Cognitive and neuropsychological trajectories in patients with mixed neurodegenerative pathologies

Abstract

Introduction: The presence and interaction of multiple comorbid neuropathologies are a major contributor to the worldwide dementia burden.

Methods: We analyzed 1183 subjects from the National Alzheimer's Coordinating Center dataset with various combinations of isolated and mixed neurodegenerative pathologies and conducted mixed-effects multiple linear regression modeling to comprehensively compare the neurocognitive and neuropsychological trajectories between groups over time.

Results: In combination with Alzheimer's disease neuropathologic change, various combinations of limbic-predominant age-related transactive response DNA-binding protein 43 encephalopathy, Lewy body dementia, and cerebrovascular disease further impair global cognition and specific neurocognitive domains; however, they do not appear to extensively affect the rate of decline with time across these domains, suggesting an additive but not synergistic effect.

Discussion: These findings corroborate the known cumulative effects of mixed pathologies on cognition and add nuance to our understanding of their specific interactions, which is crucial for the development of biomarkers and effective therapeutics.

Highlights: Mixed neurodegenerative pathologies are common in the elderly population. The most common neurodegenerative pathologies were Alzheimer's disease neuropathologic change (ADNC), cerebrovascular disease (CVD), Lewy body dementia (LBD), and limbic-predominant age-related transactive response DNA-binding protein 43 encephalopathy (LATE). The addition of various combinations of comorbid CVD, LBD, and LATE to ADNC worsened overall performance on cognitive and neuropsychological testing across time. In general, the addition of multiple comorbid neurodegenerative pathologies did not influence the rate of decline across the evaluated time period.

Keywords: Alzheimer's disease neuropathologic change (ADNC); Clinical Dementia Rating (CDR); Lewy body dementia; Mini‐Mental State Examination (MMSE); National Alzheimer's Coordinating Center (NACC); Pick's disease; cerebrovascular disease; frontotemporal lobar dementia (FTLD); limbic‐predominant age‐related TDP‐43 encephalopathy (LATE); primary age‐related tauopathy (PART); progressive supranuclear palsy (PSP).

FIGURE 1

Trajectories of global cognitive assessments in subjects with various combinations of isolated and mixed neurodegenerative pathologies. Line plots of the relative progression by combination of pathology for (A) CDR‐SB and (B) MMSE demonstrate progressive impairment with more concurrent pathologies. Heatmaps demonstrating differences in the global effects (global contrasts) of each combination of pathology relative to one another in terms of (C) CDR‐SB and (D) MMSE and heatmaps demonstrating the differences in rate of decline (slope contrasts) of each combination of pathology relative to one another in terms of (E) CDR‐SB and (F) MMSE. * denotes significant interactions with P < 0.05. Specific P values are listed in Table S4 in supporting information. ADNC, Alzheimer's disease neuropathologic change; CDR‐SB, Clinical Dementia Rating Sum of Boxes; CVD, cerebrovascular disease; LATE, limbic‐predominant age‐related transactive response DNA‐binding protein 43 encephalopathy; LBD, Lewy body dementia; MMSE, Mini‐Mental State Examination.

FIGURE 2

Trajectories of neuropsychological assessments in subjects with various combinations of isolated and mixed neurodegenerative pathologies. Heatmaps demonstrating differences in the global effects (global contrasts) of each combination of pathology relative to one another in terms of (A) LMI, (B) LMR, (C) DSF, (D) DSFL, (E) DSB, (F) DSBL, (G) TMT‐A, (H) TMT‐B, (I) WAIS DS, (J) animal naming, (K) vegetable naming, (L) BNT. * denotes significant interactions with P < 0.05. Specific P values are listed in Table S5 in supporting information. ADNC, Alzheimer's disease neuropathologic change; BNT, Boston Naming Test; CVD, cerebrovascular disease; DSB, digit span backward; DSBL, digit span backward length; DSF, digit span forward; DSFL, digit span forward length; LATE, limbic‐predominant age‐related transactive response DNA‐binding protein 43 encephalopathy; LBD, Lewy body dementia; LMI, logical memory immediate recall; LMR, logical memory remote recall; TMT‐A, Trail‐Making Test Part A; TMT‐B, Trail‐Making Test Part B; WAIS DS, Wechsler Adult Intelligence Scale digit substitution score.

FIGURE 3

Trajectories of neuropsychological assessments in subjects with various combinations of isolated and mixed neurodegenerative pathologies. Heatmaps demonstrating differences in the rate of decline (slope contrasts) of each combination of pathology relative to one another in terms of (A) LMI, (B) LMR, (C) DSF, (D) DSFL, (E) DSB, (F) DSBL, (G) TMT‐A, (H) TMT‐B, (I) WAIS DS, (J) animal naming, (K) vegetable naming, (L) BNT. * denotes significant interactions with P < 0.05. Specific P values are listed in Table S6 in supporting information. ADNC, Alzheimer's disease neuropathologic change; BNT, Boston Naming Test; CVD, cerebrovascular disease; DSB, digit span backward; DSBL, digit span backward length; DSF, digit span forward; DSFL, digit span forward length; LATE, limbic‐predominant age‐related transactive response DNA‐binding protein 43 encephalopathy; LBD, Lewy body dementia; LMI, logical memory immediate recall; LMR, logical memory remote recall; TMT‐A, Trail‐Making Test Part A; TMT‐B, Trail‐Making Test Part B; WAIS DS, Wechsler Adult Intelligence Scale digit substitution score.

FIGURE 4

Trajectories of global cognitive assessments in subjects with various isolated neurodegenerative pathologies. Line plots of the relative cognitive progression for each pathology in terms of (A) CDR‐SB and (B) MMSE. Heatmaps demonstrating differences in the global effects (global contrasts) of each isolated pathology relative to one another in terms of (C) CDR‐SB and (D) MMSE and heatmaps demonstrating the differences in rate of decline (slope contrasts) of each isolated pathology relative to one another in terms of (E) CDR‐SB and (F) MMSE. * denotes significant interactions with P < 0.05. Specific P values are listed in Table S7 in supporting information. ADNC, Alzheimer's disease neuropathologic change; CDR‐SB, Clinical Dementia Rating Sum of Boxes; CVD, cerebrovascular disease; LATE, limbic‐predominant age‐related transactive response DNA‐binding protein 43 encephalopathy; LBD, Lewy body dementia; MMSE, Mini‐Mental State Examination.

FIGURE 5

Trajectories of neuropsychological assessments in subjects with various isolated neurodegenerative pathologies. Heatmaps demonstrating differences in the global effects (global contrasts) of each isolated pathology relative to one another in terms of (A) LMI, (B) LMR, (C) DSF, (D) DSFL, (E) DSB, (F) DSBL(G) TMT‐A, (H) TMT‐B, (I) WAIS DS, (J) animal naming, (K) vegetable naming, (L) BNT. * denotes significant interactions with P < 0.05. Specific P values are listed in Table S8 in supporting information. ADNC, Alzheimer's disease neuropathologic change; BNT, Boston Naming Test; CVD, cerebrovascular disease; DSB, digit span backward; DSBL, digit span backward length; DSF, digit span forward; DSFL, digit span forward length; LATE, limbic‐predominant age‐related transactive response DNA‐binding protein 43 encephalopathy; LBD, Lewy body dementia; LMI, logical memory immediate recall; LMR, logical memory remote recall; TMT‐A, Trail‐Making Test Part A; TMT‐B, Trail‐Making Test Part B; WAIS DS, Wechsler Adult Intelligence Scale digit substitution score.

FIGURE 6

Trajectories of neuropsychological assessments in subjects with various isolated neurodegenerative pathologies. Heatmaps demonstrating differences in the rate of decline (slope contrasts) of each isolated pathology relative to one another in terms of (A) LMI, (B) LMR, (C) DSF, (D) DSFL, (E) DSB, (F) DSBL, (G) TMT‐A, (H) TMT‐B, (I) WAIS DS, (J) animal naming, (K) vegetable naming, (L) BNT. * denotes significant interactions with P < 0.05. Specific P values are listed in Table S9 in supporting information. ADNC, Alzheimer's disease neuropathologic change; BNT, Boston Naming Test; CVD, cerebrovascular disease; DSB, digit span backward; DSBL, digit span backward length; DSF, digit span forward; DSFL, digit span forward length; LATE, limbic‐predominant age‐related transactive response DNA‐binding protein 43 encephalopathy; LBD, Lewy body dementia; LMI, logical memory immediate recall; LMR, logical memory remote recall; TMT‐A, Trail‐Making Test Part A; TMT‐B, Trail‐Making Test Part B; WAIS DS, Wechsler Adult Intelligence Scale digit substitution score.