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 b-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 PiB1, 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 PiB1. 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 PiB1, 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 b-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. Studies of cognition and neurodegeneration in the oldest-old are important because these individuals are at the highest risk of developing dementia, especially Alzheimer disease (AD). 1 Furthermore, the neurodegenerative process that causes AD begins years before the clinical expression of the syndrome.2-4 The proportion of subjects without dementia who have amyloid deposition detected in vivo is approximately 20% to 30%, 4 with rates up to 65% in those aged 80 years or older. 4,5 Amyloid deposition detected with Pittsburgh compound B (PiB) is associated with the development of AD from mild cognitive impairment (MCI), 6,7 and to MCI or AD from normal cognition. 8 Similarly, low hippocampal volume, as a marker of neurodegeneration, is associated with progression to AD in cognitively normal (CN) subjects and in those with MCI.9 It has been hypothesized that AD pathology starts with amyloid deposition, followed by neuronal loss closer

Risk of dementia and death in the long‐term follow‐up of the Pittsburgh Cardiovascular Health Study–Cognition Study

“…The high incidence and prevalence of dementia is also consistent with extensive brain pathology, e.g. AD, plaques and neurofibrillary tangles, vascular disease and neurodegeneration documented by pathology and, more recently, in neuroimaging studies in older age groups [41–44] Very few of the participants survived to age 90+ free of dementia. This study is consistent with other recent studies of very elderly [45–48].…”

Subjective Cognitive Complaints, Personality and Brain Amyloid-beta in Cognitively Normal Older Adults

“…An important consequence of older age distribution is the high degree of Aβ deposition [36]. In absence of frank clinical deficits (by selection) in participants surviving and thriving into the 9 th decade of life, any effect of highly prevalent Aβ deposition at this age may be different, presumably attenuated, compared to a younger age [51, 52]. Future studies with larger samples are needed to compare age-specific effects.…”

Voxel Level Survival Analysis of Grey Matter Volume and Incident Mild Cognitive Impairment or Alzheimer’s Disease

“…However, this sequence of events is not as clear as once thought; for example, clinical dementia can develop relatively rapidly among individuals with low levels of amyloid [74]. Further, hippocampal atrophy is not necessarily a precondition for incident dementia [4]. Our data add to this discussion by showing that among cognitively normal individuals with an average age of 78 years, it is possible to detect associations between brain structural integrity and the development of MCI/AD as much as 13–14 years before the onset of symptoms.…”

“…However, this process is made difficult because the identified clusters of significant voxels may not fall neatly into clearly defined anatomical regions. However, as our understanding of the pathology of MCI and AD continues to evolve, especially in terms of the sequence of events leading to clinical disorder [4], the whole brain, voxel-level approach may be the least affected by prior expectations.…”