Dataset Information

Association Between Amyloid-?, Small-vessel Disease, and Neurodegeneration Biomarker Positivity, and Progression to Mild Cognitive Impairment in Cognitively Normal Individuals.

ABSTRACT: BACKGROUND:We estimated the prevalence and incidence of amyloid-? deposition (A), small-vessel disease (V), and neurodegeneration (N) biomarker positivity in community-dwelling cognitively normal individuals (CN). We determined the longitudinal association between the respective biomarker indices with progression to all-cause mild cognitive impairment (MCI) and its amnestic and nonamnestic subtypes. METHODS:CN participants, recruited by advertising, underwent brain [C-11]Pittsburgh Compound-B (PiB)-positron emission tomography (PET), magnetic resonance imaging, and [F-18]fluoro-2-deoxy-glucose (FDG)-PET, and were designated as having high or low amyloid-? (A+/A-), greater or lower white matter hyperintensities burden (V+/V-) and diminished or normal cortical glucose metabolism (N+/N-). MCI was adjudicated using clinical assessments. We examined the association between A, V, and N biomarker positivity at study baseline and endpoint, with progression to MCI using linear regression, Cox proportional hazards and Kaplan-Meier analyses adjusted for age and APOE-?4 carrier status. RESULTS:In 98 CN individuals (average age 74 years, 65% female), A+, V+, and N+ prevalence was 26%, 33%, and 8%, respectively. At study endpoint (median: 5.5 years), an A+, but not a V+ or N+ scan, was associated with higher odds of all-cause MCI (Chi-square = 3.9, p = .048, odds ratio, 95% confidence interval = 2.6 [1.01-6.8]). Baseline A+, V+, or N+ were not associated with all-cause MCI, however, baseline A+ (p = .018) and A+N+ (p = .049), and endpoint A+N+ (p = .025) were associated with time to progression to amnestic, not nonamnestic, MCI. CONCLUSION:Longitudinal assessments clarify the association between amyloid-? and progression to all-cause MCI in CN individuals. The association between biomarker positivity indices of amyloid-? and neurodegeneration, and amnestic MCI reflects the underlying pathology involved in the progression to prodromal Alzheimer's disease.

SUBMITTER: Nadkarni NK

PROVIDER: S-EPMC6777090 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Association Between Amyloid-β, Small-vessel Disease, and Neurodegeneration Biomarker Positivity, and Progression to Mild Cognitive Impairment in Cognitively Normal Individuals.

Nadkarni Neelesh K NK Tudorascu Dana D Campbell Elizabeth E Snitz Beth E BE Cohen Annie D AD Halligan Edye E Mathis Chester A CA Aizenstein Howard J HJ Klunk William E WE

The journals of gerontology. Series A, Biological sciences and medical sciences 20191001 11

<h4>Background</h4>We estimated the prevalence and incidence of amyloid-β deposition (A), small-vessel disease (V), and neurodegeneration (N) biomarker positivity in community-dwelling cognitively normal individuals (CN). We determined the longitudinal association between the respective biomarker indices with progression to all-cause mild cognitive impairment (MCI) and its amnestic and nonamnestic subtypes.<h4>Methods</h4>CN participants, recruited by advertising, underwent brain [C-11]Pittsburg ...[more]

PMID: 30957843

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Project description:BackgroundIndividuals on the preclinical Alzheimer's continuum, particularly those with both amyloid and tau positivity (A + T +), display a rapid cognitive decline and elevated disease progression risk. However, limited studies exist on brain atrophy trajectories within this continuum over extended periods.MethodsThis study involved 367 ADNI participants grouped based on combinations of amyloid and tau statuses determined through cerebrospinal fluid tests. Using longitudinal MRI scans, brain atrophy was determined according to the whole brain, lateral ventricle, and hippocampal volumes and cortical thickness in AD-signature regions. Cognitive performance was evaluated with the Preclinical Alzheimer's Cognitive Composite (PACC). A generalized linear mixed-effects model was used to examine group × time interactions for these measures. In addition, progression risks to mild cognitive impairment (MCI) or dementia were compared among the groups using Cox proportional hazards models.ResultsA total of 367 participants (48 A + T + , 86 A + T - , 63 A - T + , and 170 A - T - ; mean age 73.8 years, mean follow-up 5.1 years, and 47.4% men) were included. For the lateral ventricle and PACC score, the A + T - and A + T + groups demonstrated statistically significantly greater volume expansion and cognitive decline over time than the A - T - group (lateral ventricle: β = 0.757 cm3/year [95% confidence interval 0.463 to 1.050], P < .001 for A + T - , and β = 0.889 cm3/year [0.523 to 1.255], P < .001 for A + T + ; PACC: β = - 0.19 /year [- 0.36 to - 0.02], P = .029 for A + T - , and β = - 0.59 /year [- 0.80 to - 0.37], P < .001 for A + T +). Notably, the A + T + group exhibited additional brain atrophy including the whole brain (β = - 2.782 cm3/year [- 4.060 to - 1.504], P < .001), hippocampus (β = - 0.057 cm3/year [- 0.085 to - 0.029], P < .001), and AD-signature regions (β = - 0.02 mm/year [- 0.03 to - 0.01], P < .001). Cox proportional hazards models suggested an increased risk of progressing to MCI or dementia in the A + T + group versus the A - T - group (adjusted hazard ratio = 3.35 [1.76 to 6.39]).ConclusionsIn cognitively normal individuals, A + T + compounds brain atrophy and cognitive deterioration, amplifying the likelihood of disease progression. Therapeutic interventions targeting A + T + individuals could be pivotal in curbing brain atrophy, cognitive decline, and disease progression.

Project description:Understanding short-term cognitive decline in relation to Alzheimer's neuroimaging biomarkers in early stages of the development of neuropathology and neurodegeneration will inform participant recruitment and monitoring strategies in clinical trials aimed at prevention of cognitive impairment and dementia. We assessed associations among neuroimaging measures of cerebral amyloid pathology, a hallmark Alzheimer's neuropathology, hippocampal atrophy, and prospective cognition among 171 cognitively normal Baltimore Longitudinal Study of Aging participants (baseline age 56-95 years, 48% female, 562 cognitive assessments, 3.7 years follow-up). We categorized each individual based on dichotomous amyloid pathology (A) and hippocampal neurodegeneration (N) status at baseline: A-N-, A+N-, A-N+, A+N+. We conducted linear mixed effects analyses to assess cross-sectional and longitudinal trends in cognitive test z-scores by amyloid and neurodegeneration group. To investigate the effects of amyloid dose and degree of hippocampal atrophy, we assessed the associations of continuous mean cortical amyloid level and hippocampal volume with cognitive performance among individuals with detectable amyloid pathology at baseline. Individuals with amyloidosis or hippocampal atrophy had steeper longitudinal declines in verbal episodic memory and learning compared to those with neither condition (A+N- versus A-N-: β = - 0.069, P = 0.017; A-N+ versus A-N-: β = - 0.081, P = 0.025). Among individuals with hippocampal atrophy, amyloid positivity was associated with steeper declines in verbal memory (β = - 0.123, P = 0.015), visual memory (β = - 0.121, P = 0.036), language (β = - 0.144, P = 0.0004), and mental status (β = - 0.242, P = 0.002). Similarly, among individuals with amyloidosis, hippocampal atrophy was associated with steeper declines in verbal memory (β = - 0.135, P = 0.004), visual memory (β = - 0.141, P = 0.010), language (β = - 0.108, P = 0.006), and mental status (β = - 0.165, P = 0.022). Presence of both amyloidosis and hippocampal atrophy was associated with greater declines than would be expected by their additive contributions in visual memory (β = - 0.139, P = 0.036), language (β = - 0.132, P = 0.005), and mental status (β = - 0.170, P = 0.049). Neither amyloidosis nor hippocampal atrophy was predictive of declines in executive function, processing speed, or visuospatial ability. Among individuals with amyloidosis, higher baseline amyloid level was associated with lower concurrent visual memory, steeper declines in language, visuospatial ability, and mental status, whereas greater hippocampal atrophy was associated with steeper declines in category fluency. Our results suggest that both amyloid pathology and neurodegeneration have disadvantageous, in part synergistic, effects on prospective cognition. These cognitive effects are detectable early among cognitively normal individuals with amyloidosis, who are in preclinical stages of Alzheimer's disease according to research criteria. Our findings highlight the importance of early intervention to target both amyloidosis and atrophy to preserve cognitive function before further damage occurs.

Dataset Information

Association Between Amyloid-?, Small-vessel Disease, and Neurodegeneration Biomarker Positivity, and Progression to Mild Cognitive Impairment in Cognitively Normal Individuals.

Publications

Association Between Amyloid-β, Small-vessel Disease, and Neurodegeneration Biomarker Positivity, and Progression to Mild Cognitive Impairment in Cognitively Normal Individuals.

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