Thalamic nuclei in frontotemporal dementia: Mediodorsal nucleus involvement is universal but pulvinar atrophy is unique to C9orf72

Thalamic atrophy is a common feature across all forms of FTD but little is known about specific nuclei involvement. We aimed to investigate in vivo atrophy of the thalamic nuclei across the FTD spectrum. A cohort of 402 FTD patients (age: mean(SD) 64.3(8.2) years; disease duration: 4.8(2.8) years) was compared with 104 age‐matched controls (age: 62.5(10.4) years), using an automated segmentation of T1‐weighted MRIs to extract volumes of 14 thalamic nuclei. Stratification was performed by clinical diagnosis (180 behavioural variant FTD (bvFTD), 85 semantic variant primary progressive aphasia (svPPA), 114 nonfluent variant PPA (nfvPPA), 15 PPA not otherwise specified (PPA‐NOS), and 8 with associated motor neurone disease (FTD‐MND), genetic diagnosis (27 MAPT, 28 C9orf72, 18 GRN), and pathological confirmation (37 tauopathy, 38 TDP‐43opathy, 4 FUSopathy). The mediodorsal nucleus (MD) was the only nucleus affected in all FTD subgroups (16–33% smaller than controls). The laterodorsal nucleus was also particularly affected in genetic cases (28–38%), TDP‐43 type A (47%), tau‐CBD (44%), and FTD‐MND (53%). The pulvinar was affected only in the C9orf72 group (16%). Both the lateral and medial geniculate nuclei were also affected in the genetic cases (10–20%), particularly the LGN in C9orf72 expansion carriers. Use of individual thalamic nuclei volumes provided higher accuracy in discriminating between FTD groups than the whole thalamic volume. The MD is the only structure affected across all FTD groups. Differential involvement of the thalamic nuclei among FTD forms is seen, with a unique pattern of atrophy in the pulvinar in C9orf72 expansion carriers

A Jacket-Frame Mounted Oscillating Water Column with a Variable Aperture Skirt

During the last decade jacket-frames have emerged as the main kind of substructure for bottom-mounted offshore wind farms in intermediate water depths. With the offshore wind industry moving towards deeper waters, the predominance of jacket-frames is expected to increase in future years. Multipurpose platforms combining wind and wave energy are proposed as an innovative solution to enhance the sustainability of offshore wind energy. In this research, a multipurpose platform is investigated with a novel feature in its oscillating water column (OWC) wave energy converter—a variable geometry skirt. A comprehensive physical modelling campaign was carried out using a 1:50 scale model. The performance of the OWC and its interaction with the wave field were investigated under four different skirt aperture angles. It was found that the skirt aperture angle plays a significant role in the capture-width ratio and the pneumatic mean power of the OWC. The best performance was obtained with a skirt aperture angle of 140 deg. More generally, these results prove that the variable-geometry skirt is a promising innovation for hybrid wave-wind systems mounted on jacket-frame substructures

Amygdala subnuclei are differentially affected in the different genetic and pathological forms of frontotemporal dementia

Introduction Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder with multiple genetic and pathological causes. It is characterized by both cortical and subcortical atrophies, with previous studies showing early involvement of the amygdala. However, no prior study has specifically investigated the atrophy of different subnuclei of the amygdala. Methods Using an automated segmentation tool for T1-weighted volumetric magnetic resonance imaging, we investigated amygdalar subnuclei (AS) involvement in a cohort of 132 patients with genetic or pathologically confirmed FTD (age: mean = 61 years (standard deviation = 8); disease duration: 5 (3) years) compared with 107 age-matched controls. Results AS were affected in all genetic and pathological forms of FTD. MAPT mutations/FTDP-17, Pick's disease, and transactive response DNA binding protein 43 kDa type C were the forms with the smallest amygdala (35%–50% smaller than controls in the most affected hemisphere, P < .0005). In most FTD groups, medial subnuclei (particularly the superficial, accessory basal and basal/paralaminar subnuclei) tended to be affected more than the lateral subnuclei, except for the progressive supranuclear palsy group, in which the corticoamygdaloid transition area was the least-affected area. Discussion Differential involvement of the AS was seen in the different genetic and pathological forms of FTD. In general, the most affected subnuclei were the superficial, accessory basal and basal/paralaminar subnuclei, which form part of a network of regions that control reward and emotion regulation, functions known to be particularly affected in FTD

Automated Brainstem Segmentation Detects Differential Involvement in Atypical Parkinsonian Syndromes

OBJECTIVE: Brainstem segmentation has been useful in identifying potential imaging biomarkers for diagnosis and progression in atypical parkinsonian syndromes (APS). However, the majority of work has been performed using manual segmentation, which is time consuming for large cohorts. METHODS: We investigated brainstem involvement in APS using an automated method. We measured the volume of the medulla, pons, superior cerebellar peduncle (SCP) and midbrain from T1-weighted MRIs in 67 patients and 42 controls. Diagnoses were corticobasal syndrome (CBS, n = 14), multiple system atrophy (MSA, n = 16: 8 with parkinsonian syndrome, MSA-P; 8 with cerebellar syndrome, MSA-C), progressive supranuclear palsy with a Richardson’s syndrome (PSP-RS, n = 12), variant PSP (n = 18), and APS not otherwise specified (APS-NOS, n = 7). RESULTS: All brainstem regions were smaller in MSA-C (19–42% volume difference, p < 0.0005) and in both PSP groups (18–33%, p < 0.0005) than in controls. MSA-P showed lower volumes in all regions except the SCP (15–26%, p < 0.0005). The most affected region in MSA-C and MSA-P was the pons (42% and 26%, respectively), while the most affected regions in both the PSP-RS and variant PSP groups were the SCP (33% and 23%, respectively) and midbrain (26% and 24%, respectively). The brainstem was less affected in CBS, but nonetheless, the pons (14%, p < 0.0005), midbrain (14%, p < 0.0005) and medulla (10%, p = 0.001) were significantly smaller in CBS than in controls. The brainstem was unaffected in APS-NOS. CONCLUSION: Automated methods can accurately quantify the involvement of brainstem structures in APS. This will be important in future trials with large patient numbers where manual segmentation is unfeasible

In vivo hypothalamic regional volumetry across the frontotemporal dementia spectrum

Appendix A. Supplementary data: The following are the Supplementary data to this article: Supplementary data 1. Available at: https://ars.els-cdn.com/content/image/1-s2.0-S2213158222001498-mmc1.docx (Word document (15MB)).Copyright © 2022 The Author(s). Background: Frontotemporal dementia (FTD) is a spectrum of diseases characterised by language, behavioural and motor symptoms. Among the different subcortical regions implicated in the FTD symptomatology, the hypothalamus regulates various bodily functions, including eating behaviours which are commonly present across the FTD spectrum. The pattern of specific hypothalamic involvement across the clinical, pathological, and genetic forms of FTD has yet to be fully investigated, and its possible associations with abnormal eating behaviours have yet to be fully explored. Methods: Using an automated segmentation tool for volumetric T1-weighted MR images, we measured hypothalamic regional volumes in a cohort of 439 patients with FTD (197 behavioural variant FTD [bvFTD]; 7 FTD with associated motor neurone disease [FTD-MND]; 99 semantic variant primary progressive aphasia [svPPA]; 117 non-fluent variant PPA [nfvPPA]; 19 PPA not otherwise specified [PPA-NOS]) and 118 age-matched controls. We compared volumes across the clinical, genetic (29 MAPT, 32 C9orf72, 23 GRN), and pathological diagnoses (61 tauopathy, 40 TDP-43opathy, 4 FUSopathy). We correlated the volumes with presence of abnormal eating behaviours assessed with the revised version of the Cambridge Behavioural Inventory (CBI-R). Results: On average, FTD patients showed 14% smaller hypothalamic volumes than controls. The groups with the smallest hypothalamic regions were FTD-MND (20%), MAPT (25%) and FUS (33%), with differences mainly localised in the anterior and posterior regions. The inferior tuberal region was only significantly smaller in tauopathies (MAPT and Pick’s disease) and in TDP-43 type C compared to controls and was the only regions that did not correlate with eating symptoms. PPA-NOS and nfvPPA were the groups with the least frequent eating behaviours and the least hypothalamic involvement. Conclusions: Abnormal hypothalamic volumes are present in all the FTD forms, but different hypothalamic regions might play a different role in the development of abnormal eating behavioural and metabolic symptoms. These findings might therefore help in the identification of different underlying pathological mechanisms, suggesting the potential use of hypothalamic imaging biomarkers and the research of potential therapeutic targets within the hypothalamic neuropeptides.The Dementia Research Centre is supported by Alzheimer's Research UK, Alzheimer's Society, Brain Research UK, and The Wolfson Foundation. This work was supported by the NIHR UCL/H Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility, and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. JDR is supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). This work was also supported by the MRC UK GENFI grant (MR/M023664/1), the Bluefield Project and the JPND GENFI-PROX grant (2019-02248). MB is supported by a Fellowship award from the Alzheimer’s Society, UK (AS-JF-19a-004-517). MB’s work was also supported by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. MB acknowledges the support of NVIDIA Corporation with the donation of the Titan V GPU used for part of the analyses in this research. JEI is supported by the European Research Council (Starting Grant 677697, project BUNGEE-TOOLS), Alzheimer’s Research UK (ARUK-IRG2019A003) and the NIH (1RF1MH123195-01 and 1R01AG070988). JDW receives grant support from the Alzheimer's Society, Alzheimer's Research UK, the NIHR UCL/UCLH Biomedical Research Centre and a Frontotemporal Dementia Research Studentship in Memory of David Blechner (funded through The National Brain Appeal)

Activation of mGluR5 Induces Rapid and Long-Lasting Protein Kinase D Phosphorylation in Hippocampal Neurons

Metabotropic glutamate receptors (mGluRs), including mGluR5, play a central role in regulating the strength and plasticity of synaptic connections in the brain. However, the signaling pathways that connect mGluRs to their downstream effectors are not yet fully understood. Here, we report that stimulation of mGluR5 in hippocampal cultures and slices results in phosphorylation of protein kinase D (PKD) at the autophosphorylation site Ser-916. This phosphorylation event occurs within 30 s of stimulation, persists for at least 24 h, and is dependent on activation of phospholipase C and protein kinase C. Our data suggest that activation of PKD may represent a novel signaling pathway linking mGluR5 to its downstream targets. These findings have important implications for the study of the molecular mechanisms underlying mGluR-dependent synaptic plasticity.Howard Hughes Medical InstituteFRAXA Research FoundationNational Institute of Mental Health (U.S.)Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.

New Insights into the Lake Chad Basin Population Structure Revealed by High-Throughput Genotyping of Mitochondrial DNA Coding SNPs

BACKGROUND: Located in the Sudan belt, the Chad Basin forms a remarkable ecosystem, where several unique agricultural and pastoral techniques have been developed. Both from an archaeological and a genetic point of view, this region has been interpreted to be the center of a bidirectional corridor connecting West and East Africa, as well as a meeting point for populations coming from North Africa through the Saharan desert. METHODOLOGY/PRINCIPAL FINDINGS: Samples from twelve ethnic groups from the Chad Basin (n = 542) have been high-throughput genotyped for 230 coding region mitochondrial DNA (mtDNA) Single Nucleotide Polymorphisms (mtSNPs) using Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight (MALDI-TOF) mass spectrometry. This set of mtSNPs allowed for much better phylogenetic resolution than previous studies of this geographic region, enabling new insights into its population history. Notable haplogroup (hg) heterogeneity has been observed in the Chad Basin mirroring the different demographic histories of these ethnic groups. As estimated using a Bayesian framework, nomadic populations showed negative growth which was not always correlated to their estimated effective population sizes. Nomads also showed lower diversity values than sedentary groups. CONCLUSIONS/SIGNIFICANCE: Compared to sedentary population, nomads showed signals of stronger genetic drift occurring in their ancestral populations. These populations, however, retained more haplotype diversity in their hypervariable segments I (HVS-I), but not their mtSNPs, suggesting a more ancestral ethnogenesis. Whereas the nomadic population showed a higher Mediterranean influence signaled mainly by sub-lineages of M1, R0, U6, and U5, the other populations showed a more consistent sub-Saharan pattern. Although lifestyle may have an influence on diversity patterns and hg composition, analysis of molecular variance has not identified these differences. The present study indicates that analysis of mtSNPs at high resolution could be a fast and extensive approach for screening variation in population studies where labor-intensive techniques such as entire genome sequencing remain unfeasible