Basal Ganglia Atrophy Research Articles

Protocol for a randomised controlled unblinded feasibility trial of HD-DRUM: a rhythmic movement training application for cognitive and motor symptoms in people with Huntington’s disease

IntroductionHuntington’s disease (HD) is an inherited neurodegenerative disease causing progressive cognitive and motor decline, largely due to basal ganglia (BG) atrophy. Rhythmic training offers promise as therapy to counteract BG-regulated...

4-aminopyridine improves evoked potentials and ambulation in the taiep rat: A model of hypomyelination with atrophy of basal ganglia and cerebellum.

The taiep rat is a tubulin mutant with an early hypomyelination followed by progressive demyelination of the central nervous system due to a point mutation in the Tubb4a gene. It shows clinical, radiological, and pathological signs like those of the human leukodystrophy hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). Taiep rats had tremor, ataxia, immobility episodes, epilepsy, and paralysis; the acronym of these signs given the name to this autosomal recessive trait. The aim of this study was to analyze the characteristics of somatosensory evoked potentials (SSEPs) and motor evoked potentials (MEPs) in adult taiep rats and in a patient suffering from H-ABC. Additionally, we evaluated the effects of 4-aminopyridine (4-AP) on sensory responses and locomotion and finally, we compared myelin loss in the spinal cord of adult taiep and wild type (WT) rats using immunostaining. Our results showed delayed SSEPs in the upper and the absence of them in the lower extremities in a human patient. In taiep rats SSEPs had a delayed second negative evoked responses and were more susceptible to delayed responses with iterative stimulation with respect to WT. MEPs were produced by bipolar stimulation of the primary motor cortex generating a direct wave in WT rats followed by several indirect waves, but taiep rats had fused MEPs. Importantly, taiep SSEPs improved after systemic administration of 4-AP, a potassium channel blocker, and this drug induced an increase in the horizontal displacement measured in a novelty-induced locomotor test. In taiep subjects have a significant decrease in the immunostaining of myelin in the anterior and ventral funiculi of the lumbar spinal cord with respect to WT rats. In conclusion, evoked potentials are useful to evaluate myelin alterations in a leukodystrophy, which improved after systemic administration of 4-AP. Our results have a translational value because our findings have implications in future medical trials for H-ABC patients or with other leukodystrophies.

Basal Ganglia Atrophy and Impaired Cognitive Processing Speed in Multiple Sclerosis.

Impaired cognitive processing speed is among the important higher brain dysfunctions in multiple sclerosis (MS). However, the exact structural mechanisms of the dysfunction remain uncertain. This study aimed to identify the brain regions associated with the impaired cognitive processing speed in MS by comparing the cognitive processing speed, measured using the Cognitive Processing Speed Test (CogEval) z-score, and brain regional volumetric data. Altogether, 80 patients with MS (64 with relapsing-remitting MS [RRMS] and 16 with secondary progressive MS [SPMS]) were enrolled. Consequently, CogEval z-scores were worse in patients with SPMS than in those with RRMS (p=0.001). In the univariate correlation analyses, significant correlations with CogEval z-score were suggested in the MS lesion volume (p<0.001; Spearman's rank correlation test) and atrophies in the cerebral cortex (p=0.031), cerebral white matter (p=0.013), corpus callosum (p=0.001), thalamus (p=0.001), and putamen (p<0.001). Multiple linear regression analysis revealed that putamen atrophy was significantly associated with CogEval z-score (p=0.038) independent of volume in other brain regions, while thalamic atrophy was not (p=0.79). Univariate correlation analyses were further performed in each of RRMS and SPMS. None of the evaluated volumetric data indicated a significant correlation with the CogEval z-score in RRMS. Meanwhile, atrophies in the cerebral white matter (p=0.008), corpus callosum (p=0.002), putamen (p=0.011), and pallidum (p=0.017) demonstrated significant correlations with CogEval z-score in SPMS. In summary, the putamen could be an important region of atrophy contributing to the impaired cognitive speed in MS, especially in the later disease stages after a transition to SPMS.

HD-DRUM, a Tablet-Based Drumming Training App Intervention for People With Huntington Disease: App Development Study.

Huntington disease (HD) is a neurodegenerative condition that leads to progressive loss of cognitive-executive and motor functions, largely due to basal ganglia (BG) atrophy. Currently, there are no therapeutic interventions tailored to address executive and motor dysfunction in people with HD. Music-based interventions may aid executive abilities by compensating for impaired BG-reliant timing and rhythm generation using external rhythmic beats. Here, we applied an integrated knowledge translation (IKT) framework to co-design a tablet-based rhythmic drumming training app (HD-DRUM) to stimulate executive and motor abilities in people with HD. The primary aim was to develop the HD-DRUM app for at-home use that addressed the accessibility needs of people with HD and allowed for the quantification of performance improvements and adherence for controlled clinical evaluation. The IKT framework was applied to iteratively refine the design of HD-DRUM. This process involved 3 phases of knowledge user engagement and co-design: a web-based survey of people with HD (n=29) to inform about their accessibility needs, usability testing of tablet-based touch screens as hardware solutions, and usability testing of the design and build of HD-DRUM to meet the identified accessibility needs of people affected by HD and their clinicians (n=12). The survey identified accessibility problems due to cognitive and motor control impairments such as difficulties in finding and navigating through information and using PC keyboards and mouses to interact with apps. Tablet-based touch screens were identified as feasible and accessible solutions for app delivery. Key elements to ensure that the app design and build met the needs of people with HD were identified and implemented. These included the facilitation of intuitive navigation through the app using large and visually distinctive buttons; the use of audio and visual cues as training guides; and gamification, positive feedback, and drumming to background music as a means to increase motivation and engagement. The co-design development process resulted in the proof-of-concept HD-DRUM app that is described here according to the Template for Intervention Description and Replication checklist. HD-DRUM can be used at home, allowing the quantification of performance improvements and adherence for clinical evaluation, matching of training difficulty to users' performance levels using gamification, and future scale-up to reach a wide range of interested users. Applying an IKT-based co-design framework involving knowledge user engagement allowed for the iterative refinement of the design and build of the tablet-based HD-DRUM app intervention, with the aim of stimulating BG-reliant cognitive and motor functions. Mapping the intervention against the Template for Intervention Description and Replication framework to describe complex interventions allowed for the detailed description of the HD-DRUM intervention and identification of areas that required refinement before finalizing the intervention protocol.

Basal ganglia atrophy as a marker of multiple sclerosis progression

This study presents the findings of the magnetic resonance morphometric analysis of brain subcortical structures in patients with remitting relapsing multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS) phenotypes in comparison with the control group. The study revealed significant differences between the volume of the left nucleus accumbens [control:RRMS= 570,108 ± 100,024:487,851 ± 124,174; F(p) ANOVA= <0001] and the volume of the left globus pallidus [control:RRMS= 2076,247 ± 290,695: 1855,851 ± 280,476; F(p) ANOVA= <0001] in patients with the relapsing remitting phenotype. Patients with the secondary progressive phenotype showed a statistically valid decrease in volume for multiple subcortical structures: the left caudate nucleus [control:SPMS= 3686,500 ± 501,966:3108,946 ± 565,138; F(p) ANOVA= 0.001], right caudate nucleus [control:SPMS= 3772,550 ± 508,087:3242,292 ± 650,215; F(p) ANOVA= 0003], left putamen [control:SPMS= 5130,781 ± 547,844: 4164,967 ± 1076,993; F(p) ANOVA= <0001], right putamen [control:SPMS= 5096,303 ± 611,397: 4281,046 ± 1100,752; F(p) ANOVA= 0001], left globus pallidus [control:SPMS= 2076,247 ± 290.696:1800,913 ± 296,609; F(p) ANOVA= <0001], left nucleus accumbens [control:SPMS= 570,108 ± 100,024;458,904 ± 131,690; F(p) ANOVA= 0001], right nucleus accumbens [control:SPMS= 587,567 ± 100,542: 447,375 ± 103,687; F(p) ANOVA= <0001]. The increase in EDSS was significantly correlated with the decrease in right nucleus accumbens in both RRMS and SPMS. The investigation revealed potential subcortex structures (nucleus accumbens) that could be considered as markers for the transition of RRMS to SPMS.

Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders.

MED27 is a subunit of the Mediator multiprotein complex, which is involved in transcriptional regulation. Biallelic MED27 variants have recently been suggested to be responsible for an autosomal recessive neurodevelopmental disorder with spasticity, cataracts and cerebellar hypoplasia. We further delineate the clinical phenotype of MED27-related disease by characterizing the clinical and radiological features of 57 affected individuals from 30 unrelated families with biallelic MED27 variants. Using exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up 17 ± 12.4 years, range 0.1-45). Follow-up and hitherto unreported clinical features were obtained from the published 12 families. Brain MRI scans from 34 cases were reviewed. MED27-related disease manifests as a broad phenotypic continuum ranging from developmental and epileptic-dyskinetic encephalopathy to variable neurodevelopmental disorder with movement abnormalities. It is characterized by mild to profound global developmental delay/intellectual disability (100%), bilateral cataracts (89%), infantile hypotonia (74%), microcephaly (62%), gait ataxia (63%), dystonia (61%), variably combined with epilepsy (50%), limb spasticity (51%), facial dysmorphism (38%) and death before reaching adulthood (16%). Brain MRI revealed cerebellar atrophy (100%), white matter volume loss (76.4%), pontine hypoplasia (47.2%) and basal ganglia atrophy with signal alterations (44.4%). Previously unreported 39 affected individuals had seven homozygous pathogenic missense MED27 variants, five of which were recurrent. An emerging genotype-phenotype correlation was observed. This study provides a comprehensive clinical-radiological description of MED27-related disease, establishes genotype-phenotype and clinical-radiological correlations and suggests a differential diagnosis with syndromes of cerebello-lental neurodegeneration and other subtypes of 'neuro-MEDopathies'.

Generation of three induced Pluripotent Stem Cell lines from individuals with Hypomyelination with Atrophy of Basal Ganglia and Cerebellum caused by a c.745G>A (p.D249N) autosomal dominant mutation in TUBB4A

Mutations in tubulin alpha 4a (TUBB4A) result in a spectrum of leukodystrophies, including Hypomyelination with atrophy of basal ganglia and cerebellum (H-ABC), resulting from a recurring mutation p.Asp249Asn (TUBB4AD249N). H-ABC presents with dystonia, motor and cognitive impairment and pathological features of hypomyelination and loss of cerebellar and striatal neurons. We have generated three induced pluripotent stem cell (iPSC) lines from fibroblast and peripheral blood mononuclear cells (PBMCs) of individuals with TUBB4AD249N mutation. The iPSCs were assessed to confirm a normal karyotype, pluripotency, and trilineage differentiation potential. The iPSCs will allow for disease modeling, understanding mechanisms and testing of therapeutic targets.

Basal Ganglia Atrophy as a Marker for Prodromal X-Linked Dystonia-Parkinsonism.

In neurodegenerative diseases, the characterization of the prodromal phase is essential for the future application of disease-modifying therapies. X-linked dystonia-parkinsonism is a hereditary neurodegenerative movement disorder characterized by severe adult-onset dystonia accompanied by parkinsonism. Distinct striatal and pallidal atrophy is present already in early disease stages indicating a long-lasting presymptomatic degenerative process. To gain insight into the prodromal phase of X-linked dystonia-parkinsonism, structural and iron-sensitive magnetic resonance imaging (MRI) was performed in 10 non-manifesting carriers and 24 healthy controls in a double-blind fashion. Seventeen patients with X-linked dystonia-parkinsonism were recruited to replicate previous findings of basal ganglia pathology and iron accumulation. Age at onset was estimated in non-manifesting carriers and patients using the repeat length of the hexanucleotide expansion and 3 single-nucleotide polymorphisms associated with age at onset. Voxel-based morphometry and subcortical volumetry showed striatal and pallidal atrophy in non-manifesting carriers (~10%) and patients (~40%). Substantia nigra volume was similarly reduced in patients (~40%). Caudate volume correlated with time to estimated onset in non-manifesting carriers. Susceptibility-weighted imaging confirmed iron deposition in the anteromedial putamen in patients. Non-manifesting carriers also showed small clusters of iron accumulation in the same area after lowering the statistical threshold. In conclusion, basal ganglia atrophy and iron accumulation precede the clinical onset of X-linked dystonia-parkinsonism and can be detected years before the estimated disease manifestation. It thereby highlights the potential of multimodal imaging to identify clinically unaffected mutation carriers with incipient neurodegeneration and to monitor disease progression independent of clinical measures. Longitudinal studies are needed to further elucidate the onset and progression rate of neurodegeneration in prodromal X-linked dystonia-parkinsonism. ANN NEUROL 2023;93:999-1011.

Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (HABC) Due to UFM1 Mutation in Roma Patients - Severe Early Encephalopathy with Stridor and Severe Hearing and Visual Impairment. A Single Center Experience.

Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a neurodegenerative disease with neurodevelopmental delay, motor, and speech regression, pronounced extrapyramidal syndrome, and sensory deficits due to TUBB4A mutation. In 2017, a severe variant was described in 16 Roma infants due to mutation in UFM1. The objective of this study is to expand the clinical manifestations of H-ABC due to UFM1 mutation and suggest clues for clinical diagnosis. Retrospective analysis of all 9 cases with H-ABC due to c.-273_-271delTCA mutation in UFM1 treated during 2013-2020 in a Neuropediatric Ward in Plovdiv, Bulgaria. Presentation is no later than 2 months with inspiratory stridor, impaired sucking, swallowing, vision and hearing, and reduced active movements. By the age of 10 months, a monomorphic disease was observed: microcephaly (6/9), malnutrition (5/9), muscle hypertonia (9/9) and axial hypotonia (4/9), progressing to opisthotonus (6/9), dystonic posturing (5/9), nystagmoid ocular movements (6/9), epileptic seizures (4/9), non-epileptic spells (3/9). Dysphagia (7/9), inspiratory stridor (9/9), dyspnea (5/9), bradypnea (5/9), apnea (2/9) were major signs. Vision and hearing were never achieved or lost by 4-8 mo. Neurodevelopment was absent or minimal with subsequent regression after 2-5 mo. Brain imaging revealed cortical atrophy (7/9), atrophic ventricular dilatation (4/9), macrocisterna magna (5/9), reduced myelination (6/6), corpus callosum atrophy (3/6) and abnormal putamen and caput nuclei caudati. The age at death was between 8 and 18 mo. Roma patients with severe encephalopathy in early infancy with stridor, opisthotonus, bradypnea, severe hearing and visual impairment should be tested for the Roma founder mutation of H-ABC in UFM1.

Chorea in moyamoya disease with ipsilateral basal ganglia atrophy and mineralization

Chorea in moyamoya disease with ipsilateral basal ganglia atrophy and mineralization

Structural alterations of spinocerebellar ataxias type 3: from pre-symptomatic to symptomatic stage.

To investigate and characterize the structural alterations of the brain in SCA3, and their correlations with the scale for the assessment and rating of ataxia (SARA) and normal brain ATXN3 expression. We performed multimodal analyses in 52 SCA3 (15 pre-symptomatic) and healthy controls (HCs) (n = 35) to assess the abnormalities of gray and white matter (WM) of the cerebrum, brainstem, and cerebellum via FreeSurfer, SUIT, and TBSS, and their associations with disease severity. Twenty SCA3 patients (5 pre- and 15 symptomatic) were followed for at least a year. Besides, we uncovered the normal pattern of brain ATXN3 spatial distribution. Pre-symptomatic patients showed only WM damage, mainly in the cerebellar peduncles, compared to HCs. In the advanced stage, the WM damage followed a caudal-rostral pattern. Meanwhile, continuous nonlinear structure damage was characterized by brainstem volumetric reduction and relatively symmetric cerebellar and basal ganglia atrophy but spared the cerebral cortex, partially explained by the ATXN3 overexpression. The bilateral pallidum, brainstem, and cerebellar peduncles demonstrated a very large effect size. Besides, all these alterations were significantly correlated with SARA; the pons (r = -0.65) and superior cerebellar peduncle (r = -0.68) volume demonstrated a higher correlation than the cerebellum with SARA. The longitudinal study further uncovered progressive atrophy of pons in symptomatic SCA3. Significant WM damage starts before the ataxia onset. The bilateral pallidum, brainstem, and cerebellar peduncles are the most vulnerable targets. The volume of pons appears to be the most promising imaging biomarker for a longitudinal study. ClinicalTrial ID: ChiCTR2100045857 ( http://www.chictr.org.cn/edit.aspx?pid=55652&htm=4 ) KEY POINTS: • Pre- SCA3 showed WM damage mainly in cerebellar peduncles. Continuous brain damage was characterized by brainstem, widespread, and relatively symmetric cerebellar and basal ganglia atrophy. • Volumetric abnormalities were most evident in the bilateral pallidum, brainstem, and cerebellar peduncles in SCA3. • The volume of pons might identify the disease progression longitudinally.

A new entity of hypomyelination with atrophy of basal ganglia and cerebellum-like syndrome with bilateral developmental cataract.

A new entity of hypomyelination with atrophy of basal ganglia and cerebellum-like syndrome with bilateral developmental cataract.

DLPF Targeted Repetitive Transcranial Magnetic Stimulation Improves Brain Glucose Metabolism Along with the Clinical and Electrophysiological Parameters in CBD Patients.

Corticobasal Degeneration (CBD) is a rare neurological disease caused by the pathological accumulation of tau protein. The primary pathological features of CBD include progressive neurodegenerative processes resulting in remarkable frontoparietal and basal ganglia atrophy. Like in many other neurodegenerative disorders, there is still no effective disease-modifying drug therapy in CBD. Therefore, the development of new treatment methods is of great importance. In this study, we aimed to assess the stimulating effects of high-frequency DLPFC rTMS on the motor, cognitive and behavioral disturbances in four CBD patients. Four (three females, one male) CBD patients who had been diagnosed as CBD were enrolled in this study. Patients were evaluated before and after the rTMS procedure regarding the motor, neuropsychometric and behavioral tests. The results of statistical analysis of behavioral and neuropsychometric evaluation were assessed via SPSS 18.0 package program. Data are expressed as mean, standard deviation. Before and after values of the groups were compared with the Wilcoxon sign rank test, and p<0.05 was considered significant. We have provided strong preliminary evidence that the improvement in clinical parameters was associated with the normalizations of the theta activity and glucose metabolism. Our current results are consistent with some previous trials showing a strong association between DLPFC targeted rTMS and electrophysiological normalizations in the left DLPFC.

Co-occurrence of Fatigue and Depression in People With Multiple Sclerosis: A Mini-Review.

Fatigue and depression are common conditions diagnosed in people with multiple sclerosis (MS). Fatigue defined as subjective lack of physical and/or mental energy is present in 35–97% of people with MS, who classify it as one of the most serious symptoms interfering with daily activities and influencing the quality of life. Depression is diagnosed in about 50% of people with MS. Since fatigue and depression frequently coexists, it may be quite hard to differentiate them. Primary fatigue and primary depression in MS are caused by inflammatory, oxidative/nitrosative, and neurodegenerative processes leading to demyelination, axonal damage, and brain atrophy. In people with MS and comorbid fatigue and/or depression there is reported increased serum and cerebrospinal fluid concentration of inflammatory mediators such as tumor necrosis factor, interleukins (IL-1a, IL-1b, IL-6), interferon γ and neopterin. Moreover, the brain atrophy of prefrontal, frontal, parietotemporal regions, thalamus, and basal ganglia was observed in people with MS with fatigue and/or depression. The secondary fatigue and secondary depression in people with MS may be caused by emotional factors, sleep disorders, pain, the coexistence of other diseases, and the use of medications. In some studies, the use of disease-modifying therapies positively influenced fatigue, probably by reducing the inflammatory response, which proves that fatigue and depression are closely related to immunological factors. In this mini-review, the pathogenesis, methods of evaluation and differentiation, and possible therapies for fatigue and depression in MS are discussed.

Converging longitudinal patterns of atrophy in clinical variants of frontotemporal lobar degeneration

AbstractBackgroundThe aim of this study was to assess longitudinal patterns of atrophy shown by magnetic resonance imaging (MRI) in the whole‐brain GM of patients affected by different clinical variants of the FTLD spectrum.MethodFifty‐nine patients, including 26 with behavioral variant of frontotemporal dementia (bvFTD), 10 non‐fluent/agrammatic variant of primary progressive aphasia (nfvPPA), 12 semantic variant of PPA (svPPA), and 11 MND, in the absence of known pathogenic mutations, underwent MRI on a 3T scanner at 6‐month intervals for one year. Thirty‐three healthy controls underwent the same protocol. 3D T1‐weighted MRI sequences were analyzed using voxel‐based morphometry to assess the longitudinal evolution of GM atrophy in patients, compared with HC.ResultAt baseline, severe diffuse atrophy of frontotemporal cortical regions and basal ganglia was found in bvFTD, nfvPPA and svPPA groups, whereas MND did not show significant GM atrophy. At 6‐month follow‐up, bvFTD and PPA groups showed significant progression of atrophy in the insular (bvFTD, nfvPPA and svPPA) and anterior cingulate cortex (bvFTD and nfvPPA), bilaterally, as well as in the left caudate nucleus and middle temporal cortex (svPPA). At 12‐month follow‐up, similar patterns of atrophy progression were found, with the additional involvement of the superior frontal cortical gyri in nfvPPA, bilaterally, and the right hippocampus in svPPA. No significant progression of atrophy was found in MND patients.ConclusionOur data suggest that atrophy of insular and anterior cingulate cortical regions closely reflects the progression of neurodegeneration across the behavioral and linguistic presentations of frontotemporal dementia (FTD), in contrast with a substantial sparing of GM in MND. Supported by: European Research Council (StG‐2016_714388_NeuroTRACK).

Basal ganglia atrophy-associated causal structural network degeneration in Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by both motor and non‐motor symptoms. A convergent pathophysiological hallmark of PD is an early selective vulnerability within the basal ganglia circuit. However, the causal interactions between basal ganglia atrophy and progressive structural network alterations in PD remain unaddressed. Here, we adopted voxel‐based morphometry method to measure gray matter (GM) volume for each participant (n = 84 PD patients and n = 70 matched healthy controls). Patients were first divided into three stages according to the Hoehn and Yahr (H&Y) and the Part III of Unified Parkinson's Disease Rating Scale scores respectively to analyze the stage‐specific GM atrophy patterns. Then, the modulation of early caudate atrophy over other brain structures was evaluated using the whole‐brain voxel‐wise and region‐of‐interest‐wise causal structural covariance network approaches. We found that GM atrophy progressively expands from the basal ganglia to the angular gyrus, temporal areas, and eventually spreads through the subcortical–cortical networks as PD progresses. Notably, we identified a shared caudate‐associated degeneration network including the basal ganglia, thalamus, cerebellum, sensorimotor cortex, and cortical association areas with the PD progressive factors. These findings suggest that the early structural vulnerability of basal ganglia in PD may play a pivotal role in the modulation of motor and non‐motor circuits at the structural level. Our work provides evidence for a novel mechanism of network degeneration that underlies the pathology of PD and may have potential clinical applications in the development of early predictors of PD onset and progress.

Basal ganglia-orbitofrontal circuits are associated with prospective memory deficits in Wilson's disease.

Degenerative changes in the basal ganglia (BG) are thought to contribute to neurological symptoms in Wilson's disease (WD). However, very little is known about whether and how the BG have an influence on prospective memory (PM) by interacting with the cerebral cortex. Here, we employed structural magnetic resonance imaging to systematically examine the effect of volume atrophy of BG on cortical thickness and to evaluate the relationships between cortical thickness of regions associated with BG atrophy and PM performance in WD. Cortical thickness atrophy in the left temporal pole and medial frontal gyrus are not related to degenerative changes in BG. Cortical thickness in the left superior frontal gyrus and right orbitofrontal gyrus (ORB) have stronger correlations with volume atrophy of the left accumbens, pallidum, and putamen in WD when compared with healthy controls. Furthermore, the cortical thickness of the right ORB is not only significantly correlated with PM performance but can also distinguish the severity of PM impairment in WD. Additionally, the middle cingulate cortex was related to volume atrophy of the accumbens, and its cortical thickness has a significant positive correlation with event-based PM. Together, these findings highlight that BG-orbitofrontal circuits may serve as neural biomarkers of PM and provide implications for the neural mechanisms underlying cognitive impairment in WD.

Amyotrophic lateral sclerosis features predict TDP-43 pathology in frontotemporal lobar degeneration

Clinical and pathological heterogeneity is common in patients with frontotemporal lobar degeneration (FTLD) pathology. This investigated clinical or imaging characteristics that differentiate FTLD-TDP from FTLD-tau, FTLD-TDP subtypes from each other, or pathological stages of FTLD-TDP. Initial clinical, neuropsychological and neuroimaging characteristics were compared between pathologically defined FTLD-tau and FTLD-TDP groups. Voxel-based morphometry analyses contrasted grey matter atrophy patterns. Twenty-six FTLD-TDP, 28 FTLD-tau and 78 controls were included. Amyotrophic lateral sclerosis features, when present, were highly specific FTLD-TDP, which displayed greater cortical and subcortical atrophy than FTLD-tau. FTLD-TDP-43 type B had significantly shorter survival than type A. Type A patients were more cognitively impaired than type B, and basal ganglia atrophy appeared to distinguish type A from type B. Age at onset and survival duration were comparable between stages II and IV. In conclusion, Amyotrophic lateral sclerosis features may be useful in distinguishing FTLD-TDP from FTLD-tau. TDP-43 type A and B appear to present with distinct profiles. The relationship between clinical features and pathological staging in FTLD-TDP-43 is complex, and TDP-43 subtyping may have more clinical utility.

Brain Structural Signature of RFC1-Related Disorder.

The cerebellar ataxia, neuropathy, and vestibular areflexia syndrome was initially described in the early 1990s as a late-onset slowly progressive condition. Its underlying genetic cause was recently mapped to the RFC1 gene, and additional reports have expanded on the phenotypic manifestations related to RFC1, although little is known about the pattern and extent of structural brain abnormalities in this condition. The aim is to characterize the structural signature of brain damage in RFC1-related disorder, correlating the findings with clinical symptoms and normal brain RFC1 expression. We recruited 22 individuals with molecular confirmation of RFC1 expansions and submitted them to high-resolution 3T magnetic resonance imaging scans. We performed multimodal analyses to assess separately cerebral and cerebellar abnormalities within gray and white matter (WM). The results were compared with a group of 22 age- and sex-matched controls. The mean age and disease duration of patients were 62.8 and 10.9 years, respectively. Ataxia, sensory neuronopathy, and vestibular areflexia were the most frequent manifestations, but parkinsonism and pyramidal signs were also noticed. We found that RFC1-related disorder is characterized by widespread and relatively symmetric cerebellar and basal ganglia atrophy. There is brainstem volumetric reduction along all its segments. Cerebral WM is also involved-mostly the corpus callosum and deep tracts, but cerebral cortical damage is rather restricted. This study adds new relevant insights into the pathophysiological mechanisms of RFC1-related disorder. It should no longer be considered a purely cerebellar and sensory pathway disorder. Basal ganglia and deep cerebral WM are additional targets of damage. © 2021 International Parkinson and Movement Disorder Society.

Crystallographic modeling of the PNPT1:c.1453A>G variant as a cause of mitochondrial dysfunction and autosomal recessive deafness; expanding the neuroimaging and clinical features

Deficiency of the proteins involved in oxidative phosphorylation (OXPHOS) can lead to mitochondrial dysfunction. Polyribonucleotide nucleotidyltransferase 1 (PNPT1) is one of the genes involved in the OXPHOS and encodes the mitochondrial polynucleotide phosphorylase (PNPase) which is implicated in RNA-processing exoribonuclease activity. Herein, we report a 34-month-old boy who presented with global developmental delay, muscular hypotonia, hearing impairment, and movement disorders including chorea and dystonia. Mitochondrial genome sequencing and whole-exome sequencing (WES) were performed and a variant in PNPT1:c.1453A>G; p. (Met485Val) was identified. A number of patient’s neurologic problems had been already reported in previous studies, however, lower limbs spasticity and bulbar dysfunction were novel phenotypic findings. In addition, delayed myelination during infancy, progressive basal ganglia atrophy, and brain stem abnormal signals including transverse pontine fibers and superior colliculus involvement were also novel neuroimaging findings in this case. Different crystallographic modeling and stereochemical analysis of the c.1453A>G; p. (Met485Val) variant showed this variant affects the active site of the protein and disrupts the normal protein function.