UNASSIGNED: There is evidence for a significant excess of kinetic upper limb tremor in non-FXTAS female FMR1 premutation carriers. The present study explores the possibility that this tremor is associated with various other features reminiscent of those occurring in syndromic FXTAS.
UNASSIGNED: This study analyzed the data from an Australian cohort of 48 asymptomatic premutation women. We utilized spiral drawings from CRST, representing action tremor; the CRST total tremor; and ICARS- kinetic tremors/cerebellar ataxia scales. Cognitive tests (involving executive functioning) included SDMT, TMT, two subtests of the WAIS-III: MR and Similarities. Spearman Rank correlations assessed the relationships between the above measures, and the Chi-square tested hypothesis about the association between the white matter hyperintensities (wmhs) in the splenium of corpus callosum assessed from MR images and spiral drawings scores.
UNASSIGNED: The spiral drawing scores were significantly correlated with all three non-verbal cognitive test scores, and with the CRST scores; the latter correlated with all four cognitive test measures. Similarities (verbal) scores correlated with CRST, ICARS, and with the remaining cognitive scores. Ordered spiral scores\' categories were significantly associated with the degree of splenium involvement.
UNASSIGNED: This study showed that, in non-FXTAS premutation female carriers, sub-symptomatic forms of kinetic tremor were associated with a broader motor, and cognitive (especially executive) dysfunction.

BACKGROUND: Gene replacement therapy (onasemnogene abeparvovec) is associated with an improvement of the prognosis of children with spinal muscular atrophy, but information on long-term respiratory outcome is scarce. The aim of this study was to report the polysomnography findings and respiratory muscle function of infants with treatment-naive spinal muscular atrophy type 1 and 2 up to 24 months after onasemnogene abeparvovec monotherapy.
METHODS: A clinical and motor evaluation, respiratory muscle function testing, and polysomnography were performed repeatedly.
RESULTS: Fifteen spinal muscular atrophy patients (1 presymptomatic, 7 type 1b, 6 type 1c, and 1 type 2) were included at a median age of 8.6 months (range 3.8-12.6) and followed for 24 months. The thoracic over head circumference ratio was close to normal at baseline (median 1.00 (range 0.90-1.05)) and increased significantly over time. All polysomnography and nocturnal gas exchange parameters were within normal ranges at baseline (median apnea-hypopnea index 2.5 events/hour (range 0.4-5.3)) and follow-up. The inspiratory muscle strength was normal at baseline but tended to slightly decrease over time and the expiratory muscle strength was low at any time especially for patients with recurrent respiratory infections (median (range) at baseline in cmH2O: crying esophageal pressure 54 (30-110), crying transdiaphragmatic pressure 65 (35-107), gastric pressure during maximal cough 26 (10-130), esophageal pressure during maximal cough 61 (38-150)). Only 3 patients required noninvasive ventilation.
CONCLUSIONS: A continuous respiratory monitoring of spinal muscular atrophy patients during the first years of life following onasemnogene abeparvovec monotherapy seems recommended despite the normality of polysomnography parameters.

BACKGROUND: Correlations between dopamine transporter (DAT) availability and Parkinson\'s disease (PD) motor symptoms vary depending on the imaging modality, choice of regions of interest and clinical measures. We aimed to validate the PET radioligand [18F]FE-PE2I as a clinical biomarker in PD, hypothesizing negative correlations between DAT availability in specified nigrostriatal regions with symptom duration, disease stage and motor symptom scores.
METHODS: We included 41 PD patients (age 45-79 years; H&Y stage < 3) and 37 healthy control subjects in a cross-sectional study with dynamic [18F]FE-PE2I PET. Binding potential (BPND) was estimated in the caudate nucleus, putamen, ventral striatum, sensorimotor striatum, and substantia nigra using the cerebellum as reference region.
RESULTS: We found negative correlations (p < 0.02) between symptom duration and BPND in the putamen and sensorimotor striatum (rs = - .42; rs = - .51), and between H&Y stage and BPND in caudate nucleus, putamen, sensorimotor striatum, and substantia nigra (rs between - .40 and - .54). The first correlations were better described with exponential fitting. MDS-UPDRS-III in \'OFF\' state correlated negatively (p < 0.04) with BPND in the sensorimotor striatum (rs = - .47), and excluding tremor score also in the putamen (rs = - .45).
CONCLUSIONS: Results are in agreement with earlier findings in in vivo and post-mortem studies and validate [18F]FE-PE2I as a functional PD biomarker for PD severity.
BACKGROUND: EudraCT 2011-0020050, Registered April 26 2011; EudraCT 2017-003327-29, Registered October 08 2017; EudraCT 2017-001585-19, Registered August 2 2017. https://eudract.ema.europa.eu/ .

The premutation expansion of the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene on the X chromosome has been linked to a range of clinical and subclinical features. Nearly half of men with FMR1 premutation develop a neurodegenerative disorder; Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS). In this syndrome, cognitive executive decline and psychiatric changes may co-occur with major motor features, and in this study, we explored the interrelationships between these three domains in a sample of adult males affected with FXTAS. A sample of 23 adult males aged between 48 and 80 years (mean = 62.3; SD = 8.8), carrying premutation expansions between 45 and 118 CGG repeats, and affected with FXTAS, were included in this study. We employed a battery of cognitive assessments, two standard motor rating scales, and two self-reported measures of psychiatric symptoms. When controlling for age and/or educational level, where appropriate, there were highly significant correlations between motor rating score for ICARS gait domain, and the scores representing global cognitive decline (ACE-III), processing speed (SDMT), immediate memory (Digit Span), and depression and anxiety scores derived from both SCL90 and DASS instruments. Remarkably, close relationships of UPDRS scores, representing the contribution of Parkinsonism to FXTAS phenotypes, were exclusive to psychiatric scores. Highly significant relationships between CGG repeat size and most scores for three phenotypic domains suggest a close tracking with genetic liability. These findings of relationships between a constellation of phenotypic domains in male PM carriers with FXTAS are reminiscent of other conditions associated with disruption to cerebro-cerebellar circuits.

Fragile X Associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder affecting carriers of premutation alleles (PM) of the X-linked FMR1 gene, which contain CGG repeat expansions of 55-200 range in a non-coding region. This late-onset disorder is characterised by the presence of tremor/ataxia and cognitive decline, associated with the white matter lesions throughout the brain, especially involving the middle cerebellar peduncles. Nearly half of older male and ~ 20% of female PM carriers develop FXTAS. While there is evidence for mitochondrial dysfunction in neural and some peripheral tissues from FXTAS patients (though less obvious in the non-FXTAS PM carriers), the results from peripheral blood mononuclear cells (PBMC) are still controversial. Motor, cognitive, and neuropsychiatric impairments were correlated with measures of mitochondrial and non-mitochondrial respiratory activity, AMPK, and TORC1 cellular stress-sensing protein kinases, and CGG repeat size, in a sample of adult FXTAS male and female carriers. Moreover, the levels of these cellular measures, all derived from Epstein- Barr virus (EBV)- transformed and easily accessible blood lymphoblasts, were compared between the FXTAS (N = 23) and non-FXTAS (n = 30) subgroups, and with baseline data from 33 healthy non-carriers. A significant hyperactivity of cellular bioenergetics components as compared with the baseline data, more marked in the non-FXTAS PMs, was negatively correlated with repeat numbers at the lower end of the CGG-PM distribution. Significant associations of these components with motor impairment measures, including tremor-ataxia and parkinsonism, and neuropsychiatric changes, were prevalent in the FXTAS subgroup. Moreover, a striking elevation of AMPK activity, and a decrease in TORC1 levels, especially in the non-FXTAS carriers, were related to the size of CGG expansion. The bioenergetics changes in blood lymphoblasts are biomarkers of the clinical status of FMR1 carriers. The relationship between these changes and neurological involvement in the affected carriers suggests that brain bioenergetic alterations are reflected in this peripheral tissue. A possible neuroprotective role of stress sensing kinase, AMPK, in PM carriers, should be addressed in future longitudinal studies. A decreased level of TORC1-the mechanistic target of the rapamycin complex, suggests a possible future approach to therapy in FXTAS.

Expansions of the CGG repeat in the non-coding segment of the FMR1 X-linked gene are associated with a variety of phenotypic changes. Large expansions (>200 repeats), which cause a severe neurodevelopmental disorder, the fragile x syndrome (FXS), are transmitted from the mothers carrying smaller, unstable expansions ranging from 55 to 200 repeats, termed the fragile X premutation. Female carriers of this premutation may themselves experience a wide range of clinical problems throughout their lifespan, the most severe being the late onset neurodegenerative condition called \"Fragile X-Associated Tremor Ataxia Syndrome\" (FXTAS), occurring between 8 and 16% of these carriers. Male premutation carriers, although they do not transmit expanded alleles to their daughters, have a much higher risk (40-50%) of developing FXTAS. Although this disorder is more prevalent and severe in male than female carriers, specific sex differences in clinical manifestations and progress of the FXTAS spectrum have been poorly documented. Here we compare the pattern and rate of progression (per year) in three motor scales including tremor/ataxia (ICARS), tremor (Clinical Tremor Rating scale, CRST), and parkinsonism (UPDRS), and in several cognitive and psychiatric tests scores, between 13 female and 9 male carriers initially having at least one of the motor scores ≥10. Moreover, we document the differences in each of the clinical and cognitive measures between the cross-sectional samples of 21 female and 24 male premutation carriers of comparable ages with FXTAS spectrum disorder (FSD), that is, who manifest one or more features of FXTAS. The results of progression assessment showed that it was more than twice the rate in male than in female carriers for the ICARS-both gait ataxia and kinetic tremor domains and twice as high in males on the CRST scale. In contrast, sex difference was negligible for the rate of progress in UPDRS, and all the cognitive measures. The overall psychiatric pathology score (SCL-90), as well as Anxiety and Obsessive/Compulsive domain scores, showed a significant increase only in the female sample. The pattern of sex differences for progression in motor scores was consistent with the results of comparison between larger, cross-sectional samples of male and female carriers affected with the FSD. These results were in concert with sex-specific distribution of MRI T2 white matter hyperintensities: all males, but no females, showed the middle cerebellar peduncle white matter hyperintensities (MCP sign), although the distribution and severity of these hyperintensities in the other brain regions were not dissimilar between the two sexes. In conclusion, the magnitude and specific pattern of sex differences in manifestations and progression of clinically recorded changes in motor performance and MRI lesion distribution support, on clinical grounds, the possibility of certain sex-limited factor(s) which, beyond the predictable effect of the second, normal FMR1 alleles in female premutation carriers, may have neuroprotective effects, specifically concerning the cerebellar circuitry.

Conventional MRI measures of traumatic spinal cord injury severity largely rely on 2-dimensional injury characteristics such as intramedullary lesion length and cord compression. Recent advances in spinal cord (SC) analysis have led to the development of a robust anatomic atlas incorporated into an open-source platform called the Spinal Cord Toolbox (SCT) that allows for quantitative volumetric injury analysis. In the current study, we evaluate the prognostic value of volumetric measures of spinal cord injury on MRI following registration of T2-weighted (T2w) images and segmented lesions from acute SCI patients with a standardized atlas. This IRB-approved prospective cohort study involved the image analysis of 60 blunt cervical SCI patients enrolled in the TRACK-SCI clinical research protocol. Axial T2w MRI data obtained within 24 h of injury were processed using the SCT. Briefly, SC MRIs were automatically segmented using the sct_deepseg_sc tool in the SCT and segmentations were manually corrected by a neuro-radiologist. Lesion volume data were used as predictor variables for correlation with lower extremity motor scores at discharge. Volumetric MRI measures of T2w signal abnormality comprising the SCI lesion accurately predict lower extremity motor scores at time of patient discharge. Similarly, MRI measures of injury volume significantly correlated with motor scores to a greater degree than conventional 2-D metrics of lesion size. The volume of total injury and of injured spinal cord motor regions on T2w MRI is significantly and independently associated with neurologic outcome at discharge after injury.

This study explores the relationships between hemispheric and cerebellar white matter lesions and motor and cognitive impairments in male carriers of Fragile-X Mental Retardation 1 (FMR1) premutation alleles, and in a subgroup of these carriers affected with Fragile X-Associated Tremor/Ataxia syndrome (FXTAS). Regional and total white matter hyperintensities (wmhs) on MRI, assessed using semiquantitative scores, were correlated with three motor rating scales (ICARS, UPDRS, Tremor), and neuropsychological measures of non-verbal reasoning, working memory and processing speed, in a sample of 30 male premutation carriers aged 39-81 years, and separately in a subsample of 17 of these carriers affected with FXTAS. There were significant relationships between wmhs in the infratentorial region and all three motor scales, as well as several cognitive measures-Prorated IQ, Matrix Reasoning, Similarities, and the Symbol Digit Modalities Test (SDMT), in the total sample of carriers, as well as in the FXTAS group separately. This shows that whms within the infratentorial region correlates across the categories of clinical status with a range of motor and cognitive impairments. In the FXTAS group, there was a highly significant relationship between supratentorial (periventricular) lesions and parkinsonism, and between both periventricular and supratentorial deep white matter and ICARS ataxia score. These findings further support the relevance of white matter changes in different brain regions to the motor and cognitive deficits across the spectrum of premutation involvement. Future longitudinal studies using larger sample sizes will be necessary to examine the factors that lead to conversion to a greater extent of neurological involvement as seen in the progression across the FXTAS spectrum.

The fragile X premutation (PM) allele contains a CGG expansion of 55-200 repeats in the FMR1 gene\'s promoter. Male PM carriers have an elevated risk of developing neurological and psychiatric changes, including an approximately 50% risk of the fragile X-associated tremor/ataxia syndrome (FXTAS). The aim of this study was to assess the relationships of regional white matter hyperintensities (wmhs) semi-quantitative scores, clinical status, motor (UPDRS, ICARS, Tremor) scales, and cognitive impairments, with FMR1-specific genetic changes, in a sample of 32 unselected male PM carriers aged 39-81 years. Half of these individuals were affected with FXTAS, while the non-FXTAS group comprised subcategories of non-affected individuals and individuals affected with non-syndromic changes. The dynamics of pathological processes at the cellular level relevant to the clinical status of PM carriers was investigated using the enzyme AMP-activated protein kinase (AMPK), which is a highly sensitive cellular stress-sensing alarm protein. This enzyme, as well as genetic markers - CGG repeat number and the levels of the FMR1 mRNA - were assessed in blood lymphoblasts. The results showed that the repeat distribution for FXTAS individuals peaked at 85-90 CGGs; non-FXTAS carriers were distributed within the lowest end of the PM repeat range, and non-syndromic carriers assumed an intermediate position. The size of the CGG expansion was significantly correlated, across all three categories, with infratentorial and total wmhs and with all motor scores, and the FMR1 mRNA levels with all the wmh scores, whilst AMPK activity showed considerable elevation in the non-FXTAS combined group, decreasing in the FXTAS group, proportionally to increasing severity of the wmhs and tremor/ataxia. We conclude that the size of the CGG expansion relates to the risk for FXTAS, to severity of infratentorial wmhs lesions, and to all three motor scale scores. FMR1 mRNA shows a strong association with the extent of wmhs, which is the most sensitive marker of the pathological process. However, the AMPK activity findings - suggestive of a role of this enzyme in the risk of FXTAS - need to be verified and expanded in future studies using larger samples and longitudinal assessment.

Individuals with Parkinson\'s disease (PD) mainly suffer from motor impairments which increase the risk of falls and lead to a decline of quality of life. Several studies investigated the long-term effect of dance for people with PD. The aims of the present study were to investigate (i) the short-term effects of dance (i.e., the effect immediately after the dance class) on motor control in individuals with PD and (ii) the long-term effects of 8 months of participation in the weekly dance class on the quality of life of the PD patients and their caregivers. The dance lessons took place in a ballet studio and were led by a professional dancer. Eleven people with moderate to severe PD (58-85 years old) were subjected to a motor and quality of life assessments. With respect to the motor assessments the unified Parkinson disease rating scale III (UPDRS III), the timed up and go test (TUG), and the Semitandem test (SeTa) before and after the dance class were used. With respect to the quality of life and well-being we applied quality of life scale (QOLS) as well as the Westheimer questionnaire. Additionally, we asked the caregivers to fill out the Questionnaire for caregivers. We found a significant beneficial short-term effect for the total score of the UPDRS motor score. The strongest improvements were in rigidity scores followed by significant improvements in hand movements, finger taps, and facial expression. No significant changes were found for TUG and for SeTa. The results of the questionnaires showed positive effects of the dance class on social life, health, body-feeling and mobility, and on everyday life competences of the PD patients. Beneficial effect was also found for the caregivers. The findings demonstrate that dance has beneficial effect on the functional mobility of individuals with PD. Further, dance improves the quality of life of the patients and their caregivers. Dance may lead to better therapeutic strategies as it is engaging and enjoyable.