Amyloid and tau-PET in early-onset AD: Baseline data from the Longitudinal Early-onset Alzheimer's Disease Study (LEADS).

INTRODUCTION: We aimed to describe baseline amyloid-beta (Aß) and tau-positron emission tomograrphy (PET) from Longitudinal Early-onset Alzheimer's Disease Study (LEADS), a prospective multi-site observational study of sporadic early-onset Alzheimer's disease (EOAD). METHODS: We analyzed baseline [18F]Florbetaben (Aß) and [18F]Flortaucipir (tau)-PET from cognitively impaired participants with a clinical diagnosis of mild cognitive impairment (MCI) or AD dementia aged < 65 years. Florbetaben scans were used to distinguish cognitively impaired participants with EOAD (Aß+) from EOnonAD (Aß-) based on the combination of visual read by expert reader and image quantification. RESULTS: 243/321 (75.7%) of participants were assigned to the EOAD group based on amyloid-PET; 231 (95.1%) of them were tau-PET positive (A+T+). Tau-PET signal was elevated across cortical regions with a parietal-predominant pattern, and higher burden was observed in younger and female EOAD participants. DISCUSSION: LEADS data emphasizes the importance of biomarkers to enhance diagnostic accuracy in EOAD. The advanced tau-PET binding at baseline might have implications for therapeutic strategies in patients with EOAD. HIGHLIGHTS: 72% of patients with clinical EOAD were positive on both amyloid- and tau-PET. Amyloid-positive patients with EOAD had high tau-PET signal across cortical regions. In EOAD, tau-PET mediated the relationship between amyloid-PET and MMSE. Among EOAD patients, younger onset and female sex were associated with higher tau-PET.

Preventing post-stroke dementia. The MARCH Trial. Protocol and statistical analysis plan of a randomized clinical trial testing the safety and efficacy of Maraviroc in post-stroke cognitive impairment.

Background: Current evidence suggest that 25%-33% of stroke-survivors develop post-stroke cognitive impairment (PSCI). The licensed drug Maraviroc, a CCR5-antagonist, is postulated to act via a neuroprotective mechanism that may offer the potential of preventing progression to vascular dementia. Our hypothesis: Maraviroc may have the potential to augment learning skills and cognitive performance by affecting synaptic plasticity, along with neuro-inflammatory modulation in patients with cerebral small vessel disease (SVD) and PSCI. Design: MARCH is a multi-center, double-blind randomized-control Phase-II trial of Maraviroc 150 or 600 mg/day versus placebo for 12-months in five stroke centers in Israel. Included are patients diagnosed with recent (1-24 months) subcortical stroke who experience mild PSCI and have evidence of white matter lesions and SVD on neuroimaging. Outcomes: Primary outcomes: 1. Change in cognitive scores. 2. Drug related adverse events. Secondary outcomes: change in functional and affective scores, MRI-derived measures, inflammatory markers, carotid atherosclerosis, cerebrospinal-fluid biomarkers in a sub-study. A sample size of 60 in each treatment group and 30 in the placebo group (total - 150 participants) provides 80% power between the treatment and the placebo groups. Conclusions: The results of this work could lead to a novel, readily available, therapeutic avenue to reduce PSCI, and possibly other pathologies. This study will test safety and effectiveness of Maraviroc in limiting cognitive deterioration and/or post stroke cognitive impairment in patients with cerebral small vessel disease. Schedule: First-patient first-visit was May 2021. Recruitment to complete in 2023, follow-up to complete in 2024.

Memory impairment and Alzheimer's disease pathology in individuals with MCI who underestimate or overestimate their decline.

OBJECTIVES: The aim of this study was to examine whether the discrepancy between participant and informant estimation of memory decline can predict MCI prognosis. METHODS: Analyses involved data from individuals with MCI enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) who filled the Everyday Cognition questionnaire. Participants who underestimated (N = 112) and overestimated (N = 157) their memory decline were compared on memory tasks, brain volume, and cerebrospinal markers, at study entry and after 24 months. RESULTS: Individuals who underestimated their memory decline performed more poorly on memory tests, had smaller hippocampus volume, and greater Alzheimer's disease pathology than did individuals who overestimated their cognitive decline. Longitudinal comparisons demonstrated that individuals who underestimated their decline deteriorated more significantly in memory and in brain measures. CONCLUSIONS: Underestimation of memory decline should raise clinicians' suspicion of the existence of AD pathology in individuals with MCI.

Achilles tendons hypertrophy in response to high loading training.

BACKGROUND: Whether the human Achilles tendon undergoes hypertrophic changes as measured by an increase in cross-sectional area, in response to endurance training exercise remains in question. We investigated the hypothesis that transition from civilian life through 6 months of elite infantry training would induce adaptive Achilles tendon hypertrophy. METHODS: Seventy-two new elite infantry recruits had the cross-sectional area of their Achilles tendons measured at a point 2.5 cm proximal to the Achilles insertion by ultrasound before beginning elite infantry training. Measurements were repeated by the same ultrasonographer for those recruits who were still in the training program at 6 months. Prior to beginning the study the intraobserver reliability of the ultrasonographer's Achilles tendon measurements was calculated (intraclass correlation coefficient = .96). Fifty-five recruits completed 6 months of training. RESULTS: The mean cross-sectional area of their right Achilles tendon increased from 47.0 ± 11.2 to 50.2 ± 9.6 mm(2) (P = .037) and the left Achilles tendon from 47.2 ± 8.9 to 51.1 ± 8.3 mm(2) (P = .013). The change in cross-sectional area did not correlate with subject height, weight, prior sport history, or jumping and running abilities. CONCLUSIONS: An abrupt stimulus of 6 months of elite infantry training was adequate to induce hypertrophic changes in the Achilles tendon. This is the first human prospective study showing an increase in the Achilles tendon cross-sectional area in response to rigorous endurance type training. The finding supports the hypothesis that the Achilles tendon in response to sufficiently high and sustained loading can remodel its morphological properties and thereby strengthen itself. LEVEL OF EVIDENCE: Level II, etiology study.