: Functional magnetic resonance imaging (fMRI) is a noninvasive neuroimaging technique that can be used to study the neural correlates of complex cognitive processes, and the alterations in these ...processes that occur in the course of normal aging or superimposed neurodegenerative disease. Our studies have focused on the neural substrates of successful associative encoding, particularly of face–name associations. We have found that the specific regions of the hippocampus and prefrontal cortices are critical for successful memory in both young and healthy older subjects. Our fMRI studies, as well as those of several other groups, have consistently demonstrated that, compared to cognitively intact older subjects, patients with clinical Alzheimer's disease (AD) have decreased fMRI activation in the hippocampus and related structures within the medial temporal lobe during the encoding of new memories. More recently, fMRI studies of subjects at risk for AD, by virtue of their genetics or evidence of mild cognitive impairment (MCI), have yielded variable results. Some of these studies, including our own, suggest that there may be a phase of paradoxically increased activation early in the course of prodromal AD. Further studies to validate fMRI in these populations are needed, particularly longitudinal studies to investigate the pattern of alterations in functional activity over the course of prodromal AD and the relationship to AD pathology.
As the field begins to test the concept of a “preclinical” stage of neurodegenerative disease, when the pathophysiological process has begun in the brain, but clinical symptoms are not yet manifest, ...a number of intriguing questions have already arisen. In particular, in preclinical Alzheimer’s disease (AD), the temporal relationship of amyloid markers to markers of neurodegeneration and their relative utility in the prediction of cognitive decline among clinically normal older individuals remains to be fully elucidated. Secondary prevention trials in AD have already begun in both genetic at-risk and amyloid at-risk cohorts, with several more trials in the planning stages, and should provide critical answers about whether intervention at this very early stage of disease can truly bend the curve of clinical progression. This review will highlight recent progress in cognitive, imaging, and biomarker outcomes in the field of preclinical AD, and the remaining gaps in knowledge.
Sperling et al. review the rapidly evolving field of “preclinical” Alzheimer’s disease. This timely article discusses recent studies utilizing PET amyloid and tau imaging and other biomarkers of neurodegenerative disease and the implications for secondary prevention trials.
A major mystery of many types of neurological and psychiatric disorders, such as Alzheimer's disease (AD), remains the underlying, disease-specific neuronal damage. Because of the strong ...interconnectivity of neurons in the brain, neuronal dysfunction necessarily disrupts neuronal circuits. In this article, we review evidence for the disruption of large-scale networks from imaging studies of humans and relate it to studies of cellular dysfunction in mouse models of AD. The emerging picture is that some forms of early network dysfunctions can be explained by excessively increased levels of neuronal activity. The notion of such neuronal hyperactivity receives strong support from in vivo and in vitro cellular imaging and electrophysiological recordings in the mouse, which provide mechanistic insights underlying the change in neuronal excitability. Overall, some key aspects of AD-related neuronal dysfunctions in humans and mice are strikingly similar and support the continuation of such a translational strategy.
Among cognitively normal individuals, elevated brain amyloid (defined by cerebrospinal fluid assays or positron emission tomography regional summaries) can be related to risk for later ...Alzheimer-related cognitive decline.
To characterize and quantify the risk for Alzheimer-related cognitive decline among cognitively normal individuals with elevated brain amyloid.
Exploratory analyses were conducted with longitudinal cognitive and biomarker data from 445 cognitively normal individuals in the United States and Canada. Participants were observed from August 23, 2005, to June 7, 2016, for a median of 3.1 years (interquartile range, 2.0-4.2 years; maximum follow-up, 10.3 years) as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI).
Individuals were classified at baseline as having normal (n = 243) or elevated (n = 202) brain amyloid using positron emission tomography amyloid imaging or a cerebrospinal fluid assay of amyloid β.
Outcomes included scores on the Preclinical Alzheimer Cognitive Composite (PACC; a sum of 4 baseline standardized z scores, which decreases with worse performance), Mini-Mental State Examination (MMSE; 0 worst to 30 best points), Clinical Dementia Rating Sum of Boxes (CDR-Sum of Boxes; 0 best to 18 worst points), and Logical Memory Delayed Recall (0 worst to 25 best story units).
Among the 445 participants (243 with normal amyloid, 202 with elevated amyloid), mean (SD) age was 74.0 (5.9) years, mean education was 16.4 (2.7) years, and 52% were women. The mean score for PACC at baseline was 0.00 (2.60); for MMSE, 29.0 (1.2); for CDR-Sum of Boxes, 0.04 (0.14); and for Logical Memory Delayed Recall, 13.1 (3.3). Compared with the group with normal amyloid, those with elevated amyloid had worse mean scores at 4 years on the PACC (mean difference, 1.51 points 95% CI, 0.94-2.10; P < .001), MMSE (mean difference, 0.56 points 95% CI, 0.32-0.80; P < .001), and CDR-Sum of Boxes (mean difference, 0.23 points 95% CI, 0.08-0.38; P = .002). For Logical Memory Delayed Recall, between-group score was not statistically significant at 4 years (mean difference, 0.73 story units 95% CI, -0.02 to 1.48; P = .056).
Exploratory analyses of a cognitively normal cohort followed up for a median of 3.1 years suggest that elevation in baseline brain amyloid level, compared with normal brain amyloid level, was associated with higher likelihood of cognitive decline, although the findings are of uncertain clinical significance. Further research is needed to assess the clinical importance of these differences and measure longer-term associations.
To understand the role of depressive symptoms in preclinical Alzheimer's disease, it is essential to define their temporal relationship to Alzheimer's proteinopathies in cognitively normal older ...adults. The study objective was to examine associations of brain amyloid beta and longitudinal measures of depression and depressive symptom clusters in a cognitively normal sample of older adults.
A total of 270 community-dwelling, cognitively normal elderly individuals underwent baseline Pittsburgh compound B (PiB) positron emission tomography (PET) measures of cortical aggregate amyloid beta and annual assessments with the 30-item Geriatric Depression Scale (GDS). The authors evaluated continuous PiB binding as a predictor of GDS score or GDS cluster, calculated as total scores and mean scores for three GDS item clusters (apathy-anhedonia, dysphoria, and anxiety-concentration), across time (1-5 years; mean=3.8 years) in separate mixed-effects models with backward elimination. Initial predictors included PiB binding, age, sex, Hollingshead score, American National Adult Reading Test (AMNART) score, apolipoprotein E ε4 status, depression history, and their interactions with time.
Higher PiB binding predicted accelerated rates of increase in GDS score over time, adjusting for depression history. Higher PiB binding also predicted steeper rates of increase for anxiety-concentration scores, adjusting for depression history and the AMNART score-by-time interaction. In a post hoc model estimating anxiety scores without concentration disturbance items, the PiB binding-by-time interaction remained significant.
Higher amyloid beta burden was associated with increasing anxious-depressive symptoms over time in cognitively normal older individuals. Prior depression history was related to higher but not worsening symptom ratings. These results suggest a direct or indirect association of elevated amyloid beta levels with worsening anxious-depressive symptoms and support the hypothesis that emerging neuropsychiatric symptoms represent an early manifestation of preclinical Alzheimer's disease.
A new secondary prevention trial in older people with amyloid accumulation at high risk for Alzheimer's disease dementia should provide insights into whether anti-amyloid therapy can delay cognitive ...decline.
The Anti-Amyloid Treatment in Asymptomatic Alzheimer disease (A4) Study is an ongoing prevention trial in clinically normal older individuals with evidence of elevated brain amyloid. The large number ...of participants screened with amyloid positron emission tomography (PET) and standardized assessments provides an unprecedented opportunity to evaluate factors associated with elevated brain amyloid.
To investigate the association of elevated amyloid with demographic and lifestyle factors, apolipoprotein E (APOE), neuropsychological testing, and self- and study partner reports of cognitive function.
This cross-sectional study included screening data in the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study collected from April 2014 to December 2017 and classified by amyloid status. Data were was analyzed from 2018 to 2019 across 67 sites in the US, Canada, Australia, and Japan and included 4486 older individuals (age 65-85 years) who were eligible for amyloid PET (clinically normal Clinical Dementia Rating = 0 and cognitively unimpaired Mini-Mental State Examination score, ≥25; logical memory IIa 6-18).
Screening demographics, lifestyle variables, APOE genotyping, and cognitive testing (Preclinical Alzheimer Cognitive Composite), self- and study partner reports of high-level daily cognitive function (Cognitive Function Index). Florbetapir amyloid PET imaging was used to classify participants as having elevated amyloid (Aβ+) or not having elevated amyloid (Aβ-).
Amyloid PET results were acquired for 4486 participants (mean SD age, 71.29 4.67 years; 2647 women 59%), with 1323 (29.5%) classified as Aβ+. Aβ+ participants were slightly older than Aβ-, with no observed differences in sex, education, marital or retirement status, or any self-reported lifestyle factors. Aβ+ participants were more likely to have a family history of dementia (3320 Aβ+ 74% vs 3050 Aβ- 68%) and at least 1 APOE ε4 allele (2602 Aβ+ 58% vs 1122 Aβ- 25%). Aβ+ participants demonstrated worse performance on screening Preclinical Alzheimer Cognitive Composite results and reported higher change scores on the Cognitive Function Index.
Among a large group of older individuals screening for an Alzheimer disease (AD) prevention trial, elevated brain amyloid was associated with family history and APOE ε4 allele but not with multiple other previously reported risk factors for AD. Elevated amyloid was associated with lower test performance results and increased reports of subtle recent declines in daily cognitive function. These results support the hypothesis that elevated amyloid represents an early stage in the Alzheimer continuum and demonstrate the feasibility of enrolling these high-risk participants in secondary prevention trials aimed at slowing cognitive decline during the preclinical stages of AD.
Alzheimer's disease (AD) is the only leading cause of death for which no disease-modifying therapy is currently available. Recent disappointing trial results at the dementia stage of AD have raised ...multiple questions about our current approaches to the development of disease-modifying agents. Converging evidence suggests that the pathophysiological process of AD begins many years before the onset of dementia. So why do we keep testing drugs aimed at the initial stages of the disease process in patients at the end-stage of the illness?
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