Loss of awareness is a common symptom in Alzheimer's Disease (AD) and responsible for a significant loss of functional abilities. The mechanisms underlying loss of awareness in AD is unknown, ...although previous findings have implicated dysfunction of primary executive functioning (EF) or episodic memory (EM) to be the cause. Therefore, our main study objective was to explore the involvement of EF and EM dysfunction in amyloid-related loss of awareness across the clinical spectrum of AD.
A total of 895 participants (362 clinically normal CN, 422 people with mild cognitive impairment MCI and 111 with dementia) from the Alzheimer's Disease Neuroimaging Initiative were used for the analyses. A sub-analysis was performed in 202 participants who progressed in their clinical diagnosis from CN to MCI or MCI to dementia as well as dementia patients. Mediation models were used in each clinical group with awareness (assessed with the Everyday Cognitive function questionnaire) as a dependent variable to determine whether EF and/or EM would mediate the effect of amyloid on awareness. We also ran these analyses with subjective and informant complaints as dependent variables. Direct correlations between all variables were also performed.
We found evidence for a decline in awareness across the groups, with increased awareness observed in the CN group and decreased awareness observed in the MCI and dementia groups. Our results showed that EM, and not EF, partially mediated the relationship between amyloid and awareness such that greater amyloid and lower EM performance was associated with lower awareness. When analyzing each group separately, this finding was only observed in the MCI group and in the group containing progressors and dementia patients. When repeating the analyses for subjective and informant complaints separately, the results were replicated only for the informant's complaints.
Our results demonstrate that decline in EM and, to a lesser degree, EF, mediate the effect of amyloid on awareness. In line with previous studies demonstrating the development of anosognosia in the prodromal stage, our findings suggest that decreased awareness is the result of an inability for the participant to update his/her insight into his/her cognitive performance (i.e., demonstrating a petrified self).
Objective
Unawareness, or anosognosia, of memory deficits is a challenging manifestation of Alzheimer's disease (AD) that adversely affects a patient's safety and decision‐making. However, there is a ...lack of consensus regarding the presence, as well as the evolution, of altered awareness of memory function across the preclinical and prodromal stages of AD. Here, we aimed to characterize change in awareness of memory abilities and its relationship to beta‐amyloid (Aβ) burden in a large cohort (N = 1,070) of individuals across the disease spectrum.
Methods
Memory awareness was longitudinally assessed (average number of visits = 4.3) and operationalized using the discrepancy between mean participant and partner report on the Everyday Cognition scale (memory domain). Aβ deposition was measured at baseline using 18Fflorbetapir positron emission tomographic imaging.
Results
Aβ predicted longitudinal changes in memory awareness, such that awareness decreased faster in participants with increased Aβ burden. Aβ and clinical group interacted to predict change in memory awareness, demonstrating the strongest effect in dementia participants, but could also be found in the cognitively normal (CN) participants. In a subset of CN participants who progressed to mild cognitive impairment (MCI), heightened memory awareness was observed up to 1.6 years before MCI diagnosis, with memory awareness declining until the time of progression to MCI (−0.08 discrepant‐points/yr). In a subset of MCI participants who progressed to dementia, awareness was low initially and continued to decline (−0.23 discrepant‐points/yr), reaching anosognosia 3.2 years before dementia onset.
Interpretation
Aβ burden is associated with a progressive decrease in self‐awareness of memory deficits, reaching anosognosia approximately 3 years before dementia diagnosis. ANN NEUROL 2020;87:267–280
PET staging of amyloidosis using striatum Hanseeuw, Bernard J.; Betensky, Rebecca A.; Mormino, Elizabeth C. ...
Alzheimer's & dementia,
October 2018, Letnik:
14, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Amyloid positron emission tomography (PET) data are commonly expressed as binary measures of cortical deposition. However, not all individuals with high cortical amyloid will experience rapid ...cognitive decline. Motivated by postmortem data, we evaluated a three-stage PET classification: low cortical; high cortical, low striatal; and high cortical, high striatal amyloid; hypothesizing this model could better reflect Alzheimer's dementia progression than a model based only on cortical measures.
We classified PET data from 1433 participants (646 normal, 574 mild cognitive impairment, and 213 AD), explored the successive involvement of cortex and striatum using 3-year follow-up PET data, and evaluated the associations between PET stages, hippocampal volumes, and cognition.
Follow-up data indicated that PET detects amyloid first in cortex and then in striatum. Our three-category staging including striatum better predicted hippocampal volumes and subsequent cognition than a three-category staging including only cortical amyloid.
PET can evaluate amyloid expansion from cortex to subcortex. Using striatal signal as a marker of advanced amyloidosis may increase predictive power in Alzheimer's dementia research.
Ahead of Alzheimer's disease Vannini, Patrizia
Lancet neurology,
August 2021, 2021-08-00, 20210801, Letnik:
20, Številka:
8
Journal Article
Recenzirano
Over a hundred years have passed since the German psychiatrist and neuropathologist Alois Alzheimer described the symptoms and pathology of his patient August D. He described the now recognised ...hallmark pathologies of the disease: amyloid plaques and tau tangles. ...recently, neurologists could not confirm a diagnosis of Alzheimer's disease until after a post mortem analysis. Gibbs explains that his ARIA came to be a turning point and, as with a skin tattoo, his hemosiderin mark would come to symbolise “resistance to the silence that has muted the conversation about Alzheimer's among patients and doctors, family members, and society, as well as a reminder to rally attention to help break down the stigma and encourage the important discussions needed to improve the care of those with the disease and to advance the search for a cure”. In the wake of a drug that will cure this disease, there is now overwhelming evidence that life style choices (such as exercise, a Mediterranean diet, mentally stimulating activities, social engagement, and good sleep) might markedly slow down its progression.
Emerging difficulty performing cognitively complex everyday tasks, or 'instrumental activities of daily living' (IADL) may be an early clinical sign of Alzheimer's disease (AD). We aimed to ...investigate how changes over time in everyday functioning relate to cerebral tau burden across the AD clinical spectrum.
We included 581 participants (73.9 ± 7.6 years old; 52% female) from the Alzheimer's Disease Neuroimaging Initiative who underwent tau positron emission tomography (PET) and completed at least two assessments of the Functional Activities Questionnaire (FAQ). Participants were classified as cognitively normal (n = 334) or symptomatic (n = 247). We analyzed the association between longitudinal FAQ scores and baseline tau in six temporal, parietal, and frontal brain regions in mixed-effects models. Models were run in the entire sample, as well as stratified by diagnostic group (cognitively normal or symptomatic). We additionally investigated tau-PET adjusted for, as well as interacting with, amyloid-β.
Greater tau burden in several frontal, temporal, and parietal regions was associated with steeper decline over time in everyday functioning. These findings remained when adjusting for baseline global cortical amyloid-β; amyloid-β itself was only associated with change over time in FAQ scores when tau was not included in the model. When stratifying by diagnostic group, most associations between tau and everyday functioning, adjusted for amyloid-β, were present only in the symptomatic group.
The rate of change in everyday functioning is related to baseline tau burden in various brain regions, more strongly so than global cortical amyloid-β, specifically in cognitively symptomatic individuals. Longitudinal studies in incident dementia populations are needed to better understand functional changes in response to AD pathology across the disease.
Noninvasive biomarkers of early neuronal injury may help identify cognitively normal individuals at risk of developing Alzheimer's disease (AD). A recent diffusion-weighted imaging (DWI) method ...allows assessing cortical microstructure via cortical mean diffusivity (cMD), suggested to be more sensitive than macrostructural neurodegeneration. Here, we aimed to investigate the association of cMD with amyloid-β and tau pathology in older adults, and whether cMD predicts longitudinal cognitive decline, neurodegeneration and clinical progression. The study sample comprised n = 196 cognitively normal older adults (meanSD 72.5 9.4 years; 114 women 58.2%) from the Harvard Aging Brain Study. At baseline, all participants underwent structural MRI, DWI,
C-Pittsburgh compound-B-PET,
F-flortaucipir-PET imaging, and cognitive assessments. Longitudinal measures of Preclinical Alzheimer Cognitive Composite-5 were available for n = 186 individuals over 3.72 (1.96)-year follow-up. Prospective clinical follow-up was available for n = 163 individuals over 3.2 (1.7) years. Surface-based image analysis assessed vertex-wise relationships between cMD, global amyloid-β, and entorhinal and inferior-temporal tau. Multivariable regression, mixed effects models and Cox proportional hazards regression assessed longitudinal cognition, brain structural changes and clinical progression. Tau, but not amyloid-β, was positively associated with cMD in AD-vulnerable regions. Correcting for baseline demographics and cognition, increased cMD predicted steeper cognitive decline, which remained significant after correcting for amyloid-β, thickness, and entorhinal tau; there was a synergistic interaction between cMD and both amyloid-β and tau on cognitive slope. Regional cMD predicted hippocampal atrophy rate, independently from amyloid-β, tau, and thickness. Elevated cMD predicted progression to mild cognitive impairment. Cortical microstructure is a noninvasive biomarker that independently predicts subsequent cognitive decline, neurodegeneration and clinical progression, suggesting utility in clinical trials.
Abstract The direct access of olfactory afferents to memory-related cortical systems has inspired theories about the role of the olfactory pathways in the development of cortical neurodegeneration in ...Alzheimer’s disease (AD). In this study, we used baseline olfactory identification measures with longitudinal flortaucipir and PiB PET, diffusion MRI of 89 cognitively normal older adults (73.82 ± 8.44 years; 56% females), and a transcriptomic data atlas to investigate the spatiotemporal spreading and genetic vulnerabilities of AD-related pathology aggregates in the olfactory system. We find that odor identification deficits are predominantly associated with tau accumulation in key areas of the olfactory pathway, with a particularly strong predictive power for longitudinal tau progression. We observe that tau spreads from the medial temporal lobe structures toward the olfactory system, not the reverse. Moreover, we observed a genetic background of odor perception-related genes that might confer vulnerability to tau accumulation along the olfactory system.
The hallmark clinical symptom of early Alzheimer’s disease (AD) is episodic memory impairment. Recent functional imaging studies suggest that memory function is subserved by a set of distributed ...networks, which include both the medial temporal lobe (MTL) system and the set of cortical regions collectively referred to as the default network. Specific regions of the default network, in particular, the posteromedial cortices, including the precuneus and posterior cingulate, are selectively vulnerable to early amyloid deposition in AD. These regions are also thought to play a key role in both memory encoding and retrieval, and are strongly functionally connected to the MTL. Multiple functional magnetic resonance imaging (fMRI) studies during memory tasks have revealed alterations in these networks in patients with clinical AD. Similar functional abnormalities have been detected in subjects at-risk for AD, including those with genetic risk and older individuals with mild cognitive impairment. Recently, we and other groups have found evidence of functional alterations in these memory networks even among cognitively intact older individuals with occult amyloid pathology, detected by PET amyloid imaging. Taken together, these findings suggest that the pathophysiological process of AD exerts specific deleterious effects on these distributed memory circuits, even prior to clinical manifestations of significant memory impairment. Interestingly, some of the functional alterations seen in prodromal AD subjects have taken the form of increases in activity relative to baseline, rather than a loss of activity. It remains unclear whether these increases in fMRI activity may be compensatory to maintain memory performance in the setting of early AD pathology or instead, represent evidence of excitotoxicity and impending neuronal failure. Recent studies have also revealed disruption of the intrinsic connectivity of these networks observable even during the resting state in early AD and asymptomatic individuals with high amyloid burden. Research is ongoing to determine if these early network alterations will serve as sensitive predictors of clinical decline, and eventually, as markers of pharmacological response to potential disease-modifying treatments for AD.
The ability to produce novel ideas is central to societal progress and innovation; however, little is known about the biological basis of creativity. Here, we investigate the organization of brain ...networks that support creativity by combining functional neuroimaging data with gene expression information. Given the multifaceted nature of creative thinking, we hypothesized that distributed connectivity would not only be related to individual differences in creative ability, but also delineate the cortical distributions of genes involved in synaptic plasticity. We defined neuroimaging phenotypes using a graph theory approach that detects local and distributed network circuits, then characterized the spatial associations between functional connectivity and cortical gene expression distributions. Our findings reveal strong spatial correlations between connectivity maps and sets of genes devoted to synaptic assembly and signaling. This connectomic-transcriptome approach thus identifies gene expression profiles associated with high creative ability, linking cognitive flexibility to neural plasticity in the human brain.
Identifying a poor degree of awareness of cognitive decline (ACD) could represent an early indicator of Alzheimer's disease (AD).
(1) to understand whether there is evidence of poor ACD in the ...pre-dementia stages of AD; (2) to summarize the main findings obtained investigating ACD in AD; (3) to propose a conceptual framework.
We searched Scopus, Pubmed, and the reference lists for studies published up to August 2020. Original research articles must report a measure of ACD and included individuals with AD dementia, or prodromal AD (or MCI), or being at risk for AD.
All studies covering preclinical, prodromal, and AD dementia were systematically reviewed. We intended to perform a meta-analysis of empirical studies on preclinical AD or prodromal AD (or MCI), to compare ACD between clinical groups. Due to the paucity of literature on preclinical AD, meta-analysis was only possible for prodromal AD (or MCI) studies.
We systematically reviewed 283 articles, and conducted a meta-analysis of 18 articles on prodromal AD (or MCI), showing that ACD was not significantly different between patients with amnestic and non-amnestic MCI (SMD = 0.09,
= 0.574); ACD was significantly poorer in amnestic MCI (SMD = -0.56,
= 0.001) and mild AD (SMD = -1.39,
< 0.001) than in controls; ACD was also significantly poorer in mild AD than in amnestic MCI (SMD = -0.75,
< 0.001), as well as poorer than in non-amnestic MCI (SMD = -1.00,
< 0.001). We also discuss key findings on ACD in AD, such as its neural and cognitive correlates.
We propose that patients may be complaining of their initial subtle cognitive changes, but ACD would soon start to decrease. The individual would show mild anosognosia in the MCI stage, and severe anosognosia in dementia. The evaluation of ACD (comparing self-report to cognitive scores or to informant-report) could be useful to guide the clinician toward a timely diagnosis, and in trials targeting early-stage AD.
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