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Based on motor symptoms, Parkinson's disease (PD) can be classified into tremor dominant (TD) and postural instability gait difficulty (PIGD) subtypes. Few studies have examined cortical complexity differences in PD motor subtypes. This study aimed to investigate differences in cortical complexity and grey matter volume (GMV) between TD and PIGD. We enrolled 36 TD patients, 27 PIGD patients and 66 healthy controls (HC) from the PPMI (Parkinson's Progression Markers Initiative) database. Voxel-based morphometry (VBM) and surface-based morphometry (SBM) were utilized to assess differences in GMV, cortical thickness and cortical complexity. The structural MRI data of participants was analysed using CAT12/SPM12 (p < 0.05, FDR corrected). Additionally, correlations between clinical data and structural changes were examined (p < 0.05, Holm-Bonferroni corrected). In comparison to both HC and TD groups, PIGD patients exhibited a significant fractal dimension (FD) decrease in many cortical regions. A significant negative correlation between age and FD was observed in the left insula for the PIGD patients and in the bilateral insula for the TD patients. However, no significant differences were found in GMV, cortical thickness or other complexity indices. Altered FD in the bilateral insula indicates that postural instability and gait disturbances may result from a failure to integrate information from various structures, whereas parkinsonian rest tremor is not associated with this integration. Also, widespread decreases in cortical FD demonstrate that FD is more sensitive than other complexity measures and can serve as a novel biomarker for identifying subtle changes in cortical morphology in the PIGD subtype., (© 2024 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Parkinson's disease (PD) patients with postural gait abnormalities exhibit poorer motor function scores, more severe non-motor symptoms, faster cognitive function deterioration, and a less favorable response to drugs and surgery compared to PD patients with tremor. This discrepancy is believed to be associated with more pronounced gray matter atrophy and abnormal functional connectivity. To investigate the distinctive pathological mechanisms between PD subtypes, we examined gray matter volume (GMV) and functional connectivity in patients with Parkinson's disease presenting with postural instability/gait difficulty (PD-PIGD), patients with tremor-dominant Parkinson's disease (PD-TD), and healthy controls. Voxel-based morphometry (VBM) of T1-weighted images was conducted to compare GMV among 64 PD-PIGD patients, 44 PD-TD patients, and 32 controls. Subsequently, functional connectivity within regions showing reduced GMV was compared across the groups. We analyzed whether differences among the groups were associated with clinical characteristics and neuroimaging biomarkers using partial correlation and binary logistic regression. Our comparison between PD-PIGD and PD-TD patients revealed a link between PD-PIGD and more extensive frontotemporal atrophy, potentially indicating increased basal ganglia activity accompanied by decreased cerebellum activity. Furthermore, in addition to the smaller GMV in the left middle temporal gyrus, the increased functional connectivity between this brain region and the right caudate was also the independent risk factor for PD-PIGD. In addition, we compared brain network connectivity between the PIGD and TD subtypes, using an independent component analysis (ICA). We found that Compared to PD-TD, PD-PIGD patients showed an enhanced sensorimotor network (SMN) around the left supplementary motor area. These findings suggest that severe gray matter atrophy and abnormal functional connectivity and brain networks may serve as pathophysiological mechanisms distinguishing PD-PIGD patients from other subtypes., Competing Interests: Declarations. Ethical approval: All authors certify that they abide by the principles of ethical publishing, and the study has been approved by the Research Ethics Committee of the First Affiliated Hospital of Kunming Medical University. Informed consent: The patient has informed consent. Conflict of interest: The authors declare that they have no conflicts of interest., (© 2024. The Author(s) under exclusive licence to Belgian Neurological Society.)

Background: Premutation alleles of the FMR1 X-linked gene containing CGG repeat expansions ranging from 55 to 200 are associated with diverse late-onset neurological involvements, including most severe disorder termed Fragile X-associated Tremor/Ataxia Syndrome (FXTAS). It is intriguing that at least one-third of male, and a much lower than predicted from the X-linkage proportion of female carriers are free of this syndrome. This suggests the existence of secondary genetic factors modifying the risk of neurological involvements in these carriers. Considering the occasional presence of parkinsonian features in FXTAS, we explored the possibility that the Parkinson's Disease Polygenic Risk Score (PD PRS) is related to the occurrence of FXTAS or less severe neurological involvements, in premutation carriers., Methods: The Genome-wide SNP genotyping and clinical data on neurological status were obtained from 250 unrelated affected and non-affected male and female adult carriers of the premutation. The medians for the Parkinson's Disease Polygenic Risk Score (PD PRS) were compared between the groups of asymptomatic and neurologically affected carriers, and the association of PD PRS with neurological involvement in context with the other known risk factors was explored by fitting univariate and multiple logistic regression models., Results: There was a significant difference between the medians from the asymptomatic versus neurologically affected (FXTAS+) groups (p = 0.009). The FXTAS+ status was significantly associated with age at testing (p < 0.001), gender (p = 0.026), and with PD PRS (p = 0.021). The contribution of PD PRS remained significant after adjusting for age and gender (p = 0.044)., Conclusions: We have obtained the first evidence for the relationship between PD PRS and the risk of FXTAS or lesser neurological involvements in the FMR1 premutation carriers. This suggests the role of Parkinson's disease polygenic variants as genetic modifiers of the risk of late onset neurological changes in these carriers., (© 2024 The Author(s). Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Background: POLIII-related leukodystrophies are a group of recently recognized hereditary white matter diseases with a similar clinical and radiological phenotype. No Tunisian studies have been published about POLIII-related leukodystrophy due to POLR3A variants. The aim of this study was to contribute to the clinical, radiological, and genetic characterization of POLR3A-related leukodystrophy in a Tunisian cohort., Methods: We report six cases of genetically confirmed POLR3A-related leukodystrophy belonging to six unrelated Tunisian families, along with a review of previously published pediatric cases., Results: All patients were born to consanguineous marriages and originated from the North or the Center of Tunisia. Age at onset varied between 15 months and 6 years. The clinical phenotype was similar in all patients with cerebellar ataxia, tremor, and nystagmus being the key features. Brain imaging showed diffuse hypomyelination in all patients with progressive cerebellar atrophy in three patients. Molecular analysis identified the same bi-allelic NM&#95;007055.4:c.2011T>C; p.(Trp671Arg) variant in the POLR3A gene in all patients., Conclusion: We hypothesize a founder effect for the identified variant given its recurrence in six unrelated individuals with a similar clinical phenotype. Given the apparent genetic homogeneity of Tunisian POLR3A patients, the recurrent variant should be directly targeted. This should facilitate diagnosis in index patients, and genetic counseling., (© 2024 The Author(s). Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Background: Essential tremor (ET) and dystonic tremor (DT) are the two most common tremor disorders, and misdiagnoses are very common due to similar tremor symptoms. In this study, we explore the structural network mechanisms of ET and DT using brain grey matter (GM) morphological networks and combine those with machine learning models., Methods: 3D-T1 structural images of 75 ET patients, 71 DT patients, and 79 healthy controls (HCs) were acquired. We used voxel-based morphometry to obtain GM images and constructed GM morphological networks based on the Kullback-Leibler divergence-based similarity (KLS) method. We used the GM volumes, morphological relations, and global topological properties of GM-KLS morphological networks as input features. We employed three classifiers to perform the classification tasks. Moreover, we conducted correlation analysis between discriminative features and clinical characteristics., Results: 16 morphological relations features and 1 global topological metric were identified as the discriminative features, and mainly involved the cerebello-thalamo-cortical circuits and the basal ganglia area. The Random Forest (RF) classifier achieved the best classification performance in the three-classification task, achieving a mean accuracy (mACC) of 78.7%, and was subsequently used for binary classification tasks. Specifically, the RF classifier demonstrated strong classification performance in distinguishing ET vs. HCs, ET vs. DT, and DT vs. HCs, with mACCs of 83.0 %, 95.2 %, and 89.3 %, respectively. Correlation analysis demonstrated that four discriminative features were significantly associated with the clinical characteristics., Conclusion: This study offers new insights into the structural network mechanisms of ET and DT. It demonstrates the effectiveness of combining GM-KLS morphological networks with machine learning models in distinguishing between ET, DT, and HCs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

FMR1 premutation carriers (55-200 CGG repeats) are at risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder associated with motor and cognitive impairment. Bilateral hyperintensities of the middle cerebellar peduncles (MCP sign) are the major radiological hallmarks of FXTAS. In the general population, enlarged perivascular spaces (PVS) are biomarkers of small vessel disease and glymphatic dysfunction and are associated with cognitive decline. Our aim was to determine if premutation carriers show higher ratings of PVS than controls and whether enlarged PVS are associated with motor and cognitive impairment, MRI features of neurodegeneration, cerebrovascular risk factors and CGG repeat length. We evaluated 655 MRIs (1-10 visits/participant) from 229 carriers (164 with FXTAS and 65 without FXTAS) and 133 controls. PVS in the basal ganglia (BG-EPVS), centrum semiovale, and midbrain were evaluated with a semiquantitative scale. Mixed-effects models were used for statistical analysis adjusting for age. In carriers with FXTAS, we revealed that (1) BG-PVS ratings were higher than those of controls and carriers without FXTAS; (2) BG-PVS severity was associated with brain atrophy, white matter hyperintensities, enlarged ventricles, FXTAS stage and abnormal gait; (3) age-related increase in BG-PVS was associated with cognitive dysfunction; and (4) PVS ratings of all three regions showed robust associations with CGG repeat length and were higher in carriers with the MCP sign than carriers without the sign. This study demonstrates clinical relevance of PVS in FXTAS especially in the basal ganglia region and suggests microangiopathy and dysfunctional cerebrospinal fluid circulation in FXTAS physiopathology., Competing Interests: Declaration of competing interest R.J.H. has received funding from Zynerba,Tetra Pharma and the Azrieli Foundation to carry out treatment studies in fragile X syndrome and has also consulted with Zynerba regarding treatment studies in fragile X syndrome. D.H. has received funding from the following, all of which are directed to the UC Davis, in support of fragile X treatment programs, and he receives no personal funds and has no relevant financial interest in any of the commercial entities listed: Autifony, Ovid, Tetra/Shionogi, Healx, and Zynerba pharmaceutical companies to consult on outcome measures and clinical trial design. F.T. has received funding from Zynerba and the Azrieli Foundation to carry out molecular studies in fragile X syndrome. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Mitochondrial impairments have been implicated in the pathogenesis of Fragile X-associated tremor/ataxia syndrome (FXTAS) based on analysis of mitochondria in peripheral tissues and cultured cells. We sought to assess whether mitochondrial abnormalities present in postmortem brain tissues of patients with FXTAS are also present in plasma neuron-derived extracellular vesicles (NDEVs) from living carriers of fragile X messenger ribonucleoprotein1 (FMR1) gene premutations at an early asymptomatic stage of the disease continuum., Methods: We utilized postmortem frozen cerebellar and frontal cortex samples from a cohort of eight patients with FXTAS and nine controls and measured the quantity and activity of the mitochondrial proteins complex IV and complex V. In addition, we evaluated the same measures in isolated plasma NDEVs by selective immunoaffinity capture targeting L1CAM from a separate cohort of eight FMR1 premutation carriers and four age-matched controls., Results: Lower complex IV and V quantity and activity were observed in the cerebellum of FXTAS patients compared to controls, without any differences in total mitochondrial content. No patient-control differences were observed in the frontal cortex. In NDEVs, FMR1 premutation carriers compared to controls had lower activity of Complex IV and Complex V, but higher Complex V quantity., Interpretation: Quantitative and functional abnormalities in mitochondrial electron transport chain complexes IV and V seen in the cerebellum of patients with FXTAS are also manifest in plasma NDEVs of FMR1 premutation carriers. Plasma NDEVs may provide further insights into mitochondrial pathologies in this syndrome and could potentially lead to the development of biomarkers for predicting symptomatic FXTAS among premutation carriers and disease monitoring., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Rest tremor is a movement disorder commonly found in diseases like Parkinson's disease (PD) and essential tremor (ET). Rest tremor typically shows slower progression in PD, but more severe progression in ET. However, the underlying white matter organization of rest tremor behind PD and ET remains unclear., Methods: This study included 57 ET patients (40 without rest tremor (ETWR), 17 with rest tremor (ETRT)), 68 PD patients (34 without rest tremor (PDWR), 34 with rest tremor (PDRT)), and 62 normal controls (NC). Fixel-based analysis was used to evaluate the structural changes of white matter in rest tremor in these different diseases., Results: The fiber-bundle cross-section (FC) of the right non-decussating dentato-rubro-thalamic tract and several fibers outside the dentato-rubro-thalamic pathway in ETWR were significantly higher than that in NC. The fiber density and cross-section of the left nigro-pallidal in PDWR is significantly lower than that in NC, while the FC of bilateral nigro-pallidal in PDRT is significantly lower than that in NC., Conclusion: ET patients with pure action tremor showed over-activation of fiber tracts. However, when superimposed with rest tremor, ET patients no longer exhibited over-activation of fiber tracts, but rather showed a trend of fiber tract damage. Except for the nigro-pallidal degeneration in all PD, PDRT will not experience further deterioration in fiber organization. These results provide important insights into the unique effects of rest tremor on brain fiber architecture in ET and PD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Rationale and Objectives: This study aimed to investigate the structural and functional alterations occurring within bilateral premotor thalamus (mPMtha) in motor subtypes of Parkinson's disease (PD)., Materials and Methods: Sixty-one individuals with instability and gait difficulty (PIGD) subtype, 60 individuals with tremor-dominant (TD) subtype and 66 healthy controls (HCs) participated in the study. All participants underwent resting-state functional magnetic resonance imaging (rs-fMRI) and 3D T1-weighted (3DT1) scans. Functional connectivity (FC) analysis and Voxel-based morphometry (VBM) analysis were performed to evaluate the function and volume of mPMtha. Additionally, correlations between motor performance and FC values, volumes were examined separately. Support vector machine (SVM) model based on FC values and thalamic volumes was conducted to assist in the clinical diagnosis of PD motor subtype., Results: Compared to HCs and PIGD, TD subtype showed increased FC between the bilateral mPMtha and left middle occipital gyrus, left inferior parietal lobule (IPL). While PIGD subtype demonstrated decreased FC between right mPMtha and precentral gyrus (PreCG), supramarginal, IPL and superior parietal lobule. FC of bilateral mPMtha with the identified regions were significantly correlated with motor performance scores in PD patients. The SVM classification based on FC values demonstrated a high level of efficiency (AUC=0.874). The volumes of the bilateral mPMtha were indifferent among three groups., Conclusion: We noted distinct FC alterations of mPMtha in TD and PIGD subtypes, and these changes were correlated with motor performance. Furthermore, the machine learning based on statistically significant FC might be served as an alternative approach for automatically classifying PD motor subtypes individually., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Objective : Hypertrophic Olivary Degeneration is a rare condition causing transneuronal degeneration of the inferior olivary nucleus. Symptoms manifest as progressively worsening palatal tremor, ataxia, and eye movement disturbances that plateau after several months. Though rarely documented in the literature of this specific condition, disconnection of the inferior olivary nucleus from the cerebellum, and cerebellar atrophy represent a pathway to developing subsequent cerebellar cognitive affective syndrome. The presented case documents the neuropsychological sequelae of a 39-year-old female with a history of hypertrophic olivary degeneration and symptoms of palatal tremor, opsoclonus myoclonus, ataxia, and delusions. Method: Review of the patient's medical records, interviews with the patient and her father, and a neuropsychological assessment battery were used to collect data. Review of currently published literature lent to case conceptualization. Results: Neuropsychological testing revealed deficits in executive functioning, attention, and language. An anomalous, fixed persecutory delusion was revealed. Conclusion: Hypertrophic olivary degeneration creates disconnection syndromes between the inferior olivary nucleus, red nucleus, and cerebellum. Late stages of the disorder cause atrophy of the inferior olivary nucleus and adjacent structures. While the motor sequela is well documented, the neuropsychological and psychiatric impact is infrequently discussed in existing literature. We present the first case to detail the neuropsychological sequelae of hypertrophic olivary degeneration and propose a mechanism for the development of cognitive impairment and psychotic features within this condition.

Essential tremor (ET) is a common, progressive neurological disease characterized by an 8-12-Hz kinetic tremor. Despite its high prevalence, the patho-mechanisms of tremor in ET are not fully known. Through comprehensive studies in postmortem brains, we identified major morphological changes in the ET cerebellum that reflect cellular damage in Purkinje cells (PCs), suggesting that PC damage is central to ET pathogenesis. We previously performed a transcriptome analysis in ET cerebellar cortex, identifying candidate genes and several dysregulated pathways. To directly target PCs, we purified RNA from PCs isolated by laser capture microdissection and performed the first ever PC-specific RNA-sequencing analysis in ET versus controls. Frozen postmortem cerebellar cortex from 24 ETs and 16 controls underwent laser capture microdissection, obtaining ≥2000 PCs per sample. RNA transcriptome was analyzed via differential gene expression, principal component analysis (PCA), and gene set enrichment analyses (GSEA). We identified 36 differentially expressed genes, encompassing multiple cellular processes. Some ET (13/24) had greater dysregulation of these genes and segregated from most controls and remaining ETs in PCA. Characterization of genes/pathways enriched in this PCA and GSEA identified multiple pathway dysregulations in ET, including RNA processing/splicing, synapse organization/ion transport, and oxidative stress/inflammation. Furthermore, a different set of pathways characterized marked heterogeneity among ET patients. Our data indicate a range of possible mechanisms for the pathogenesis of ET. Significant heterogeneity among ET combined with dysregulation of multiple cellular processes supports the notion that ET is a family of disorders rather than one disease entity., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Cerebellum modulates the amplitude of resting tremor in Parkinson's disease (PD) via cerebello-thalamo-cortical (CTC) circuit. Tremor-related white matter alterations have been identified in PD patients by pathological studies, but in vivo evidence is limited; the influence of such cerebellar white matter alterations on tremor-related brain network, including CTC circuit, is also unclear. In this study, we investigated the cerebral and cerebellar white matter alterations in PD patients with resting tremor using diffusion tensor imaging (DTI)., Methods: In this study, 30 PD patients with resting tremor (PDWR), 26 PD patients without resting tremor (PDNR), and 30 healthy controls (HCs) from the Parkinson's Progression Markers Initiative (PPMI) cohort were included. Tract-based spatial statistics (TBSS) and region of interest-based analyses were conducted to determine white matter difference. Correlation analysis between DTI measures and clinical characteristics was also performed., Results: In the whole brain, TBSS and region of interest-based analyses identified higher fractional anisotropy (FA) value, lower mean diffusivity (MD) value, and lower radial diffusivity (RD) in multiple fibers. In the cerebellum, TBSS analysis revealed significantly higher FA value, decreased RD value as well as MD value in multiple cerebellar tracts including the inferior cerebellar peduncle (ICP) and middle cerebellar peduncle (MCP) when comparing the PDWR with HC, and higher FA value in the MCP when compared with PDNR., Conclusion: We identified better white matter integrity in the cerebrum and cerebellum in PDWR indicating a potential association between the cerebral and cerebellar white matter and resting tremor in PD., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that appears in adult FMR1 premutation carriers. The neuropathological hallmark of FXTAS is an intranuclear inclusion in neurons and astrocytes. Nearly 200 different proteins have been identified in FXTAS inclusions, being the small ubiquitin-related modifier 2 (SUMO2), ubiquitin and p62 the most highly abundant. These proteins are components of the protein degradation machinery. This study aimed to characterize SUMO2/3 expression levels and autophagy process in human postmortem brain samples and skin fibroblast cultures from FXTAS patients. Results revealed that FXTAS postmortem brain samples are positive for SUMO2/3 conjugates and supported the idea that SUMO2/3 accumulation is involved in inclusion formation. Insights from RNA-sequencing data indicated that SUMOylation processes are significantly upregulated in FXTAS samples. In addition, the analysis of the autophagy flux showed the accumulation of p62 protein levels and autophagosomes in skin fibroblasts from FXTAS patients. Similarly, gene set analysis evidenced a significant downregulation in gene ontology terms related to autophagy in FXTAS samples. Overall, this study provides new evidence supporting the role of SUMOylation and autophagic processes in the pathogenic mechanisms underlying FXTAS.

Background: T1-hyperintensity of the basal ganglia (BG) due to manganese deposition is a known radiologic finding in patients with hereditary hemorrhagic telangiectasia (HHT), but risk factors and associated clinical manifestations are unclear. This study conducted a quantitative analysis of the association of T1-hyperintensity in HHT patients with specific risk factors, signs, and symptoms., Methods: Patients seen at our center between 2005 and 2020 with a definitive diagnosis of HHT who had an available non-contrast T1-weighted brain MRI were included. Hyperintensity was evaluated using oval regions of interest measurements. The BG: thalamus intensity ratio was used to quantitatively evaluate T1-hyperintensity. Patient laboratory values and clinical findings were collected from electronic medical records. Hyperintensity was analyzed for its association with laboratory values, and clinical findings. Variables were analyzed through regression analysis., Results: A total of 239 patients were included in this study. On 1.5 T scanners, values that were significant on multivariable regression analysis were age (p < .001), hepatic AVMs (p < .001), iron deficiency anemia (p = .0021), and cirrhosis (p = .016). On 3 T scanners, values that were significant on multivariable analysis were hepatic AVMs (p = .0024) and cirrhosis (p = .0056). On 3 T scanners, hyperintensity was significantly associated with tremor (OR = 1.17, p = .033), restless leg syndrome (OR = 1.22, p = .0086), and memory problems (OR = 1.17, p = .046)., Conclusions: BG hyperintensity due to manganese deposition is significantly associated with hepatic risk factors on 1.5 T and 3 T scanners and iron deficiency anemia on 1.5 T scanners. On 3 T scanners, T1-hyperintensity is associated with neuropsychiatric signs and symptoms, such as tremor, restless leg syndrome, and memory problems., Competing Interests: Declaration of competing interest All authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Brain changes at the end-stage of fragile X-associated tremor/ataxia syndrome (FXTAS) are largely unknown due to mobility impairment. We conducted a postmortem MRI study of FXTAS to quantify cerebrovascular disease, brain atrophy and iron content, and examined their relationships using principal component analysis (PCA). Intracranial hemorrhage (ICH) was observed in 4/17 FXTAS cases, among which one was confirmed by histologic staining. Compared with seven control brains, FXTAS cases showed higher ratings of T2-hyperintensities (indicating cerebral small vessel disease) in the cerebellum, globus pallidus and frontoparietal white matter, and significant atrophy in the cerebellar white matter, red nucleus and dentate nucleus. PCA of FXTAS cases revealed negative associations of T2-hyperintensity ratings with anatomic volumes and iron content in the white matter, hippocampus and amygdala, that were independent from a highly correlated number of regions with ICH and iron content in subcortical nuclei. Post-hoc analysis confirmed PCA findings and further revealed increased iron content in the white matter, hippocampus and amygdala in FXTAS cases compared to controls, after adjusting for T2-hyperintensity ratings. These findings indicate that both ischemic and hemorrhagic brain damage may occur in FXTAS, with the former being marked by demyelination/iron depletion and atrophy, and the latter by ICH and iron accumulation in basal ganglia.

New histological techniques are needed to examine protein distribution in human tissues, which can reveal cell shape and disease pathology connections. Spatial proteomics has changed the study of tumor microenvironments by identifying spatial relationships of immunomodulatory cells and proteins and contributing to the discovery of new cancer immunotherapy biomarkers. However, the fast-expanding toolkit of spatial proteomic approaches has yet to be systematically applied to investigate pathological alterations in the aging human brain in health and disease states. Moreover, post-mortem human brain tissue presents distinct technical problems due to fixation procedures and autofluorescence, which limit fluorescence methodologies. This study sought to develop a multiplex immunohistochemistry approach (visualizing the immunostain with brightfield microscopy). Quantitative multiplex Immunohistochemistry with Visual colorimetric staining to Enhance Regional protein localization (QUIVER) was developed to address these technical challenges. Using QUIVER, a ten-channel pseudo-fluorescent image was generated using chromogen removal and digital microscopy to identify unique molecular microglia phenotypes. Next, the study asked if the tissue environment, specifically the amyloid plaques and neurofibrillary tangles characteristic of Alzheimer's disease, has any bearing on microglia's cellular and molecular phenotypes. QUIVER allowed the visualization of five molecular microglia/macrophage phenotypes using digital pathology tools. The recognizable reactive and homeostatic microglia/macrophage phenotypes demonstrated spatial polarization towards and away from amyloid plaques, respectively. Yet, microglia morphology appearance did not always correspond to molecular phenotype. This research not only sheds light on the biology of microglia but also offers QUIVER, a new tool for examining pathological alterations in the brains of the elderly., (© 2023. The Author(s).)

Background: Neuronal intranuclear inclusion disease (NIID) is a rare slowly progressive neurodegenerative disorder that is characterized pathologically by the presence of eosinophilic intranuclear inclusions. NIID is a heterogeneous disease with diverse clinical manifestations, making diagnosis difficult. Here, we analyzed the clinical, pathological, and radiological features of Chinese NIID patients to improve our understanding of NIID., Methods: A total of 17 patients with sporadic NIID were recruited from the Ruijin Hospital Database between 2014 and 2021. Clinical patient information and brain MRI data were collected. All of the patients underwent standard skin biopsy procedures., Results: The average age of onset for symptoms was 60.18 years, and the average duration of illness was 4.06 years. All patients were diagnosed with NIID due to the presence of intranuclear inclusions confirmed by skin biopsy. Tremor was the most common initial symptom. The average ages at onset and at diagnosis were both lower in patients with tremor than in patients without tremor. NIID may be a systemic disease that affects multiple organs, for one patient had a history of chronic renal insufficiency for more than 10 years. In addition to high-intensity U-fibers signals on diffusion-weighted imaging, there were several other MRI findings, such as focal leukoencephalopathy and cortical swelling. Encephalitic episodes followed by reversible leukoencephalopathy was another important imaging feature of NIID., Conclusion: The clinical manifestations of NIID are highly variable. Tremor may be the most common initial symptom in certain cohorts. Encephalitic episodes followed by reversible asymmetric leukoencephalopathy may also indicate this disease.

Parkinson's disease (PD) is a neurodegenerative condition characterized by the progressive deterioration of dopaminergic neurons in the central and peripheral autonomous system and the intraneuronal cytoplasmic accumulation of misfolded α-synuclein. The clinical features are the classic triad of tremor, rigidity, and bradykinesia and a set of non-motor symptoms, including visual deficits. The latter seems to arise years before the onset of motor symptoms and reflects the course of brain disease. The retina, by virtue of its similarity to brain tissue, is an excellent site for the analysis of the known histopathological changes of PD that occur in the brain. Numerous studies conducted on animal and human models of PD have shown the presence of α-synuclein in retinal tissue. Spectral-domain optical coherence tomography (SD-OCT) could be a technique that enables the study of these retinal alterations in vivo. The objective of this review is to describe recent evidence on the accumulation of native or modified α-synuclein in the human retina of patients with PD and its effects on the retinal tissue evaluated through SD-OCT.

Background: The pathophysiology of essential tremor (ET) is not fully understood, and studies suggest pathological changes mainly occur in the cerebellum and locus coeruleus (LC)., Methods: Fifty-three ET patients, including 30 patients with head tremor (h-ET), 23 patients without head tremor (nh-ET), 71 age and education matched healthy controls (HCs) were enrolled. All participants underwent Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) and T1 scans on a 3-Tesla MR system. Next, we assessed the relationship between the contrast-to-noise ratio of LC (CNR LC ) and the score of The Essential Tremor Rating Assessment Scale (TETRAS) and cerebellum gray matter (GM) volume., Results: Significant difference of CNR LC was found between ET and HC groups. The CNR LC of ET groups is lower than the HC group (p = 0.031). Subgroup analysis showed that the CNR LC in nh-ET was significantly lower than HCs (p = 0.016). Compared to HCs, h-ETs showed marked atrophy in the cerebellum: the vermis IV-V and lobule VI (GRF corrected, p < 0.05). A significant negative correlation was found between CNR LC and the vermis lobule IV-V in h-ETs (r = - 0.651, p < 0.001). No significant correlation was found between CNR LC and TETRAS scores., Conclusion: The LC and the cerebellum might both involve in the pathophysiology of ET. LC evaluation using NM-MRI might be an effective tool for us to explore the pathophysiology of ET further., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Repeat-associated non-AUG (RAN) translation is a pathogenic mechanism in which repetitive sequences are translated into aggregation-prone proteins from multiple reading frames, even without a canonical AUG start codon. Since its discovery in spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy type 1 (DM1), RAN translation is now known to occur in the context of 12 disease-linked repeat expansions. This review discusses recent advances in understanding the regulatory mechanisms controlling RAN translation and its contribution to the pathophysiology of repeat expansion diseases. We discuss the key findings in the context of Fragile X Tremor Ataxia Syndrome (FXTAS), a neurodegenerative disorder caused by a CGG repeat expansion in the 5' untranslated region of FMR1.

Background: Differential diagnosis of essential tremor (ET) and Parkinson's disease (PD) can still be a challenge in clinical practice. These two tremor disorders may have different pathogenesis related to the substantia nigra (SN) and locus coeruleus (LC). Characterizing neuromelanin (NM) in these structures may help improve the differential diagnosis., Methods: Forty-three subjects with tremor-dominant PD (PD TD ), 31 subjects with ET, and 30 age- and sex-matched healthy controls were included. All subjects were scanned with NM magnetic resonance imaging (NM-MRI). NM volume and contrast measures for the SN and contrast for the LC were evaluated. Logistic regression was used to calculate predicted probabilities by using the combination of SN and LC NM measures. The discriminative power of the NM measures in detecting subjects with PD TD from ET was assessed with a receiver operative characteristic curve, and the area under the curve (AUC) was calculated., Results: The NM contrast-to-noise ratio (CNR) of the LC, the NM volume, and CNR of the SN on the right and left sides were significantly lower in PD TD subjects than in ET subjects or healthy controls (all P < 0.05). Furthermore, when combining the best model constructed from the NM measures, the AUC reached 0.92 in differentiating PD TD from ET., Conclusion: The NM volume and contrast measures of the SN and contrast for the LC provided a new perspective on the differential diagnosis of PD TD and ET, and the investigation of the underlying pathophysiology., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Tremor is an involuntary, rhythmic movement disorder. Despite its prevalence, the underlying pathophysiology remains poorly understood, and effective treatment options are limited. Animal models are essential in enhancing our understanding of the mechanisms of tremorogenesis and developing new therapeutic interventions. Although tremor is amenable to measurement by automated systems, visual observation is still the most prevalent method for recording tremor in animal studies. This review gives a brief summary of two behavioral methods that enable quantitative measurement of forelimb tremor (the press-while-licking task) and whole-body tremor (the force-plate actometer) in rodents. These methods utilize force transducer and computing technologies to generate high-resolution force-time waveforms for automated detection and characterization of tremor. The focus will be on the sensitive, precise, and quantitative measurement of tremors induced in rodents by low-dose pharmacological agents, brain lesion, physical training, and genetic mutations. The methods reviewed here provide new tools that can facilitate preclinical assessment of treatment strategies for tremor., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Neuronal intranuclear inclusion disease (NIID) is a heterogeneous neurodegenerative disease with multiple clinical subtypes. Recent breakthroughs on neuroimaging, skin biopsy and genetic testing have facilitated the diagnosis. We aim to investigate the clinical characteristics of Chinese NIID patients to further refine the spectrum. We analyzed the clinical features of 25 NIID patients from 24 unrelated families and performed skin biopsy and/or sural nerve biopsy on 24 probands. Repeat-primed PCR and fluorescence amplicon length PCR were conducted to detect GGC repeats of NOTCH2NLC. Onset age ranged from 24 to 72 years old, and the disease duration ranged from 12 h to 25 years with the mode of onset characterized as acute, recurrent or chronic progressive type. Tremor was a common phenotype, often observed in the early stages, next to dementia and paroxysmal encephalopathy. Symptoms infrequently reported such as oromandibular dystonia, recurrent vomiting, dizziness and headache of unknown origin, as well as pure peripheral neuropathy were also suggestive of NIID. Reversible leukoencephalopathy following encephalitic episodes and the absence of apparent DWI abnormality were noticed. Two genetically confirmed NIID patients failed to be identified intranuclear inclusions, and one patient was simultaneously found significant mitochondrial swelling and fingerprint profiles depositing in lysosomes. All the patients were identified abnormal GGC repeats of NOTCH2NLC. We identify some atypical clinicopathological features and consider that pathological examinations combined with genetic testing is the gold standard for diagnosis. Whether lysosomal and mitochondrial dysfunction is involved in the pathogenesis of NIID deserves further study., (© 2021. Belgian Neurological Society.)

BACKGROUND The SARS-CoV-2 viral infection is associated with respiratory and multi-organ systemic disease. It has been shown to affect the central nervous system and produce varied neurological symptoms, including ischemic strokes, seizures, and encephalitis. Neurological manifestations of this viral infection are thought to be due to neurotropic reactions on the central nervous system or post-infectious immune-mediated damage. This report presents a case of bilateral tremor of the upper limbs more than 6 weeks after a diagnosis of COVID-19, with confirmed volumetric brain loss shown by follow-up brain magnetic resonance imaging (MRI) combined with 3-dimensional volumetric NeuroQuant image analysis. CASE REPORT We report a case of new-onset tremors in a 62-year-old man after SARS-CoV-2 infection. MRI of the brain was performed shortly after the onset of tremors, and a follow-up MRI after 2 months showed evidence of rapid parenchymal volume, loss of midbrain substance, and increased cerebrospinal fluid volume within 2 months of the initial examination. CONCLUSIONS This case report shows central neurological effects of COVID-19, which can be evaluated by quantitative volumetric MRI analysis, although further studies are warranted to determine how this type of brain imaging can be used to evaluate the effects of SARS-CoV-2 infection over time.

Objective: Although previous imaging studies have reported cerebellar gray matter loss in patients with familial cortical myoclonic tremor with epilepsy (FCMTE), the corresponding white matter alterations remain unknown. We investigated white matter structural changes in FCMTE1 and compared them with clinical and electrophysiological features., Methods: We enrolled 36 patients carrying heterozygous pathogenic intronic pentanucleotide insertions in the SAMD12 gene and 52 age- and sex-matched healthy controls. Diffusion tensor imaging-derived metrics, including fractional anisotropy, mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), were calculated along with white matter voxel-based morphometry (VBM) analysis. We also examined correlations between magnetic resonance metrics and clinical and electrophysiological features., Results: We detected widespread white matter reductions in MD, RD, and AD values in FCMTE1 patients, including in the commissural, projection, and association fibers. VBM analysis revealed that increases in white matter volume predominantly occurred in the right cerebellum and sagittal stratum. MD, RD, AD, and VBM analysis clearly indicated changes in the sagittal stratum. We found a positive correlation between VBM values in the right cerebellum and somatosensory-evoked potential P25-N33 amplitude. Decreased MD and AD values in the right sagittal stratum were detected in patients with versus without photophobia., Significance: FCMTE is a network disorder involving a wide range of cortical and subcortical structures, including the cerebellum, thalamus, thalamocortical connections, and corticocortical connections. The right sagittal stratum is closely related with visual symptoms, especially photophobia. Our findings indicate that cerebellum and cortical hyperexcitability are closely linked, and emphasize the important role of the cerebellum in the pathophysiological mechanisms of cortical tremor., (© 2022 International League Against Epilepsy.)

Non-coding CGG repeat expansions cause multiple neurodegenerative disorders, including fragile X-associated tremor/ataxia syndrome, neuronal intranuclear inclusion disease, oculopharyngeal myopathy with leukodystrophy, and oculopharyngodistal myopathy. The underlying genetic causes of several of these diseases have been identified only in the past 2-3 years. These expansion disorders have substantial overlapping clinical, neuroimaging and histopathological features. The shared features suggest common mechanisms that could have implications for the development of therapies for this group of diseases - similar therapeutic strategies or drugs may be effective for various neurodegenerative disorders induced by non-coding CGG expansions. In this Review, we provide an overview of clinical and pathological features of these CGG repeat expansion diseases and consider the likely pathological mechanisms, including RNA toxicity, CGG repeat-associated non-AUG-initiated translation, protein aggregation and mitochondrial impairment. We then discuss future research needed to improve the identification and diagnosis of CGG repeat expansion diseases, to improve modelling of these diseases and to understand their pathogenesis. We also consider possible therapeutic strategies. Finally, we propose that CGG repeat expansion diseases may represent manifestations of a single underlying neuromyodegenerative syndrome in which different organs are affected to different extents depending on the gene location of the repeat expansion., (© 2022. Springer Nature Limited.)

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a cytosine-guanine-guanine repeat expansion neurological disease that occurs in a subset of aging carriers of the premutation (55-200 cytosine-guanine-guanine repeats) in the FMR1 gene located on the X chromosome. The clinical core involves intention tremor and gait ataxia. Current research seeks to clarify the pathophysiology and neuropathology of FXTAS, as well as the development of useful biomarkers to track the progression of FXTAS. Efforts to implement quantitative measures of clinical features, such as kinematics and cognitive measures, are of special interest, in addition to characterize the differences in progression in males compared with females and the efficacy of new treatments., Competing Interests: Conflict of interest statement Nothing declared., (Copyright © 2021. Published by Elsevier Ltd.)

The precise associations between dysphagia and palatal tremor (PT) remain unknown. We aimed to identify the association between PT and dysphagia among patients with midbrain/pontine stroke, compare the characteristics of dysphagia between patients with PT (PT + dysphagia) and without PT (PT- dysphagia), and verify neuroanatomical predictors of PT + dysphagia in this patient population. This retrospective observational study enrolled 40 patients (34 males, 6 females; mean age: 95% confidence interval [CI], 56.6 ± 14.6 years) with first-ever midbrain or pontine stroke exhibiting brain stem lesions admitted to the stroke unit of a single rehabilitation hospital between January 2010 and April 2020. Main outcome measures included dysphagia and aspiration rates and videofluoroscopic swallowing study findings. Lesion localization was stratified according to established vascular territories. Associations between PT and dysphagia and lesion location according to PT and dysphagia were analyzed. Dysphagia and aspiration rates were greater among patients with PT than among those without PT (95% CI, p = 0.030 and p = 0.017, respectively). The proportion of patients exhibiting oral stage impairment (95% CI, p = 0.007) was greater in the PT + dysphagia group than in the PT- dysphagia group. The posterolateral portion of the midbrain and pons (95% CI, p = 0.001 and p < 0.001, respectively) were the lesions more often involved in the PT + dysphagia group. Patients with PT following midbrain/pontine stroke more frequently present with dysphagia than those without PT. Thus, they should be carefully examined for PT and delayed dysphagia, including oral stage impairment, if initial brain images show posterolateral midbrain and pons lesions., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Introduction: Global hippocampal atrophy has been repeatedly reported in patients with Parkinson's disease (PD). However, there is limited literature on the differential involvement of hippocampal subfields among PD motor subtypes. This study aimed to investigate hippocampal subfield alterations in patients with PD based on their predominant symptoms., Method: We enrolled 31 PD patients with the tremor-dominant (TD) subtype, 27 PD patients with postural instability and gait disturbance-dominant (PIGD) subtype, and 40 healthy controls (HCs). All participants underwent high-spatial-resolution T1-weighted magnetic resonance imaging. The volume of hippocampal subfields was measured using FreeSurfer software, compared across groups, and correlated with clinical features., Results: We found volumetric reductions in the hippocampal subfield in both patient subtypes compared to HCs, which were more pronounced in the PIGD subtype. The PIGD subtype had accelerated age-related alterations in the hippocampus compared to the TD subtype. Bilateral hippocampal volumes were positively associated with cognitive performance levels, but not with disease severity and duration in patients., Conclusions: Alterations in the hippocampal subfields of patients with PD differed based on their predominant symptoms. These findings are of relevance for understanding the pathophysiology of the increased risk of cognitive impairment in PIGD., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Essential tremor (ET) is among the most prevalent movement disorders, and by some accounts, the most common form of cerebellar degeneration. Over the past 15 years, we have carefully documented a large number of postmortem changes within the cerebellum; these cerebellar changes differ significantly between ET and controls. A recent Consensus Classification of tremor proposed that ET patients with other neurological signs aside from action tremor (e.g., parkinsonism, ataxia, cognitive changes, dystonia) should be segregated off as "ET-plus". This diagnostic concept has raised considerable controversy and its validity is not yet established. Indeed, "ET-plus" has not been distinguished from ET based on differences in genetics, pathology or prognosis. Here we determine whether ET cases differ from "ET-plus" cases in underlying pathological changes in the postmortem brain. We examined postmortem brains from 50 ET cases (24 ET and 26 ET-plus), using a set of 14 quantitative metrics of cerebellar pathology determined by histologic and immunohistochemical methods. These metrics reflect changes across the Purkinje cell (PC) body (PC counts, empty baskets, heterotopias), PC dendrites (swellings), PC axon (torpedoes and associated axonal changes), basket cell axonal hypertrophy and climbing fiber-PC dendrite synaptic changes. ET and ET-plus were similar with respect to 13 of 14 cerebellar pathologic metrics (p > 0.05). Only one metric, the linear density of thickened PC axon profiles, differed between these groups (ET = 0.529 ± 0.397, ET-plus = 0.777 ± 0.477, p = 0.013), although after correcting for multiple comparisons, there were no differences. If ET-plus were indeed a different entity, then the underlying pathological basis should be distinct from that of ET. This study demonstrated there were no pathological differences in cerebellar cortex between ET versus ET-plus cases. These data do not support the notion that ET and ET-plus represent distinct clinical-pathological entities., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hyperventilation changes the extracellular pH modulating many central pathologies, such as tremor. The questions that remain unanswered are the following: (1) Hyperventilation modulates which aspects of the oscillations? (2) Whether the effects of hyperventilation are instantaneous and the recovery is rapid and complete? Here we study the effects of hyperventilation on eye oscillations in the syndrome of oculopalatal tremor (OPT), a disease model affecting the inferior olive and cerebellar system. These regions are commonly involved in the pathogenesis of many movement disorders. The focus on the ocular motor system also allows access to the well-known physiology and precise measurement techniques. We found that hyperventilation causes modest but insignificant changes in the intensity of oscillation displacement (i.e., how large the eye excursions are) and velocity (i.e., how fast do the eyes move during oscillations). We found the robust increase in the randomness of the oscillatory waveform during hyperventilation and it instantaneously reverts to the baseline after hyperventilation. The subsequent analysis classified the oscillations according to their waveform shape and randomness into different clusters. The hyperventilation substantially changed the cluster type in 60% of the subjects, but it reverted to the pre-hyperventilation cluster at the conclusion of the hyperventilation. In summary, hyperventilation instantaneously affects the randomness of the oscillatory waveforms but there are less substantial effects on the intensity. The deficits reverse immediately at the end of the hyperventilation., (© 2020. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by a limited expansion of CGG repeats in the FMR1 gene. Degeneration of neurons in FXTAS cell models can be triggered by accumulation of polyglycine protein (FMRpolyG), a by-product of translation initiated upstream to the repeats. Specific aims of our work included testing if naphthyridine-based molecules could (i) block FMRpolyG synthesis by binding to CGG repeats in RNA, (ii) reverse pathological alterations in affected cells and (iii) preserve the content of FMRP, translated from the same FMR1 mRNA. We demonstrate that cyclic mismatch binding ligand CMBL4c binds to RNA structure formed by CGG repeats and attenuates translation of FMRpolyG and formation of nuclear inclusions in cells transfected with vectors expressing RNA with expanded CGG repeats. Moreover, our results indicate that CMBL4c delivery can reduce FMRpolyG-mediated cytotoxicity and apoptosis. Importantly, its therapeutic potential is also observed once the inclusions are already formed. We also show that CMBL4c-driven FMRpolyG loss is accompanied by partial FMRP reduction. As complete loss of FMRP induces FXS in children, future experiments should aim at evaluation of CMBL4c therapeutic intervention in differentiated tissues, in which FMRpolyG translation inhibition might outweigh adverse effects related to FMRP depletion., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Abnormal trinucleotide expansions cause rare disorders that compromise quality of life and, in some cases, lifespan. In particular, the expansions of the CGG-repeats stretch at the 5'-UTR of the Fragile X Mental Retardation 1 ( FMR1 ) gene have pleiotropic effects that lead to a variety of Fragile X-associated syndromes: the neurodevelopmental Fragile X syndrome (FXS) in children, the late-onset neurodegenerative disorder Fragile X-associated tremor-ataxia syndrome (FXTAS) that mainly affects adult men, the Fragile X-associated primary ovarian insufficiency (FXPOI) in adult women, and a variety of psychiatric and affective disorders that are under the term of Fragile X-associated neuropsychiatric disorders (FXAND). In this review, we will describe the pathological mechanisms of the adult "gain-of-function" syndromes that are mainly caused by the toxic actions of CGG RNA and FMRpolyG peptide. There have been intensive attempts to identify reliable peripheral biomarkers to assess disease progression and onset of specific pathological traits. Mitochondrial dysfunction, altered miRNA expression, endocrine system failure, and impairment of the GABAergic transmission are some of the affectations that are susceptible to be tracked using peripheral blood for monitoring of the motor, cognitive, psychiatric and reproductive impairment of the CGG-expansion carriers. We provided some illustrative examples from our own cohort. Understanding the association between molecular pathogenesis and biomarkers dynamics will improve effective prognosis and clinical management of CGG-expansion carriers.

Women heterozygous for an expansion of CGG repeats in the 5'UTR of FMR1 risk developing fragile X-associated primary ovarian insufficiency (FXPOI) and/or tremor and ataxia syndrome (FXTAS). We show that expanded CGGs, independent of FMR1, are sufficient to drive ovarian insufficiency and that expression of CGG-containing mRNAs alone or in conjunction with a polyglycine-containing peptide translated from these RNAs contribute to dysfunction. Heterozygous females from two mouse lines expressing either CGG RNA-only (RNA-only) or CGG RNA and the polyglycine product FMRpolyG (FMRpolyG+RNA) were used to assess ovarian function in aging animals. The expression of FMRpolyG+RNA led to early cessation of breeding, ovulation and transcriptomic changes affecting cholesterol and steroid hormone biosynthesis. Females expressing CGG RNA-only did not exhibit decreased progeny during natural breeding, but their ovarian transcriptomes were enriched for alterations in cholesterol and lipid biosynthesis. The enrichment of CGG RNA-only ovaries for differentially expressed genes related to cholesterol processing provided a link to the ovarian cysts observed in both CGG-expressing lines. Early changes in transcriptome profiles led us to measure ovarian function in prepubertal females that revealed deficiencies in ovulatory responses to gonadotropins. These include impairments in cumulus expansion and resumption of oocyte meiosis, as well as reduced ovulated oocyte number. Cumulatively, we demonstrated the sufficiency of ectopically expressed CGG repeats to lead to ovarian insufficiency and that co-expression of CGG-RNA and FMRpolyG lead to premature cessation of breeding. However, the expression of CGG RNA-alone was sufficient to lead to ovarian dysfunction by impairing responses to hormonal stimulation., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Noradrenergic neurotransmission may play an important role in tremor modulation through its innervation of key structures of the central tremor circuits. Here, Parkinson's disease (PD) patients with (PD T+ ) or without (PD T- ) rest tremor had 11 C-methylreboxetine( 11 C-MeNER) positron emission tomography (PET) to test the hypothesis that noradrenaline terminal function was relatively preserved in PD T+ compared to PD T- ., Methods: Sixty-five PD patients and 28 healthy controls (HC) were scanned with 11 C-MeNER PET. Patients were categorized as PD T+ if subscores in UPDRS-III item 3 or MDS-UPDRS-III item 17 was ≥2; remaining were categorized as PD T- . Simplified reference tissue model 2 distribution volume ratios (DVR) for 11 C-MeNER were calculated for thalamus, dorsal and median raphe, locus coeruleus (LC) and red nucleus using time activity curves (TACs) obtained from volumes of interest (VOI). Data were statistically interrogated with a general linear mixed model using 'region', and 'group' as factors and the interaction of 'region x group' was examined., Results: Tremor positive PD patients had a significantly higher mean 11 C-MeNER DVR compared to PD T- in LC and thalamus. The PD T+ mean LC DVR was similar to that of HC. PD T+ mean 11 C-MeNER DVRs were significantly lower than HC in the dorsal raphe while the PD T- group showed significantly lower mean 11 C-MeNER DVR across all regions compared to HC., Conclusion: While both PD T+ and PD T- groups showed a significant loss of noradrenaline terminal function compared to controls, noradrenergic neurons were relatively preserved in PD T+ in LC and thalamus. The greater loss of noradrenergic transporters in PD T- in LC and thalamus compared with PD T+ is in line with earlier in-vitro studies and could potentially contribute to their tremor negative phenotype., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: In vivo dopamine transporter imaging is a useful tool for distinguishing nigrostriatal pathologies (e.g. Parkinson's disease) from other causes of tremor. However, while many of the motoric features of Parkinson's disease (e.g. bradykinesia, rigidity, hypomimia) correlate well with reduced striatal dopamine transporter binding, the same relationship has not been demonstrated for tremor. We investigated the relationship between striatal dopamine transporter binding and quantitative measures of tremor., Methods: 23 participants with Parkinson's disease underwent standardised clinical assessment including structured, videotaped clinical examination, tremor neurophysiology study of both upper limbs using accelerometry and surface EMG, and Technitium-99 m TRODAT-1 brain SPECT imaging. Normalised striatal uptake values were calculated. Tremor EMG and accelerometry time series were processed with Fourier transformation to identify peak tremor power within a window of 3-10Hz and to calculate the tremor stability index (TSI)., Results: Spearman correlation analyses revealed an association between tremor power and contralaterally reduced striatal uptake in a number of recording conditions. This association was strongest for rest tremor, followed by postural tremor, with the weakest association observed for kinetic tremor. Lower TSI was also associated with lower contralateral striatal uptake in a number of rest and postural conditions., Conclusion: These data suggest a relationship between Parkinsonian rest tremor and contralateral reduction in striatal dopamine binding. Use of quantitative neurophysiology techniques may allow the demonstration of clinico-pathophysiological relationships in tremor that have remained occult to previous studies., (Copyright © 2021. Published by Elsevier Ltd.)

The objective of this study is to examine the role of the cerebellum in the tremor-dominant subtype of cervical dystonia (CD). CD patients with head tremor at onset (Tr-CD) were age- and sex-matched to CD patients without head tremor at onset (nTr-CD). All patients were evaluated for cerebellar disability using the Scale for the Assessment and Rating of Ataxia (SARA), gait variability using ProtoKinetics Zeno Walkway, and cerebellar volume analysis extracted from brain magnetic resonance imaging (MRI) using a semiquantitative scale. Compared to nTr-CD (n = 10, median age, 70.5 years), Tr-CD patients (n = 10, 71.5 years) exhibited higher median SARA scores (9 vs 7.5, p = 0.03) and greater median gait variability index (131 vs 124, p = 0.03). SARA scores inversely correlated with cerebellar volume in all patients (- 0.4, p = 0.04). Tr-CD patients exhibited greater superior vermian atrophy than nTr-CD patients (p = 0.01). Head tremor at onset heralds a CD subtype with prominent axial cerebellar disability and atrophy of the superior vermis of the cerebellum.

The fragile X premutation is defined by the expansion of the CGG trinucleotide repeat at the 5' UTR of the FMR1 gene to between 55 and 200 repeats, while repeat tracks longer than 200 are defined as full mutations. Men carrying a premutation are at increased risk for fragile X-associated tremor/ataxia syndrome (FXTAS); those with > 200 repeats have fragile X syndrome, a common genetic form of intellectual disabilities. In our study, we tested the hypothesis that men carrying a fragile X premutation or full mutation are "biologically older", as suggested by the associated age-related disorder in the presence of the fragile X premutation or the altered cellular pathology that affects both the fragile X premutation and full mutation carriers. Thus, we predicted that both groups would have shorter telomeres than men carrying the normal size repeat allele. Using linear regression models, we found that, on average, premutation carriers had shorter telomeres compared with non-carriers (n = 69 vs n = 36; p = 0.02) and that there was no difference in telomere length between full mutation carriers and non-carriers (n = 37 vs n = 29; p > 0.10). Among premutation carriers only, we also asked whether telomere length was shorter among men with vs without symptoms of FXTAS (n = 28 vs n = 38 and n = 27 vs n = 41, depending on criteria) and found no evidence for a difference (p > 0.10). Previous studies have shown that the premutation is transcribed whereas the full mutation is not, and the expanded repeat track in FMR1 transcript is thought to lead to the risk for premutation-associated disorders. Thus, our data suggest that the observed premutation-only telomere shortening may be a consequence of the toxic effect of the premutation transcript and suggest that premutation carriers are "biologically older" than men carrying the normal size allele in the same age group.

Introduction: In recent years, cerebellar abnormalities have gained increasing attention as possible physiopathological substratum of idiopathic cervical dystonia (ICD), but a consistent pattern of cerebellar structural modifications has not yet been established. We systematically investigated the presence of volumetric alterations of cerebellar gray (GM) and white matter (WM) in ICD patients, as well as their clinical relevance., Methods: In this two-centers prospective cross-sectional study, from May 2013 to December 2017, 27 patients with ICD and 27 age- and sex-comparable healthy controls underwent brain MRI including 3D T1-weighted sequences for volumetric analyses. Between-group differences in terms of gray matter and cerebellar peduncles volumes were investigated using both region of interest (ROI)-based and voxel-based approaches using the SUIT tool (SPM12), and significant volumetric changes were correlated with clinical impairment (as measured with the Tsui score) and presence of tremor., Results: ICD patients showed significant volumetric reduction of cerebellar GM in the anterior lobe and lobule VI, resulting from both ROI-based (p ≤ 0.009) and voxel-based (p ≤ 0.04) analyses, while small clusters of reduced WM volume were found in the right cerebellum and left midbrain (p = 0.04), along with reduced volume of the bilateral superior (p = 0.04) and middle (p = 0.03) cerebellar peduncles. Furthermore, higher middle cerebellar peduncles volume was associated with the presence of tremor (p = 0.04)., Conclusion: Our data show evidence of a specific pattern of cerebellar structural abnormalities in ICD patients, with volume loss mainly involving cortical GM regions related to the somatotopic representation of the affected body parts and, to a lesser extent, cerebellar peduncles., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Primary deficiency of coenzyme Q10 deficiency-4 (COQ10D4) is an autosomal recessive cerebellar ataxia with mitochondrial respiratory chain disfunction. The main clinical manifestation involves early-onset exercise intolerance, progressive cerebellar ataxia, and movement disorders. COQ8A gene mutations are responsible for this disease. Here, we provide clinical, laboratory, and genetic findings of a patient with cerebellar ataxia caused by compound heterozygous mutations in COQ8A gene., Methods: A male patient from a non-consanguineous Chinese family underwent detailed physical and auxiliary examination. After exclusion of acquired causes of ataxia, Friedreich's Ataxia, and common types of spinocerebellar ataxia, the patient was subjected to whole exome sequencing (WES) followed by confirmation of sequence variants using Sanger sequencing. His asymptomatic parents, two brothers and one sister were genotyped for these variants., Results: This patient showed early-onset exercise intolerance and progressive cerebellar ataxia, wide-based gait and tremor, accompanied by symptoms of dysautonomia. His serum lactate level was elevated and plasma total Coenzyme Q10 (CoQ10) was decreased. Brain MRI showed cerebellar atrophy, and X-ray of the spine revealed thoraco-lumbar scoliosis. Compound heterozygous mutations in the COQ8A gene were identified through WES: c.1844&#95;1845insG, p.Ser616Leufs*114 and c.902G>A, p.Arg301Gln. After treatment with ubidecarenone, 40 mg three times per day for 2 years, the symptoms dramatically improved., Conclusions: We identified a patient with COQ10D4 caused by novel COQ8A mutations. Our findings widen the spectrum of COQ8A gene mutations and clinical manifestations., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Fragile X associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by expansion of CGG repeats in the 5' UTR of the fragile X mental retardation 1 (FMR1) gene. Using the well-established FXTAS Drosophila model, we performed a high-throughput chemical screen using 3200 small molecules. NSC363998 was identified to suppress the neurodegeneration caused by riboCGG (rCGG) repeats. Three predicted targets of a NSC363998 derivative are isopeptidases in the neddylation pathway and could modulate the neurotoxicity caused by the rCGG repeats. Decreasing levels of neddylation resulted in enhancing neurodegeneration phenotypes, while up-regulation could rescue the phenotypes. Furthermore, known neddylation substrates, Cul3 and Vhl, and their downstream target, Sima, were found to modulate rCGG 90 -dependent neurotoxicity. Our results suggest that altered neddylation activity can modulate the rCGG repeat-mediated toxicity by regulating Sima protein levels, which could serve as a potential therapeutic target for FXTAS., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Taiep rat is a myelin mutant with a progressive motor syndrome characterized by tremor, ataxia, immobility episodes, epilepsy and paralysis of the hindlimbs. Taiep had an initial hypomyelination followed by a progressive demyelination associated with an increased expression of some interleukins and their receptors. The pathology correlated with an increase in nitric oxide activity and lipoperoxidation. In base of the above evidences taiep rat is an appropriate model to study neuroimmune interactions. The aim of this study was to analyze the immune responses in male taiep rats after acute infection with Trichinella spiralis. Our results show that there is an important decrease in the number of intestinal larvae in the taiep rat with respect to Sprague-Dawley control rats. We also found differences in the percentage of innate and adaptive immune cell profile in the mesenteric lymphatic nodes and the spleen that correlated with the demyelination process that took place on taiep subjects. Finally, a clear pro-inflammatory cytokine pattern was seen on infected taiep rats, that could be responsible of the decrement in the number of larvae number. These results sustain the theory that neuroimmune interaction is a fundamental process capable of modulating the immune response, particularly against the parasite Trichinella spiralis in an animal model of progressive demyelination due to tubulinopathy, that could be an important mechanism for the clinical course of autoimmune diseases associated with parasite infection., Competing Interests: The authors have declared that no competing interests exist.

The age at onset (AAO) is an important determinant in Parkinson's disease (PD). Neuroimaging genetics is suitable for studying AAO in PD as it jointly analyzes imaging and genetics. We aimed to identify features associated with AAO in PD by applying the objective-specific neuroimaging genetics approach and constructing an AAO prediction model. Our objective-specific neuroimaging genetics extended the sparse canonical correlation analysis by an additional data type related to the target task to investigate possible associations of the imaging-genetic, genetic-target, and imaging-target pairs simultaneously. The identified imaging, genetic, and combined features were used to construct analytical models to predict the AAO in a nested five-fold cross-validation. We compared our approach with those from two feature selection approaches where only associations of imaging-target and genetic-target were explored. Using only imaging features, AAO prediction was accurate in all methods. Using only genetic features, the results from other methods were worse or unstable compared to our model. Using both imaging and genetic features, our proposed model predicted the AAO well (r = 0.5486). Our findings could have significant impacts on the characterization of prodromal PD and contribute to diagnosing PD early because genetic features could be measured accurately from birth.

Intranuclear inclusions present in the brains of patients with Fragile X-associated tremor/ataxia syndrome (FXTAS) have historically been difficult to study due to their location and scarcity. The recent finding that these particles autofluoresce has complicated the use of immunofluorescence techniques, but also offers new opportunities for purification. We have ascertained the features of the autofluorescence, including its excitation/emission spectrum, similarities and differences compared with lipofuscin autofluorescence, and its presence/absence under various fixation, mounting and UV light exposure conditions. Immunofluorescence at various wavelengths was conducted to determine which conditions are ideal for minimizing autofluorescence confounds. We also present a technique for autofluorescence-based sorting of FXTAS inclusions using flow cytometry, which will allow researchers in the field to purify inclusions more successfully for unbiased analyses.

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder seen in older premutation (55-200 CGG repeats) carriers of FMR1. The premutation has excessive levels of FMR1 mRNA that lead to toxicity and mitochondrial dysfunction. The clinical features usually begin in the 60 s with an action or intention tremor followed by cerebellar ataxia, although 20% have only ataxia. MRI features include brain atrophy and white matter disease, especially in the middle cerebellar peduncles, periventricular areas, and splenium of the corpus callosum. Neurocognitive problems include memory and executive function deficits, although 50% of males can develop dementia. Females can be less affected by FXTAS because of a second X chromosome that does not carry the premutation. Approximately 40% of males and 16% of female carriers develop FXTAS. Since the premutation can occur in less than 1 in 200 women and 1 in 400 men, the FXTAS diagnosis should be considered in patients that present with tremor, ataxia, parkinsonian symptoms, neuropathy, and psychiatric problems. If a family history of a fragile X mutation is known, then FMR1 DNA testing is essential in patients with these symptoms.