMSE scores ≥24 (mean 28.4 ± 1.7), no dementia or stroke, were examined with neuropsychological test battery, and their rCBF was estimated using 99mTc-HMPAO SPECT. RESULTS MMSE was very sparsely correlated with rCBF. Instead, visuo-spatial tests were correlated with rCBF in parietal and occipital lobe, verbal tests with rCBF in frontal and temporal-parietal lobes, and most of all between Digit Symbol and all rCBF regions, especially in subcortical gray and white matter. In a cluster of low achievers, test of Synonyms, followed by Digit Symbol and Benton test, had highest discriminatory importance. Low achievers had generalized rCBF changes especially in subcortical areas. Only lower scores on two MMSE items, figure drawing and calculation, could discriminate the clusters. CONCLUSION A substantial number of octogenarian men with MMSE ≥ 24p have widespread rCBF changes corresponding to a decreased speeded performance and verbal capacity.
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Affiliation(s)
- Lena André-Petersson
- a Department of Clinical Sciences in Malmö , Neurology Unit , Malmö , Sweden.,d Lund University , Lund , Sweden
| | - Ola Thorsson
- b Department of Clinical Physiology and Nuclear Medicine , Scania University Hospital , Malmö , Sweden.,d Lund University , Lund , Sweden
| | - Arkadiusz Siennicki-Lantz
- c Department of Clinical Sciences in Malmö , Geriatric Medicine Unit , Malmö , Sweden .,d Lund University , Lund , Sweden
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Predictors of Cognitive and Functional Decline in Patients With Alzheimer Disease Dementia From Brazil. Alzheimer Dis Assoc Disord 2016; 30:243-50. [DOI: 10.1097/wad.0000000000000117] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Osone A, Arai R, Hakamada R, Shimoda K. Impact of lifestyle-related disease on conversion and reversion in patients with mild cognitive impairment: after 12 months of follow-up. Int J Geriatr Psychiatry 2016; 31:740-8. [PMID: 26593034 DOI: 10.1002/gps.4386] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Accepted: 10/09/2015] [Indexed: 11/06/2022]
Abstract
OBJECTIVE The objective of the study is to investigate whether the lifestyle-related disease (LSRD) hypertension, type II diabetes mellitus, and lipid abnormality are associated with conversion and reversion in patients with mild cognitive impairment (MCI) over 12 months of follow-up. METHODS One hundred and thirteen patients with MCI were prospectively enrolled and longitudinally assessed. Methods used include mini-mental state examination, the Japanese version of the cognitive subscale of the Alzheimer's Disease Assessment Scale, the Clinical Dementia Rating, the Frontal Assessment Battery, the Neuropsychiatric Inventory, magnetic resonance imaging, and quantitative single-photon emission computed tomography. In addition, laboratory examinations of glucose and lipids were also performed. All measurements were performed at first intake and again at the end of the 12-month follow-up. Conversion was identified as a change in Clinical Dementia Rating from 0.5 to 1 and reversion as a change from 0.5 to 0. RESULTS Patients with MCI with reversion had lower comorbid lipid abnormality at baseline and higher cognitive and behaviour function across the 12-month follow-up compared with those with no change or conversion. Patients without comorbid LSRD had lower systolic pressure and lower glucose and triglyceride levels at baseline, as well as less cognitive decline compared with other groups across the follow-up period. CONCLUSIONS The absence of lipid abnormality at baseline may contribute to reversion in patients with MCI. The presence of multiple LSRD was associated with cognitive decline. Our results highlight the contribution of multiple LSRD on increasing conversion and decreasing reversion in patients with MCI. Copyright © 2015 John Wiley & Sons, Ltd.
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Affiliation(s)
- Akira Osone
- Department of Psychiatry and Center for Dementia-Related Diseases, Dokkyo Medical University School of Medicine, Mibu, Shimotsuga, Tochigi, Japan
| | - Reiko Arai
- Department of Psychiatry and Center for Dementia-Related Diseases, Dokkyo Medical University School of Medicine, Mibu, Shimotsuga, Tochigi, Japan
| | - Rina Hakamada
- Department of Psychiatry and Center for Dementia-Related Diseases, Dokkyo Medical University School of Medicine, Mibu, Shimotsuga, Tochigi, Japan
| | - Kazutaka Shimoda
- Department of Psychiatry and Center for Dementia-Related Diseases, Dokkyo Medical University School of Medicine, Mibu, Shimotsuga, Tochigi, Japan
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Qu J, Zhou Q, Du Y, Zhang W, Bai M, Zhang Z, Xi Y, Li Z, Miao J. Rutin protects against cognitive deficits and brain damage in rats with chronic cerebral hypoperfusion. Br J Pharmacol 2016; 171:3702-15. [PMID: 24758388 DOI: 10.1111/bph.12725] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Revised: 03/14/2014] [Accepted: 04/10/2014] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND AND PURPOSE Chronic cerebral hypoperfusion is a critical causative factor for the development of cognitive decline and dementia in the elderly, which involves many pathophysiological processes. Consequently, inhibition of several pathophysiological pathways is an attractive therapeutic strategy for this disorder. Rutin, a biologically active flavonoid, protects the brain against several insults through its antioxidant and anti-inflammatory properties, but its effect on cognitive deficits and brain damage caused by chronic cerebral hypoperfusion remains unknown. Here, we investigated the neuroprotective effect of rutin on cognitive impairments and the potential mechanisms underlying its action in rats with chronic cerebral hypoperfusion. EXPERIMENTAL APPROACH We used Sprague-Dawley rats with permanent bilateral common carotid artery occlusion (BCCAO), a well-established model of chronic cerebral hypoperfusion. After rutin treatment for 12 weeks, the neuroprotective effect of rutin in rats was evaluated by behavioural tests, biochemical and histopathological analyses. KEY RESULTS BCCAO rats showed marked cognitive deficits, which were improved by rutin treatment. Moreover, BCCAO rats exhibited central cholinergic dysfunction, oxidative damage, inflammatory responses and neuronal damage in the cerebral cortex and hippocampus, compared with sham-operated rats. All these effects were significantly alleviated by treatment with rutin. CONCLUSION AND IMPLICATIONS Our results provide new insights into the pharmacological actions of rutin and suggest that rutin has multi-targeted therapeutical potential on cognitive deficits associated with conditions with chronic cerebral hypoperfusion such as vascular dementia and Alzheimer's disease.
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Affiliation(s)
- Jie Qu
- Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, China
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17
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de Oliveira FF, Pivi GAK, Chen ES, Smith MC, Bertolucci PHF. Risk factors for cognitive and functional change in one year in patients with Alzheimer's disease dementia from São Paulo, Brazil. J Neurol Sci 2015; 359:127-32. [DOI: 10.1016/j.jns.2015.10.051] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Revised: 10/09/2015] [Accepted: 10/28/2015] [Indexed: 10/22/2022]
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18
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Icariin, a major constituent of flavonoids from Epimedium brevicornum, protects against cognitive deficits induced by chronic brain hypoperfusion via its anti-amyloidogenic effect in rats. Pharmacol Biochem Behav 2015; 138:40-8. [DOI: 10.1016/j.pbb.2015.09.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Revised: 09/02/2015] [Accepted: 09/04/2015] [Indexed: 11/20/2022]
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Husaini B, Gudlavalleti AS, Cain V, Levine R, Moonis M. Risk Factors and Hospitalization Costs of Dementia Patients: Examining Race and Gender Variations. Indian J Community Med 2015; 40:258-63. [PMID: 26435599 PMCID: PMC4581146 DOI: 10.4103/0970-0218.164396] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
AIMS To examine the variation in risk factors and hospitalization costs among four elderly dementia cohorts by race and gender. MATERIALS AND METHODS The 2008 Tennessee Hospital Discharged database was examined. The prevalence, risk factors and cost of inpatient care of dementia were examined for individuals aged 65 years and above, across the four race gender cohorts - white males (WM), black males (BM), white females (WF), and black females (BF). RESULTS 3.6% of patients hospitalized in 2008 had dementia. Dementia was higher among females than males, and higher among blacks than whites. Further, BF had higher prevalence of dementia than WF; similarly, BM had a higher prevalence of dementia than WM. Overall, six risk factors were associated with dementia for the entire sample including HTN, DM, CKD, CHF, COPD, and stroke. These risk factors varied slightly in predicting dementia by race and gender. Hospital costs were 14% higher among dementia patients compared to non-dementia patients. CONCLUSIONS There exist significant race and gender disparities in prevalence of dementia. A greater degree of co-morbidity, increased duration of hospital stay, and more frequent hospitalizations, may result in a higher cost of inpatient dementia care. Aggressive management of risk factors may subsequently reduce stroke and cost of dementia care, especially in the black population. Race and gender dependent milestones for management of these risk factors should be considered.
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Affiliation(s)
- Baqar Husaini
- Center for Prevention Research, Tennessee State University, Nashville, Tennessee, USA
| | | | - Van Cain
- Center for Prevention Research, Tennessee State University, Nashville, Tennessee, USA
| | - Robert Levine
- Department of Preventive and Family Medicine, Meharry Medical College, Nashville, Tennessee, USA
| | - Majaz Moonis
- Department of Neurology, University of Massachusetts, Massachusetts, USA
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20
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Pasha EP, Kaur SS, Gonzales MM, Machin DR, Kasischke K, Tanaka H, Haley AP. Vascular function, cerebral cortical thickness, and cognitive performance in middle-aged Hispanic and non-Hispanic Caucasian adults. J Clin Hypertens (Greenwich) 2015; 17:306-12. [PMID: 25720950 PMCID: PMC4390456 DOI: 10.1111/jch.12512] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Revised: 01/05/2015] [Accepted: 01/07/2015] [Indexed: 11/26/2022]
Abstract
Hispanics are at increased risk for acquiring cardiovascular risk factors that contribute to cognitive dysfunction. To compare indices of vascular health with measures of cerebral gray matter integrity, 60 middle-aged Hispanic and non-Hispanic Caucasian participants were matched across age, sex, years of education, and mental status. Arterial stiffness was characterized by β-stiffness index and carotid-femoral pulse wave velocity, and magnetic resonance imaging estimated cortical thickness in a priori regions of interest known to be susceptible to vascular risk factors. Measures of arterial stiffness were significantly higher in Hispanics than in non-Hispanic Caucasians. Hispanics exhibited thinner left inferior frontal gyrus (LIFG) cortical thickness (P=.04) with concurrently lower language (P=.02), memory (P=.03), and attention-executive functioning (P=.02). These results suggest that compromised vascular health may occur simultaneously with cortical thinning of the LIFG as an early neuropathological alteration in Hispanics.
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Affiliation(s)
- Evan P Pasha
- Department of Kinesiology and Health Education, The University of Texas at Austin, Austin, TX
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21
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de Oliveira FF, Bertolucci PHF, Chen ES, Smith MC. Risk factors for age at onset of dementia due to Alzheimer's disease in a sample of patients with low mean schooling from São Paulo, Brazil. Int J Geriatr Psychiatry 2014; 29:1033-9. [PMID: 24596166 DOI: 10.1002/gps.4094] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2013] [Accepted: 01/23/2014] [Indexed: 12/21/2022]
Abstract
OBJECTIVE In view of the mild effects of pharmacological treatment for dementia due to Alzheimer's disease (AD), the search for modifiable risk factors is an important challenge. Although risk factors for AD are widely recognized, elements that influence the time of onset of the dementia syndrome have not been comprehensively reported. We aimed to investigate which risk factors might be associated with the age at onset of AD in a sample of patients with low mean schooling from São Paulo, Brazil. METHODS We included 210 consecutive patients with late-onset AD to investigate whether education, gender, nationality, urban living and sanitation, occupation, cognitive and physical inactivity, head trauma, depression, systemic infections, surgical interventions, cerebrovascular risk factors, family history of neurodegenerative diseases or cardiovascular diseases and apolipoprotein E gene (APOE) haplotypes might be related to the age at AD onset. RESULTS Each copy of APOE-ε4 led to onset of AD almost 2 years earlier, while depression, smoking, higher body mass index and family history of cardiovascular diseases were also highly significant. Protective factors included non-Brazilian nationality, use of a pacemaker and waist circumference. Cerebrovascular risk factors had a mild combined effect for earlier onset of AD. CONCLUSION APOE haplotypes, depression, nationality and cerebrovascular risk factors were the most important elements to influence the age at AD onset in this sample, whereas gender, education, occupation and physical activities had no isolated effects over the age at onset of this dementia syndrome.
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Affiliation(s)
- Fabricio Ferreira de Oliveira
- Department of Neurology and Neurosurgery, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil; Department of Morphology and Genetics, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil
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Husaini B, Cain V, Novotny M, Samad Z, Levine R, Moonis M. Variation in risk factors of dementia among four elderly patient cohorts. World J Neurol 2014; 4:7-11. [DOI: 10.5316/wjn.v4.i2.7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Revised: 05/07/2014] [Accepted: 06/16/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine variation in risk factors that contributed to dementia among four elderly cohorts by race and gender.
METHODS: We examined 2008 Tennessee Hospital Discharged database for vascular factors that play a role in both stroke and dementia. Risk factors for dementia were examined for black and white patients aged 65+. Four race-gender groups of patients-white males (WM), black males (BM), white females (WF), and black females (BF) were compared for prevalence of dementia and stroke. A logistic model predicting dementia in each group separately used several vascular factors affecting dementia directly or indirectly through stroke.
RESULTS: Three point six percent of patients hospitalized in 2008 had dementia and dementia was higher among females than males (3.9% vs 3.2%, P < 0.001), and higher among blacks than whites (4.2% vs 3.5%, P < 0.000). Further, BF had higher prevalence of dementia than WF (4.2% vs 3.8%, P < 0.001); similarly BM had more dementia than WM (4.1% vs 3.1%, P < 0.001). In logistic regression models, however, different patterns of risk factors were associated with dementia in four groups: among WF and WM, hypertension, diabetes, congestive heart failure, and stroke predicted dementia. Among BF and BM, only stroke and diabetes were related to dementia.
CONCLUSION: Aggressive management of risk factors (hypertension and diabetes) may subsequently reduce stroke and dementia hospitalization.
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Ferreira LK, Tamashiro-Duran JH, Squarzoni P, Duran FL, Alves TC, Buchpiguel CA, Busatto GF. The link between cardiovascular risk, Alzheimer's disease, and mild cognitive impairment: support from recent functional neuroimaging studies. ACTA ACUST UNITED AC 2014; 36:344-57. [PMID: 24918525 DOI: 10.1590/1516-4446-2013-1275] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2013] [Accepted: 01/03/2014] [Indexed: 11/22/2022]
Abstract
OBJECTIVE To review functional neuroimaging studies about the relationship between cardiovascular risk factors (CVRFs), Alzheimer's disease (AD), and mild cognitive impairment (MCI). METHODS We performed a comprehensive literature search to identify articles in the neuroimaging field addressing CVRF in AD and MCI. We included studies that used positron emission tomography (PET), single photon emission computerized tomography (SPECT), or functional magnetic resonance imaging (fMRI). RESULTS CVRFs have been considered risk factors for cognitive decline, MCI, and AD. Patterns of AD-like changes in brain function have been found in association with several CVRFs (both regarding individual risk factors and also composite CVRF measures). In vivo assessment of AD-related pathology with amyloid imaging techniques provided further evidence linking CVRFs and AD, but there is still limited information resulting from this new technology. CONCLUSION There is a large body of evidence from functional neuroimaging studies supporting the hypothesis that CVRFs may play a causal role in the pathophysiology of AD. A major limitation of most studies is their cross-sectional design; future longitudinal studies using multiple imaging modalities are expected to better document changes in CVRF-related brain function patterns and provide a clearer picture of the complex relationship between aging, CVRFs, and AD.
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Affiliation(s)
- Luiz K Ferreira
- Laboratory of Psychiatric Neuroimaging (LIM-21), Department and Institute of Psychiatry, School of Medicine, Universidade de São Paulo (USP), São Paulo, SP, Brazil
| | - Jaqueline H Tamashiro-Duran
- Laboratory of Psychiatric Neuroimaging (LIM-21), Department and Institute of Psychiatry, School of Medicine, Universidade de São Paulo (USP), São Paulo, SP, Brazil
| | - Paula Squarzoni
- Laboratory of Psychiatric Neuroimaging (LIM-21), Department and Institute of Psychiatry, School of Medicine, Universidade de São Paulo (USP), São Paulo, SP, Brazil
| | - Fabio L Duran
- Laboratory of Psychiatric Neuroimaging (LIM-21), Department and Institute of Psychiatry, School of Medicine, Universidade de São Paulo (USP), São Paulo, SP, Brazil
| | - Tania C Alves
- Laboratory of Psychiatric Neuroimaging (LIM-21), Department and Institute of Psychiatry, School of Medicine, Universidade de São Paulo (USP), São Paulo, SP, Brazil
| | - Carlos A Buchpiguel
- Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), USP, São Paulo, SP, Brazil
| | - Geraldo F Busatto
- Laboratory of Psychiatric Neuroimaging (LIM-21), Department and Institute of Psychiatry, School of Medicine, Universidade de São Paulo (USP), São Paulo, SP, Brazil
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24
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Sherva R, Tripodis Y, Bennett DA, Chibnik LB, Crane PK, de Jager PL, Farrer LA, Saykin AJ, Shulman JM, Naj A, Green RC. Genome-wide association study of the rate of cognitive decline in Alzheimer's disease. Alzheimers Dement 2014; 10:45-52. [PMID: 23535033 PMCID: PMC3760995 DOI: 10.1016/j.jalz.2013.01.008] [Citation(s) in RCA: 135] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Revised: 12/17/2012] [Accepted: 01/24/2013] [Indexed: 01/13/2023]
Abstract
BACKGROUND Substantial interindividual variability exists in the disease trajectories of Alzheimer's disease (AD) patients. Some decline rapidly whereas others decline slowly, and there are no known explanations for this variability. We describe the first genome-wide association study to examine rate of cognitive decline in a sample of AD patients with longitudinal measures of cognition. METHODS The discovery sample was 303 AD cases recruited in the Alzheimer's Disease Neuroimaging Initiative and the replication sample was 323 AD cases from the Religious Orders Study and Rush Memory and Aging Project. In the discovery sample, Alzheimer's Disease Assessment Scale-cognitive subscale responses were tested for association with genome-wide single-nucleotide polymorphism (SNP) data using linear regression. We tested the 65 most significant SNPs from the discovery sample for association in the replication sample. RESULTS We identified SNPs in the spondin 1 gene (SPON1), the minor alleles of which were significantly associated with a slower rate of decline (rs11023139, P = 7.0 × 10(-11)) in the discovery sample. A SPON1 SNP 5.5 kb upstream was associated with decline in the replication sample (rs11606345, P = .002). CONCLUSION SPON1 has not been previously associated with AD risk, but is plausibly related because the gene product binds to the amyloid precursor protein and inhibits its cleavage by β-secretase. These data suggest that SPON1 may be associated with the differential rate of cognitive decline in AD.
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Affiliation(s)
- Richard Sherva
- Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
| | - Yorghos Tripodis
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
| | - David A Bennett
- Rush Alzheimer's Disease Center, Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA
| | - Lori B Chibnik
- Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology & Psychiatry, Brigham and Women's Hospital Boston, MA, USA; Department of Neurology, Harvard Medical School, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Paul K Crane
- School of Medicine, University of Washington, Seattle, WA, USA
| | - Philip L de Jager
- Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology & Psychiatry, Brigham and Women's Hospital Boston, MA, USA; Department of Neurology, Harvard Medical School, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Lindsay A Farrer
- Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; Departments Ophthalmology, Neurology, and Epidemiology, Boston University Schools of Medicine and Public Health, Boston, MA, USA
| | - Andrew J Saykin
- Department of Medical and Molecular Genetics, Center for Neuroimaging, Department of Radiology and Imaging Sciences, Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Joshua M Shulman
- Departments of Neurology and Molecular and Human Genetics Baylor College of Medicine Jan and Dan Duncan Neurological Research Institute, Houston, TX, USA
| | - Adam Naj
- Department of Biostatics and Epidemiology and Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA, USA
| | - Robert C Green
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
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Xi Y, Wang M, Zhang W, Bai M, Du Y, Zhang Z, Li Z, Miao J. Neuronal damage, central cholinergic dysfunction and oxidative damage correlate with cognitive deficits in rats with chronic cerebral hypoperfusion. Neurobiol Learn Mem 2013; 109:7-19. [PMID: 24315928 DOI: 10.1016/j.nlm.2013.11.016] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Revised: 11/14/2013] [Accepted: 11/24/2013] [Indexed: 12/31/2022]
Abstract
Chronic cerebral hypoperfusion has been identified to be a risk factor for cognitive decline in aging, vascular dementia, and Alzheimer's disease. Substantial evidence has shown that chronic cerebral hypoperfusion may cause cognitive impairment, but the underlying neurobiological mechanism is poorly understood so far. In this study, we used a rat model of chronic cerebral hypoperfusion by permanent bilateral common carotid artery occlusion (BCCAO) to investigate the alterations of neuronal damage, glial activation oxidative stress and central cholinergic dysfunction, and their causal relationship with the cognitive deficits induced by chronic cerebral hypoperfusion. We found that BCCAO rats exhibited spatial learning and memory impairments and working memory dysfunction 12 weeks after BCCAO compared with sham-operated rats, simultaneously accompanied by significantly increased neuronal damage and glial cell activation in the cerebral cortex and hippocampus. Twelve weeks of BCCAO treatment in rats resulted in central cholinergic dysfunction and increased oxidative damage compared with sham-operated rats. Correlational analyses revealed that spatial learning and memory impairments and working memory dysfunction were significantly correlated with the measures of neuronal damage, central cholinergic dysfunction and oxidative damage in the cerebral cortex and hippocampus of rats with BCCAO. Moreover, the measures of neuronal damage and central cholinergic dysfunction were significantly correlated with the indexes of oxidative damage in rats with BCCAO. Collectively, this study provides novel evidence that neuronal damage and central cholinergic dysfunction is likely due to increased oxidative stress under the condition of chronic cerebral hypoperfusion. Furthermore, the results of the present study suggest that neuronal damage, central cholinergic dysfunction and oxidative damage in the brain following the reduction of cerebral blood flow could be involved in cognitive deficits induced by chronic cerebral hypoperfusion.
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Affiliation(s)
- Ye Xi
- Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an City, Shaanxi Province 710038, China
| | - Man Wang
- Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an City, Shaanxi Province 710038, China; Institute of Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi'an City, Shaanxi Province 710038, China
| | - Wei Zhang
- Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an City, Shaanxi Province 710038, China
| | - Miao Bai
- Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an City, Shaanxi Province 710038, China; Institute of Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi'an City, Shaanxi Province 710038, China
| | - Ying Du
- Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an City, Shaanxi Province 710038, China; Institute of Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi'an City, Shaanxi Province 710038, China
| | - Zhuo Zhang
- Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an City, Shaanxi Province 710038, China
| | - Zhuyi Li
- Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an City, Shaanxi Province 710038, China; Institute of Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi'an City, Shaanxi Province 710038, China.
| | - Jianting Miao
- Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an City, Shaanxi Province 710038, China.
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The influence of vascular risk factors on cognitive decline in patients with dementia: A systematic review. Maturitas 2013; 76:113-7. [DOI: 10.1016/j.maturitas.2013.06.011] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2013] [Revised: 06/07/2013] [Accepted: 06/14/2013] [Indexed: 11/22/2022]
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Kimura N, Nakama H, Nakamura K, Aso Y, Kumamoto T. Effect of white matter lesions on brain perfusion in Alzheimer's disease. Dement Geriatr Cogn Disord 2013. [PMID: 23183589 DOI: 10.1159/000345184] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND This study examined the effect of white matter lesions (WMLs) on regional cerebral blood flow (rCBF) in patients with Alzheimer's disease (AD). METHODS Ninety-eight patients with AD were included in the study (40 men and 58 women; mean age, 78.1 years). Cognitive function was assessed using the Mini-Mental State Examination. Brain magnetic resonance imaging (MRI) and (99m)Tc ethyl cysteinate dimer single photon emission computed tomography were performed in all subjects. AD patients were divided into two subgroups according to the presence of WMLs on MRI. A voxel-by-voxel group analysis using Statistical Parametric Mapping 8 was used to detect the differences in rCBF between the two groups. RESULTS Fifty-seven of 98 AD patients (58%) showed mild to moderate WMLs on MRI. The prevalence of hypertension was significantly higher in AD patients with WMLs than in those without WMLs. AD patients with WMLs exhibited a significantly decreased rCBF in the anterior cingulate gyrus and insula, compared to AD patients without WMLs. CONCLUSION We suggest that WMLs might influence brain regions associated with the limbic system in patients with AD.
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Affiliation(s)
- Noriyuki Kimura
- Department of Neurology and Neuromuscular Disorders, Oita University, Faculty of Medicine, Yufu, Japan.
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Abstract
Alzheimer's disease (AD) is an urgent public health challenge that is rapidly approaching epidemic proportions. New therapies that defer or prevent the onset, delay the decline, or improve the symptoms are urgently needed. All phase 3 drug development programs for disease-modifying agents have failed thus far. New approaches to drug development are needed. Translational neuroscience focuses on the linkages between basic neuroscience and the development of new diagnostic and therapeutic products that will improve the lives of patients or prevent the occurrence of brain disorders. Translational neuroscience includes new preclinical models that may better predict human efficacy and safety, improved clinical trial designs and outcomes that will accelerate drug development, and the use of biomarkers to more rapidly provide information regarding the effects of drugs on the underlying disease biology. Early translational research is complemented by later stage translational approaches regarding how best to use evidence to impact clinical practice and to assess the influence of new treatments on the public health. Funding of translational research is evolving with an increased emphasis on academic and NIH involvement in drug development. Translational neuroscience provides a framework for advancing development of new therapies for AD patients.
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Agosta F, Caso F, Filippi M. Dementia and neuroimaging. J Neurol 2012; 260:685-91. [PMID: 23241895 DOI: 10.1007/s00415-012-6778-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2012] [Revised: 11/23/2012] [Accepted: 11/24/2012] [Indexed: 12/12/2022]
Abstract
Early diagnosis of dementing conditions and an accurate monitoring of their progression are important clinical and research goals, especially given the improving prospects of disease-modifying therapies. Neuroimaging has played and is playing an important role in detecting reversible, treatable causes of dementia, and in characterizing the dementia syndromes by demonstrating structural and functional signatures that can aid in their differentiation. Many new imaging techniques and modalities are also available that allow the assessment of specific aspects of brain structure and function, such as positron emission tomography with new ligands, diffusion tensor magnetic resonance imaging (MRI) and functional MRI. In this review, we report the most recent findings from the papers published in the Journal of Neurology that used conventional and advanced neuroimaging techniques for the study of various dementing conditions.
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Affiliation(s)
- Federica Agosta
- Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, via Olgettina 60, 20132 Milan, Italy
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Olazarán J, Navarro E, Rojo JM. Alzheimer's disease with vascular component: a distinct clinical entity? Dement Geriatr Cogn Dis Extra 2012; 2:400-10. [PMID: 23139685 PMCID: PMC3493007 DOI: 10.1159/000342346] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Background Longitudinal reports on the clinical features of patients with Alzheimer's disease (AD) and concomitant cerebrovascular disease are scarce. Methods We elaborated a working definition of AD with vascular component (ADVC), and this definition was retrospectively investigated in a cohort of patients with cognitive deterioration who were prescribed a cholinesterase inhibitor during usual practice. Results A total of 137 patients with probable AD and 66 patients with ADVC were studied during a mean follow-up period of 2.8 years. Univariate analyses demonstrated worse functional evolution and anticipation of psychotic symptoms and agitation in the ADVC group. Conclusions The present results are consistent with an additive model of predominantly frontal-subcortical vascular damage in AD.
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Affiliation(s)
- Javier Olazarán
- Hermanos Sangro Specialties Clinic, Service of Neurology, Gregorio Marañón University Hospital, Spain ; Alzheimer Disease Research Unit, CIEN Foundation, Carlos III Institute of Health, Alzheimer Center Reina Sofía Foundation, Spain
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Quintessential Risk Factors: Their Role in Promoting Cognitive Dysfunction and Alzheimer’s Disease. Neurochem Res 2012; 37:2627-58. [DOI: 10.1007/s11064-012-0854-6] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2012] [Accepted: 07/21/2012] [Indexed: 12/13/2022]
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Hanyu H. [Internal medicine and neurological diseases: progress in diagnosis and treatment. Topics: III. Dyslipidemia and neurological disorders (cerebral infarction, dementia)]. NIHON NAIKA GAKKAI ZASSHI. THE JOURNAL OF THE JAPANESE SOCIETY OF INTERNAL MEDICINE 2012; 101:2188-2194. [PMID: 22973689 DOI: 10.2169/naika.101.2188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Affiliation(s)
- Haruo Hanyu
- Department of Geriatric Medicine, Tokyo Medical University, Japan
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Carvalho C, Cardoso S, Correia SC, Santos RX, Santos MS, Baldeiras I, Oliveira CR, Moreira PI. Metabolic alterations induced by sucrose intake and Alzheimer's disease promote similar brain mitochondrial abnormalities. Diabetes 2012; 61:1234-42. [PMID: 22427376 PMCID: PMC3331754 DOI: 10.2337/db11-1186] [Citation(s) in RCA: 114] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Evidence shows that diabetes increases the risk of developing Alzheimer's disease (AD). Many efforts have been done to elucidate the mechanisms linking diabetes and AD. To demonstrate that mitochondria may represent a functional link between both pathologies, we compared the effects of AD and sucrose-induced metabolic alterations on mouse brain mitochondrial bioenergetics and oxidative status. For this purpose, brain mitochondria were isolated from wild-type (WT), triple transgenic AD (3xTg-AD), and WT mice fed 20% sucrose-sweetened water for 7 months. Polarography, spectrophotometry, fluorimetry, high-performance liquid chromatography, and electron microscopy were used to evaluate mitochondrial function, oxidative status, and ultrastructure. Western blotting was performed to determine the AD pathogenic protein levels. Sucrose intake caused metabolic alterations like those found in type 2 diabetes. Mitochondria from 3xTg-AD and sucrose-treated WT mice presented a similar impairment of the respiratory chain and phosphorylation system, decreased capacity to accumulate calcium, ultrastructural abnormalities, and oxidative imbalance. Interestingly, sucrose-treated WT mice presented a significant increase in amyloid β protein levels, a hallmark of AD. These results show that in mice, the metabolic alterations associated to diabetes contribute to the development of AD-like pathologic features.
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Affiliation(s)
- Cristina Carvalho
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- Department of Life Sciences–Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal
| | - Susana Cardoso
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- Department of Life Sciences–Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal
| | - Sónia C. Correia
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- Department of Life Sciences–Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal
| | - Renato X. Santos
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- Department of Life Sciences–Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal
| | - Maria S. Santos
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- Department of Life Sciences–Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal
| | - Inês Baldeiras
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- Laboratory of Neurochemistry-Coimbra University Hospital and Neurology Department-Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Catarina R. Oliveira
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- Institute of Biochemistry –Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Paula I. Moreira
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- Institute of Physiology–Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Corresponding author: Paula I. Moreira, or
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Abstract
Despite an archive of over 73,000 research papers published in the last two decades on the subject of Alzheimer's disease (AD), little clinical progress has been made relative to how people get sporadic AD and what can be done to help them avoid it. This review spotlights strategic steps that could be a turning point in the dramatic lowering of Alzheimer prevalence. The main strategy includes application of four pillars of prevention: 1) early identification of AD vascular risk factors; 2) early detection of AD vascular risk factors; 3) early intervention of AD vascular risk factors based on evidence-based medical decisions; 4) patient follow-up to assess and modify interventions as needed. Tandem to these four pillars of prevention, a proactive lifestyle consisting of a healthy diet coupled to physical and mental activity should be applied as part of any therapeutic intervention. We are persuaded by mounting and compelling evidence that AD is a multifactorial disorder kindled by vascular risk factors that generate chronic brain hypoperfusion (CBH) during advanced aging. A pathobiological cascade of biochemical events in the presence of CBH that leads to oxidative stress and neurodegeneration appears to involve multiple biofactors including micronutrients, trace metals, lipids, and pro-oxidants, as reviewed in this special issue of BioFactors. Modulation of these biofactors may help prevent or control incipient AD. © 2012 International Union of Biochemistry and Molecular Biology, Inc.
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Affiliation(s)
- Jack C de la Torre
- Department of Psychology, University of Texas at Austin, Austin, TX, USA.
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Hanyu H. [Treatment of vascular risk factors]. Nihon Ronen Igakkai Zasshi 2012; 49:284-287. [PMID: 23268964 DOI: 10.3143/geriatrics.49.284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
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CSF Biomarkers for Amyloid and Tau Pathology in Alzheimer's Disease. J Mol Neurosci 2011; 47:1-14. [DOI: 10.1007/s12031-011-9665-5] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2011] [Accepted: 10/13/2011] [Indexed: 12/16/2022]
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Leoni V, Caccia C. Relationship between cholesterol metabolism, ApoE and brain volumes in Alzheimer’s disease. FUTURE NEUROLOGY 2011. [DOI: 10.2217/fnl.11.38] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
APOE genotype, aging and midlife hypercholesterolemia are well-established risk factors for late-onset Alzheimer’s disease (AD). ApoE and cholesterol are involved in the pathogenesis of AD since they influence amyloid-β accumulation and Tau pathology. APOE ε4 carriers were found to present lower levels of amyloid-β1–42, higher tau and phosphorylated tau and a higher degree of brain atrophy at any disease stage. Presence of ApoE4 shifts the onset of the disease towards a younger age and makes progression faster. Hypercholesterolemia together with other major cardiovascular risk factors were found to be involved in the pathogenesis of AD, but reduced plasma cholesterol levels were described in demented patients. Significant correlations were found between cholesterol precursors lathosterol, lanosterol and 24S-hydroxycholesterol (a putative marker of brain cholesterol turnover) in plasma and brain atrophy as quantified by MRI. It is likely that neurodegeneration affects both brain and whole-body cholesterol metabolism in AD.
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Affiliation(s)
- Valerio Leoni
- Laboratory of Clinical Pathology & Medical Genetics, R17, IRCCS National Institute of Neurology ‘C Besta’, Via Celoria 11, 20133 Milano, Italy
| | - Claudio Caccia
- Laboratory of Clinical Pathology & Medical Genetics, R17, IRCCS National Institute of Neurology ‘C Besta’, Via Celoria 11, 20133 Milano, Italy
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