Brain

Androdias, Géraldine; Lünemann, Jan D; Maillart, Elisabeth; Amato, Maria Pia; Audoin, Bertrand; Bruijstens, Arlette L; Bsteh, Gabriel; Butzkueven, Helmut; Ciccarelli, Olga; Cobo-Calvo, Alvaro; Derfuss, Tobias; Di Pauli, Franziska; Edan, Gilles; Enzinger, Christian; Geraldes, Ruth; Granziera, Cristina; Hacohen, Yael; Hartung, Hans-Peter; Hynes, Sinéad; Inglese, Matilde; Kappos, Ludwig; Kuusisto, Hanna; Langer-Gould, Annette; Magyari, Melinda; Marignier, Romain; Montalban, Xavier; Mycko, Marcin P; Nourbakhsh, Bardia; Oh, Jiwon; Oreja-Guevara, Celia; Piehl, Fredrik; Prosperini, Luca; Sastre-Garriga, Jaume; Sellebjerg, Finn; Selmaj, Krzysztof; Siva, Aksel; Tallantyre, Emma; van Pesch, Vincent; Vukusic, Sandra; Weinstock-Guttman, Bianca; Zipp, Frauke; Tintoré, Mar; Iacobaeus, Ellen; Stankoff, Bruno

doi: 10.1093/brain/awae409pmid: 39707906

The development of disease-modifying therapies (DMTs) for the treatment of multiple sclerosis (MS) has been highly successful in recent decades. It is now widely accepted that early initiation of DMTs after disease onset is associated with a better long-term prognosis. However, the question of when and how to de-escalate or discontinue DMTs remains open and critical.This topic was discussed during an international focused workshop organized by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in 2023. The aim was to review the current evidence on the rationale for, and the potential pitfalls of, treatment de-escalation in MS. Several clinical scenarios emerged, mainly driven by a change in the benefit-risk ratio of DMTs over the course of the disease and with ageing. The workshop also addressed the issue of de-escalation by the type of DMT used and in specific situations, including pregnancy and paediatric onset MS. Finally, we provide practical guidelines for selecting appropriate patients, defining de-escalation and monitoring modalities and outlining unmet needs in this field.

Belelli, Delia; Lambert, Jeremy J; Wan, Murphy Lam Yim; Monteiro, Ana Rita; Nutt, David J; Swinny, Jerome D

doi: 10.1093/brain/awae413pmid: 39716883

Convergent data across species paint a compelling picture of the critical role of the gut and its resident microbiota in several brain functions and disorders. The chemicals mediating communication along these sophisticated highways of the brain–gut–microbiome (BGM) axis include both microbiota metabolites and classical neurotransmitters. Amongst the latter, GABA is fundamental to brain function, mediating most neuronal inhibition. Until recently, GABA's role and specific molecular targets in the periphery within the BGM axis had received limited attention. Yet, GABA is produced by neuronal and non-neuronal elements of the BGM, and recently, GABA-modulating bacteria have been identified as key players in GABAergic gut systems, indicating that GABA-mediated signalling is likely to transcend physiological boundaries and species.We review the available evidence to better understand how GABA facilitates the integration of molecularly and functionally disparate systems to bring about overall homeostasis and how GABA perturbations within the BGM axis can give rise to multi-system medical disorders, thereby magnifying the disease burden and the challenges for patient care.Analysis of transcriptomic databases revealed significant overlaps between GABAAR subunits expressed in the human brain and gut. However, in the gut, there are notable expression profiles for a select number of subunits that have received limited attention to date but could be functionally relevant for BGM axis homeostasis.GABAergic signalling, via different receptor subtypes, directly regulates BGM homeostasis by modulating the excitability of neurons within brain centres responsible for gastrointestinal (GI) function in a sex-dependent manner, potentially revealing mechanisms underlying the greater prevalence of GI disturbances in females. Apart from such top-down regulation of the BGM axis, a diverse group of cell types, including enteric neurons, glia, enteroendocrine cells, immune cells and bacteria, integrate peripheral GABA signals to influence brain functions and potentially contribute to brain disorders.We propose several priorities for this field, including the exploitation of available technologies to functionally dissect components of these GABA pathways within the BGM, with a focus on GI and brain-behaviour-disease. Furthermore, in silico ligand-receptor docking analyses using relevant bacterial metabolomic datasets, coupled with advances in knowledge of GABAAR 3D structures, could uncover new ligands with novel therapeutic potential. Finally, targeted design of dietary interventions is imperative to advancing their therapeutic potential to support GABA homeostasis across the BGM axis.

Hong, Hui; Tozer, Daniel J; Chen, Yutong; Brown, Robin B; Low, Audrey; Markus, Hugh S

doi: 10.1093/brain/awae357pmid: 39509331

Enlarged perivascular spaces are a feature of cerebral small vessel disease, and it has been hypothesized that they might reflect impaired glymphatic drainage. The mechanisms underlying enlargement of perivascular spaces are not fully understood, but both increased inflammation and blood–brain barrier (BBB) permeability have been hypothesized to play a role. We investigated the relationship between perivascular spaces and both CNS and peripheral inflammation, in addition to BBB permeability, in cerebral small vessel disease.Fifty-four symptomatic sporadic cerebral small vessel disease patients were studied. Perivascular spaces were quantified both using a visual rating scale and by measurement of the volume of perivascular spaces in the white matter and the basal ganglia. PET-MRI was used to measure microglial activation using the radioligand 11C-PK11195, and simultaneously, BBB permeability was acquired using dynamic contrast-enhanced MRI. We determined 11C-PK11195 binding and BBB permeability in the local vicinity of individual perivascular spaces in concentric shells surrounding the perivascular spaces. In addition, both mean 11C-PK11195 binding and BBB permeability in both the white matter and the basal ganglia were determined. To assess systemic inflammation, a panel of 93 blood biomarkers relating to cardiovascular disease, inflammation and endothelial activation were measured.Within the white matter, tissue in closest proximity to perivascular spaces displayed greater 11C-PK11195 binding (P < 0.001) in the vicinity of perivascular spaces. Higher white matter perivascular spaces burden on the visual rating scale was associated with higher white matter 11C-PK11195 binding (ρ = 0.469, false discovery rate-corrected P = 0.009); values for the volume of perivascular spaces showed a similar trend. In contrast, there were no associations between the burden of basal ganglia perivascular spaces and 11C-PK11195 binding. No marker of perivascular spaces was correlated with blood–brain barrier permeability. There was no association between markers of perivascular spaces and blood biomarkers of systemic inflammation.Our findings demonstrate that white matter perivascular spaces are associated with increased 11C-PK11195 binding, consistent with neuroinflammation playing a role in enlargement of white matter perivascular spaces. Further longitudinal and intervention studies are required to determine whether the relationship between neuroinflammation and enlarged perivascular spaces is causal.

Ali, Pauline; Pieruccini-Faria, Frederico; Annweiler, Cédric; Dinomais, Mickaël; Son, Surim; Wilson, Scott K; Camicioli, Richard; Muir-Hunter, Susan; Bartha, Robert; Montero-Odasso, Manuel

doi: 10.1093/brain/awae356pmid: 39499666

Individuals with mild cognitive impairment who have high dual-task gait cost (≥20% slowing in gait speed while performing a cognitive brain-demanding task) are 3-fold more likely to progress to dementia. However, the cortical regions that might explain this association are unknown, which might identify potentially treatable areas.The aim of the present study was to investigate whether brain grey matter volume loss and motor cortex metabolite levels explain the association between dual-task cost and incident dementia in individuals with mild cognitive impairment.We included participants with mild cognitive impairment from the Gait and Brain Study Cohort, who had a baseline MRI and were followed up for 9 years with cognitive and gait assessments every 6 months. Gait performance was investigated in four conditions: usual gait, counting backwards by ones, naming animals and subtracting serial sevens. Dual-task cost was calculated as the percentage change in gait speed in dual-task conditions relative to usual gait speed. Data were collected from July 2007 to June 2023.From the 139 individuals with mild cognitive impairment included at baseline [mean (standard deviation) age, 73 (6) years; 62 (44%) female], 33 (24%) progressed to dementia. Baseline high dual-task cost (≥20%) during counting backwards by ones and naming animals conditions were associated with smaller grey matter volume in several brain structures. A higher ratio of choline to creatine in the primary motor cortex was associated with higher serial sevens dual-task cost. High dual-task cost while counting backwards by ones and naming animals was associated with a 3-fold risk of incident dementia (P = 0.02). Mediation analyses revealed that grey matter volume clusters localized in the right anterior and middle cingulate cortices mediated the association between counting backwards by ones dual-task cost and incident dementia (effect: 48%; P = 0.045) with no mediation observed in grey matter loss in other brain regions or through motor cortex metabolite levels.Smaller grey matter volume of the right anterior and middle cingulate cortices explained the association between high dual-task cost and incident dementia in mild cognitive impairment. This result sheds light on the neural mechanisms of cognitive–motor interaction linked with cognitive decline and dementia in mild cognitive impairment and supports the use of gait under dual-tasking as a motor biomarker of dementia.

Colloby, Sean J; McAleese, Kirsty E; Walker, Lauren; Erskine, Daniel; Toledo, Jon B; Donaghy, Paul C; McKeith, Ian G; Thomas, Alan J; Attems, Johannes; Taylor, John-Paul

doi: 10.1093/brain/awae372pmid: 39531734

Alzheimer’s disease (AD) is neuropathologically defined by deposits of misfolded hyperphosphorylated tau (HP-tau) and amyloid-β. Lewy body (LB) dementia, which includes dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), is characterized pathologically by α-synuclein aggregates. HP-tau and amyloid-β can also occur as co-pathologies in LB dementia, and a diagnosis of mixedAD/DLB can be made if present in sufficient quantities. We hypothesized that the spread of these abnormal proteins selectively affects vulnerable areas, resulting in pathologic regional covariance that differentially associates with pre-mortem clinical characteristics. Our aims were to map regional quantitative pathology (HP-tau, amyloid-β, α-synuclein) and investigate the spatial distributions from tissue microarray post-mortem samples across healthy aging, AD and LB dementia.The study involved 159 clinico-pathologically diagnosed human post-mortem brains (48 controls, 47 AD, 25 DLB, 20 mixedAD/DLB, 19 PDD). The burden of HP-tau, amyloid-β and α-synuclein was quantitatively assessed in cortical and subcortical areas. Principal components (PC) analysis was applied across all cases to determine the pattern nature of HP-tau, amyloid-β and α-synuclein. Further analyses explored the relationships of these pathological patterns with cognitive and symptom variables.Cortical (tauPC1) and temporo-limbic (tauPC2) patterns were observed for HP-tau. For amyloid-β, a cortical-subcortical pattern (amylPC1) was identified. For α-synuclein, four patterns emerged: ‘posterior temporal-occipital’ (synPC1), ‘anterior temporal-frontal’ (synPC2), ‘parieto-cingulate-insula’ (synPC3), and ‘frontostriatal-amygdala’ (synPC4). Distinct synPC scores were apparent among DLB, mixedAD/DLB and PDD, and may relate to different spreading patterns of α-synuclein pathology. In dementia, cognitive measures correlated with tauPC1,tauPC2 and amylPC1 pattern scores (P ≤ 0.02), whereas such variables did not relate to α-synuclein parameters in these or combined LB dementia cases. Mediation analysis then revealed that in the presence of amylPC1, tauPC1 had a direct effect on global cognition in dementia (n = 65, P = 0.04), while tauPC1 mediated the relationship between amylPC1 and cognition through the indirect pathway (amylPC1 → tauPC1 → global cognition) (P < 0.05). Last, in synucleinopathies, synPC1 and synPC4 pattern scores were associated with visual hallucinations and motor impairment, respectively (P = 0.02).In conclusion, distinct patterns of α-synuclein pathology were apparent in LB dementia, which could explain some of the disease heterogeneity and differing spreading patterns among these conditions. Visual hallucinations and motor severity were associated with specific α-synuclein topographies in LB dementia that may be important to the clinical phenotype and could, after necessary testing/validation, be integrated into semiquantitative routine pathological assessment.

Duong, Michael Tran; Das, Sandhitsu R; Khandelwal, Pulkit; Lyu, Xueying; Xie, Long; McGrew, Emily; Dehghani, Nadia; McMillan, Corey T; Lee, Edward B; Shaw, Leslie M; Yushkevich, Paul A; Wolk, David A; Nasrallah, Ilya M

Nido, Gonzalo S; Castelli, Martina; Mostafavi, Sepideh; Rubiolo, Anna; Shadad, Omnia; Alves, Guido; Tysnes, Ole-Bjørn; Flønes, Irene H; Dölle, Christian; Tzoulis, Charalampos

doi: 10.1093/brain/awae355pmid: 39546628

α-Synucleinopathies are progressive neurodegenerative disorders characterized by intracellular aggregation of α-synuclein, but their molecular pathogenesis remains unknown. Here, we explore cell-specific changes in gene expression across different α-synucleinopathies. We perform single-nucleus RNA sequencing on nearly 300 000 nuclei from the prefrontal cortex of individuals with idiopathic Parkinson’s disease (PD, n = 20), Parkinson’s disease caused by LRRK2 mutations (LRRK2-PD, n = 7), multiple system atrophy (n = 6) and healthy controls (n = 13).Idiopathic PD and LRRK2-PD exhibit a largely overlapping cell type-specific signature, which is distinct from that of multiple system atrophy and includes an overall decrease of the transcriptional output in neurons. Notably, most of the differential expression signal in idiopathic PD and LRRK2-PD is concentrated in a specific deep cortical neuronal subtype expressing adrenoceptor alpha 2A. Although most differentially expressed genes are highly cell type and disease specific, PDE10A is found to be downregulated consistently in most cortical neurons and across all three diseases. Finally, exploiting the variable presence and/or severity of α-synuclein pathology in LRRK2-PD and idiopathic PD, we identify cell type-specific signatures associated with α-synuclein pathology, including a neuronal upregulation of SNCA itself, encoding α-synuclein.Our findings provide new insights into the cell-specific transcriptional landscape of the α-synucleinopathy spectrum.

Zheng, Yuxi; Wang, Panfeng; Li, Shiqiang; Long, Yuxi; Jiang, Yi; Guo, Dongwei; Jia, Xiaoyun; Liu, Mengchu; Zeng, Yiyan; Xiao, Xueshan; Hejtmancik, J Fielding; Zhang, Qingjiong; Sun, Wenmin

doi: 10.1093/brain/awae324pmid: 39423307

Hereditary optic neuropathies (HON) comprise a group of diseases caused by genetic defects in either the mitochondrial or nuclear genomes. The increasing availability of genetic testing has expanded the genetic and phenotypic spectrum of HON more broadly than previously recognized. The genetic and phenotypic landscape of HON is attributed to 50 nuclear genes, so we genetically analysed patients with suspected HON from a group of 4776 index cases following our previous study on 1516 probands with Leber’s HON (LHON) who had mitochondrial DNA variants.Exome sequencing was performed in 473 probands diagnosed with nuclear gene-related HON (nHON) and 353 cases with unsolved LHON. Sequencing and variant interpretation of the 50 nuclear genes indicated that the diagnostic yield of exome sequencing for nHON was 31.50% (149/473), while it was markedly lower [1.42% (5/353)] for LHON patients without primary mtDNA mutations. The top five genes implicated in nHON in our in-house cohort were OPA1, WFS1, FDXR, ACO2 and AFG3L2, which accounted for 82.46% of probands. Although OPA1 was the most prevalent nHON-causative gene in both our cohort (53.25%) and a literature review (37.09%), the predominance of OPA1, WFS1 and FDXR differed significantly between our in-house cohort and the literature review (P-adjusted < 0.001). Fundus changes in nHON could be stratified into three categories: the most common was optic atrophy at examination (78.79%); the rarest was LHON-like optic atrophy (3.64%); and optic atrophy with concurrent retinal degeneration (17.57%), an independent risk factor for visual prognosis in nHON, occurred at an intermediate frequency. A systematic genotype-phenotype analysis highlighted different genetic contributions for ocular, extraocular neurological and extraocular non-neurological phenotypes. In addition, systemic variant analysis at the individual gene level suggested a revised interpretation of the pathogenicity of a WFS1 heterozygous truncation variant.This study provides a panoramic view of the genetic and phenotypic profiles of HON in a real-world study and the literature. The categories of nHON fundus phenotypes will benefit future studies on the molecular mechanisms underlying HON and targeted therapies. In addition to routine ophthalmic examinations, careful examination of extraocular symptoms and meaningful genetic counselling are warranted for patients with nHON.

Lado, Wudu; Ham, Ahrom; Li, Hongyu; Zhang, Hong; Chang, Audrey Yuen; Sardi, Sergio Pablo; Alcalay, Roy N; Arancio, Ottavio; Przedborski, Serge; Tang, Guomei

doi: 10.1093/brain/awae380pmid: 39562000

Cognitive impairment is a common but poorly understood non-motor aspect of Parkinson’s disease, negatively affecting the patient’s functional capacity and quality of life. The mechanisms underlying cognitive impairment in Parkinson’s disease remain elusive, limiting treatment and prevention strategies.This study investigates the molecular and cellular basis of cognitive impairment associated with heterozygous mutations in GBA1, the strongest risk gene for Parkinson’s disease, which encodes glucocerebrosidase, a lysosome enzyme that degrades the glycosphingolipid glucosylceramide into glucose and ceramide. Using a Gba1L444P/+ mouse model, we provide evidence that L444P heterozygous Gba1 mutation (L444P/+) causes hippocampus-dependent spatial and reference memory deficits independently of α-synuclein (αSyn) accumulation, glucocerebrosidase lipid substrate accumulation, dopaminergic dysfunction and motor deficits. The mutation disrupts hippocampal synaptic plasticity and basal synaptic transmission by reducing the density of hippocampal CA3–CA1 synapses, a mechanism that is dissociated from αSyn-mediated presynaptic neurotransmitter release. Using a well-characterized Thy1-αSyn pre-manifest Parkinson’s disease mouse model overexpressing wild-type human αSyn, we find that the L444P/+ mutation exacerbates hippocampal synaptic αSyn accumulation, synaptic and cognitive impairment in young Gba1L444P/+:Thy1-αSyn double mutant animals. With age, Thy1-αSyn mice manifest motor symptoms, and the double mutant mice exhibit more exacerbated synaptic and motor impairment than the Thy1-αSyn mice.Taken together, our results suggest that heterozygous L444P GBA1 mutation alone perturbs hippocampal synaptic structure and function, imposing a subclinical pathological burden for cognitive impairment. When co-existing αSyn overexpression is present, heterozygous L444P GBA1 mutation interacts with αSyn pathology to accelerate Parkinson’s disease-related cognitive impairment and motor symptoms.

Lee, Sang Hoon; Tonello, Raquel; Lee, Kihwan; Roh, Jueun; Prudente, Arthur Silveira; Kim, Yong Ho; Park, Chul-Kyu; Berta, Temugin

doi: 10.1093/brain/awae341pmid: 39486088

Parkinson’s disease is a progressive neurodegenerative disease with well-documented motor symptoms and less recognized, but significant, non-motor symptoms. These non-motor symptoms include prodromal pain and peripheral neuropathy, the causes of which are unknown.We investigated the role of DJ-1/PARK7, a Parkinson’s disease-associated gene, in prodromal pain and peripheral neuropathy. Using Dj-1-deficient mice, we conducted comprehensive sensory tests, cutaneous staining, molecular analyses and electrophysiological studies on mouse and human primary sensory neurons from dorsal root ganglia.We found that these mice exhibited cold hypersensitivity, oxidative stress, and neuropathy of the cutaneous fibres of primary sensory neurons before any motor impairments were observed. Mechanistically, DJ-1 in primary sensory neurons regulated this hypersensitivity and neuropathy via TRPA1 signalling. Interestingly, we discovered that DJ-1 also plays a role in the progression of chemotherapy-induced peripheral neuropathies. Pain and mechanisms associated with these neuropathies were exacerbated in Dj-1-deficient mice but were significantly reduced by the pharmacological activation of Dj-1. Importantly, we also confirmed the expression of DJ-1 and its therapeutic potential in human primary sensory neurons.Thus, we uncover a peripheral mechanism of DJ-1 and propose that it might serve as a new target for developing therapeutic approaches for Parkinson’s disease-linked and other painful neuropathies.