Evolocumab intensive lipid-lowering therapy on prognosis of post-cerebral infarction depression

Table 1 Baseline characteristics after propensity score matching, n (%)/mean ± SD

Characteristic	Intensive group (n = 72)	Standard group (n = 72)	P value
Demographics
Age (years)	63.8 ± 9.6	64.5 ± 10.1	0.658
Female gender	34 (47.2)	32 (44.4)	0.733
College education or above	23 (31.9)	21 (29.2)	0.716
Stroke characteristics
NIHSS score at admission	7.5 ± 2.3	7.3 ± 2.1	0.584
Anterior circulation infarction	42 (58.3)	40 (55.6)	0.730
Time from stroke to enrollment (days)	14.2 ± 3.8	13.9 ± 3.6	0.621
Vascular risk factors
Hypertension	48 (66.7)	46 (63.9)	0.721
Type 2 diabetes mellitus	21 (29.2)	20 (27.8)	0.848
Atrial fibrillation	9 (12.5)	8 (11.1)	0.797
Current smoking	23 (31.9)	21 (29.2)	0.716
Baseline depression and anxiety assessment
HAMD-17 total score	20.6 ± 4.8	20.1 ± 4.5	0.510
HAMA total score	17.8 ± 4.0	17.3 ± 3.8	0.436
Severe depression (HAMD-17 ≥ 24)	18 (25.0)	17 (23.6)	0.845
Baseline cognitive and functional status
MoCA score	21.8 ± 3.4	21.5 ± 3.2	0.581
Barthel Index	62.8 ± 17.5	63.4 ± 16.9	0.831
Modified Rankin Scale (median, IQR)	3 (2-3)	3 (2-3)	0.763
Baseline biomarkers
LDL-C (mmol/L)	3.12 ± 0.68	3.05 ± 0.65	0.523
PCSK9 (ng/mL)	392.4 ± 81.6	386.8 ± 78.3	0.667
IL-6 (pg/mL)	9.7 ± 2.3	9.5 ± 2.1	0.594
TNF-α (pg/mL)	18.4 ± 3.6	18.1 ± 3.4	0.616
hs-CRP (mg/L)	6.2 ± 1.8	6.0 ± 1.7	0.523
BDNF (ng/mL)	14.2 ± 3.5	14.5 ± 3.3	0.611

NIHSS: National Institutes of Health Stroke Scale; HAMD-17: 17-item Hamilton Depression Rating Scale; HAMA: Hamilton Anxiety Rating Scale; MoCA: Montreal Cognitive Assessment; IQR: Interquartile range; LDL-C: Low-density lipoprotein cholesterol; PCSK9: Proprotein convertase subtilisin/kexin type 9; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-alpha; hs-CRP: High-sensitivity C-reactive protein; BDNF: Brain-derived neurotrophic factor.

Table 2 Longitudinal depression severity and treatment response, n (%)/mean ± SD

Time point/outcome	Intensive group (n = 72)	Standard group (n = 72)	P value
HAMD-17 total score
Baseline	20.6 ± 4.8	20.1 ± 4.5	0.510
Week 4	17.8 ± 4.2	19.1 ± 4.3	0.074
Week 8	15.2 ± 3.6	17.4 ± 3.9	0.001
Week 12	11.4 ± 3.3	15.2 ± 4.1	< 0.001
Week 24	7.8 ± 2.9	12.5 ± 3.6	< 0.001
Treatment response (≥ 50 reduction from baseline)
Week 12	45 (62.5)	27 (37.5)	0.002
Week 24	57 (79.2)	36 (50.0)	< 0.001
Remission (HAMD-17 < 7)
Week 12	21 (29.2)	9 (12.5)	0.013
Week 24	42 (58.3)	23 (31.9)	0.001
Time to response (weeks)	8.3 ± 2.1	11.7 ± 3.4	< 0.001
Time to remission (weeks)	16.5 ± 4.2	20.8 ± 3.9	< 0.001

Treatment response defined as ≥ 50% reduction in 17-item Hamilton Depression Rating Scale score from baseline. Remission defined as 17-item Hamilton Depression Rating Scale score < 7. HAMD-17: 17-item Hamilton Depression Rating Scale.

Table 3 Anxiety scores and treatment response, n (%)/mean ± SD

Outcome measure	Intensive group (n = 72)	Standard group (n = 72)	P value
HAMA total score
Baseline	17.8 ± 4.0	17.3 ± 3.8	0.436
Week 12	11.2 ± 2.8	14.5 ± 3.3	< 0.001
Week 24	7.2 ± 2.1	11.8 ± 3.0	< 0.001
HAMD-17 response
Week 12	45 (62.5)	27 (37.5)	0.002
Week 24	57 (79.2)	36 (50.0)	< 0.001
HAMD-17 remission
Week 12	21 (29.2)	9 (12.5)	0.013
Week 24	42 (58.3)	23 (31.9)	0.001

HAMA: Hamilton Anxiety Rating Scale; HAMD-17: 17-item Hamilton Depression Rating Scale.

Table 4 Biomarkers and neuroprotective indicators at 24 weeks, mean ± SD

Biomarker	Intensive group (n = 72)	Standard group (n = 72)	P value
Lipid and PCSK9 pathway
PCSK9 (ng/mL)	148.7 ± 38.5	285.3 ± 62.4	< 0.001
Reduction from baseline	62.1 ± 8.3	26.2 ± 7.1	< 0.001
LDL-C (mmol/L)	1.2 ± 0.3	2.0 ± 0.5	< 0.001
LDL-C < 1.4 mmol/L achieved, n (%)	59 (81.9)	20 (27.8)	< 0.001
Total cholesterol (mmol/L)	3.3 ± 0.6	4.1 ± 0.7	< 0.001
HDL-C (mmol/L)	1.3 ± 0.3	1.2 ± 0.3	0.054
Triglycerides (mmol/L)	1.4 ± 0.5	1.5 ± 0.6	0.274
Inflammatory markers
IL-6 (pg/mL)	2.8 ± 0.7	4.9 ± 1.1	< 0.001
Reduction from baseline	71.1 ± 9.2	48.4 ± 10.3	< 0.001
TNF-α (pg/mL)	7.6 ± 1.4	11.8 ± 2.3	< 0.001
hs-CRP (mg/L)	2.2 ± 0.7	3.9 ± 1.2	< 0.001
Neurotrophic factors
BDNF (ng/mL)	26.8 ± 5.2	18.3 ± 4.1	< 0.001
Increase from baseline	88.7 ± 18.4	26.2 ± 12.7	< 0.001
Oxidative stress markers
Malondialdehyde (μmol/L)	3.2 ± 0.8	5.1 ± 1.2	< 0.001
SOD activity (U/mL)	148.7 ± 22.3	112.4 ± 18.6	< 0.001

PCSK9: Proprotein convertase subtilisin/kexin type 9; LDL-C: Low-density lipoprotein cholesterol; HDL-C: High-density lipoprotein cholesterol; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-alpha; hs-CRP: High-sensitivity C-reactive protein; BDNF: Brain-derived neurotrophic factor; SOD: Superoxide dismutase.

Table 5 Cognitive function and functional outcomes at 24 weeks, n (%)/mean ± SD

Outcome measure	Intensive group (n = 72)	Standard group (n = 72)	P value
Global cognitive function
MoCA total score	26.2 ± 1.9	23.8 ± 2.5	< 0.001
Change from baseline	+4.4 ± 2.1	+2.3 ± 1.8	< 0.001
MoCA ≥ 26 (normal cognition)	48 (66.7)	28 (38.9)	< 0.001
Functional independence
Barthel Index	86.5 ± 12.3	76.8 ± 15.7	< 0.001
Change from baseline	+23.7 ± 8.9	+13.4 ± 7.2	< 0.001
mRS 0-2 (good outcome)	52 (72.2)	37 (51.4)	0.009
Mean mRS score	1.8 ± 0.9	2.4 ± 1.1	0.001
Quality of life (SF-36)
Physical component score	45.8 ± 8.2	39.2 ± 9.1	< 0.001
Mental component score	48.5 ± 7.6	38.7 ± 8.9	< 0.001

A positive change indicates improvement. MoCA: Montreal Cognitive Assessment; mRS: Modified Rankin Scale; SF-36: 36-Item Short Form Health Survey.

Table 6 Clinical events and safety outcomes during 24-week follow-up, n (%)

Event	Intensive group (n = 72)	Standard group (n = 72)	P value
Recurrent cerebrovascular events
Any event	3 (4.2)	9 (12.5)	0.065
Ischemic stroke	2 (2.8)	7 (9.7)	0.085
Transient ischemic attack	1 (1.4)	2 (2.8)	0.560
Hospitalization
All-cause rehospitalization	11 (15.3)	22 (30.6)	0.027
Cardiovascular rehospitalization	5 (6.9)	13 (18.1)	0.038
Depression-related hospitalization	3 (4.2)	11 (15.3)	0.021
Depression relapse
HAMD-17 ≥ 14 after response	8 (11.1)	21 (29.2)	0.007
Mean time to relapse (weeks), mean ± SD	18.3 ± 2.7	14.6 ± 3.1	0.003
Adverse events
Any adverse event	15 (20.8)	12 (16.7)	0.518
Injection site reaction	7 (9.7)	0 (0)	0.006
Myalgia (without CK elevation)	4 (5.6)	3 (4.2)	0.699
Elevated ALT (> 3 × ULN)	0 (0)	1 (1.4)	0.316
New-onset diabetes	2 (2.8)	4 (5.6)	0.403
Serious adverse events	1 (1.4)	2 (2.8)	0.560
All-cause death	0 (0)	1 (1.4)	0.316

Depression relapse defined as 17-item Hamilton Depression Rating Scale ≥ 14 after achieving treatment response. HAMD-17: 17-item Hamilton Depression Rating Scale; CK: Creatine kinase; ALT: Alanine aminotransferase; ULN: Upper limit of normal.

Table 7 Correlations between changes in biomarkers and clinical outcomes

Correlation pair (Δ baseline to week 24)	Pearson r	P value
PCSK9 and depression severity
Δ PCSK9 vs Δ HAMD-17	0.618	< 0.001
Δ PCSK9 vs Δ HAMA	0.542	< 0.001
PCSK9 and inflammation
Δ PCSK9 vs Δ IL-6	0.523	< 0.001
Δ PCSK9 vs Δ TNF-α	0.487	< 0.001
Δ PCSK9 vs Δ hs-CRP	0.456	< 0.001
PCSK9 and cognition
Δ PCSK9 vs Δ MoCA	-0.412	< 0.001
Inflammation and depression
Δ IL-6 vs Δ HAMD-17	0.578	< 0.001
Δ TNF-α vs Δ HAMD-17	0.503	< 0.001
Δ hs-CRP vs Δ HAMD-17	0.445	< 0.001
Neurotrophic factors and outcomes
Δ BDNF vs Δ HAMD-17	-0.528	< 0.001
Δ BDNF vs Δ MoCA	0.492	< 0.001
Depression and cognitive function
Δ HAMD-17 vs Δ MoCA	-0.465	< 0.001
Δ HAMD-17 vs Δ Barthel Index	-0.521	< 0.001

Δ denotes change from baseline to week 24. Negative correlations indicate inverse relationships (e.g., greater proprotein convertase subtilisin/kexin type 9 reduction associated with greater Montreal Cognitive Assessment improvement). All correlations are statistically significant. PCSK9: Proprotein convertase subtilisin/kexin type 9; HAMD-17: 17-item Hamilton Depression Rating Scale; HAMA: Hamilton Anxiety Rating Scale; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-alpha; hs-CRP: High-sensitivity C-reactive protein; BDNF: Brain-derived neurotrophic factor; MoCA: Montreal Cognitive Assessment.