There is a pressing need to capture and track subtle cognitive change at the preclinical stage of Alzheimer's disease (AD) rapidly, cost‐effectively, and with high sensitivity. Concurrently, the ...landscape of digital cognitive assessment is rapidly evolving as technology advances, older adult tech‐adoption increases, and external events (i.e., COVID‐19) necessitate remote digital assessment. Here, we provide a snapshot review of the current state of digital cognitive assessment for preclinical AD including different device platforms/assessment approaches, levels of validation, and implementation challenges. We focus on articles, grants, and recent conference proceedings specifically querying the relationship between digital cognitive assessments and established biomarkers for preclinical AD (e.g., amyloid beta and tau) in clinically normal (CN) individuals. Several digital assessments were identified across platforms (e.g., digital pens, smartphones). Digital assessments varied by intended setting (e.g., remote vs. in‐clinic), level of supervision (e.g., self vs. supervised), and device origin (personal vs. study‐provided). At least 11 publications characterize digital cognitive assessment against AD biomarkers among CN. First available data demonstrate promising validity of this approach against both conventional assessment methods (moderate to large effect sizes) and relevant biomarkers (predominantly weak to moderate effect sizes). We discuss levels of validation and issues relating to usability, data quality, data protection, and attrition. While still in its infancy, digital cognitive assessment, especially when administered remotely, will undoubtedly play a major future role in screening for and tracking preclinical AD.
Animal models of Alzheimer's disease have suggested that tau pathology propagation, facilitated by amyloid pathology, may occur along connected pathways. To investigate these ideas in humans, we ...combined amyloid scans with longitudinal data on white matter connectivity, hippocampal volume, tau positron emission tomography and memory performance in 256 cognitively healthy older individuals. Lower baseline hippocampal volume was associated with increased mean diffusivity of the connecting hippocampal cingulum bundle (HCB). HCB diffusivity predicted tau accumulation in the downstream-connected posterior cingulate cortex in amyloid-positive but not in amyloid-negative individuals. Furthermore, HCB diffusivity predicted memory decline in amyloid-positive individuals with high posterior cingulate cortex tau binding. Our results provide in vivo evidence that higher amyloid pathology strengthens the association between HCB diffusivity and tau accumulation in the downstream posterior cingulate cortex and facilitates memory decline. This confirms amyloid's crucial role in potentiating neural vulnerability and memory decline marking the onset of preclinical Alzheimer's disease.
Objectives
To summarize and critically evaluate research on the effects of Tai Chi on cognitive function in older adults.
Design
Systematic review with meta‐analysis.
Setting
Community and ...residential care.
Participants
Individuals aged 60 and older (with the exception of one study) with and without cognitive impairment.
Measurements
Cognitive ability using a variety of neuropsychological testing.
Results
Twenty eligible studies with a total of 2,553 participants were identified that met inclusion criteria for the systematic review; 11 of the 20 eligible studies were randomized controlled trials (RCTs), one was a prospective nonrandomized controlled study, four were prospective noncontrolled observational studies, and four were cross‐sectional studies. Overall quality of RCTs was modest, with three of 11 trials categorized as high risk of bias. Meta‐analyses of outcomes related to executive function in RCTs of cognitively healthy adults indicated a large effect size when Tai Chi participants were compared with nonintervention controls (Hedges' g = 0.90; P = .04) and a moderate effect size when compared with exercise controls (Hedges' g = 0.51; P = .003). Meta‐analyses of outcomes related to global cognitive function in RCTs of cognitively impaired adults, ranging from mild cognitive impairment to dementia, showed smaller but statistically significant effects when Tai Chi was compared with nonintervention controls (Hedges' g = 0.35; P = .004) and other active interventions (Hedges' g = 0.30; P = .002). Findings from nonrandomized studies add further evidence that Tai Chi may positively affect these and other domains of cognitive function.
Conclusion
Tai Chi shows potential to enhance cognitive function in older adults, particularly in the realm of executive functioning and in individuals without significant impairment. Larger and methodologically sound trials with longer follow‐up periods are needed before more‐definitive conclusions can be drawn.
Mounting evidence suggests that sex differences exist in the pathologic trajectory of Alzheimer disease. Previous literature shows elevated levels of cerebrospinal fluid tau in women compared with ...men as a function of apolipoprotein E (APOE) ε4 status and β-amyloid (Aβ). What remains unclear is the association of sex with regional tau deposition in clinically normal individuals.
To examine sex differences in the cross-sectional association between Aβ and regional tau deposition as measured with positron emission tomography (PET).
This is a study of 2 cross-sectional, convenience-sampled cohorts of clinically normal individuals who received tau and Aβ PET scans. Data were collected between January 2016 and February 2018 from 193 clinically normal individuals from the Harvard Aging Brain Study (age range, 55-92 years; 118 women 61%) who underwent carbon 11-labeled Pittsburgh Compound B and flortaucipir F18 PET and 103 clinically normal individuals from the Alzheimer's Disease Neuroimaging Initiative (age range, 63-94 years; 55 women 51%) who underwent florbetapir and flortaucipir F 18 PET.
A main association of sex with regional tau in the entorhinal cortices, inferior temporal lobe, and a meta-region of interest, which was a composite of regions in the temporal lobe. Associations between sex and global Aβ as well as sex and APOE ε4 on these regions after controlling for age were also examined.
The mean (SD) age of all individuals was 74.2 (7.6) years (81 APOE ε4 carriers 31%; 89 individuals 30% with high Aβ). There was no clear association of sex with regional tau that was replicated across studies. However, in both cohorts, clinically normal women exhibited higher entorhinal cortical tau than men (meta-analytic estimate: β male = -0.11 0.05; 95% CI, -0.21 to -0.02; P = .02), which was associated with individuals with higher Aβ burden. A sex by APOE ε4 interaction was not associated with regional tau (meta-analytic estimate: β male, APOE ε4+ = -0.15 0.09; 95% CI, -0.32 to 0.01; P = .07).
Early tau deposition was elevated in women compared with men in individuals on the Alzheimer disease trajectory. These findings lend support to a growing body of literature that highlights a biological underpinning for sex differences in Alzheimer disease risk.
Objectives
Amyloid‐beta (Aβ) and tau pathologies are commonly observed among clinically normal older individuals at postmortem and can now be detected with in vivo neuroimaging. The association and ...interaction of these proteinopathies with prospective cognitive decline in normal aging and preclinical Alzheimer's disease (AD) remains to be fully elucidated.
Methods
One hundred thirty‐seven older individuals (age = 76.3 ± 6.22 years) participating in the Harvard Aging Brain Study underwent Aβ (11C‐Pittsburgh compound B) and tau (18F‐flortaucipir) positron emission tomography (PET) with prospective neuropsychological assessments following PET imaging (mean number of cognitive visits = 2.8 ± 1.1). Tau and Aβ PET measures were assessed in regions of interest (ROIs) as well as vertex‐wise map analyses. Cognitive change was evaluated with Memory and Executive Function composites.
Results
Higher levels of Aβ and tau were both associated with greater memory decline, but not with change in executive function. Higher cortical Aβ was associated with higher tau levels in all ROIs, independent of age, and very elevated levels of tau were observed primarily in clinically normal with elevated Aβ. A significant interaction between tau and Aβ was observed in both ROI and map‐level analyses, such that rapid prospective memory decline was observed in participants who had high levels of both pathologies.
Interpretation
Our results are consistent with the supposition that both Aβ and tau are necessary for memory decline in the preclinical stages of AD. These findings may be relevant for disambiguating aging and early cognitive manifestations of AD, and to inform secondary prevention trials in preclinical AD. Ann Neurol 2019;00:1–3 ANN NEUROL 2019;85:181–193.
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.
Animal and human imaging research reported that the presence of cortical Alzheimer's Disease's (AD) neuropathology, beta-amyloid and neurofibrillary tau, is associated with altered neuronal activity ...and circuitry failure, together facilitating clinical progression. The locus coeruleus (LC), one of the initial subcortical regions harboring pretangle hyperphosphorylated tau, has widespread connections to the cortex modulating cognition. Here we investigate whether LC's in-vivo neuronal activity and functional connectivity (FC) are associated with cognitive decline in conjunction with beta-amyloid. We combined functional MRI of a novel versus repeated face-name paradigm, beta-amyloid-PET and longitudinal cognitive data of 128 cognitively unimpaired older individuals. We show that LC activity and LC-FC with amygdala and hippocampus was higher during novelty. We also demonstrated that lower novelty-related LC activity and LC-FC with hippocampus and parahippocampus were associated with steeper beta-amyloid-related cognitive decline. Our results demonstrate the potential of LC's functional properties as a gauge to identify individuals at-risk for AD-related cognitive decline.
The thioredoxin system, composed of thioredoxin reductase (TrxR), thioredoxin (Trx), and NADPH, exerts a wide range of activities in cellular redox control, antioxidant function, cell viability, and ...proliferation. Recently, the selenocysteine (Sec)-containing mammalian TrxR has emerged as a new target for anticancer drug development because TrxR and Trx are overexpressed in many aggressive tumors and the tumor cells seem to be more dependent on Trx system than normal cells. Here we have investigated the inhibition of mammalian TrxR by flavonoids which have been presumed to be cancer chemoprevention agents because of their antioxidant activities. Myricetin and quercetin were found to have strong inhibitory effects on mammalian TrxRs with IC50 values of 0.62 and 0.97 micromol/L, respectively. The inhibition was shown to be concentration, NADPH, and time dependent and involved an attack on the reduced COOH-terminal -Cys-Sec-Gly active site of TrxR. Oxygen-derived superoxide anions enhanced the inhibitory effect whereas anaerobic conditions attenuated inhibition. Spectral analysis suggested that the flavonols might perform their inhibitory effects via semiquinone radicals. Additionally, the flavonols had the potential to inhibit the growth of A549 cells with the same potency as inhibition of TrxR. TrxR activity in the cell lysates was reduced on treatment with myricetin >50 micromol/L, which coincided with the oxidization of Trx. The cell cycle was arrested in S phase by quercetin and an accumulation of cells in sub-G1 was observed in response to myricetin. Thus, the anticancer activity of quercetin and myricetin may be due to inhibition of TrxR, consequently inducing cell death.
Research on the potential effects of cognitive intervention in healthy elderly has been motivated by (1) the apparent effectiveness of cognitive rehabilitation in Alzheimer's disease (AD) patients; ...(2) the face validity of bolstering skills eventually burdened by disease; (3) interest in low-cost/noninvasive methods of preventing or delaying onset of disease; (4) the epidemiologic research suggesting protective effects of educational attainment and lifelong participation in cognitively stimulating activities; (5) the burgeoning industry of brain training products and requisite media attention; and (6) the aging world population.
We performed a systematic review with meta-analytic techniques to analyze randomized controlled trials of cognitive interventions in healthy elderly.
The weighted mean effect size (Cohen's d) of cognitive intervention across all outcome measures after training was .16 (95% confidence interval, .138 to .186). The existing literature is limited by a lack of consensus on what constitutes the most effective type of cognitive training, insufficient follow-up times, a lack of matched active controls, and few outcome measures showing changes in daily functioning, global cognitive skills, or progression to early AD.
Our review was limited by a small, heterogeneous, and methodologically limited literature. Within this literature, we found no evidence that structured cognitive intervention programs delay or slow progression to AD in healthy elderly. Further work that accounts for the limitations of past efforts and subsequent clear and unbiased reporting to the public of the state and progress of research on this topic will help the elderly make informed decisions about a range of potential preventive lifestyle measures including cognitive intervention.
The beneficial role of the trace element selenium (Se) in human health has been known for several decades and is attributed both to low-molecular-weight Se compounds and to its presence within 25 ...selenoproteins in the form of the amino acid selenocysteine (Sec). Incorporation of Sec into selenoproteins involves decoding of the UGA codon. This process requires multiple features, such as the Sec-insertion sequence (SECIS) element and protein factors, including a specific elongation factor EFSec and the SECIS-binding protein 2, SBP2. Although many selenoproteins remain functionally uncharacterized, some of their known functions include redox regulation of intracellular signaling, redox homeostasis, and thyroid hormone metabolism. Pathologically, reduced expression of selenoproteins has been directly linked with the congenital muscle disease referred to as selenoprotein N (SEPN)-related myopathy and with thyroid-hormone metabolism defects (deficiency of deiodinases due to genetic defects in SBP2). From a broader, less well defined aspect, selenium compounds and selenoproteins have been linked to prevention of some forms of cancer, Alzheimer's disease, cardiovascular disease, and life span. This forum summarizes recent advances in our understanding of important roles of selenium, selenoproteins, and factors involved in selenoprotein synthesis in health and disease and discusses potential targets for therapy.
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