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Results in Journal Brain: 17,366

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Masato Hosokawa, Masami Masuda-Suzukake, Hiroshi Shitara, Aki Shimozawa, Genjiro Suzuki, Hiromi Kondo, Takashi Nonaka, William Campbell, Tetsuaki Arai, Masato Hasegawa
Published: 13 September 2021
Abstract:
The phenomenon of "prion-like propagation" in which aggregates of abnormal amyloid-fibrilized protein propagate between neurons and spread pathology, is attracting attention as a new mechanism in neurodegenerative diseases. There is a strong correlation between the accumulation or spread of abnormal tau aggregates and the clinical symptoms of tauopathies. Microtubule-associated protein of tau contains a microtubule-binding domain which consists of 3-repeats or 4-repeats due to alternative mRNA splicing of transcripts for the Microtubule-associated protein of tau gene. Although a number of models for tau propagation have been reported, most utilize 4-repeat human tau transgenic mice or adult wild-type mice expressing only endogenous 4-repeat tau and these models have not been able to reproduce the pathology of Alzheimer's disease in which 3-repeat and 4-repeat tau accumulate simultaneously, or that of Pick’s disease in which only 3-repeat tau is aggregated. These deficiencies may reflect differences between human and rodent tau isoforms in the brain. To overcome this problem, we used genome editing techniques to generate mice that express an equal ratio of endogenous 3-repeat and 4-repeat tau, even after they become adults. We injected these mice with sarkosyl-insoluble fractions derived from the brains of human tauopathy patients such as those afflicted with Alzheimer’s disease (3- and 4-repeat tauopathy), corticobasal degeneration (4-repeat tauopathy) or Pick’s disease (3-repeat tauopathy). At 8-9 months following intracerebral injection of mice, histopathological and biochemical analyses revealed that the abnormal accumulation of tau was seed-dependent, with 3- and 4-repeat tau in Alzheimer’s disease-injected brains, 4-repeat tau only in corticobasal degeneration-injected brains, and 3-repeat tau only in Pick disease-injected brains, all of which contained isoforms related to those found in the injected seeds. The injected abnormal tau was seeded, and accumulated at the site of injection and at neural connections, predominantly within the same site. The abnormal tau newly accumulated was found to be endogenous in these mice and to have crossed the species barrier. Of particular importance, Pick’s body-like inclusions were observed in Pick’s disease-injected mice, and accumulations characteristic of Pick’s disease were reproduced, suggesting that we have developed the first model that recapitulates the pathology of Pick’s disease. These models are not only useful for elucidating the mechanism of propagation of tau pathology involving both 3- and 4-repeat-isoforms, but can also reproduce the pathology of tauopathies, which should lead to the discovery of new therapeutic agents.
Jorge Alonso-Pérez, Lidia González-Quereda, Claudio Bruno, Chiara Panicucci, Afagh Alavi, Shahriar Nafissi, Yalda Nilipour, Edmar Zanoteli, Lucas Michielon de Augusto Isihi, Béla Melegh, et al.
Published: 13 September 2021
Abstract:
Sarcoglycanopathies include four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. Delta-sarcoglycanopathy (LGMDR6) is the least frequent and is considered an ultra-rare disease. Our aim was to characterize the clinical and genetic spectrum of a large international cohort of LGMDR6 patients and to investigate whether or not genetic or protein expression data could predict diseasés severity. This is a retrospective study collecting demographic, genetic, clinical and histological data of patients with genetically confirmed LGMDR6 including protein expression data from muscle biopsies. We contacted 128 pediatric and adult neuromuscular units around the world that reviewed genetic data of patients with a clinical diagnosis of a neuromuscular disorder. We identified 30 patients with a confirmed diagnosis of LGMDR6 of which 23 patients were included in this study. Eighty seven percent of the patients had consanguineous parents. Ninety one percent of the patients were symptomatic at the time of the analysis. Proximal muscle weakness of the upper and lower limbs was the most common presenting symptom. Distal muscle weakness was observed early over the course of the disease in 56.5% of the patients. Cardiac involvement was reported in 5 patients (21.7%) and 4 patients (17.4%) required non-invasive ventilation. Sixty percent of patients were wheelchair-bound since early teens (median age of 12.0 years old). Patients with absent expression of the sarcoglycan complex on muscle biopsy had a significant earlier onset of symptoms and an earlier age of loss of ambulation compared to patients with residual protein expression. This study confirmed that delta-sarcoglycanopathy is an ultra-rare neuromuscular condition and described the clinical and molecular characteristics of the largest yet-reported collected cohort of patients. Our results showed that this is a very severe and quickly progressive disease characterized by generalized muscle weakness affecting predominantly proximal and distal muscles of the limbs. Similar to other forms of sarcoglycanopathies, the severity and rate of progressive weakness correlates inversely with the abundance of protein on muscle biopsy.
Lukoye Atwoli, Abdullah H Baqui, Thomas Benfield, Raffaella Bosurgi, Fiona Godlee, Stephen Hancocks, Richard Horton, , Carlos Augusto Monteiro, Ian Norman, et al.
Published: 6 September 2021
Abstract:
The UN General Assembly in September 2021 will bring countries together at a critical time for marshalling collective action to tackle the global environmental crisis. They will meet again at the biodiversity summit in Kunming, China, and the climate conference (COP26) in Glasgow, UK. Ahead of these pivotal meetings, we—the editors of health journals worldwide—call for urgent action to keep average global temperature increases below 1.5°C, halt the destruction of nature and protect health.
Leon Sobesky, Lukas Goede, Vincent J J Odekerken, Qiang Wang, Ningfei Li, Clemens Neudorfer, Nanditha Rajamani, Bassam Al-Fatly, Martin Reich, Jens Volkmann, et al.
Published: 28 August 2021
Abstract:
The subthalamic nucleus and internal pallidum are main target sites for deep brain stimulation in Parkinson’s disease. Multiple trials that investigated subthalamic versus pallidal stimulation were unable to settle on a definitive optimal target between the two. One reason could be that the effect is mediated via a common functional network. To test this hypothesis, we calculated connectivity profiles seeding from deep brain stimulation electrodes in 94 patients that underwent subthalamic and 28 patients with pallidal treatment based on a normative connectome atlas calculated from 1,000 healthy subjects. In each cohort, we calculated connectivity profiles that were associated with optimal clinical improvements. The two maps showed striking similarity and were able to cross-predict outcomes in the respective other cohort (R = 0.37 at p < 0.001; R = 0.34 at p = 0.032). Next, we calculated an agreement map which retained regions common to both target sites. Crucially, this map was able to explain an additional amount of variance in clinical improvements of either cohort when compared to the maps calculated on the two cohorts alone. Finally, we tested profiles and predictive utility of connectivity maps calculated from different motor symptom subscores with a specific focus on bradykinesia and rigidity. While our study is based on retrospective data and indirect connectivity metrics, it may deliver empirical data to support the hypothesis of a largely overlapping network associated with effective deep brain stimulation in Parkinson’s disease irrespective of the specific target.
Erratum
Published: 26 August 2021
Abstract:
Jiaxi Yu, Jianwen Deng, Xueyu Guo, Jingli Shan, Xinghua Luan, Li Cao, Juan Zhao, Meng Yu, Wei Zhang, He Lv, Zhiying Xie, LingChao Meng, Yiming Zheng, Yawen Zhao, Qiang Gang, Qingqing Wang, Jing Liu, Min Zhu, Binbin Zhou, Pidong Li, Yinzhe Liu, Yang Wang, Chuanzhu Yan, Daojun Hong, Yun Yuan, Zhaoxia Wang. The GGC repeat expansion in NOTCH2NLC is associated with oculopharyngodistal myopathy type 3. Brain. 2021;144(6):1819-1832. doi:10.1093/brain/awab077
Katrine M Johannesen, Yuanyuan Liu, Mahmoud Koko, Cathrine E Gjerulfsen, Lukas Sonnenberg, Julian Schubert, Christina D Fenger, Ahmed Eltokhi, Maert Rannap, Nils A Koch, et al.
Published: 25 August 2021
Abstract:
We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel NaV1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups could be identified: 1) Benign familial infantile epilepsy (BFIE) (n = 15, normal cognition, treatable seizures), 2) intermediate epilepsy (n = 33, mild ID, partially pharmaco-responsive), 3) developmental and epileptic encephalopathy (DEE, n = 177, severe ID, majority pharmaco-resistant), 4) generalized epilepsy (n = 20, mild to moderate ID, frequently with absence seizures), 5) unclassifiable epilepsy (n = 127), and 6) neurodevelopmental disorder without epilepsy (n = 20, mild to moderate ID). Groups 1–3 presented with focal or multifocal seizures (median age of onset: four months) and focal epileptiform discharges, whereas the onset of seizures in group 4 was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human NaV1.6 channels and whole-cell patch-clamping. Two variants causing DEE showed a strong gain-of-function (GOF, hyperpolarising shift of steady-state activation, strongly increased neuronal firing rate), and one variant causing BFIE or intermediate epilepsy showed a mild GOF (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (LOF, reduced current amplitudes, depolarising shift of steady-state activation, reduced neuronal firing). Including previous studies, functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested GOF variant had either focal (97, groups 1–3), or unclassifiable epilepsy (39), whereas 34 with a LOF variant had either generalized (14), no (11) or unclassifiable (6) epilepsy; only three had DEE. Computational modeling in the GOF group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. GOF variant carriers responded significantly better to sodium channel blockers (SCBs) than to other anti-seizure medications, and the same applied for all individuals of groups 1–3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of LOF variant carriers and the extent of the electrophysiological dysfunction of the GOF variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that SCBs present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life.
Lauren A Lau, , Kyle P Lillis
Published: 25 August 2021
Abstract:
Seizure initiation is the least understood and most disabling element of epilepsy. Studies of ictogenesis require high speed recordings at cellular resolution in the area of seizure onset. However, in vivo seizure onset areas can’t be determined at the level of resolution necessary to enable such studies. To circumvent these challenges, we used novel GCaMP7-based calcium imaging in the organotypic hippocampal slice culture model of post-traumatic epilepsy in mice. Organotypic hippocampal slice cultures generate spontaneous, recurrent seizures in a preparation in which it is feasible to image the activity of the entire network (with no unseen inputs existing). Chronic calcium imaging of the entire hippocampal network, with paired electrophysiology, revealed 3 patterns of seizure onset: low amplitude fast activity, sentinel spike, and spike burst + low amplitude fast activity onset. These patterns recapitulate common features of human seizure onset, including low voltage fast activity and spike discharges. Weeks-long imaging of seizure activity showed a characteristic evolution in onset type and a refinement of the seizure onset zone. Longitudinal tracking of individual neurons revealed that seizure onset is stochastic at the single neuron level, suggesting that seizure initiation activates neurons in non-stereotyped sequences seizure to seizure. This study demonstrates for the first time that transitions to seizure are not initiated by a small number of neuronal “bad actors” (such as overly connected hub cells), but rather by network changes which enable the onset of pathology among a large populations of neurons.
Yalun Zhang, Yi Zhang, Yahyah Aman, Cheung Toa Ng, Wing-Hin Chau, Zhigang Zhang, , Christopher Bohm, Yizhen Jia, Siwen Li, et al.
Published: 24 August 2021
Abstract:
The molecular link between amyloid-β plaques and neurofibrillary tangles, the two pathological hallmarks of Alzheimer’s disease, is still unclear. Increasing evidence suggests that amyloid-β peptide activates multiple regulators of cell cycle pathways, including transcription factors CDKs and E2F1, leading to hyperphosphorylation of tau protein. However, the exact pathways downstream of amyloid-β-induced cell cycle imbalance are unknown. Here, we show that PAX6, a transcription factor essential for eye and brain development which is quiescent in adults, is increased in the brains of patients with Alzheimer’s disease and in APP transgenic mice, and plays a key role between amyloid-β and tau hyperphosphorylation. Downregulation of PAX6 protects against amyloid-β peptide-induced neuronal death, suggesting that PAX6 is a key executor of the amyloid-β toxicity pathway. Mechanistically, amyloid-β upregulates E2F1, followed by the induction of PAX6 and c-Myb, while Pax6 is a direct target for both E2F1 and its downstream target c-Myb. Furthermore, PAX6 directly regulates transcription of GSK-3β, a kinase involved in tau hyperphosphorylation and neurofibrillary tangles formation, and its phosphorylation of tau at Ser356, Ser396 and Ser404. In conclusion, we show that signalling pathways that include CDK/pRB/E2F1 modulate neuronal death signals by activating downstream transcription factors c-Myb and PAX6, leading to GSK-3β activation and tau pathology, providing novel potential targets for pharmaceutical intervention.
, Anna Pisarenko, Ewgeni Jakubovski, Carolin Fremer
Published: 23 August 2021
Abstract:
We report the first outbreak of a new type of mass sociogenic illness (MSI) that in contrast to all previously reported episodes is spread solely via social media. Accordingly, we suggest the more specific term “mass social media-induced illness” (MSMI). In Germany, current outbreak of MSMI is initiated by a “virtual” index case, who is the second most successful YouTube creator in Germany and enjoys enormous popularity among young people. Affected teenagers present with similar or identical functional “Tourette-like” behaviours, which can be clearly differentiated from tics in Tourette syndrome. Functional “Tourette-like” symptoms can be regarded as the “modern” form of the well-known motor variant of MSI. Moreover, they can be viewed as the 21th century expression of a culture-bound stress reaction of our post-modern society emphasizing the uniqueness of individuals and valuing their alleged exceptionality, thus promoting attention-seeking behaviours and aggravating the permanent identity crisis of modern man. We wish to raise awareness of the current global “Tourette-like” MSMI outbreak. A large number of young people across different countries are affected, with considerable impact on health care systems and society as a whole, since spread via social media is no longer restricted to specific locations such as local communities or school environments.spread via social media is no longer restricted to specific locations such as schools or towns.
Eva Dávila-Bouziguet, Arnau Casòliba-Melich, Georgina Targa-Fabra, Lorena Galera-López, Andrés Ozaita, Rafael Maldonado, Jesús Ávila, José M Delgado-García, Agnès Gruart, Eduardo Soriano, et al.
Published: 23 August 2021
Abstract:
Alzheimer’s disease comprises amyloid-β and hyperphosphorylated Tau accumulation, imbalanced neuronal activity, aberrant oscillatory rhythms, and cognitive deficits. Non-Demented with Alzheimer’s disease Neuropathology (NDAN) defines a novel clinical entity with amyloid-β and Tau pathologies but preserved cognition. The mechanisms underlying such neuroprotection remain undetermined and animal models of NDAN are currently unavailable. We demonstrate that J20/VLW mice (accumulating amyloid-β and hyperphosphorylated Tau) exhibit preserved hippocampal rhythmic activity and cognition, as opposed to J20 and VLW animals, which show significant alterations. Furthermore, we show that the overexpression of mutant human Tau in coexistence with amyloid-β accumulation renders a particular hyperphosphorylated Tau signature in hippocampal interneurons. The GABAergic septohippocampal pathway, responsible for hippocampal rhythmic activity, is preserved in J20/VLW mice, in contrast to single mutants. Our data highlight J20/VLW mice as a suitable animal model in which to explore the mechanisms driving cognitive preservation in NDAN. Moreover, they suggest that a differential Tau phosphorylation pattern in hippocampal interneurons prevents the loss of GABAergic septohippocampal innervation and alterations in local field potentials, thereby avoiding cognitive deficits.
Claire G Salter, Yiying Cai, Bernice Lo, Guy Helman, Henry Taylor, Amber McCartney, Joseph S Leslie, Andrea Accogoli, Frederico Zara, Monica Traverso, et al.
Published: 20 August 2021
Abstract:
Phosphatidylinositol 4-kinase IIIα (PI4KIIIα/PI4KA/OMIM:600286) is a lipid kinase generating phosphatidylinositol 4-phosphate (PI4P), a membrane phospholipid with critical roles in the physiology of multiple cell types. PI4KIIIα’s role in PI4P generation requires its assembly into a heterotetrameric complex with EFR3, TTC7 and FAM126. Sequence alterations in two of these molecular partners, TTC7 (encoded by TTC7A or TCC7B) and FAM126, have been associated with a heterogeneous group of either neurological (FAM126A) or intestinal and immunological (TTC7A) conditions. Here we show that biallelic PI4KA sequence alterations in humans are associated with neurological disease, in particular hypomyelinating leukodystrophy. In addition, affected individuals may present with inflammatory bowel disease, multiple intestinal atresia and combined immunodeficiency. Our cellular, biochemical and structural modelling studies indicate that PI4KA-associated phenotypical outcomes likely stem from impairment of molecular roles requiring organ specific PI4KIIIα-TTC7-FAM126 complex functional interactions. Together these data define PI4KA gene alteration as a cause of a variable phenotypical spectrum and provide fundamental new insight into the combinatorial biology of the PI4KIIIα-FAM126-TTC7-EFR3 molecular complex.
Edgard Verdura, Agustí Rodríguez-Palmero, Valentina Vélez-Santamaria, Laura Planas-Serra, Irene de la Calle, , Agathe Roubertie, Mehdi Benkirane, , , et al.
Published: 20 August 2021
Abstract:
Phosphoinositides are lipids that play a critical role in processes such as cellular signalling, ion channel activity and membrane trafficking. When mutated, several genes that encode proteins that participate in the metabolism of these lipids give rise to neurological or developmental phenotypes. PI4KA is a phosphoinositide kinase that is highly expressed in the brain and is essential for life. Here we used whole exome or genome sequencing to identify 10 unrelated patients harbouring biallelic variants in PI4KA that caused a spectrum of conditions ranging from severe global neurodevelopmental delay with hypomyelination and developmental brain abnormalities to pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Functional analyses by western blotting and immunofluorescence showed decreased PI4KA levels in the patients’ fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells. In conclusion, we report a novel severe metabolic disorder caused by PI4KA malfunction, highlighting the importance of phosphoinositide signalling in human brain development and the myelin sheath.
Evgeniia Lobanova, Daniel Whiten, Francesco S Ruggeri, Chris Taylor, Antonina Kouli, Zengjie Xia, Derya Emin, Yu P Zhang, Jeff Y L Lam, Caroline H Williams-Gray, et al.
Published: 19 August 2021
Abstract:
Aggregation of α-synuclein plays a key role in the development of Parkinson’s disease. Soluble aggregates are present not only within human brain but also the CSF and blood. Characterising the aggregates present in these biofluids may provide insights into disease mechanisms and also have potential for aiding diagnosis. We have used two optical single-molecule imaging methods called aptamer DNA-PAINT and single-aggregate confocal fluorescence together with high-resolution atomic force microscopy for specific detection and characterisation of individual aggregates with intermolecular β-sheet structure, present in the CSF and serum of 15 early stage Parkinson’s disease patients compared to 10 healthy age-matched controls. We found aggregates ranging in size from 20 nm to 200 nm, in both CSF and serum. There was a difference in aggregate size distribution between Parkinson’s and control groups with a significantly increased number of larger aggregates (longer than 150 nm) in the serum of patients with Parkinson’s disease. In order to determine the chemical composition of the aggregates, we performed aptamer DNA-PAINT on serum following α-synuclein and amyloid-β immunodepletion in an independent cohort of 11 early stage Parkinson’s disease patients and 10 controls. β-sheet aggregates in the serum of Parkinson’s disease patients were found to consist of, on average, 50% α-synuclein and 50% amyloid-β in contrast to 30% α-synuclein and 70% amyloid-β in control serum (the differences in the proportion of these aggregates were statistically significant between diseased and control groups (p = 1.7 x 10−5 for each species). The ratio of the number of β-sheet α-synuclein aggregates to β-sheet amyloid-β aggregates in serum extracted using our super-resolution method discriminated Parkinson’s disease cases from controls with an accuracy of 98.2% (AUC = 98.2%, p = 4.3 x 10−5). Our data suggest that studying the protein aggregates present in serum can provide information about the disruption of protein homeostasis occurring in Parkinson’s disease and warrants further investigation as a potential biomarker of disease.
Amanda L Gross, Heather L Gray-Edwards, Cassie N Bebout, Nathan L Ta, Kayly Nielsen, Brandon L Brunson, Kalajan R Lopez Mercado, Devin E Osterhoudt, Ana Rita Batista, Stacy Maitland, et al.
Published: 19 August 2021
Abstract:
GM1 gangliosidosis is a fatal neurodegenerative disease caused by a deficiency of lysosomal β-galactosidase. In its most severe form, GM1 gangliosidosis causes death by 4 years of age, and no effective treatments exist. Previous work has shown that injection of the brain parenchyma with an adeno-associated viral vector provides pronounced therapeutic benefit in a feline GM1 model. To develop a less invasive treatment for the brain and increase systemic biodistribution, intravenous injection of AAV9 was evaluated. AAV9 expressing feline β-galactosidase was intravenously administered at 1.5x1013 vector genomes/kilogram body weight to six GM1 cats at approximately 1 month of age. The animals were divided into two cohorts: 1) a long-term group, which was followed to humane endpoint, and 2) a short-term group, which was analyzed 16-weeks post treatment. Clinical assessments included neurological exams, cerebrospinal fluid and urine biomarkers, and 7-Telsa magnetic resonance imaging and spectroscopy. Postmortem analysis included β-galactosidase and virus distribution, histological analysis, and ganglioside content. Untreated GM1 animals survived 8.0 ± 0.6 months while intravenous treatment increased survival to an average of 3.5 years (n = 2) with substantial improvements in quality of life and neurologic function. Neurological abnormalities, which in untreated animals progress to the inability to stand and debilitating neurological disease by 8 months of age, were mild in all treated animals. Cerebrospinal fluid biomarkers were normalized, indicating decreased central nervous system cell damage in the treated animals. Urinary glycosaminoglycans decreased to normal levels in the long-term cohort. Magnetic resonance imaging and spectroscopy showed partial preservation of the brain in treated animals, which was supported by postmortem histological evaluation. β-galactosidase activity was increased throughout the central nervous system, reaching carrier levels in much of the cerebrum and normal levels in the cerebellum, spinal cord and cerebrospinal fluid. Ganglioside accumulation was significantly reduced by treatment. Peripheral tissues such as heart, skeletal muscle, and sciatic nerve also had normal β-galactosidase activity in treated GM1 cats. GM1 histopathology was largely corrected with treatment. There was no evidence of tumorigenesis or toxicity. Restoration of β-galactosidase activity in the central nervous system and peripheral organs by intravenous gene therapy led to profound increases in lifespan and quality of life in GM1 cats. This data supports the promise of intravenous gene therapy as a safe, effective treatment for GM1 gangliosidosis.
, Laura McWhirter, , , Daniel J Blackburn, Mark J Edwards, Nick C Fox, Robert Howard, Jonathan Huntley, Jeremy D Isaacs, et al.
Published: 16 August 2021
Abstract:
We welcome the comments from Kapur et al.1 and the opportunity to clarify the meaning of internal inconsistency. This is not equivalent to identifying fluctuations over time, since that could occur for many reasons. Rather, the defining feature of internal inconsistency is contrasting function and dysfunction, ideally demonstrable at the same time, analogous to Hoover’s sign in functional motor weakness. Function should be tested using different approaches to see if discrepant results are obtained. This would indicate a lack of factors other than attention and focus that can explain it. When one encounters either temporal variability, or subjective cognitive concern but no objective...
Negin Holland, Maura Malpetti, Timothy Rittman, Elijah E Mak, Luca Passamonti, Sanne S Kaalund, Frank H Hezemans, P Simon Jones, George Savulich, Young T Hong, et al.
Published: 16 August 2021
Abstract:
The relationship between in vivo synaptic density and molecular pathology in primary tauopathies is key to understanding the impact of tauopathy on functional decline and in informing new early therapeutic strategies. In this cross-sectional observational study, we determine the in vivo relationship between synaptic density and molecular pathology, in the primary tauopathies of Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD), as a function of disease severity. Twenty three people with PSP, and twelve people with Corticobasal Syndrome (CBS) were recruited from a tertiary referral centre. Nineteen education, sex and gender-matched control participants were recruited from the National Institute for Health Research ‘Join Dementia Research’ platform. Cerebral synaptic density and molecular pathology, in all participants, were estimated using PET imaging with the radioligands [11C]UCB-J and [18F]AV-1451, respectively. Patients with CBS also underwent amyloid PET imaging with [11C]PiB to exclude those with likely Alzheimer’s pathology—we refer to the amyloid negative cohort as having CBD although acknowledge other pathologies exist. Disease severity was assessed with the PSP rating scale; regional non-displaceable binding potentials (BPND) of [11C]UCB-J and [18F]AV-1451 were estimated in regions of interest from the Hammersmith Atlas, excluding those with known off-target binding for [18F]AV-1451. As an exploratory analysis, we also investigated the relationship between molecular pathology in cortical brain regions, and synaptic density in subcortical areas. Across brain regions, there was a positive correlation between [11C]UCB-J and [18F]AV-1451 BPND (ß = 0.4, t = 3.6, p = 0.001), independent of age or time between PET scans. However, this correlation became less positive as a function of disease severity in patients (ß = - 0.02, t = -2.9, p = 0.007, R = -0.41). Between regions, cortical [18F]AV-1451 binding was negatively correlated with synaptic density in subcortical areas (caudate nucleus, putamen). Brain regions with higher synaptic density are associated with a higher [18F]AV-1451 binding in PSP/CBD, but this association diminishes with disease severity. Moreover, higher cortical [18F]AV-1451 binding correlates with lower subcortical synaptic density. Longitudinal imaging is required to confirm the mediation of synaptic loss by molecular pathology. However, the effect of disease severity suggests a biphasic relationship between synaptic density and molecular pathology with synapse-rich regions vulnerable to accrual of pathological aggregates, followed by a loss of synapses in response to pathology. Given the importance of synaptic function for cognition, our study elucidates the pathophysiology of primary tauopathies and may inform the design of future clinical trials.
Erin F Balcom, Avindra Nath,
Published: 16 August 2021
Abstract:
COVID-19 is a global pandemic caused by SARS-CoV-2 infection and is associated with both acute and chronic disorders affecting the nervous system. Acute neurological disorders affecting patients with COVID-19 range widely from anosmia, stroke, encephalopathy/encephalitis, and seizures to Guillain-Barre Syndrome. Chronic neurological sequelae are less well defined although exercise intolerance, dysautonomia, pain, as well as neurocognitive and psychiatric dysfunctions are commonly reported. Molecular analyses of cerebrospinal fluid and neuropathological studies highlight both vascular and immunologic perturbations. Low levels of viral RNA have been detected in the brains of few acutely ill individuals. Potential pathogenic mechanisms in the acute phase include coagulopathies with associated cerebral hypoxic-ischemic injury, blood-brain barrier abnormalities with endotheliopathy and possibly viral neuroinvasion accompanied by neuro-immune responses. Established diagnostic tools are limited by a lack of clearly defined COVID-19 specific neurological syndromes. Future interventions will require delineation of specific neurological syndromes, diagnostic algorithm development, and uncovering the underlying disease mechanisms that will guide effective therapies.
Shanice Beerepoot, Hans Heijst, Birthe Roos, Mirjam M C Wamelink, Jaap Jan Boelens, Caroline A Lindemans, Peter M van Hasselt, Edwin H Jacobs, Marjo S van der Knaap, Charlotte E Teunissen, et al.
Published: 16 August 2021
Abstract:
Metachromatic leukodystrophy is a lethal metabolic leukodystrophy, with emerging treatments for early disease stages. Biomarkers to measure disease activity are required for clinical assessment and treatment follow-up. This retrospective study compared neurofilament light chain and glial fibrillary acidic protein levels in CSF (n = 11) and blood (n = 92) samples of 40 patients with metachromatic leukodystrophy (aged 0–42 years) with 38 neurologically healthy children (aged 0–17 years) and 38 healthy adults (aged 18–45 years), and analyzed the associations between these levels with clinical phenotype and disease evolution in untreated and transplanted patients. Metachromatic leukodystrophy subtype was determined based on the (expected) age of symptom onset. Disease activity was assessed by measuring gross motor function deterioration and brain MRI. Longitudinal analyses with measurements up to 23 years after diagnosis were performed using linear mixed models. CSF and blood neurofilament light chain and glial fibrillary acidic protein levels in pediatric controls were negatively associated with age (all P < 0.001). Blood neurofilament light chain level at diagnosis (median, interquartile range; picogram per milliliter) was significantly increased in both pre-symptomatic (14.7, 10.6–56.7) and symptomatic patients (136, 40.8–445) compared to controls (5.6, 4.5–7.1), and highest amongst patients with late-infantile (456, 201–854) or early-juvenile MLD (291.0, 104–445) and those ineligible for treatment based on best practice (291, 57.4–472). Glial fibrillary acidic protein level (median, interquartile range; picogram per milliliter) was only increased in symptomatic patients (591, 224–1150) compared to controls (119, 78.2–338) and not significantly associated with treatment eligibility (P = 0.093). Higher blood neurofilament light chain and glial fibrillary acidic protein levels at diagnosis were associated with rapid disease progression in late-infantile (P = 0.006 and P = 0.051, respectively) and early-juvenile patients (P = 0.048 and P = 0.039, respectively). Finally, blood neurofilament light chain and glial fibrillary acidic protein levels decreased during follow-up in untreated and transplanted patients but remained elevated compared with controls. Only neurofilament light chain levels were associated with MRI deterioration (P < 0.001). This study indicates that both proteins may be considered as non-invasive biomarkers for clinical phenotype and disease stage at clinical assessment, and that neurofilament light chain might enable neurologists to make better informed treatment decisions. In addition, neurofilament light chain holds promise assessing treatment response. Importantly, both biomarkers require pediatric reference values, given that their levels first decrease before increasing with advancing age.
Serena Galosi, Ban H Edani, Simone Martinelli, Hana Hansikova, Erik A Eklund, Caterina Caputi, Laura Masuelli, Nicole Corsten-Janssen, Myriam Srour, Renske Oegema, et al.
Published: 11 August 2021
Abstract:
Subcellular membrane systems are highly enriched in dolichol, whose role in organelle homeostasis and endosomal-lysosomal pathway remains largely unclear besides being involved in protein glycosylation. DHDDS encodes for the catalytic subunit (DHDDS) of the enzyme cis-prenyltransferase (cis-PTase), involved in dolichol biosynthesis and dolichol-dependent protein glycosylation in the endoplasmic reticulum. An autosomal recessive form of retinitis pigmentosa (retinitis pigmentosa 59) has been associated with a recurrent DHDDS variant. Moreover, two recurring de novo substitutions were detected in a few cases presenting with neurodevelopmental disorder, epilepsy, and movement disorder. We evaluated a large cohort of patients (n=25) with de novo pathogenic variants in DHDDS and provided the first systematic description of the clinical features and long-term outcome of this new neurodevelopmental and neurodegenerative disorder. The functional impact of the identified variants was explored by yeast complementation system and enzymatic assay. Patients presented during infancy or childhood with a variable association of neurodevelopmental disorder, generalized epilepsy, action myoclonus/cortical tremor, and ataxia. Later in the disease course they experienced a slow neurological decline with the emergence of hyperkinetic and/or hypokinetic movement disorder, cognitive deterioration, and psychiatric disturbances. Storage of lipidic material and altered lysosomes were detected in myelinated fibers and fibroblasts, suggesting a dysfunction of the lysosomal enzymatic scavenger machinery. Serum glycoprotein hypoglycosylation was not detected and, in contrast to retinitis pigmentosa and other congenital disorders of glycosylation involving dolichol metabolism, the urinary dolichol D18/D19 ratio was normal. Mapping the disease-causing variants into the protein structure revealed that most of them clustered around the active site of the DHDDS subunit. Functional studies using yeast complementation assay and in vitro activity measurements confirmed that these changes affected the catalytic activity of the cis-PTase and showed growth defect in yeast complementation system as compared with the wild-type enzyme and retinitis pigmentosa-associated protein. In conclusion, we characterized a distinctive neurodegenerative disorder due to de novo DHDDS variants, which clinically belongs to the spectrum of genetic progressive encephalopathies with myoclonus. Clinical and biochemical data from this cohort depicted a condition at the intersection of congenital disorders of glycosylation and inherited storage diseases with several features akin to of progressive myoclonus epilepsy such as neuronal ceroid lipofuscinosis and other lysosomal disorders.
Amelia Strom, Leonardo Iaccarino, Lauren Edwards, Orit H Lesman-Segev, David N Soleimani-Meigooni, Julie Pham, Suzanne L Baker, Susan Landau, William J Jagust, Bruce L Miller, et al.
Published: 9 August 2021
Abstract:
Posterior cortical hypometabolism measured with [18F]-Fluorodeoxyglucose (FDG)-PET is a well-known marker of Alzheimer’s disease-related neurodegeneration, but its associations with underlying neuropathological processes are unclear. We assessed cross-sectionally the relative contributions of three potential mechanisms causing hypometabolism in the retrosplenial and inferior parietal cortices: local molecular (amyloid and tau) pathology and atrophy, distant factors including contributions from the degenerating medial temporal lobe or molecular pathology in functionally connected regions, and the presence of the apolipoprotein E (APOE) ε4 allele. Two hundred and thirty-two amyloid-positive cognitively impaired patients from two cohorts (University of California, San Francisco, UCSF, and Alzheimer’s Disease Neuroimaging Initiative, ADNI) underwent MRI and PET with FDG, amyloid-PET using [11C]-Pittsburgh Compound B, [18F]-Florbetapir, or [18F]-Florbetaben, and [18F]-Flortaucipir tau-PET within one year. Standard uptake value ratios (SUVR) were calculated using tracer-specific reference regions. Regression analyses were run within cohorts to identify variables associated with retrosplenial or inferior parietal FDG SUVR. On average, ADNI patients were older and were less impaired than UCSF patients. Regional patterns of hypometabolism were similar between cohorts, though there were cohort differences in regional gray matter atrophy. Local cortical thickness and tau-PET (but not amyloid-PET) were independently associated with both retrosplenial and inferior parietal FDG SUVR (ΔR2 = .09 to .21) across cohorts in models that also included age and disease severity (local model). Including medial temporal lobe volume improved the retrosplenial FDG model in ADNI (ΔR2 = .04, p = .008) but not UCSF (ΔR2 < .01, p = .52), and did not improve the inferior parietal models (ΔR2s < .01, ps > .37). Interaction analyses revealed that medial temporal volume was more strongly associated with retrosplenial FDG SUVR at earlier disease stages (p = .06 in UCSF, p = .046 in ADNI). Exploratory analyses across the cortex confirmed overall associations between hypometabolism and local tau pathology and thickness and revealed associations between medial temporal degeneration and hypometabolism in retrosplenial, orbitofrontal, and anterior cingulate cortices. Finally, our data did not support hypotheses of a detrimental effect of pathology in connected regions or of an effect of the APOE ε4 allele in impaired participants. Overall, in two independent groups of patients at symptomatic stages of Alzheimer’s disease, cortical hypometabolism mainly reflected structural neurodegeneration and tau, but not amyloid, pathology.
Meritxell Llorca-Torralba, Carmen Camarena-Delgado, Irene Suárez-Pereira, Lidia Bravo, Patricia Mariscal, Jose Antonio Garcia-Partida, Carolina López-Martín, Hong Wei, Antti Pertovaara, Juan Antonio Mico, et al.
Published: 9 August 2021
Abstract:
There is strong comorbidity between chronic pain and depression, although the neural circuits and mechanisms underlying this association remain unclear. By combining immunohistochemistry, tracing studies and western-blotting, with the use of different DREADDs (Designer Receptor Exclusively Activated by Designer Drugs) and behavioural approaches in a rat model of neuropathic pain (chronic constriction injury), we explore how this comorbidity arises. To this end, we evaluated the time-dependent plasticity of noradrenergic-locus coeruleus (LC) neurons relative to the site of injury: ipsilateral (LCipsi) or contralateral (LCcontra) at three different time points: short- (2 days), mid- (7 days), and long-term (30–35 days from nerve injury). Nerve injury led to sensorial hypersensitivity from the onset of injury, whereas depressive-like behavior was only evident following long-term pain. Global chemogenetic blockade of the LCipsi system alone increased short-term pain sensitivity while the blockade of the LCipsi or LCcontra relieved pain-induced depression. The asymmetric contribution of LC-modules was also evident as neuropathy develops. Hence, chemogenetic blockade of the LCipsi→spinal cord projection, increased pain-related behaviours in the short-term. However, this lateralized circuit is not universal as the bilateral chemogenetic inactivation of the LC-rostral anterior cingulate cortex (rACC) pathway or the intra-rACC antagonism of alpha1- and alpha2-adrenoreceptors reversed long-term pain-induced depression. Furthermore, chemogenetic LC to spinal cord activation, mainly through LCipsi, reduced sensorial hypersensitivity irrespective of the time post-injury. Our results indicate that asymmetric activation of specific LC modules promotes early restorative-analgesia, as well as late depressive-like behavior in chronic pain and depression comorbidity.
Clement Hamani, Erich T Fonoff, Daniella C Parravano, Valquiria A Silva, Ricardo Galhardoni, Bernardo Monaco, Jessie Navarro, Lin T Yeng, Manoel J Teixeira, Daniel Ciampi de Andrade
Published: 9 August 2021
Abstract:
Motor cortex stimulation (MCS) via surgically implanted electrodes has been used as an off-label treatment for chronic neuropathic pain (cNeP) but its efficacy has not been fully established. We aimed to objectively study the efficacy of MCS and characterize potential predictors of response. In this randomised, double-blind, sham-controlled, single centre trial, we recruited 18 cNeP patients who did not adequately respond to conventional treatment and had a numerical rating pain scale (NRS) score ≥ 6. Patients were initially assigned to receive three months of active (“on”) or sham (“off”) stimulation in a double-blind cross-over phase. This was followed by a 3-month single-blind phase, and 6 months of open-label follow-up. A meaningful response in our trial was defined as a ≥ 30% or 2-point reduction in NRS scores during active stimulation. Using Bayesian statistics, we found a 41.4% probability of response towards “on” vs. “off” MCS. The probability of improvement during active stimulation (double-blind, single-blind and open label phases) compared to baseline was of 47.2–68.5%. 39% of patients were long-term responders, 71.4% of whom had facial pain, phantom limb pain, or complex regional pain syndrome. In contrast, 72.7% of non-responders had either post-stroke pain or pain associated with brachial plexus avulsion. 39% of patients had a substantial post-operative analgesic effect after electrode insertion in the absence of stimulation. Individuals with diagnoses associated with a good postoperative outcome or those who developed an insertional effect had a near 100% probability of response to MCS. In summary, we found that approximately 40% of patients responded to MCS, particularly those who developed an insertional effect or had specific clinical conditions that seemed to predict an appropriate postoperative response.
Eva Medico Salsench, Reza Maroofian, Ruizhi Deng, Kristina Lanko, Anita Nikoncuk, Belén Pérez, Obdulia Sánchez-Lijarcio, Salvador Ibáñez-Mico, Antonina Wojcik, Marcelo Vargas, et al.
Published: 9 August 2021
, Rainer Malik, Benno Gesierich,
Published: 6 August 2021
Abstract:
Age-related loss of white matter microstructural integrity is a major determinant of cognitive decline, dementia, and gait disorders. However, the mechanisms and molecular pathways that contribute to this loss of integrity remain elusive. We performed a GWAS of white matter microstructural integrity as quantified by diffusion MRI metrics (mean diffusivity, MD; and fractional anisotropy, FA) in up to 31,128 individuals from UK Biobank (age 45–81 years) based on a 2 degrees of freedom (2df) test of single nucleotide polymorphism (SNP) and SNP x age effects. We identified 18 loci that were associated at genome-wide significance with either MD (N = 16) or FA (N = 6). Among the top loci was a region on chromosome 6 encoding the human major histocompatibility complex (MHC). Variants in the MHC region were strongly associated with both MD (best SNP: 6:28866209_TTTTG_T, beta(SE)=-0.069(0.009); 2df p = 6.5x10−15) and FA (best SNP: rs3129787, beta(SE)=-0.056(0.008); 2df p = 3.5x10−12). Of the imputed HLA alleles and complement component 4 (C4) structural haplotype variants in the human MHC, the strongest association was with the C4-BS variant (for MD: beta(SE)=-0.070(0.010); p = 2.7x10−11; for FA: beta(SE)=-0.054(0.011); p = 1.6x10−7). After conditioning on C4-BS no associations with HLA alleles remained significant. The protective influence of C4-BS was stronger in older subjects (age ≥ 65; interaction p = 0.0019 (MD), p = 0.015 (FA)) and in subjects without a history of smoking (interaction p = 0.00093 (MD), p = 0.021 (FA)). Taken together, our findings demonstrate a role of the complement system and of gene-environment interactions in age-related loss of white matter microstructural integrity.
Seong Ho Jeong, Hye Sun Lee, Seok Jong Chung, Han Soo Yoo, Jin Ho Jung, Kyoungwon Baik, Yang Hyun Lee, Young H Sohn,
Published: 4 August 2021
Abstract:
Statins are more widely used not only for the primary and secondary prevention of cardiovascular disease by blocking cholesterol biosynthesis but also for the potential neuroprotective agents during neurological disorders due to their pleiotropic effects. In this study, we investigate whether the prior use of statins affect baseline nigrostriatal dopamine loss at the time of diagnosis and longitudinal motor and cognitive outcomes in patients with Parkinson’s disease. Five hundred drug-naïve patients with Parkinson’s disease who underwent dopamine transporter imaging were classified into two groups according to the prior use of statins: patients with and without statin use. Multivariate linear regression was used to determine inter-group differences in dopamine transporter availability. We evaluated the longitudinal changes in levodopa-equivalent dose and dementia conversion between the groups using a linear mixed model and survival analysis, respectively. In addition, mediation analysis was applied to examine the effect of total cholesterol. Patients with Parkinson’s disease treated with statin had a lower baseline dopamine transporter availability in the anterior (2.13 ± 0.55 vs. 2.37 ± 0.67; p = 0.002), posterior (1.31 ± 0.43 vs. 1.49 ± 0.54; p = 0.003), and ventral putamina (1.40 ± 0.39 vs. 1.56 ± 0.47; p = 0.002) than that in matched patients with Parkinson’s disease without statin. After adjusting for age at symptom onset, sex, disease duration and vascular risk factors, linear regression models showed that a prior treatment of statin remained significantly and independently associated with more severely decreased dopamine transporter availability in the anterior putamen (Beta = −0.140, p = 0.004), posterior putamen (Beta = −0.162, p = 0.001), and ventral putamen (Beta = −0.140, p = 0.004). A linear mixed model revealed that patients with Parkinson’s disease being treated with statin had a faster longitudinal increase in levodopa-equivalent dose than those without statin. A survival analysis showed that the rate of dementia conversion was significantly higher in patients with Parkinson’s disease with statin (hazard ratio, 2.019; 95% CI, 1.108 − 3.678; P = 0.022) than those without statin. Mediation analyses revealed that the effect of statin treatment on baseline dopamine transporter availability and longitudinal outcome was not mediated by total cholesterol levels. This study suggests that statin use may have a detrimental effect on baseline nigrostriatal dopamine degeneration and long-term outcomes in patients with Parkinson’s disease.
, Yelena G Bodien, Joseph T Giacino, Joseph J Fins, Robert D Truog, Leigh R Hochberg, Brian L Edlow
Published: 4 August 2021
Abstract:
Neuroethical questions raised by recent advances in the diagnosis and treatment of disorders of consciousness are rapidly expanding, increasingly relevant, and yet underexplored. The aim of this thematic review is to provide a clinically applicable framework for understanding the current taxonomy of disorders of consciousness and to propose an approach to identifying and critically evaluating actionable neuroethical issues that are frequently encountered in research and clinical care for this vulnerable population. Increased awareness of these issues and clarity about opportunities for optimizing ethically-responsible care in this domain are especially timely given recent surges in critically ill patients with unusually prolonged disorders of consciousness associated with coronavirus disease 2019 (COVID-19) around the world. We begin with an overview of the field of neuroethics: what it is, its history and evolution in the context of biomedical ethics at large. We then explore nomenclature used in disorders of consciousness, covering categories proposed by the American Academy of Neurology, the American Congress of Rehabilitation Medicine, and the National Institute on Disability, Independent Living, and Rehabilitation Research, including definitions of terms such as coma, the vegetative state, unresponsive wakefulness syndrome, minimally conscious state, covert consciousness, and the confusional state. We discuss why these definitions matter, and why there has been such evolution in this nosology over the years, from Jennett and Plum in 1972 to the Multi-Society Task Force in 1994, the Aspen Working Group in 2002 and up until the 2018 American and 2020 European Disorders of Consciousness guidelines. We then move to a discussion of clinical aspects of disorders of consciousness, the natural history of recovery, and ethical issues that arise within the context of caring for persons with disorders of consciousness. We conclude with a discussion of key challenges associated with assessing residual consciousness in disorders of consciousness, potential solutions and future directions, including integration of crucial disability rights perspectives.
Tim A Guth, Lukas Kunz, Armin Brandt, Matthias Dümpelmann, Kerstin A Klotz, Peter C Reinacher, Andreas Schulze-Bonhage, Julia Jacobs, Jan Schönberger
Published: 3 August 2021
Abstract:
Interictal epileptiform discharges (IEDs) are a widely used biomarker in patients with epilepsy but lack specificity. It has been proposed that there are truly epileptogenic and less pathologic or even protective IEDs. Recent studies suggest that highly pathologic IEDs are characterized by high-frequency oscillations (HFOs). Here, we aimed to dissect these ‘HFO-IEDs’ at the single-neuron level, hypothesizing that the underlying mechanisms are distinct from ‘non-HFO-IEDs’. Analyzing hybrid depth electrode recordings from patients with temporal lobe epilepsy, we found that single-unit firing rates were higher in HFO- than in non-HFO-IEDs. HFO-IEDs were characterized by a pronounced pre-peak increase in firing, which coincided with the preferential occurrence of HFOs, whereas in non-HFO-IEDs, there was only a mild pre-peak increase followed by a post-peak suppression. Comparing each unit's firing during HFO-IEDs to its baseline activity, we found many neurons with a significant increase during the HFO component or ascending part, but almost none with a decrease. During non-HFO-IEDs, no such imbalance was observed. Finally, comparing each unit's firing directly between HFO- and non-HFO-IEDs, we found that most cells had higher rates during HFO-IEDs and moreover identified a distinct subset of neurons with a significant preference for this IED subtype. In summary, our study reveals that HFO- and non-HFO-IEDs have different single-unit correlates. In HFO-IEDs, many neurons are moderately activated, and some participate selectively, suggesting that both types of increased firing contribute to highly pathologic IEDs.
Mark A Petersen, Reshmi Tognatta, Anke Meyer-Franke, Eric A Bushong, Andrew S Mendiola, Zhaoqi Yan, Abinaya Muthusamy, Mario Merlini, Rosa Meza-Acevedo, Belinda Cabriga, et al.
Published: 1 August 2021
Brain, Volume 144, pp 2291-2301; https://doi.org/10.1093/brain/awab106

Abstract:
Extrinsic inhibitors at sites of blood–brain barrier disruption and neurovascular damage contribute to remyelination failure in neurological diseases. However, therapies to overcome the extrinsic inhibition of remyelination are not widely available and the dynamics of glial progenitor niche remodelling at sites of neurovascular dysfunction are largely unknown. By integrating in vivo two-photon imaging co-registered with electron microscopy and transcriptomics in chronic neuroinflammatory lesions, we found that oligodendrocyte precursor cells clustered perivascularly at sites of limited remyelination with deposition of fibrinogen, a blood coagulation factor abundantly deposited in multiple sclerosis lesions. By developing a screen (OPC-X-screen) to identify compounds that promote remyelination in the presence of extrinsic inhibitors, we showed that known promyelinating drugs did not rescue the extrinsic inhibition of remyelination by fibrinogen. In contrast, bone morphogenetic protein type I receptor blockade rescued the inhibitory fibrinogen effects and restored a promyelinating progenitor niche by promoting myelinating oligodendrocytes, while suppressing astrocyte cell fate, with potent therapeutic effects in chronic models of multiple sclerosis. Thus, abortive oligodendrocyte precursor cell differentiation by fibrinogen is refractory to known promyelinating compounds, suggesting that blockade of the bone morphogenetic protein signalling pathway may enhance remyelinating efficacy by overcoming extrinsic inhibition in neuroinflammatory lesions with vascular damage.
Erratum
Manuela Wiessner, Reza Maroofian, Meng-Yuan Ni, Andrea Pedroni, Juliane S Müller, Rolf Stucka, Christian Beetz, Stephanie Efthymiou, Filippo M Santorelli, Ahmed A Alfares, et al.
Published: 1 August 2021
Abstract:
Manuela Wiessner, Reza Maroofian, Meng-Yuan Ni, Andrea Pedroni, Juliane S. Müller, Rolf Stucka, Christian Beetz, Stephanie Efthymiou, Filippo M. Santorelli, Ahmed A. Alfares, Changlian Zhu, Anna Uhrova Meszarosova, Elham Alehabib, Somayeh Bakhtiari, Andreas R. Janecke, Maria Gabriela Otero, Jin Yun Helen Chen, James T. Peterson, Tim M. Strom, Peter De Jonghe, Tine Deconinck, Willem De Ridder, Jonathan De Winter, Rossella Pasquariello, Ivana Ricca, Majid Alfadhel, Bart P. van de Warrenburg, Ruben Portier, Carsten Bergmann, Saghar Ghasemi Firouzabadi, Sheng Chih Jin, Kaya Bilguvar, Sherifa Hamed, Mohammed Abdelhameed, Nourelhoda A. Haridy, Shazia Maqbool, Fatima Rahman, Najwa Anwar, Jenny Carmichael, Alistair T. Pagnamenta, Nick W. Wood, Frederic Tran Mau-Them, Tobias Haack, Genomics England Research Consortium, PREPARE network, Maja Di Rocco, Isabella Ceccherini, Michele Iacomino, Federico Zara, Vincenzo Salpietro, Marcello Scala, Marta Rusmini, Yiran Xu, Yinghong Wang, Yasuhiro Suzuki, Kishin Koh, Haitian Nan, Hiroyuki Ishiura, Shoji Tsuji, Laëtitia Lambert, Emmanuelle Schmitt, Elodie Lacaze, Hanna Küpper, David Dredge, Cara Skraban, Amy Goldstein, Mary J. H. Willis, Katheryn Grand, John M. Graham Jr, Richard A. Lewis, Francisca Millan, Özgür Duman, Nihal Olgac Dundar, Gökhan Uyanik, Ludger Schöls, Peter Nürnberg, Gudrun Nürnberg, Andrea Català-Bordes, Pavel Seeman, Martin Kuchar, Hossein Darvish, Adriana Rebelo, Filipa Bouçanova, Jean-Jacques Medard, Roman Chrast, Michaela Auer-Grumbach, Fowzan S. Alkuraya, Hanan Shamseldin, Saeed Al Tala, Jamileh Rezazadeh Varaghchi, Maryam Najafi, Selina Deschner, Dieter Gläser, Wolfgang Hüttel, Michael C. Kruer, Erik-Jan Kamsteeg, Yoshihisa Takiyama, Stephan Züchner, Jonathan Baets, Matthis Synofzik, Rebecca Schüle, Rita Horvath, Henry Houlden, Luca Bartesaghi, Hwei-Jen Lee, Konstantinos Ampatzis, Tyler Mark Pierson and Jan Senderek. Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia. Brain 2021;144(5):1422–1434. doi:10.1093/brain/awab041
Michelle Naughton,
Published: 1 August 2021
Brain, Volume 144, pp 2231-2233; https://doi.org/10.1093/brain/awab269

Abstract:
This scientific commentary refers to ‘MOG autoantibodies trigger a tightly controlled FcR and BTK-driven microglia proliferative response’ by Pellerin et al. (doi:10.1093/brain/awab231).
Gavin J B Elias, Jürgen Germann, Alexandre Boutet, Aditya Pancholi, Michelle E Beyn, Kartik Bhatia, Clemens Neudorfer, Aaron Loh, Sakina J Rizvi, Venkat Bhat, et al.
Published: 29 July 2021
Abstract:
Subcallosal cingulate deep brain stimulation (SCC-DBS) produces long-term clinical improvement in approximately half of patients with severe treatment-resistant depression (TRD). We hypothesized that both structural and functional brain attributes may be important in determining responsiveness to this therapy. In a TRD SCC-DBS cohort, we retrospectively examined baseline and longitudinal differences in MRI-derived brain volume (n = 65) and 18F-fluorodeoxyglucose-PET glucose metabolism (n = 21) between responders and non-responders. Support-vector machines (SVMs) were subsequently trained to classify patients’ response status based on extracted baseline imaging features. A machine learning model incorporating pre-operative frontopolar, precentral/frontal opercular, and orbitofrontal local volume values classified binary response status (12 months) with 83% accuracy (leave-one-out cross-validation (LOOCV): 80% accuracy) and explained 32% of the variance in continuous clinical improvement. It was also predictive in an out-of-sample SCC-DBS cohort (n = 21) with differing primary indications (bipolar disorder/anorexia nervosa) (76% accuracy). Adding pre-operative glucose metabolism information from rostral anterior cingulate cortex and temporal pole improved model performance, enabling it to predict response status in the TRD cohort with 86% accuracy (LOOCV: 81% accuracy) and explain 67% of clinical variance. Response-related patterns of metabolic and structural post-DBS change were also observed, especially in anterior cingulate cortex and neighbouring white matter. Areas where responders differed from non-responders – both at baseline and longitudinally – largely overlapped with depression-implicated white matter tracts, namely uncinate fasciculus, cingulum bundle, and forceps minor/rostrum of corpus callosum. The extent of patient-specific engagement of these same tracts (according to electrode location and stimulation parameters) also served as a predictor of TRD response status (72% accuracy; LOOCV: 70% accuracy) and augmented performance of the volume-based (88% accuracy; LOOCV: 82% accuracy) and combined volume/metabolism-based SVMs (100% accuracy; LOOCV: 94% accuracy). Taken together, these results indicate that responders and non-responders to SCC-DBS exhibit differences in brain volume and metabolism, both pre- and post-surgery. Baseline imaging features moreover predict response to treatment (particularly when combined with information about local tract engagement) and could inform future patient selection and other clinical decisions.
Erratum
Joachim Mazere, Bixente Dilharreguy, Gwenaëlle Catheline, Marie Vidailhet, Marc Deffains, Delphine Vimont, Bastien Ribot, Elodie Barse, Laura Cif, Bernard Mazoyer, et al.
Published: 29 July 2021
Abstract:
Joachim Mazere, Bixente Dilharreguy, Gwenaëlle Catheline, Marie Vidailhet, Marc Deffains, Delphine Vimont, Bastien Ribot, Elodie Barse, Laura Cif, Bernard Mazoyer, Nicolas Langbour, Antonio Pisani, Michèle Allard, Frédéric Lamare, Dominique Guehl, Philippe Fernandez, Pierre Burbaud. Striatal and cerebellar vesicular acetylcholine transporter expression is disrupted in human DYT1 dystonia. Brain. 2021;144(3):909–923. doi:10.1093/brain/awaa465
Juliane S Müller,
Published: 26 July 2021
Brain, Volume 144, pp 2234-2236; https://doi.org/10.1093/brain/awab278

Abstract:
This scientific commentary refers to ‘Induced pluripotent stem cell-derived motor neurons of CMT type 2 patients reveal progressive mitochondrial dysfunction’, by Van Lent et al. (doi:10.1093/brain/awab226).
Adrien Paumier, Sylvie Boisseau, Muriel Jacquier-Sarlin, Karin Pernet-Gallay, Alain Buisson,
Published: 24 July 2021
Abstract:
The sequence of cellular dysfunctions in preclinical Alzheimer’s disease must be understood if we are to plot new therapeutic routes. Hippocampal neuronal hyperactivity is one of the earliest events occurring during the preclinical stages of Alzheimer’s disease in both humans and mouse models. The most common hypothesis describes amyloid β accumulation as the triggering factor of the disease but the effects of this accumulation and the cascade of events leading to cognitive decline remain unclear. In mice, we previously showed that amyloid β-dependent TRPA1 channel activation triggers hippocampal astrocyte hyperactivity, subsequently inducing hyperactivity in nearby neurons. In this work, we investigated the potential protection against Alzheimer’s disease progression provided by early chronic pharmacological inhibition of TRPA1 channel. A specific inhibitor of TRPA1 channel (HC030031) was administered intraperitoneally from the onset of amyloid β overproduction in the APP/PS1-21 mouse model of Alzheimer’s disease. Short-, medium-, and long-term effects of this chronic pharmacological TRPA1 blockade were characterized on Alzheimer’s disease progression at functional (astrocytic and neuronal activity), structural, biochemical, and behavioural levels. Our results revealed that the first observable disruptions in the Alzheimer’s disease transgenic mouse model used correspond to aberrant hippocampal astrocyte and neuron hyperactivity. We showed that chronic TRPA1 blockade normalizes astrocytic activity, avoids perisynaptic astrocytic process withdrawal, prevents neuronal dysfunction and preserves structural synaptic integrity. These protective effects preserved spatial working-memory in this Alzheimer’s disease mouse model. The toxic effect of amyloid β on astrocytes triggered by TRPA1 channel activation is pivotal to Alzheimer’s disease progression. TRPA1 blockade prevents irreversible neuronal dysfunction, making this channel a potential therapeutic target to promote neuroprotection.
Alessandro Tozzi, Miriam Sciaccaluga, Vittorio Loffredo, Alfredo Megaro, Ada Ledonne, Antonella Cardinale, Mauro Federici, Laura Bellingacci, Silvia Paciotti, Elena Ferrari, et al.
Published: 23 July 2021
Abstract:
Misfolding and aggregation of α-synuclein are specific features of Parkinson’s disease and other neurodegenerative diseases defined as synucleinopathies. Parkinson’s disease progression has been correlated with the formation and the extracellular release of α-synuclein aggregates, as well as with their spreading from neuron to neuron. Therapeutic interventions in the initial stages of Parkinson’s disease require a clear understanding of the mechanisms by which α-synuclein disrupts the physiological synaptic and plastic activity of the basal ganglia. For this reason, here we have identified two early time points to clarify how the intrastriatal injection of α-synuclein preformed fibrils in rodents, via retrograde transmission, induces time-dependent electrophysiological and behavioral alterations. We found that intrastriatal α-synuclein preformed fibrils perturb the firing rate of dopaminergic neurons of the substantia nigra pars compacta while the discharge of putative GABAergic cells of the substantia nigra pars reticulata is unchanged. The α-synuclein-induced dysregulation of nigrostriatal function also impairs, in a time-dependent manner, the two main forms of striatal synaptic plasticity, long-term potentiation and long-term depression. We also observed an increased glutamatergic transmission measured as an augmented frequency of spontaneous excitatory synaptic currents. These changes in neuronal function in the substantia nigra pars compacta and striatum were observed before overt neuronal death occurred. In an additional set of experiments, we were able to rescue α-synuclein-induced alterations of motor function, striatal synaptic plasticity, and increased spontaneous excitatory synaptic currents by a sub-chronic treatment with L-Dopa, a precursor of dopamine widely used in the therapy of Parkinson’s disease, clearly demonstrating that a dysfunctional dopamine system plays a critical role in the early phases of the disease.
Ashley L B Raghu, John Eraifej, Nagaraja Sarangmat, John Stein, James J FitzGerald, Stephen Payne, Tipu Z Aziz, Alexander L Green
Published: 22 July 2021
Abstract:
Cervical dystonia is a non-degenerative movement disorder characterised by dysfunction of both motor and sensory cortico-basal ganglia networks. Deep brain stimulation targeted to the internal pallidum (GPi) is an established treatment, but its specific mechanisms remain elusive, and response to therapy is highly variable. Modulation of key dysfunctional networks via axonal connections is likely important. Fifteen patients underwent pre-operative diffusion-MRI acquisitions and then progressed to bilateral DBS targeting the posterior GPi. Severity of disease was assessed pre-operatively and later at follow-up. Scans were used to generate tractography-derived connectivity estimates between the bilateral regions of stimulation and relevant structures. Connectivity to the putamen correlated with clinical improvement, and a series of cortical connectivity-based putaminal parcellations identified the primary motor (M1) putamen as the key node (r = 0.70, p = 0.004). A regression model with this connectivity and electrode coordinates explained 68% of variance in outcomes (r = 0.83, p = 0.001), with both as significant explanatory variables. We conclude that modulation of the M1 putamen-posterior GPi limb of the cortico-basal ganglia loop is characteristic of successful DBS treatment of cervical dystonia. Pre-operative diffusion imaging contains additional information that predicts outcomes, implying utility for patient selection and/or individualised targeting.
Samuel Shribman, Martina Bocchetta, Carole H Sudre, Julio Acosta-Cabronero, Maggie Burrows, Paul Cook, David L Thomas, Godfrey T Gillett, Emmanuel A Tsochatzis, Oliver Bandmann, et al.
Published: 20 July 2021
Abstract:
Wilson’s disease is an autosomal-recessive disorder of copper metabolism with neurological and hepatic presentations. Chelation therapy is used to ‘de-copper’ patients but neurological outcomes remain unpredictable. A range of neuroimaging abnormalities have been described and may provide insights into disease mechanisms, in addition to prognostic and monitoring biomarkers. Previous quantitative MRI analyses have focussed on specific sequences or regions of interest, often stratifying chronically-treated patients according to persisting symptoms as opposed to initial presentation. In this cross-sectional study, we performed a combination of unbiased, whole-brain analyses on T1-weighted, fluid-attenuated inversion recovery, diffusion-weighted and susceptibility-weighted imaging data from 40 prospectively-recruited patients with Wilson’s disease (age range 16–68). We compared patients with neurological (n = 23) and hepatic (n = 17) presentations to determine the neuroradiological sequelae of the initial brain injury. We also subcategorized patients according to recent neurological status, classifying those with neurological presentations or deterioration in the preceding six months as having ‘active’ disease. This allowed us to compare patients with active (n = 5) and stable (n = 35) disease and identify imaging correlates for persistent neurological deficits and copper indices in chronically-treated, stable patients. Using a combination of voxel-based morphometry and region-of-interest volumetric analyses, we demonstrate that grey matter volumes are lower in the basal ganglia, thalamus, brainstem, cerebellum, anterior insula and orbitofrontal cortex when comparing patients with neurological and hepatic presentations. In chronically-treated, stable patients, the severity of neurological deficits correlated with grey matter volumes in similar, predominantly subcortical regions. In contrast, the severity of neurological deficits did not correlate with the volume of white matter hyperintensities, calculated using an automated lesion segmentation algorithm. Using tract-based spatial statistics, increasing neurological severity in chronically-treated patients was associated with decreasing axial diffusivity in white matter tracts whereas increasing serum non-caeruloplasmin-bound (‘free’) copper and active disease were associated with distinct patterns of increasing mean, axial and radial diffusivity. Whole-brain quantitative susceptibility mapping identified increased iron deposition in the putamen, cingulate and medial frontal cortices of patients with neurological presentations relative to those with hepatic presentations and neurological severity was associated with iron deposition in widespread cortical regions in chronically-treated patients. Our data indicate that composite measures of subcortical atrophy provide useful prognostic biomarkers, whereas abnormal mean, axial and radial diffusivity are promising monitoring biomarkers. Finally, deposition of brain iron in response to copper accumulation may directly contribute to neurodegeneration in Wilson’s disease.
Jennifer Z Cheng,
Published: 20 July 2021
Brain, Volume 144, pp 2237-2239; https://doi.org/10.1093/brain/awab259

Abstract:
This scientific commentary refers to ‘Common molecular mechanisms of SLC6A1 variant-mediated neurodevelopmental disorders in astrocytes and neurons’ by Mermer et al. (doi:10.1093/brain/awab207).
Diego Centonze, Mario Stampanoni Bassi
Published: 20 July 2021
Brain, Volume 144, pp 2228-2230; https://doi.org/10.1093/brain/awab211

Abstract:
Neurology, and medicine in general, is torn by opposing tensions: between universality, which is the goal of guidelines and protocols derived from clinical trials, and singularity, which personalized medicine seeks to understand. Centonze and Stampanoni Bassi argue that psychoanalysis could provide a bridge between these domains.
Erratum
Chin-Hsien Lin, Matthew J Farrer, Ruey-Meei Wu
Published: 19 July 2021
Abstract:
Chin-Hsien Lin, Matthew J. Farrer and Ruey-Meei Wu. Reply: UQCRC1 variants in Parkinson’s disease: a large cohort study in Chinese mainland population. Brain. 2021; awab138. doi:10.1093/brain/awab138
, Guy Hindley, Bendik Slagsvold Winsvold, Kevin S O’Connell, Oleksandr Frei, Alexey Shadrin, Weiqiu Cheng, Francesco Bettella, Linn Rødevand, Ketil J Odegaard, et al.
Published: 17 July 2021
Abstract:
Migraine is three times more prevalent in people with bipolar disorder or depression. The relationship between schizophrenia and migraine is less certain although glutamatergic and serotonergic neurotransmission are implicated in both. A shared genetic basis to migraine and mental disorders has been suggested but previous studies have reported weak or non-significant genetic correlations and five shared risk loci. Using the largest samples to date and novel statistical tools, we aimed to determine the extent to which migraine’s polygenic architecture overlaps with bipolar disorder, depression, and schizophrenia beyond genetic correlation, and to identify shared genetic loci. Summary statistics from genome-wide association studies were acquired from large-scale consortia for migraine (n cases=59,674; n controls=316,078), bipolar disorder (n cases=20,352; n controls=31,358), depression (n cases=170,756; n controls=328,443) and schizophrenia (n cases=40,675, n controls=64,643). We applied the bivariate causal mixture model to estimate the number of disorder-influencing variants shared between migraine and each mental disorder, and the conditional/conjunctional false discovery rate method to identify shared loci. Loci were functionally characterised to provide biological insights. Univariate MiXeR analysis revealed that migraine was substantially less polygenic (2.8K disorder-influencing variants) compared to mental disorders (8.1K-12.3K disorder-influencing variants). Bivariate analysis estimated that 0.8K (0.3K), 2.1K (SD = 0.1K) and 2.3K (SD = 0.3K) variants were shared between bipolar disorder, depression and schizophrenia, respectively. There was also extensive overlap with intelligence (1.8K, SD = 0.3K) and educational attainment (2.1K, SD = 0.3K) but not height (1K, SD = 0.1K). We next identified 14 loci jointly associated with migraine and depression and 36 loci jointly associated with migraine and schizophrenia, with evidence of consistent genetic effects in independent samples. No loci were associated with migraine and bipolar disorder. Functional annotation mapped 37 and 298 genes to migraine and each of depression and schizophrenia, respectively, including several novel putative migraine genes such as L3MBTL2, CACNB2, SLC9B1. Gene-set analysis identified several putative gene-sets enriched with mapped genes including transmembrane transport in migraine and schizophrenia. Most migraine-influencing variants were predicted to influence depression and schizophrenia, although a minority of mental disorder-influencing variants were shared with migraine due to the difference in polygenicity. Similar overlap with other brain-related phenotypes suggests this represents a pool of ‘pleiotropic’ variants which influence vulnerability to diverse brain-related disorders and traits. We also identified specific loci shared between migraine and each of depression and schizophrenia, implicating shared molecular mechanisms and highlighting candidate migraine genes for experimental validation.
Thibault Coste, Dominique Hervé, Jean Philippe Neau, Eric Jouvent, Fatoumata Ba, Françoise Bergametti, Matthias Lamy, Julien Cogez, Nathalie Derache, Romain Schneckenburger, et al.
Published: 16 July 2021
Abstract:
Heterozygous missense HTRA1 mutations have been associated with an autosomal dominant cerebral small vessel disease whereas the pathogenicity of heterozygous HTRA1 stop codon variants is unclear. We performed a targeted high throughput sequencing of all known cerebral small vessel disease genes, including HTRA1, in 3,853 unrelated consecutive CSVD patients referred for molecular diagnosis. The frequency of heterozygous HTRA1 mutations leading to a premature stop codon in this patient cohort was compared with their frequency in large control databases. An analysis of HTRA1 messenger RNA was performed in several stop codon carrier patients. Clinical and neuroimaging features were characterized in all probands. Twenty unrelated patients carrying a heterozygous HTRA1 variant leading to a premature stop codon were identified. A highly significant difference was observed when comparing our patient cohort with control databases (gnomAD v3.1.1 (p = 3.12 x 10−17, OR = 21.9), TOPMed freeze 5 (p = 7.6 x 10−18, OR = 27.1) and 1000 Genomes (p = 1.5 x 10−5). Messenger RNA analysis performed in eight patients showed a degradation of the mutated allele strongly suggesting a haploinsufficiency. Clinical and neuroimaging features are similar to those previously reported in heterozygous missense mutation carriers, except for penetrance, which seems lower. Altogether, our findings strongly suggest that heterozygous HTRA1 stop codons are pathogenic through a haploinsufficiency mechanism. Future work will help to estimate their penetrance, an important information for genetic counseling
Saed Khawaldeh, Gerd Tinkhauser, Flavie Torrecillos, Shenghong He, Thomas Foltynie, Patricia Limousin, Ludvic Zrinzo, Ashwini Oswal, Andrew J Quinn, Diego Vidaurre, et al.
Published: 15 July 2021
Abstract:
Exaggerated bursts of activity at frequencies in the low beta band are a well-established phenomenon in the subthalamic nucleus (STN) of patients with Parkinson’s disease. However, such activity is only moderately correlated with motor impairment. Here we test the hypothesis that beta bursts are just one of several dynamic states in the STN local field potential (LFP) in Parkinson’s disease, and that together these different states predict motor impairment with high fidelity. LFPs were recorded in 32 patients (64 hemispheres) undergoing deep brain stimulation surgery targeting the STN. Recordings were performed following overnight withdrawal of anti-parkinsonian medication, and after administration of levodopa. LFPs were analysed using Hidden Markov Modelling to identify transient spectral states with frequencies under 40 Hz. Findings in the low beta frequency band were similar to those previously reported; levodopa reduced occurrence rate and duration of low beta states, and the greater the reductions, the greater the improvement in motor impairment. However, additional LFP states were distinguished in the theta, alpha and high beta bands, and these behaved in an opposite manner. They were increased in occurrence rate and duration by levodopa, and the greater the increases, the greater the improvement in motor impairment. In addition, levodopa favoured the transition of low beta states to other spectral states. When all LFP states and corresponding features were considered in a multivariate model it was possible to predict 50% of the variance in patients’ hemibody impairment OFF medication, and in the change in hemibody impairment following levodopa. This only improved slightly if signal amplitude or gamma band features were also included in the multivariate model. In addition, it compares with a prediction of only 16% of the variance when using beta bursts alone. We conclude that multiple spectral states in the STN LFP have a bearing on motor impairment, and that levodopa-induced shifts in the balance between these states can predict clinical change with high fidelity. This is important in suggesting that some states might be upregulated to improve parkinsonism and in suggesting how LFP feedback can be made more informative in closed-loop deep brain stimulation systems.
, Karin Sadoul
Published: 15 July 2021
Brain, Volume 144, pp 2240-2242; https://doi.org/10.1093/brain/awab265

Abstract:
This scientific commentary refers to ‘Neuronal SETD2 activity links microtubule methylation to an anxiety-like phenotype in mice’, by Koenning et al. (doi:10.1093/brain/awab200).
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