Effects of amyloid pathology and neurodegeneration on cognitive change in cognitively normal adults.

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-: ß = - 0.069, P = 0.017; A-N+ versus A-N-: ß = - 0.081, P = 0.025). Among individuals with hippocampal atrophy, amyloid positivity was associated with steeper declines in verbal memory (ß = - 0.123, P = 0.015), visual memory (ß = - 0.121, P = 0.036), language (ß = - 0.144, P = 0.0004), and mental status (ß = - 0.242, P = 0.002). Similarly, among individuals with amyloidosis, hippocampal atrophy was associated with steeper declines in verbal memory (ß = - 0.135, P = 0.004), visual memory (ß = - 0.141, P = 0.010), language (ß = - 0.108, P = 0.006), and mental status (ß = - 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 (ß = - 0.139, P = 0.036), language (ß = - 0.132, P = 0.005), and mental status (ß = - 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.

Frontal, Striatal, and Medial Temporal Sensitivity to Value Distinguishes Risk-Taking from Risk-Aversive Older Adults during Decision Making.

Aging compromises the frontal, striatal, and medial temporal areas of the reward system, impeding accurate value representation and feedback processing critical for decision making. However, substantial variability characterizes age-related effects on the brain so that some older individuals evince clear neurocognitive declines whereas others are spared. Moreover, the functional correlates of normative individual differences in older-adult value-based decision making remain unclear. We performed a functional magnetic resonance imaging study in 173 human older adults during a lottery choice task in which costly to more desirable stakes were depicted using low to high expected values (EVs) of points. Across trials that varied in EVs, participants decided to accept or decline the offered stakes to maximize total accumulated points. We found that greater age was associated with less optimal decisions, accepting stakes when losses were likely and declining stakes when gains were likely, and was associated with increased frontal activity for costlier stakes. Critically, risk preferences varied substantially across older adults and neural sensitivity to EVs in the frontal, striatal, and medial temporal areas dissociated risk-aversive from risk-taking individuals. Specifically, risk-averters increased neural responses to increasing EVs as stakes became more desirable, whereas risk-takers increased neural responses with decreasing EV as stakes became more costly. Risk preference also modulated striatal responses during feedback with risk-takers showing more positive responses to gains compared with risk-averters. Our findings highlight the frontal, striatal, and medial temporal areas as key neural loci in which individual differences differentially affect value-based decision-making ability in older adults. SIGNIFICANCE STATEMENT: Frontal, striatal, and medial temporal functions implicated in value-based decision processing of rewards and costs undergo substantial age-related changes. However, age effects on brain function and cognition differ across individuals. How this normative variation relates to older-adult value-based decision making is unclear. We found that although the ability make optimal decisions declines with age, there is still much individual variability in how this deterioration occurs. Critically, whereas risk-averters showed increased neural activity to increasingly valuable stakes in frontal, striatal, and medial temporal areas, risk-takers instead increased activity as stakes became more costly. Such distinct functional decision-making processing in these brain regions across normative older adults may reflect individual differences in susceptibility to age-related brain changes associated with incipient cognitive impairment.

Cerebral white matter disease is associated with Alzheimer pathology in a prospective cohort.

BACKGROUND: Although magnetic resonance imaging (MRI)-detected white matter disease has been correlated with cognitive decline in the elderly individuals, it is unclear whether white matter disease is primarily responsible for the cognitive deterioration or whether another process is common to both white matter disease and dementia. METHODS: We examined the relationship between Alzheimer-type brain pathology at autopsy and MRI-detected cerebral white matter disease in 50 participants from the Baltimore Longitudinal Study of Aging Autopsy Program, a prospective study of aging that includes detailed cognitive assessments. RESULTS: White matter disease was quantitated in pre- and postmortem MRI scans using the Cardiovascular Health Study (CHS) criteria in a blinded manner. We found that several measures of Alzheimer's disease (AD) pathology, including the Consortium to Establish a Registry for Alzheimer's Disease score, Braak score, and a composite AD pathology score, along with hypertension, were significantly associated with CHS white matter score using univariate and multivariate ordinal regression. In contrast, amyloid angiopathy was not independently associated with CHS score. Although a clinical diagnosis of dementia was associated with CHS score in univariate analysis, the association disappeared after accounting for AD pathology. CONCLUSION: AD pathology at autopsy is associated with MRI-detected cerebral white matter disease. This relationship may explain, in part, the association between cerebral white matter disease and cognitive decline in the elderly individuals.

Tau pathology in cognitively normal older adults.

INTRODUCTION: Tau pathology, a hallmark of Alzheimer's disease, is observed in the brains of virtually all individuals over 70 years. METHODS: Using 18F-AV-1451 (18F-flortaucipir) positron emission tomography, we evaluated tau pathology in 54 cognitively normal participants (mean age: 77.5 years, SD: 8.9) from the Baltimore Longitudinal Study of Aging. We assessed associations between positron emission tomography signal and age, sex, race, and amyloid positivity. We investigated relationships between regional signal and retrospective rates of change in regional volumes and cognitive function adjusting for age, sex, and amyloid status. RESULTS: Greater age, male sex, black race, and amyloid positivity were associated with higher 18F-AV-1451 retention in distinct brain regions. Retention in the entorhinal cortex was associated with lower entorhinal volume (ß = -1.124, SE = 0.485, P = .025) and a steeper decline in memory performance (ß = -0.086, SE = 0.039, P = .029). DISCUSSION: Assessment of medial temporal tau pathology will provide insights into early structural brain changes associated with later cognitive impairment and Alzheimer's disease.

The impact of magnetic resonance imaging-detected white matter hyperintensities on longitudinal changes in regional cerebral blood flow.

White matter hyperintensities are frequently detected on cranial magnetic resonance imaging (MRI) scans of older adults. Given the presumed ischemic contribution to the etiology of these lesions and the posited import of resting brain activity on cognitive function, we hypothesized that longitudinal changes in MRI-detected white matter disease, and its severity at a given time point, would be associated with changes in regional cerebral blood flow (rCBF) over time. We evaluated MRI scans and resting H(2)(15)O positron emission tomographic rCBF at baseline and after an average of 7.7-year follow-up in Baltimore Longitudinal Study of Aging participants without dementia. Differences in patterns of rCBF were evident at baseline and at follow-up between the group of subjects showing increased white matter disease over the 8-year interval compared with the group with stable white matter ratings. Furthermore, longitudinal changes over time in rCBF also differed between the two groups. Specifically, the group with progressive white matter abnormalities showed greater increase in the right inferior temporal gyrus/fusiform gyrus, right anterior cingulate, and the rostral aspect of the left superior temporal gyrus. Regions of greater longitudinal decrease in this group were evident in the right inferior parietal lobule and at the right occipital pole. Changes in white matter disease over time and its severity at any given time are associated significantly with both cross-sectional and longitudinal patterns of rCBF. The longitudinal increases may reflect cortical compensation mechanisms for reduced efficacy of interregional neural communications that result from white matter deterioration.

Ventricular and Periventricular Anomalies in the Aging and Cognitively Impaired Brain.

Ventriculomegaly (expansion of the brain's fluid-filled ventricles), a condition commonly found in the aging brain, results in areas of gliosis where the ependymal cells are replaced with dense astrocytic patches. Loss of ependymal cells would compromise trans-ependymal bulk flow mechanisms required for clearance of proteins and metabolites from the brain parenchyma. However, little is known about the interplay between age-related ventricle expansion, the decline in ependymal integrity, altered periventricular fluid homeostasis, abnormal protein accumulation and cognitive impairment. In collaboration with the Baltimore Longitudinal Study of Aging (BLSA) and Alzheimer's Disease Neuroimaging Initiative (ADNI), we analyzed longitudinal structural magnetic resonance imaging (MRI) and subject-matched fluid-attenuated inversion recovery (FLAIR) MRI and periventricular biospecimens to map spatiotemporally the progression of ventricle expansion and associated periventricular edema and loss of transependymal exchange functions in healthy aging individuals and those with varying degrees of cognitive impairment. We found that the trajectory of ventricle expansion and periventricular edema progression correlated with degree of cognitive impairment in both speed and severity, and confirmed that areas of expansion showed ventricle surface gliosis accompanied by edema and periventricular accumulation of protein aggregates, suggesting impaired clearance mechanisms in these regions. These findings reveal pathophysiological outcomes associated with normal brain aging and cognitive impairment, and indicate that a multifactorial analysis is best suited to predict and monitor cognitive decline.

Age differences in the neural systems supporting human allocentric spatial navigation.

Age-related declines in spatial navigation are well-known in human and non-human species. Studies in non-human species suggest that alteration in hippocampal and other neural circuitry may underlie behavioral deficits associated with aging but little is known about the neural mechanisms of human age-related decline in spatial navigation. The purpose of the present study was to examine age differences in functional brain activation during virtual environment navigation. Voxel-based analysis of activation patterns in young subjects identified activation in the hippocampus and parahippocampal gyrus, retrosplenial cortex, right and left lateral parietal cortex, medial parietal lobe and cerebellum. In comparison to younger subjects, elderly participants showed reduced activation in the hippocampus and parahippocampal gyrus, medial parietal lobe and retrosplenial cortex. Relative to younger participants elderly subjects showed increased activation in anterior cingulate gyrus and medial frontal lobe. These results provide evidence of age specific neural networks supporting spatial navigation and identify a putative neural substrate for age-related differences in spatial memory and navigational skill.