Psychological Status of the Participants in Alzheimer's Prevention Initiative Autosomal Dominant Alzheimer's Disease Colombia.

BACKGROUND: The SARS-CoV2 global pandemic impacted participants in the Alzheimer's Prevention Initiative (API) Autosomal Dominant Alzheimer's Disease (ADAD) clinical trial, who faced three stressors: 1) fear of developing dementia; 2) concerns about missing treatment; and 3) risk of SARS-CoV2 infection. OBJECTIVE: To describe the frequency of psychological disorders among the participants of the API ADAD Colombia clinical study, treated by a holistic mental health team during the COVID-19 pandemic. The extent of use of mental health team services was explored considering different risk factors, and users and non-users of these services were compared. METHODS: Participants had free and optional access to psychology and psychiatry services, outside of the study protocol. Descriptive statistics was used to analyze the frequency of the mental health difficulties. A multivariable logistic regression model has been used to assess associations with using this program. RESULTS: 66 participants were treated by the Mental Health Team from March 1, 2020, to December 31, 2020. Before and after the start of the pandemic, the most common psychological problems were anxiety (36.4% before, 63.6% after) and depression (34.8% before, 37.9% after). 70% of users assisted by psychology and 81.6% of those assisted by psychiatry felt that the services were useful for them. Female sex, depression, and anxiety before the pandemic were positively associated with being assisted by either psychology or psychiatry, while the association with hyperlipidemia was negative. CONCLUSIONS: A holistic mental health program, carried out in the context of a study, could mitigate psychopathology during pandemics such as COVID-19.

Baseline demographic, clinical, and cognitive characteristics of the Alzheimer's Prevention Initiative (API) Autosomal-Dominant Alzheimer's Disease Colombia Trial.

INTRODUCTION: The API AutosomalDominant AD (ADAD) Colombia Trial is a placebo-controlled clinical trial of crenezumab in 252 cognitively unimpaired 30 to 60-year-old Presenilin 1 (PSEN1) E280A kindred members, including mutation carriers randomized to active treatment or placebo and non-carriers who receive placebo. METHODS: Of the 252 enrolled, we present data on a total of 242 mutation carriers and non-carriers matched by age range, excluding data on 10 participants to protect participant confidentiality, genetic status, and trial integrity. RESULTS: We summarize demographic, clinical, cognitive, and behavioral data from 167 mutation carriers and 75 non-carriers, 30 to 53 years of age. Carriers were significantly younger than non-carriers ((mean age ± SD) 37 ± 5 vs 42 ± 6), had significantly lower Mini Mental Status Exam (MMSE) scores (28.8 ± 1.4 vs 29.2 ± 1.0), and had consistently lower memory scores. DISCUSSION: Although PSEN1 E280A mutation carriers in the Trial are cognitively unimpaired, they have slightly lower MMSE and memory scores than non-carriers. Their demographic characteristics are representative of the local population.

Long-Term Physical Exercise and Mindfulness Practice in an Aging Population.

Previous studies have shown that physical exercise and mindfulness meditation can both lead to improvement in physical and mental health. However, it is unclear whether these two forms of training share the same underlying mechanisms. We compared two groups of older adults with 10 years of mindfulness meditation (integrative body-mind training, IBMT) or physical exercise (PE) experience to demonstrate their effects on brain, physiology and behavior. Healthy older adults were randomly selected from a large community health project and the groups were compared on measures of quality of life, autonomic activity (heart rate, heart rate variability, skin conductance response, respiratory amplitude/rate), immune function (secretory Immunoglobulin A, sIgA), stress hormone (cortisol) and brain imaging (resting state functional connectivity, structural differences). In comparison with PE, we found significantly higher ratings for the IBMT group on dimensions of life quality. Parasympathetic activity indexed by skin conductance response and high-frequency heart rate variability also showed more favorable outcomes in the IBMT group. However, the PE group showed lower basal heart rate and greater chest respiratory amplitude. Basal sIgA level was significantly higher and cortisol concentration was lower in the IBMT group. Lastly, the IBMT group had stronger brain connectivity between the dorsal anterior cingulate cortex (dACC) and the striatum at resting state, as well as greater volume of gray matter in the striatum. Our results indicate that mindfulness meditation and physical exercise function in part by different mechanisms, with PE increasing physical fitness and IBMT inducing plasticity in the central nervous systems. These findings suggest combining physical and mental training may achieve better health and quality of life results for an aging population.

Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD.

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e - 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e - 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e - 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n ≥ 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.

CAP--advancing the evaluation of preclinical Alzheimer disease treatments.

If we are to find treatments to postpone, reduce the risk of, or completely prevent the clinical onset of Alzheimer disease (AD), we need faster methods to evaluate promising preclinical AD treatments, new ways to work together in support of common goals, and a determination to expedite the initiation and performance of preclinical AD trials. In this article, we note some of the current challenges, opportunities and emerging strategies in preclinical AD treatment. We describe the Collaboration for Alzheimer's Prevention (CAP)-a convening, harmonizing and consensus-building initiative to help stakeholders advance AD prevention research with rigour, care and maximal impact-and we demonstrate the impact of CAP on the goals and design of new preclinical AD trials.

Subjective cognitive decline: self and informant comparisons.

BACKGROUND: It is unclear whether self- or informant-based subjective cognition better distinguishes emotional factors from early-stage Alzheimer's disease (AD). METHODS: Healthy members (n = 447) of the Arizona apolipoprotein E (APOE) cohort and their informants completed the self and informant paired Multidimensional Assessment of Neurodegenerative Symptoms questionnaire (MANS). RESULTS: Decline on the MANS was endorsed by 30.6% of members and 26.2% of informants. Self- and informant-based decliners had higher scores of psychological distress and slightly lower cognitive scores than nondecliners. Over the next 6.7 years, 20 developed mild cognitive impairment (MCI). Converters were older at entry than nonconverters (63.8 [7.0] vs 58.8 [7.3] years, P = .003), 85% were APOE ε4 carriers (P < .0001), and they self-endorsed decline earlier than informants (58.9 [39.2] vs 28.0 [40.4] months before MCI; P = .002). CONCLUSIONS: Self- and informant-based subjective decline correlated with greater psychological distress and slightly lower cognitive performance. Those with incident MCI generally self-endorsed decline earlier than informants.

APOE and neuroenergetics: an emerging paradigm in Alzheimer's disease.

APOE is the major known genetic risk factor for late-onset Alzheimer's disease. Though relationships between APOE-encoded apolipoprotein E and ß-amyloid are increasingly well described, mounting evidence supports wide-ranging effects of APOE on the brain. Specifically, APOE appears to affect brain network activity and closely related neuroenergetic functions that might be involved in vulnerability to neurodegenerative pathophysiology. These effects highlight the salience of further investigation into the diverse influences of APOE. Therefore, this article reviews the interplay between APOE and neuroenergetics and proposes areas for further investigation. This research might lead to the identification of novel therapeutic targets for the treatment and/or prevention of Alzheimer's disease.

Network analysis of single-subject fMRI during a finger opposition task.

The analysis of functional magnetic resonance imaging (fMRI) data has typically relied on univariate methods to identify areas of brain activity related to cognitive and behavioral task performance. We investigated the ability of multivariate network analysis using a modified form of principal component analysis, the Scaled Subprofile Model (SSM), applied to single-subject fMRI data to identify patterns of interactions among brain regions over time during an anatomically well-characterized simple motor task. We hypothesized that each subject would exhibit correlated patterns of brain activation in several regions known to participate in the regulation of movement including the contralateral motor cortex and the ipsilateral cerebellum. EPI BOLD images were acquired in six healthy participants as they performed a visually and auditorally paced finger opposition task. SSM analysis was applied to the fMR time series on a single-subject basis. Linear combinations of the major principal components that predicted the expected hemodynamic response to the order of experimental conditions were identified for each participant. These combinations of SSM patterns were highly associated with the expected hemodynamic response, an indicator of local neuronal activity, in each participant (0.84