Cerebellar cognitive affective syndrome with psychotic features in a patient with hypertrophic olivary degeneration.

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.

Structural and Functional Alterations of Motor-Thalamus in Different Motor Subtype of Parkinson's Disease: An Individual Study.

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.

Exploration of SUMO2/3 Expression Levels and Autophagy Process in Fragile X-Associated Tremor/Ataxia Syndrome: Addressing Study Limitations and Insights for Future Research.

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.

Cerebellar and cerebral white matter changes in Parkinson's disease with resting tremor.

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.

A Postmortem MRI Study of Cerebrovascular Disease and Iron Content at End-Stage of Fragile X-Associated Tremor/Ataxia Syndrome.

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.

Risk factors and clinical features associated with basal ganglia manganese deposition in patients with hereditary hemorrhagic telangiectasia.

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.

Locus coeruleus and substantia nigra neuromelanin magnetic resonance imaging differentiates Parkinson's disease and essential tremor.

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 (PDTD), 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 PDTD 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 PDTD 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 PDTD 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 PDTD and ET, and the investigation of the underlying pathophysiology.

The Role of Alpha-Synuclein Deposits in Parkinson's Disease: A Focus on the Human Retina.

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.

The localization of molecularly distinct microglia populations to Alzheimer's disease pathologies using QUIVER.

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.

Between Order and Chaos: Understanding the Mechanism and Pathology of RAN Translation.

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.

Gene Expression Analysis of Laser-Captured Purkinje Cells in the Essential Tremor Cerebellum.

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.

The clinical and neuroimaging features of sporadic adult-onset neuronal intranuclear inclusion disease.

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.

Locus coeruleus degeneration and cerebellar gray matter changes in essential tremor.

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 (CNRLC) and the score of The Essential Tremor Rating Assessment Scale (TETRAS) and cerebellum gray matter (GM) volume. RESULTS: Significant difference of CNRLC was found between ET and HC groups. The CNRLC of ET groups is lower than the HC group (p = 0.031). Subgroup analysis showed that the CNRLC 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 CNRLC and the vermis lobule IV-V in h-ETs (r = - 0.651, p < 0.001). No significant correlation was found between CNRLC 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.

A 62-Year-Old Man Presenting with Bilateral Tremor of the Upper Limb After a Diagnosis of COVID-19 with Confirmed Volumetric Brain Loss.

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.

Quantitative behavioral models for high-resolution measurement and characterization of tremor in rodents.

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.

White matter alterations in familial cortical myoclonic tremor with epilepsy type 1.

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.

Neurodegenerative diseases associated with non-coding CGG tandem repeat expansions.

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.

Expanding the clinical spectrum of adult-onset neuronal intranuclear inclusion disease.

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.

Recent research in fragile X-associated tremor/ataxia syndrome.

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.

Distinct hippocampal subfield atrophy in Parkinson's disease regarding motor subtypes.

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.