Hypothalamic atrophy in primary lateral sclerosis, assessed by convolutional neural network-based automatic segmentation.

Primary lateral sclerosis (PLS) is a motor neuron disease (MND) which mainly affects upper motor neurons. Within the MND spectrum, PLS is much more slowly progressive than amyotrophic laterals sclerosis (ALS). `Classical` ALS is characterized by catabolism and abnormal energy metabolism preceding onset of motor symptoms, and previous studies indicated that the disease progression of ALS involves hypothalamic atrophy.

Precuneus activity during retrieval is positively associated with amyloid burden in cognitively normal older carriers.

The precuneus is a site of early amyloid-beta (Aβ) accumulation. Previous cross-sectional studies reported increased precuneus fMRI activity in older adults with mild cognitive deficits or elevated Aβ. However, longitudinal studies in early Alzheimer's disease (AD) are lacking and the relationship to the Apolipoprotein-E () genotype is unclear.

Neurocan regulates axon initial segment organization and neuronal activity.

The neural extracellular matrix (ECM) accumulates in the form of perineuronal nets (PNNs), particularly around fast-spiking GABAergic interneurons in the cortex and hippocampus, but also around synapses and in association with the axon initial segments (AIS) and nodes of Ranvier. Increasing evidence highlights the role of Neurocan (Ncan), a brain-specific component of ECM, in the pathophysiology of neuropsychiatric disorders like bipolar disorder and schizophrenia. Ncan localizes at PNNs, perisynaptically, and at the nodes of Ranvier and the AIS, highlighting its potential role in regulating axonal excitability.

Cross-sectional study on the impact of adverse childhood experiences on psychological distress in patients with an implantable cardioverter-defibrillator.

Objective: Previous studies implied detrimental effects of adverse childhood experiences (ACE) on cardiovascular disease and mental health. Still, data on the influence of ACE on psychological distress in patients with an implantable cardioverter-defibrillator (ICD) are lacking.

Methods: We prospectively recruited 423 patients with an ICD.

Biomarkers.

Background: Speech abnormalities are increasingly recognized as a manifestation of cognitive deficits in Alzheimer's disease (AD) and its preclinical and prodromal stages. Here, we investigated whether MRI measures of brain atrophy, specifically in the basal forebrain and cortical language areas, can predict cognitive decline and speech difficulties in older adults within the AD spectrum.

Method: The ongoing Prospect-AD study aims to develop an algorithm to automatically identify speech biomarkers in individuals with early signs of AD.

Biomarkers.

Background: There is a strong link between tau and progression of Alzheimer's disease (AD), necessitating an understanding of tau spreading mechanisms. Prior research, predominantly in typical AD, suggested that tau propagates from epicenters (regions with earliest tau) to functionally connected regions. However, given the constrained spatial heterogeneity of tau in typical AD, validating this connectivity-based tau spreading model in AD variants with distinct tau deposition patterns is crucial.

Biomarkers.

Background: Subjective cognitive decline (SCD), in the absence of objective cognitive impairment, may be the first symptomatic manifestation of Alzheimer's disease (AD). Previous studies have suggested that its combination with amyloid-positivity (Aβ+) may represent stage 2 AD, and is associated with a higher risk of future cognitive decline. Here, we aim to (1) confirm this using the plasma Aβ42/40 ratio, and (2) test whether the addition of plasma phospho-tau181 (ptau, a marker of Aβ and tau pathology) could help refine the prediction of future cognitive decline in SCD patients.

Biomarkers.

Background: With a global ageing population, there is an increasing demand for fast and reliable early diagnosis of individuals. Convolutional neural networks (CNNs) have an immense potential in assisting clinicians in diagnosing dementia. Regional atrophy patterns, which are visible in T1-weighted MRI scans, have been consistently identified by the CNNs with high accuracy.

Biomarkers.

Background: Alzheimer's disease (AD) is associated with substantial synaptic loss potentially due to synaptotoxicity of fibrillar tau, but the association between tau deposition and synaptic loss remains unclear. Based on previous observations that pathology spreads preferentially between closely connected regions, we tested in the current multi-PET tracer study the hypothesis that synaptic loss propagates to regions closely connected to epicenters of high tau accumulation.

Method: We assessed 18F-SynVesT-1 PET as a measure of synaptic vesicle glycoprotein 2A (SV2A), and 18F-flortaucipir tau-PET in fourty-five 18F-florbetapir-PET-positive (Aβ+) subjects with MCI or AD dementia, and 23 cognitivly normal (CN) Aβ- controls.

Biomarkers.

Background: Differences in task-fMRI activation have recently been found to be related to neuropathological hallmarks of AD. However, the evolution of fMRI-based activation throughout AD disease progression and its relationship with other biomarkers remains elusive. Applying a disease progression model (DPM) to a multicentric cohort with up to four annual task-fMRI visits, we hope to provide a deeper insight into these relationships.

Biomarkers.

Background: The posterior-medial network is crucial for episodic memory. However, the medial temporal lobe (MTL) and posteromedial cortex (PMC) regions are vulnerable to aging and early Alzheimer's disease (AD). Both processes might elicit distinct early functional connectivity (FC) changes which could be detrimental or protective/ compensatory regarding cognition.

Biomarkers.

Background: While some memory decline in old age is "normal", there are some older individuals with maintained high cognitive performance. Using a multimodal approach including neuroimaging, fitness, genetic and questionnaire data (Figure 1A), we aimed to identify factors that are related to successful cognitive aging and whether these differ between sexes.

Method: We analyzed 165 cognitively normal older adults age ≥ 60 years from an ongoing study (SFB1436) (age=71±8years, 43% female).

Biomarkers.

Background: To date, all computerised perivascular spaces (PVS) quantification methods require case-wise, imaging modality, or study-specific parameter adjustments, and suffer from generalisability problems in clinical settings, and misdetection of other cerebral small vessel disease (CSVD) markers. We propose a deep learning-based PVS detection method to overcome these issues. We compare our proposal on magnetic resonance imaging data of CSVD participants against the performance of the Frangi filter.

Biomarkers.

Background: In Alzheimer's disease (AD), cortical tau aggregation is a strong predictor of cortical brain atrophy as shown by MRI and PET studies, particularly driving the degeneration of neuronal somata in the grey matter. However, tau's physiological role is to stabilize microtubules within axons in the brain's white matter (WM) pathways. Therefore, tau's white-to-grey-matter translocation and aggregation in neurofibrillary tangles close to neuronal somata may induce WM degeneration through destabilization of axonal microtubule integrity.

Biomarkers.

Background: Memory clinic patients are a heterogeneous population representing various aetiologies of pathological aging. It is unknown if divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease (AD) patients, are prevalent and clinically meaningful in this group of older adults.

Method: To uncover atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to structural MRI data from 813 participants (mean ± SD age = 70.

Biomarkers.

Background: Training studies report beneficial effects of physical (PP) on cognitive performance (COG) in older adults, but are often accompanied by potentially biased parameters, conclusions, and lack of directionality. To address these issues, we used a dynamic Bayesian approach to analyse the dynamic session-to-session change and coupling of PP and COG over time.

Methods: We used two studies (N = 17 each): Study 1 contained 24-weeks (72 sessions) of training of older adults with suspected Alzheimer's disease (AD).

Biomarkers.

Background: For over three decades, the concomitance of cortical neurodegeneration and white matter hyperintensities (WMH) has sparked discussion about their coupled temporal dynamics (Garnier-Crussard et al. 2023). Longitudinal evidence supporting this hypothesis remains nonetheless scarce (Ter Telgte et al.

Biomarkers.

Background: Perivascular spaces (PVS) can become large enough to be visible in magnetic resonance imaging (MRI). The exact aetiology of PVS enlargement in humans remains, however, elusive and under continuous debate [1-5]. Here, we tracked PVS volumes longitudinally over three years in 525 individuals along AD syndromal cognitive stages, namely cognitively unimpaired (CU), mild cognitive impairment (MCI), and Alzheimer's disease (AD), to pinpoint conditions related to PVS enlargement.

Biomarkers.

Background: In Alzheimer's disease, Aβ triggers tau spreading which drives neurodegeneration and cognitive decline. However, the mechanistic link between Aβ and tau remains unclear, which hinders therapeutic efforts to attenuate Aβ-related tau accumulation. Preclinical research could show that tau spreads across connected neurons in an activity-dependent manner, and Aβ was shown to trigger neuronal hyperactivity and hyperconnectivity.

Biomarkers.

Background: Alzheimer disease (AD) related cognitive decline occurs at relatively young ages in individuals with Down syndrome (DS, early-mid 50s) and in those with autosomal dominant mutations (ADAD, 40-50s). Both groups show similar patterns of amyloid accumulation. We examined if brain volumes are similarly affected by AD pathology in individuals with DS and ADAD.

Biomarkers.

Background: Increased stress, a proposed risk factor for Alzheimer's disease (AD), is associated with increased brain and cognitive vulnerabilities in older populations, which may be different in women and men.

Objective: To examine cross-sectional associations between circulating stress hormones (epinephrine, norepinephrine, cortisol, dehydroepiandrosterone sulfate (DHEAS), and DHEAS/cortisol ratio) and multimodal measures of brain health and cognition sensitive to AD.

Method: 132 cognitively unimpaired older participants without clinical depression (age = 74.

Biomarkers.

Background: Amyloid PET imaging is an established diagnostic tool for Alzheimer's disease, but its successful integration into clinical practice requires a comprehensive understanding of its impact on patients and the healthcare system. In 2022, the coverage with evidence development (CED) ENABLE study has been approved by the German Federal Joint Committee (trial registration: DRKS00030839). The study is scheduled to start in early 2024.

Biomarkers.

Background: Co-pathology between Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB) remains poorly understood but is relevant for trial design. We aimed to compare CSF markers of amyloid, tau, and neurodegeneration (ATN) and α-synuclein between AD, PD, DLB and controls, and investigate the influence of demographical, genetic, and clinical factors on amyloid positivity.

Method: As part of the EPND study, we included 337 individuals with AD, PD, DLB and controls from 6 centers.

Biomarkers.

Background: Understanding modulators of Alzheimer's disease's (AD) progression is crucial for determining optimal treatment windows and targets. Apolipoprotein E ε4 (ApoE4), i.e.

Biomarkers.

Background: Lewy body pathology consisting of aggregated alpha-Synuclein (a-Syn) is the hallmark pathology in Parkinson's disease, yet a-Syn aggregates are also commonly observed post-mortem as a co-pathology in Alzheimer's disease (AD) patients. Preclinical research has shown that a-Syn can amplify Ab-associated tau seeding and aggregation, hence a-Syn co-pathology may contribute to the Ab-induced progression of tau pathology in AD. To address this, we combined a novel CSF-based RT-QuIC seed-amplification assay to determine a-Syn positivity, with PET-neuroimaging in a large patient cohort ranging from cognitively normal to dementia, to determine whether a-Syn co-pathology accelerates Ab-driven tau accumulation.