Shafferdudley9035

We discuss DNA damage pathways uncovered by HD GWAS, known roles of other polyglutamine disease proteins in DNA damage repair, and a panel of hypotheses for pathogenic mechanisms.

Advanced machine learning methods can aid in the identification of dementia risk using neuroimaging-derived features including FDG-PET. However, to enable the translation of these methods and test their usefulness in clinical practice, it is crucial to conduct independent validation on real clinical samples, which has yet to be properly delineated in the current literature.

In this paper, we present our efforts to enable such clinical translational through the evaluation and comparison of two machine-learning methods for discrimination between dementia of Alzheimer's type (DAT) and Non-DAT controls.

FDG-PET-based dementia scores were generated on an independent clinical sample whose clinical diagnosis was blinded to the algorithm designers. A feature-engineered approach (multi-kernel probability classifier) and a non-feature-engineered approach (3D convolutional neural network) were analyzed. Both classifiers were pre-trained on cognitively normal subjects as well as subjects with DAT. These two methodsata from an independent clinical sample for assessing the performance in DAT classification models in a clinical setting. Our results showed good generalizability for two machine-learning approaches, marking an important step for the translation of pre-trained machine-learning models into clinical practice.

Central arterial stiffness and brain hypoperfusion are emerging risk factors of Alzheimer's disease (AD). Aerobic exercise training (AET) may improve central arterial stiffness and brain perfusion.

To investigate the effects of AET on central arterial stiffness and cerebral blood flow (CBF) in patients with amnestic mild cognitive impairment (MCI), a prodromal stage of AD.

This is a proof-of-concept, randomized controlled trial that assigned 70 amnestic MCI patients into a 12-month program of moderate-to-vigorous AET or stretching-and-toning (SAT) intervention. Carotid β-stiffness index and CBF were measured by color-coded duplex ultrasonography and applanation tonometry. Total CBF was measured as the sum of CBF from both the internal carotid and vertebral arteries, and divided by total brain tissue mass assessed with MRI to obtain normalized CBF (nCBF). Episodic memory and executive function were assessed using standard neuropsychological tests (CVLT-II and D-KEFS). Changes in cardiorespiratory fitness were measured by peak oxygen uptake (VO2peak).

Total 48 patients (29 in SAT and 19 in AET) were completed one-year training. 5-Fluorouracil concentration AET improved VO2peak, decreased carotid β-stiffness index and CBF pulsatility, and increased nCBF. Changes in VO2peak were associated positively with changes in nCBF (r = 0.388, p = 0.034) and negatively with carotid β-stiffness index (r = -0.418, p = 0.007) and CBF pulsatility (r = -0.400, p = 0.014). Decreases in carotid β-stiffness were associated with increases in cerebral perfusion (r = -0.494, p = 0.003). AET effects on cognitive performance were minimal compared with SAT.

AET reduced central arterial stiffness and increased CBF which may precede its effects on neurocognitive function in patients with MCI.

AET reduced central arterial stiffness and increased CBF which may precede its effects on neurocognitive function in patients with MCI.

White matter hyperintensities (WMH) on MRI have been reported to increase the risk of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD). However, effects of the progression of WMH on the cognition of patients with MCI remains unclear to date.

To investigate the association between WMH progression and cognitive decline in amnestic MCI patients.

Thirty-eight subjects with amnestic MCI were analyzed prospectively every year for 2 years. Fourteen MCI subjects dropped out on the final visit, and therefore 24 subjects with MCI were analyzed for the entire duration. The volumes of periventricular hyperintensities (PVH) and deep WMH (DWMH) were measured on T2 FLAIR using the 3D-slicer. The associations between PVH/DWMH progression and cognitive decline were investigated.

An increase in DWMH volume significantly correlated with changes in Mini-Mental State Examination and category verbal fluency scores, whereas an increase in PVH volume did not correlate with changes in any item.

DWMH progression was closely associated with a decline in frontal lobe function and semantic memory, suggesting that WMH progression might affect some AD pathophysiologies in amnestic MCI patients.

DWMH progression was closely associated with a decline in frontal lobe function and semantic memory, suggesting that WMH progression might affect some AD pathophysiologies in amnestic MCI patients.

Social isolation and social interaction have been suggested to be associated with Alzheimer's disease. However, the causality cannot be unambiguously assessed as traditional epidemiological methods are easily subject to unmeasured confounders and potential bias.

To examine bidirectional relationships between social isolation, social interaction, and Alzheimer's disease using Mendelian randomization method for assessing potential causal inference.

This bidirectional two-sample Mendelian randomization study used independent genetic variants associated with social isolation and social interaction (n = 302,567-487,647), and Alzheimer's disease (n = 455,258). MR analyses were performed using the inverse-variance-weighted (IVW) as the main MR analytical method to estimate the causal effect. For sensitivity analyses, we applied weighted median, MR Egger to further assess the credibility of the causal effect.

Of the five types of social engagement examined in our study, only one showed evidence of an association with the risk of Alzheimer's disease. Attendance at a gym or sports club (IVW OR per SD change 0.670; 95% CI 0.463-0.970; p = 0.034) was inversely associated with the risk of Alzheimer's disease. We also found that AD may reduce the attendance at religious group (IVW OR per SD change 1.017; 95% CI 1.005-1.030; p = 0.004).

This study suggests that regular attendance at a gym or sports club is causally associated with reduced risk of Alzheimer's disease. Further studies are warranted to elucidate potential mechanisms.

This study suggests that regular attendance at a gym or sports club is causally associated with reduced risk of Alzheimer's disease. Further studies are warranted to elucidate potential mechanisms.