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Aims: Histological analysis of brain tissue samples provides valuable information about the pathological processes leading to common neurodegenerative disorders. In this context, the development of novel high‐resolution imaging approaches is a current challenge in neuroscience. Methods: To this end, we used a recent super‐resolution imaging technique called STochastic Optical Reconstruction Microscopy (STORM) to analyse human brain sections. We combined STORM cell imaging protocols with neuropathological techniques to image cryopreserved brain samples from control subjects and patients with neurodegenerative diseases. Results: This approach allowed us to perform 2D‐, 3D‐ and two‐colour‐STORM in neocortex, white matter and brainstem samples. STORM proved to be particularly effective at visualizing the organization of dense protein inclusions and we imaged with a <50 nm resolution pathological aggregates within the central nervous system of patients with Alzheimer's disease, Parkinson's disease, Lewy body dementia and fronto‐temporal lobar degeneration. Aggregated Aβ branches appeared reticulated and cross‐linked in the extracellular matrix, with widths from 60 to 240 nm. Intraneuronal Tau and TDP‐43 inclusions were denser, with a honeycomb pattern in the soma and a filamentous organization in the axons. Finally, STORM imaging of α‐synuclein pathology revealed the internal organization of Lewy bodies that could not be observed by conventional fluorescence microscopy. Conclusions: STORM imaging of human brain samples opens further gates to a more comprehensive understanding of common neurological disorders. The convenience of this technique should open a straightforward extension of its application for super‐resolution imaging of the human brain, with promising avenues to current challenges in neuroscience. [ABSTRACT FROM AUTHOR]

Abstract Background The ganglioside-induced differentiation-associated protein 1 gene (GDAP1), which is involved in the Charcot-Marie-Tooth disease (CMT), the most commonly inherited peripheral neuropathy, encodes a protein anchored to the mitochondrial outer membrane. The phenotypic presentations of patients carrying GDAP1 mutations are heterogeneous, making it difficult to determine genotype-phenotype correlations, since the majority of the mutations have been found in only a few unrelated patients. Locus-specific databases (LSDB) established in the framework of the Human Variome Project provide powerful tools for the investigation of such rare diseases. Methods and Results We report the development of a publicly accessible LSDB for the GDAP1 gene. The GDAP1 LSDB has adopted the Leiden Open-source Variation Database (LOVD) software platform. This database, which now contains 57 unique variants reported in 179 cases of CMT, offers a detailed description of the molecular, clinical and electrophysiological data of the patients. The usefulness of the GDAP1 database is illustrated by the finding that GDAP1 mutations lead to primary axonal damage in CMT, with secondary demyelination in the more severe cases of the disease. Conclusion Findings of this nature should lead to a better understanding of the pathophysiology of CMT. Finally, the GDAP1 LSDB, which is part of the mitodyn.org portal of databases of genes incriminated in disorders involving mitochondrial dynamics and bioenergetics, should yield new insights into mitochondrial diseases.

Abstract Background Leber's hereditary optic neuropathy (LHON) is caused by mutations in the complex I subunits of the respiratory chain. Although patients have been treated with idebenone since 1992, the efficacy of the drug is still a matter of debate. Methods We evaluated the effect of idebenone in fibroblasts from LHON patients using enzymatic and polarographic measurements. Results Complex I activity was 42% greater in treated fibroblasts compared to controls (p = 0.002). Despite this complex I activity improvement, the effects on mitochondrial respiration were contradictory, leading to impairment in some cases and stimulation in others. Conclusion These results indicate that idebenone is able to compensate the complex I deficiency in LHON patient cells with variable effects on respiration, indicating that the patients might not be equally likely to benefit from the treatment.

Caffeine consumption outcomes on Amyotrophic Lateral Sclerosis (ALS) including progression, survival and cognition remain poorly defined and may depend on its metabolization influenced by genetic variants. 378 ALS patients with a precise evaluation of their regular caffeine consumption were monitored as part of a prospective multicenter study. Demographic, clinical characteristics, functional disability as measured with revised ALS Functional Rating Scale (ALSFRS-R), cognitive deficits measured using Edinburgh Cognitive and Behavioural ALS Screen (ECAS), survival and riluzole treatment were recorded. 282 patients were genotyped for six single nucleotide polymorphisms tagging different genes involved in caffeine intake and/or metabolism: CYP1A1 (rs2472297), CYP1A2 (rs762551), AHR (rs4410790), POR (rs17685), XDH (rs206860) and ADORA2A (rs5751876) genes. Association between caffeine consumption and ALSFRS-R, ALSFRS-R rate, ECAS and survival were statistically analyzed to determine the outcome of regular caffeine consumption on ALS disease progression and cognition. No association was observed between caffeine consumption and survival (p = 0.25), functional disability (ALSFRS-R; p = 0.27) or progression of ALS (p = 0.076). However, a significant association was found with higher caffeine consumption and better cognitive performance on ECAS scores in patients carrying the C/T and T/T genotypes at rs2472297 (p-het = 0.004). Our results support the safety of regular caffeine consumption on ALS disease progression and survival and also show its beneficial impact on cognitive performance in patients carrying the minor allele T of rs2472297, considered as fast metabolizers, that would set the ground for a new pharmacogenetic therapeutic strategy., Competing Interests: Declaration of competing interest The authors have declared that no conflict of interest exists., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The diagnosis of amyotrophic lateral sclerosis (ALS) is based on evidence of upper and lower motor neuron degeneration in the bulbar, cervical, thoracic, and lumbar regions in a patient with progressive motor weakness, in the absence of differential diagnosis. Despite these well-defined criteria, ALS can be difficult to diagnose, given the wide variety of clinical phenotypes. Indeed, the central or peripheral location of the disease varies with a spectrum ranging from predominantly central to exclusively peripheral, symptoms can be extensive or limited to the limbs, bulbar area or respiratory muscles, and the duration of the disease may range from a few months to several decades. In the absence of a specific test, the diagnostic strategy relies on clinical, electrophysiological, biological and radiological investigations to confirm the disease and exclude ALS mimics. The main challenge is to establish a diagnosis based on robust clinical and paraclinical evidence without delaying treatment initiation by increasing the number of additional tests. This approach requires a thorough knowledge of the phenotypes of ALS and its main differential diagnoses.

Mitochondrial dynamics is a process that balances fusion and fission events, the latter providing a mechanism for segregating dysfunctional mitochondria. Fission is controlled by the mitochondrial membrane potential (ΔΨm), optic atrophy 1 (OPA1) cleavage, and DRP1 recruitment. It is thought that this process is closely linked to the activity of the mitochondrial respiratory chain (MRC). However, we report here that MRC inhibition does not decrease ΔΨm nor increase fission, as evidenced by hyperconnected mitochondria. Conversely, blocking F0F1-ATP synthase activity induces fragmentation. We show that the F0F1-ATP synthase is sensing the inhibition of MRC activity by immediately promoting its reverse mode of action to hydrolyze matrix ATP and restoring ΔΨm, thus preventing fission. While this reverse mode is expected to be inhibited by the ATPase inhibitor ATPIF1, we show that this sensing is independent of this factor. We have unraveled an unexpected role of F0F1-ATP synthase in controlling the induction of fission by sensing and maintaining ΔΨm., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

Background: X-Linked Charcot-Marie-Tooth disease type 1 (CMTX1) is characterized by gender differences in clinical severity. Women are usually clinically affected later and less severely than men. However, their clinical presentation appears to be heterogenous. Our aim was to extend the phenotypic description in a large series of women with CMTX1., Methods: We retrospectively evaluated 263 patients with CMTX1 from 11 French reference centers. Demographic, clinical, and nerve conduction data were collected. The severity was assessed by CMT Examination Score (CMTES) and Overall Neuropathy Limitations Scale (ONLS) scores. We looked for asymmetrical strength, heterogeneous motor nerve conduction velocity (MNCV), and motor conduction blocks (CB)., Results: The study included 137 women and 126 men from 151 families. Women had significantly more asymmetric motor deficits and MNCV than men. Women with an age of onset after 19 years were milder. Two groups of women were identified after 48 years of age. The first group represented 55%, with women progressing as severely as men, however, with a later onset age. The second group had mild or no symptoms. Some 39% of women had motor CB. Four women received intravenous immunoglobulin before being diagnosed with CMTX1., Conclusions: We identified two subgroups of women with CMTX1 who were over 48 years of age. Additionally, we have demonstrated that women with CMTX can exhibit an atypical clinical presentation, which may result in misdiagnosis. Therefore, in women presenting with chronic neuropathy, the presence of clinical asymmetry, heterogeneous MNCV, and/or motor CB should raise suspicion for X-linked CMT, particularly CMTX1, and be included in the differential diagnosis., (© 2023 European Academy of Neurology.)

The centrosome, as the main microtubule organizing centre, plays key roles in cell polarity, genome stability and ciliogenesis. The recent identification of ribosomes, RNA-binding proteins and transcripts at the centrosome suggests local protein synthesis. In this context, we hypothesized that TDP-43, a highly conserved RNA binding protein involved in the pathophysiology of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, could be enriched at this organelle. Using dedicated high magnification sub-diffraction microscopy on human cells, we discovered a novel localization of TDP-43 at the centrosome during all phases of the cell cycle. These results were confirmed on purified centrosomes by western blot and immunofluorescence microscopy. In addition, the co-localization of TDP-43 and pericentrin suggested a pericentriolar enrichment of the protein, leading us to hypothesize that TDP-43 might interact with local mRNAs and proteins. Supporting this hypothesis, we found four conserved centrosomal mRNAs and 16 centrosomal proteins identified as direct TDP-43 interactors. More strikingly, all the 16 proteins are implicated in the pathophysiology of TDP-43 proteinopathies, suggesting that TDP-43 dysfunction in this organelle contributes to neurodegeneration. This first description of TDP-43 centrosomal enrichment paves the way for a more comprehensive understanding of TDP-43 physiology and pathology., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The diagnosis of neurodegenerative diseases is made complex by the heterogenous phenotype of the patients and the regular occurrence of concomitant pathology. Studying clinicopathological correlations in autopsy series is a central approach to improve pathological prediction in clinical practice. However, such method requires a wealth of information, and the use of standard spreadsheet software is hardly suitable. To overcome this constraint, we designed a customizable and freely available neuropathology form with 456 data entry fields driven by an open-source DataBase Management Systems (DBMS) using Structured Query Language (SQL). This approach allowed us to optimize the compilation of clinical and pathological data from our brain collection (264 autopsied patients, 22,885 data points). Information was then easily retrieved using general and specific queries, facilitating the analysis of demographics, clinicopathological correlations, and incidental and concomitant proteinopathies. Tau, amyloid-β and α-synuclein incidental pathology was observed in respectively 78.1%, 42.8%, and 10.7% of all the patients. These proportions increased with age, reaching 100% for Tau pathology after 80. Concomitant proteinopathy was observed in 46.4% of the patients diagnosed with neurodegenerative diseases and prion disease. We observed a particularly high rate of co-pathology in patients with Dementia with Lewy bodies (81.3% of associated Tau and amyloid-β pathology) and Creutzfeldt-Jakob disease (68.4% of associated Tau pathology). Finally, we used specific queries to identify old cases that could meet newly defined neuropathological criteria and revised the diagnosis of a 90-year-old patient to LATE Stage 2. Increasing our understanding of clinicopathological correlations in neurodegenerative diseases is crucial given the implications in clinical diagnosis, biomarker identification and targeted therapies assessment. The precise characterization of clinical and pathological data of autopsy series remains a central approach but the large amount of generated data should encourage a more systematic use of DBMS., (© 2022 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Background and Purpose: In this retrospective study involving 14 university hospitals from France and Switzerland, the aim was to define the clinicopathological features of chronic neuropathies with anti-disialosyl ganglioside immunoglobulin M (IgM) antibodies (CNDA)., Results: Fifty-five patients with a polyneuropathy evolving for more than 2 months and with at least one anti-disialosyl ganglioside IgM antibody, that is, anti-GD1b, -GT1b, -GQ1b, -GT1a, -GD2 and -GD3, were identified. Seventy-eight percent of patients were male, mean age at disease onset was 55 years (30-76) and disease onset was progressive (82%) or acute (18%). Patients presented with limb sensory symptoms (94% of cases), sensory ataxia (85%), oculomotor weakness (36%), limb motor symptoms (31%) and bulbar muscle weakness (18%). Sixty-five percent of patients had a demyelinating polyradiculoneuropathy electrodiagnostic profile and 24% a sensory neuronopathy profile. Anti-GD1b antibodies were found in 78% of cases, whilst other anti-disialosyl antibodies were each observed in less than 51% of patients. Other features included nerve biopsy demyelination (100% of cases), increased cerebrospinal fluid protein content (75%), IgM paraprotein (50%) and malignant hemopathy (8%). Eighty-six percent of CNDA patients were intravenous immunoglobulins-responsive, and rituximab was successfully used as second-line treatment in 50% of cases. Fifteen percent of patients had mild symptoms and were not treated. CNDA course was progressive (55%) or relapsing (45%), and 93% of patients still walked after a mean disease duration of 11 years., Conclusion: Chronic neuropathies with anti-disialosyl ganglioside IgM antibodies have a recognizable phenotype, are mostly intravenous immunoglobulins-responsive and present with a good outcome in a majority of cases., (© 2022 European Academy of Neurology.)