Early-onset familial essential tremor is associated with nucleotide expansions of spinocerebellar ataxia in China.

BACKGROUND: Essential tremor (ET) is a neurological disease characterized by action tremor in upper arms. Although its high heritability and prevalence worldwide, its etiology and association with other diseases are still unknown. METHOD: We investigated 10 common spinocerebellar ataxias (SCAs), including SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17, SCA36, dentatorubral-pallidoluysian atrophy (DRPLA) in 92 early-onset familial ET pedigrees in China collected from 2016 to 2022. RESULT: We found one SCA12 proband carried 51 CAG repeats within PPP2R2B gene and one SCA3 proband with intermediate CAG repeats (55) with ATXN3 gene. The other 90 ET probands all had normal repeat expansions. CONCLUSION: Tremor can be the initial phenotype of certain SCA. For early-onset, familial ET patients, careful physical examinations are needed before genetic SCA screening.

Association Analysis of 27 Single Nucleotide Polymorphisms in a Chinese Population with Essential Tremor.

Genetic factors play a major role in essential tremor (ET) pathogenesis. This study aimed to assess variant burden in ET-associated genes in a relatively large Chinese population cohort. We genotyped 27 single nucleotide polymorphisms (SNPs) previously reported to be associated with ET by multiplex PCR amplicon sequencing assay in 488 familial and sporadic ET patients and 514 healthy controls (HCs). Then, we performed allelic and genotypic association test by Pearson chi-square test or Fisher's exact test. A total of 1002 samples were included in our analysis, consisting of 488 ET patients and 514 sex and age-matched HCs. For rs10937625, the C allele was linked to increased risk of ET (P = 0.019, OR = 1.503, 95% CI = 1.172-1.928). The carriers of the C/C homozygote and C/T heterozygote showed a significantly higher risk of ET, compared with the T/T homozygote under the dominant model (P = 0.019, OR = 1.628, 95% CI = 1.221-2.170). There were no statistically significant differences in the frequency of other SNPs between ET patients and healthy controls. Rs10937625 (STK32B) may increase the risk of ET in eastern Chinese population.

Brain microstructural changes in essential tremor patients and correlations with clinical characteristics: a diffusion kurtosis imaging study.

OBJECTIVE: Essential tremor (ET) is the second most common movement disorder; however, the pathophysiological mechanism of ET is unclear. We aimed to investigate the microstructural degeneration of gray matter (GM) and white matter (WM) and their correlations with cognition and tremor in patients with ET. METHODS: The participants were 63 patients with ET and 63 matched healthy controls (HCs) who underwent 3D-T1 weighted and diffusion kurtosis images (DKI). Microstructural degeneration was measured using high-level diffusion parameters derived from DKI. A voxel-wise analysis of the means of the GM-based spatial statistics and tract-based spatial statistics were conducted to assess differences in diffusion parameters between the ET and HC groups. The volume differences between the two groups were also assessed, and tremor severity and multi-domain cognitive performance were evaluated. Finally, the relationship between microstructural degeneration and clinical characteristics were assessed. RESULTS: The ET group had significantly lower mean kurtosis of the temporal, parietal, and occipital lobes and the cerebellum and lower radial kurtosis in several tracts. These microstructural changes in GM and WM were correlated with tremor and cognitive scores. However, no significant difference in volume was found between the groups. CONCLUSION: Our findings suggest that ET entails extensive GM and WM microstructural alterations, which support the neurodegenerative hypothesis of ET. Our study contributes to a better understanding of the mechanisms underlying tremor and cognitive impairment in ET.

Noninvasive neuroimaging provides evidence for deterioration of the glymphatic system in Parkinson's disease relative to essential tremor.

INTRODUCTION: Growing evidence has demonstrated dysfunction of the glymphatic system in α-synucleinopathy and related diseases. In this study, we aimed to use diffusion tensor image analysis along the perivascular space (DTI-ALPS) and MRI-visible enlarged perivascular spaces (EPVS) to evaluate glymphatic system function quantitatively and qualitatively and its relationship to clinical scores of disease severity in Parkinson's disease (PD) and essential tremor (ET). METHODS: Overall, 124 patients with PD, 74 with ET, and 106 healthy controls (HC) were enrolled. Two trained neurologists performed quantitative calculations of ALPS on DTI and visual ratings of EPVS on T2-weighted images in the centrum semiovale (CSO), basal ganglia (BG), midbrain, and cerebellum. RESULTS: The ALPS index was lower in patients with PD than in patients with ET (p < 0.001) and HC (p < 0.001). Similarly, patients with PD showed a more severe EPVS burden in the CSO, BG, and midbrain compared to ET and HC. Moreover, the ALPS index was negatively correlated with disease severity in the PD subgroups; however, it did not differ within the ET subgroup. No differences in ALPS or EPVS were observed between the ET and HC groups. CONCLUSION: In conclusion, DTI-ALPS and EPVS both provide neuroimaging evidence of glymphatic system dysfunction in PD, which further supports that PD is an α-synucleinopathy disease, while ET is a cerebellar dysfunction-related 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.

Autosomal dominant sleep-related hypermotor epilepsy associated with a novel mutation of KCNT1.

Autosomal dominant sleep-related hypermotor epilepsy (ADSHE) is characterized by severe sleep-related rigid hypermotor seizures. The pathogenic genes of ADSHE include genes encoding subunits of the neuronal nicotinic acetylcholine receptor, KCNT1, DEPDC5, NPRL2/3, CABP4, and CRH. Individuals with KCNT1-related ADSHE are more likely to develop seizures at a younger age, have cognitive comorbidity, and display psychiatric and behavioral problems. In this study, a 12-year-old Chinese girl was referred for genetic evaluation of grand mal seizures. She had paroxysmal convulsions of the limbs and loss of consciousness just after falling asleep without obvious triggers. A novel heterozygous missense mutation c.2797C > T (p.Arg933Cys) in exon 24 of the KCNT1 was identified in the proband by whole-exome sequencing and Sanger sequencing, and the clinical symptoms were compatible with ADSHE. The proband's father has been showing similar symptoms for more than 20 years and had the same site mutation. Her mother and sister were physically and genetically normal. The study revealed a novel variant in the KCNT1 and expanded the mutation spectrum for this clinical condition. Our results provide further evidence supporting a causative role in KCNT1 variants in ADSHE.

Risk factors of impulsive-compulsive behaviors in PD patients: a meta-analysis.

OBJECTIVE: To summarize the reliable risk factors of impulsive-compulsive behaviors (ICBs) in Parkinson's disease (PD) patients through a meta-analysis on studies in which PD-ICBs were diagnosed by clinical interview. METHODS: PubMed, Embase, Web of Science, CNKI and Wanfang databases were searched. We selected studies ensuring that diagnosis of ICBs in PD patients depends on semi-structured interviews according to the clinical diagnostic criteria of ICBs. The Newcastle-Ottawa Scale was used to evaluate quality of the included studies. The analyzed factors included demographic information, clinical characteristics of PD and medications. RESULTS: A total of 856 records were screened and 66 full texts were evaluated, and 13 studies (684 PD patients with ICBs [PD-ICBs] and 3,382 PD patients without ICBs [PD-non-ICBs]) were included. Compared with PD-non-ICBs, PD-ICBs were younger in age (- 3.7 [- 5.53, - 1.87], P < 0.0001), with a greater proportion of males (1.64 [1.21, 2.22], P = 0.001), with a younger age of PD onset (- 5.42 [- 7.87, - 2.97], P < 0.0001) and a longer course of PD (1.30 [0.38, 2.22], P = 0.005). PD-ICBs were also associated with higher HAM-D (1.74 [0.47, 3.01], P = 0.007), more levodopa dosage (1.74 [1.09, 2.77], P = 0.02) and dopamine receptor agonists (DA) use (3.96 [2.74, 5.71), P < 0.00001), and higher average dose (levodopa 117.53 [53.59, 181.46], P = 0.0003; DA 80.03 [46.16, 113.90], P < 0.00001), as well as more amantadine use (2.20 [1.42, 3.40], P = 0.0004). The meta-analysis of most factors showed less heterogeneity, except age, age of onset, PD duration, Hoehn and Yahr stage, MMSE and drug dosage. However, whether rapid eye movement sleep behavior disorder, dyskinesia, genetic polymorphism and other factors are risk factors for PD-ICBs remains unclear. CONCLUSION: This meta-analysis suggests that males, young, early disease onset, long disease duration, depression, dose of levodopa, dopamine receptor agonists and amantadine are risk factors of ICBs in PD patients.

The effect of polygenic risk on white matter microstructural degeneration in Parkinson's disease: A longitudinal Diffusion Tensor Imaging study.

BACKGROUND AND PURPOSE: This study was undertaken to investigate the effect of genetic risk on whole brain white matter (WM) integrity in patients with Parkinson disease (PD). METHODS: Data were acquired from the Parkinson's Progression Markers Initiative (PPMI) database. Polygenic load was estimated by calculating weighted polygenic risk scores (PRS) using (i) all available 26 PD-risk single nucleotide polymorphisms (SNPs) (PRS1) and (ii) 23 SNPs with minor allele frequency (MAF) > 0.05 (PRS2). According to the PRS2, and combined with clinical and diffusion tensor imaging (DTI) data over 3-year follow-up, 60 PD patients were screened and assigned to the low-PRS group (n = 30) and high-PRS group (n = 30) to investigate intergroup differences in clinical profiles and WM microstructure measured by DTI cross-sectionally and longitudinally. RESULTS: PRS were associated with younger age at onset in patients with PD (PRS1, Spearman ρ = -0.190, p = 0.003; PRS2, Spearman ρ = -0.189, p = 0.003). The high-PRS group showed more extensive WM microstructural degeneration compared with the low-PRS group, mainly involving the anterior thalamic radiation (AThR) and inferior fronto-occipital fasciculus (IFOF) (p < 0.05). Furthermore, WM microstructural changes in AThR correlated with declining cognitive function (r = -0.401, p = 0.028) and increasing dopaminergic deficits in caudate (r = -0.405, p = 0.030). CONCLUSIONS: These findings suggest that PD-associated polygenic load aggravates the WM microstructural degeneration and these changes may lead to poor cognition with continuous dopamine depletion. This study provides advanced evidence that combined with a cumulative PRS and DTI methods may predict disease progression in PD patients.