Dataset Information

Amyloid, neurodegeneration, and small vessel disease as predictors of dementia in the oldest-old.

ABSTRACT:

Objective

To examine the association between brain structural changes and ?-amyloid deposition, and incident dementia in 183 elderly subjects without dementia (mean age 85.5 years) 2 years later.

Methods

Subjects had a brain structural MRI scan and a PET scan with (11)C-labeled Pittsburgh compound B (PiB) in 2009, and were evaluated clinically in 2011.

Results

At baseline evaluation, of the 183 participants (146 cognitively normal [CN]); 37 mild cognitive impairment [MCI]), 139 (76%) were PiB+, had small hippocampal volume (<25th percentile), or had high white matter lesion (WML) volume (>75th percentile). Two years later, 111 (61%) were classified as CN, 51 (28%) as MCI, and 21 (11%) as dementia. At baseline, 51% of the CN participants and 67.5% of the MCI cases were PiB+. Thirty percent of the CN and 51% of the MCI cases had small hippocampi, and 24% of the CN and 40.5% of the MCI cases had abnormal WMLs. Of the 21 participants who progressed to dementia, 20 (95%) had at least one imaging abnormality. Only 3 (14%) were only PiB+, 1 (5%) had only small hippocampi, 1 (5%) had only WMLs, 1 (5%) was biomarker negative, and the other 16 had various pairs of imaging abnormalities. Continuous variables of PiB retention, left and right hippocampal volume, and WML volume were independent predictors of dementia in a logistic regression analysis controlling for age, sex, education level, and Mini-Mental State Examination scores.

Conclusions

The prevalence of ?-amyloid deposition, neurodegeneration (i.e., hippocampal atrophy), and small vessel disease (WMLs) is high in CN older individuals and in MCI. A combination of 2 or 3 of these factors is a powerful predictor of short-term incidence of dementia.

SUBMITTER: Lopez OL

PROVIDER: S-EPMC4240431 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Amyloid, neurodegeneration, and small vessel disease as predictors of dementia in the oldest-old.

Lopez Oscar L OL Klunk William E WE Mathis Chester C Coleman Rhaven L RL Price Julie J Becker James T JT Aizenstein Howard J HJ Snitz Beth B Cohen Ann A Ikonomovic Milos M McDade Eric E DeKosky Steven T ST Weissfeld Lisa L Kuller Lewis H LH

Neurology 20141010 20

<h4>Objective</h4>To examine the association between brain structural changes and β-amyloid deposition, and incident dementia in 183 elderly subjects without dementia (mean age 85.5 years) 2 years later.<h4>Methods</h4>Subjects had a brain structural MRI scan and a PET scan with (11)C-labeled Pittsburgh compound B (PiB) in 2009, and were evaluated clinically in 2011.<h4>Results</h4>At baseline evaluation, of the 183 participants (146 cognitively normal [CN]); 37 mild cognitive impairment [MCI]), ...[more]

PMID: 25305156

Similar Datasets

Project description:The emergence of longevity in the modern world has brought a sense of urgency to understanding age-related neurodegenerative diseases such as Alzheimer's disease. Unfortunately, there is a lack of consensus regarding the correlation between the pathological substrates of neurodegeneration and dementia status, particularly in the oldest-old. To better understand the pathological correlates of dementia in the oldest-old, we characterized the topographical spread and severity of amyloid-?, tau, TDP-43 and ?-synuclein pathologies in the 90+ Study, a prospective longitudinal population-based study of ageing and dementia. Neuropathological analysis with immunohistochemically labelled sections was carried out blind to clinical diagnosis on the first 108 participants of the 90+ Study who came to autopsy including participants with dementia (n = 66) and without dementia (n = 42). We used quantitative and/or semi-quantitative measures to assess the burden of amyloid-?, tau, TDP-43 and ?-synuclein pathologies as well as hippocampal sclerosis. Amyloid-? and tau were the predominant pathologies in the 90+ Study cohort and both amyloid-? area and tau area occupied measures were strongly associated with the presence of dementia, as was Braak staging but semi-quantitative plaque scores were not. Notably, TDP-43 pathology also correlated with dementia, while ?-synuclein distribution did not. In addition, hippocampal sclerosis was specific to participants with dementia and correlated with the presence of limbic TDP-43. In contrast to previous reports, we found that tau and amyloid-? continue to be robust pathological correlates of dementia, even in the oldest-old. While individuals with no dementia had limited hippocampal tau and neocortical amyloid-? pathology, dementia associated with an expansion in pathology, including increased neocortical tau and hippocampal amyloid-? plaques, more abundant neocortical amyloid-? deposition and hippocampal sclerosis with its attendant TDP-43 pathology.

Project description:Importance:The prevalence of pathologic conditions of the brain associated with Alzheimer disease increases strongly with age. Little is known about the distribution and clinical significance of preclinical biomarker staging in the oldest old, when most individuals without dementia are likely to have positive biomarkers. Objective:To compare the patterns of long-term cognitive decline in multiple domains by preclinical biomarker status in the oldest old without dementia. Design, Setting, and Participants:A longitudinal observational study with a mean (SD) of 12.2 (2.2) years (range 7.2-15.1 years) of follow-up was conducted in an academic medical center from August 24, 2000, to January 14, 2016, including and extending observations from the Ginkgo Evaluation of Memory study. A total of 197 adults who had completed the Ginkgo Evaluation of Memory study, were free of dementia, and were able to undergo magnetic resonance imaging were eligible for a neuroimaging study in 2009. Of these patients, 175 were included in the present analyses; 140 (80%) were cognitively normal and 35 (20%) had mild cognitive impairment. Main Outcomes and Measures:Biomarker groups included amyloid β negative (Aβ-)/neurodegeneration negative (ND-), amyloid β positive (Aβ+)/ND-, Aβ-/neurodegeneration positive (ND+), and Aβ+/ND+ based on Pittsburgh Compound B retention and hippocampal volume in 2009. Participants completed baseline neuropsychological testing from 2000 to 2002 and annual testing from 2004 to 2016. Domains included memory, executive function, language, visual-spatial reasoning, and attention and psychomotor speed. Slopes of decline were evaluated with linear mixed models adjusted for age, sex, and years of education. Results:Of the 175 participants (71 women and 104 men), at imaging, mean (SD) age was 86.0 (2.9) years (range, 82-95 years). A total of 42 participants (24.0%) were Aβ-/ND-, 32 (18.3%) were Aβ+/ND-, 35 (20.0%) were Aβ-/ND+, and 66 (37.7%) were Aβ+/ND+. On all cognitive measures, the Aβ+/ND+ group showed the steepest decline. Compared with the Aβ-/ND- group, the amyloid deposition alone (Aβ+/ND-) group showed faster decline on tests of verbal and visual memory (-0.3513; 95% CI, -0.5269 to -0.1756), executive function (0.0158; 95% CI, 0.0013-0.0303), and language (-0.1934; 95% CI, -0.3520 to -0.0348). The Aβ-/ND+ group showed faster visual memory decline than the Aβ-/ND- reference group (-0.3007; 95% CI, -0.4736 to -0.1279). Conclusions and Relevance:In the oldest old without dementia, presence of either or both Aβ and hippocampal atrophy is typical (>75%). Isolated hippocampal volume atrophy is associated only with greater decline in memory. However, isolated Aβ is associated with decline in memory plus language and executive functions. These findings suggest different underlying pathophysiologic processes in the Aβ+/ND- and Aβ-/ND+ groups.

Project description:Sporadic cerebral small vessel disease is an important cause of vascular dementia, a syndrome of cognitive impairment together with vascular brain damage. At post-mortem pure vascular dementia is rare, with evidence of co-existing Alzheimer's disease pathology in 95% of cases. This work used MRI to characterize structural abnormalities during the preclinical phase of vascular dementia in symptomatic small vessel disease. 121 subjects were recruited into the St George's Cognition and Neuroimaging in Stroke study and followed up longitudinally for five years. Over this period 22 individuals converted to dementia. Using voxel-based morphometry, we found structural abnormalities present at baseline in those with preclinical dementia, with reduced grey matter density in the left striatum and hippocampus, and more white matter hyperintensities in the frontal white-matter. The lacunar data revealed that some of these abnormalities may be due to lesions within the striatum and centrum semiovale. Using support vector machines, future dementia could be best predicted using hippocampal and striatal Jacobian determinant data, achieving a balanced classification accuracy of 73%. Using cluster ward linkage we identified four anatomical subtypes. Successful predictions were restricted to groups with lower levels of vascular damage. The subgroup that could not be predicted were younger, further from conversion, had the highest levels of vascular damage, with milder cognitive impairment at baseline but more rapid deterioration in processing speed and executive function, consistent with a primary vascular dementia. In contrast, the remaining groups had decreasing levels of vascular damage and increasing memory impairment consistent with progressively more Alzheimer's-like pathology. Voxel-wise rates of hippocampal atrophy supported these distinctions, with the vascular group closely resembling the non-dementing cohort, whereas the Alzheimer's like group demonstrated global hippocampal atrophy. This work reveals distinct anatomical endophenotypes in preclinical vascular dementia, forming a spectrum between vascular and Alzheimer's like pathology. The latter group can be identified using baseline MRI, with 73% converting within 5 years. It was not possible to predict the vascular dominant dementia subgroup, however 19% of negative predictions with high levels of vascular disease would ultimately develop dementia. It may be that techniques more sensitive to white matter damage, such as diffusion weighted imaging, may prove more useful for this vascular dominant subgroup in the future. This work provides a way to accurately stratify patients using a baseline MRI scan, and has utility in future clinical trials designed to slow or prevent the onset of dementia in these high-risk cohorts.

Dataset Information

Amyloid, neurodegeneration, and small vessel disease as predictors of dementia in the oldest-old.

Objective

Methods

Results

Conclusions

Publications

Amyloid, neurodegeneration, and small vessel disease as predictors of dementia in the oldest-old.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets