Longitudinal grey and white matter changes in frontotemporal dementia and Alzheimer's disease

Behavioural variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) dementia are characterised by progressive brain atrophy. Longitudinal MRI volumetry may help to characterise ongoing structural degeneration and support the differential diagnosis of dementia subtypes. Automated, observer-independent atlas-based MRI volumetry was applied to analyse 102 MRI data sets from 15 bvFTD, 14 AD, and 10 healthy elderly control participants with consecutive scans over at least 12 months. Anatomically defined targets were chosen a priori as brain structures of interest. Groups were compared regarding volumes at clinic presentation and annual change rates. Baseline volumes, especially of grey matter compartments, were significantly reduced in bvFTD and AD patients. Grey matter volumes of the caudate and the gyrus rectus were significantly smaller in bvFTD than AD. The bvFTD group could be separated from AD on the basis of caudate volume with high accuracy (79% cases correct). Annual volume decline was markedly larger in bvFTD and AD than controls, predominantly in white matter of temporal structures. Decline in grey matter volume of the lateral orbitofrontal gyrus separated bvFTD from AD and controls. Automated longitudinal MRI volumetry discriminates bvFTD from AD. In particular, greater reduction of orbitofrontal grey matter and temporal white matter structures after 12 months is indicative of bvFTD

Insights into pathophysiology, biomarkers, and therapeutics in tauopathies: Proceedings of the Tau2024 Global Conference

Recent years have seen major advances in tau‐associated brain disorders through interdisciplinary research spanning molecular biology, neuroimaging, clinical trials, and therapeutic development. The Tau2024 Global Conference, hosted by the Alzheimer's Association, CurePSP, and Rainwater Charitable Foundation, showcased these efforts by bringing together researchers and experts worldwide to discuss the latest advancements in tau research. The conference aimed to attract talent and funding to study tauopathies, particularly among early‐career researchers, and to foster interdisciplinary alignment and collaboration around challenges in tau research. In this manuscript, we summarize proceedings of the Tau2024 Global Conference, covering a wide range of topics, including lived experiences of individuals with genetic forms of tauopathies, global perspectives on tauopathies, and molecular mechanisms, brain microenvironments, biomarker developments, clinical trials, and therapeutic approaches to tauopathies. Through international, collaborative efforts, innovative research, and a commitment to inclusivity, researchers worldwide have demonstrated transformative breakthroughs toward diagnosing, treating, and, ultimately, preventing tau‐related diseases. Highlights: The Tau2024 Global Conference presented updates and advances in tau research. Blood‐based biomarkers offer specificity and longitudinal monitoring capabilities. There are a range of targetable mechanisms in the cascade of pathogenesis. International collaboration is vital to address disparities in tauopathies

Cytoplasmic Accumulation and Aggregation of TDP-43 upon Proteasome Inhibition in Cultured Neurons

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are characterized by intraneuronal deposition of the nuclear TAR DNA-binding protein 43 (TDP-43) caused by unknown mechanisms. Here, we studied TDP-43 in primary neurons under different stress conditions and found that only proteasome inhibition by MG-132 or lactacystin could induce significant cytoplasmic accumulation of TDP-43, a histopathological hallmark in disease. This cytoplasmic accumulation was accompanied by phosphorylation, ubiquitination and aggregation of TDP-43, recapitulating major features of disease. Proteasome inhibition produced similar effects in both hippocampal and cortical neurons, as well as in immortalized motor neurons. To determine the contribution of TDP-43 to cell death, we reduced TDP-43 expression using small interfering RNA (siRNA), and found that reduced levels of TDP-43 dose-dependently rendered neurons more vulnerable to MG-132. Taken together, our data suggests a role for the proteasome in subcellular localization of TDP-43, and possibly in disease