Fragile X–associated tremor/ataxia syndrome (FXTAS) is a debilitating late-onset neurodegenerative disease in premutation carriers of the expanded CGG repeat in FMR1 that presents with a spectrum of neurological manifestations, such as gait ataxia, intention tremor, and parkinsonism [P. J. Hagerman, R. J. Hagerman, Ann. N. Y. Acad. Sci. 1338, 58–70 (2015); S. Jacquemont et al., JAMA 291, 460–469 (2004)]. Here, we performed whole-genome sequencing (WGS) on male premutation carriers (CGG55–200) and prioritized candidate variants to screen for candidate genetic modifiers using a Drosophila model of FXTAS. We found 18 genes that genetically modulate CGG-associated neurotoxicity in Drosophila, such as Prosbeta5 (PSMB5), pAbp (PABPC1L), e(y)1 (TAF9), and CG14231 (OSGEPL1). Among them, knockdown of Prosbeta5 (PSMB5) suppressed CGG-associated neurodegeneration in the fly as well as in N2A cells. Interestingly, an expression quantitative trait locus variant in PSMB5, PSMB5rs11543947-A, was found to be associated with decreased expression of PSMB5 and delayed onset of FXTAS in human FMR1 premutation carriers. Finally, we demonstrate evidence that PSMB5 knockdown results in suppression of CGG neurotoxicity via both the RAN translation and RNA-mediated toxicity mechanisms, thereby presenting a therapeutic strategy for FXTAS.

Objective Carriers of the FMR1 premutation allele are at a significantly increased risk for a late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). The primary features of FXTAS are late-onset intention tremor and gait ataxia. Previous reports have shown global deficits in neuropsychological measures among males with FXTAS, particularly those related to executive functioning. The purpose of this study was to investigate the neuropsychological profile among older males with the premutation who are at risk for FXTAS. Method Premutation carriers, 66 with motor symptoms and 23 without, and 18 non-carrier siblings were recruited from pedigrees diagnosed with fragile X syndrome, all over age 50. Subjects were examined with a neurological test battery to identify symptoms of FXTAS and a neuropsychological test battery to investigate cognitive and behavioral profiles. Linear regression and ANCOVA were used to determine the effect of the premutation on outcome measures adjusting for age and education. Results We identified a significant decrease in scores of general intelligence and a marginally significant decrease in scores of logical memory among premutation carrier males with motor symptoms compared to the non-carrier male siblings. We did not identify deficits in executive functioning in our sample of premutation carrier males with motor symptoms. Discussion Similar to other reports, we found that the FMR1 premutation is associated with deficits in general intelligence and memory among older males with symptoms of FXTAS. However, our results differed in that we found no evidence of premutation-associated executive dysfunction. We provide possible explanations for this difference.

The objective of this paper was to assess the phenotypic variance in patients with the Fragile X-associated Tremor Ataxia Syndrome (FXTAS) and to further elucidate genotype–phenotype correlations in the illness. A second goal was to generate hypotheses regarding symptom progression based on careful histories in our sample that can now be tested in ongoing longitudinal studies. The variability of clinical signs and symptom progression in FXTAS complicates our understanding of its phenotype and presents a series of problems in clinical trial design. Similarly, pre-motor and non-motor symptoms have not been adequately explored to answer outstanding questions regarding genotype–phenotype associations in FXTAS. This was a cross-sectional study of FMR1 premutation carriers from known fragile X syndrome pedigrees. We report on the first 50 subjects who have completed a full neurologic evaluation and a brain MRI. Subjects were selected on the basis of motor symptoms or abnormal results (>1 SD) on a quantitative instrument designed to detect mild tremor and ataxia (CATSYS 1994). A neuropsychological battery included the WAIS-III, COWA, and WCST. Statistical analysis used ANOVA and Fisher's exact test with p<0.05. All FMR1 premutation carriers were men of mean age 65±7 years. According to the diagnostic criteria of Jacquemont et al. (Am J Hum Genet 72(4):869–878, 2003), 21 subjects met criteria for definite FXTAS, 10 for probable, 9 for possible, and 10 were indeterminate. Duration of motor symptoms was significantly longer in the definitive group (8.6±6) compared to the other groups (p<0.01). The presentations in 40 subjects, excluding the indeterminate group, included: tremor 24, ataxia 5, memory symptoms 3, parkinsonism 2, and torticollis 1. The data suggest at least two dominant phenotypic presentations: (a) a tremor-dominant subtype in which the onset of ataxia is delayed; (b) a second in which ataxia is the dominant presentation from the outset. In both subtypes, once ataxia emerges it tends to track frontal cognitive changes (p<0.01). The data support the view that FXTAS is a late-life neurodegenerative disorder with involvement of motor, non-motor, and cognitive systems. The results suggest at least two presentations with tremor-and ataxia-predominant phenotypes. In both, global cognitive decline appears to track ataxia. Prospective longitudinal studies are needed to validate this proposed evolution of FXTAS and its relevance to future clinical trials design.

Introduction We investigated olfactory defects in fragile X-associated tremor/ataxia syndrome (FXTAS), a finding reported on in other neurodegenerative disorders with clinical features that overlap those of FXTAS. Methods We measured olfactory identification capacity in 41 FMR1 premutation carriers and 42 controls using the University of Pennsylvania Smell Identification Test (UPSIT). Carriers received neurologic evaluations using motor rating scales for tremor, ataxia, and parkinsonism. Cognitive function was measured using the Montreal Cognitive Assessment test. Results Frequency of olfactory defects was higher in carriers, compared to controls (61% versus 29%; P = 0.003). There was no statistically significant group difference in severity of olfaction defects, after accounting for differences in age, and in rates of head injury and smoking. However, both the frequency (odds ratio = 3.9; 95% confidence interval: 0.81–19.1) and severity (28.6 versus 33.4; P = 0.01) of these defects were greater in cognitively impaired, compared to cognitively intact, carriers. There was no correlation between UPSIT scores and the above-mentioned motor rating scales. Conclusions FMR1 premutation carriers are susceptible to olfactory identification defects. The severity of these defects is comparable to that reported in hereditary ataxias, but less than that in PD and Alzheimer’s disease. This concurrence across neurodegenerative disorders suggests a shared system vulnerability that correlates with, but is not limited to, cognitive impairment, because it is also found in cognitively intact carriers. These results need to be corroborated in a larger prospective study of FMR1 premutation carriers that extends beyond olfactory identification to include measures of smell thresholds.

Objective The absence of atonia during rapid eye movement (REM) sleep and dream-enactment behavior (REM sleep behavior disorder [RBD]) are common features of sleep in the alpha-synucleinopathies. This study examined this phenomenon quantitatively, using the phasic electromyographic metric (PEM), in relation to clinical features of idiopathic Parkinson disease (PD). Based on previous studies suggesting that RBD may be prognostic for the development of later parkinsonism, we hypothesized that clinical indicators of disease severity and more rapid progression would be related to PEM. Methods A cross-sectional convenience sample of 55 idiopathic PD patients from a movement disorders clinic in a tertiary care medical center underwent overnight polysomnography. PEM, the percentage of 2.5-second intervals containing phasic muscle activity, was quantified separately for REM and non-REM (NREM) sleep from 5 different electrode sites. Results Higher PEM rates were seen in patients with symmetric disease, as well as in akinetic-rigid versus tremor-predominant patients. Men had higher PEM relative to women. Results occurred in all muscle groups in both REM and NREM sleep. Interpretation Although our data were cross-sectional, phasic muscle activity during sleep suggests disinhibition of descending motor projections in PD broadly reflective of more advanced and/or progressive disease. Elevated PEM during sleep may represent a functional window into brainstem modulation of spinal cord activity and is broadly consistent with the early pathologic involvement of non-nigral brainstem regions in PD, as described by Braak.

Aims: While behavior-based pelvic floor muscle exercise therapy is an effective treatment for overactive bladder in Parkinson's disease (PD) patients, cognitive function may be a predictor of rehabilitation outcomes. Methods: In a planned exploratory analysis, participants who had a Montreal Cognitive Assessment (MoCA) with a score ≥18 who were randomized in a clinical trial to behavioral treatment were classified by perceived improvement (Benefit vs. No Benefit) as reported on a validated Satisfaction and Benefit Questionnaire. General cognition (MoCA), motor procedural learning (Serial reaction time task), verbal memory (Buschke delayed recall), spatial memory (Nonverbal/Spatial selective reminding test), and working memory (Wisconsin card sorting task) were compared between the two groups using Wilcoxon rank-sum test. Results: Of the 26 participants randomized to behavioral treatment (70% male, mean age 71 ± 6.1 years), 22 participants (85%) reported Benefit and four reported No Benefit. General cognition, motor procedural learning, verbal memory, spatial memory, and working memory did not differ between these groups. While the difference between the time to complete the final practiced series and the random series of the Serial Reaction Time Task (SRTT) was statistically similar between the groups, the Benefit group performed the random sequence more quickly (567.0 ± 136.5 ms) compared to the No Benefit group (959.4 ± 443.0 ms; p = 0.03) and trended toward faster performance in the final practiced series. Conclusions: Perceived benefit from behavioral treatment for overactive bladder was not associated with measures of baseline cognition other than faster completion of the SRTT. This is noteworthy because many behavior-based therapy studies exclude participants with mild cognitive impairment. Additional studies may evaluate if domain-specific cognitive function, particularly the assessment of implicit memory, could lead to individualized behavioral therapy recommendations.

Studies of saccadic eye movements in subjects with Tourette syndrome (TS) have provided additional evidence that there is a link between TS symptoms and deficits in fronto-striato-thalamic networks. These studies revealed impaired timing and inhibition of saccades. We compared fixational eye movements, such as microsaccades and ocular drifts, in subjects with TS and healthy controls.We measured horizontal and vertical eye positions with video-oculography in 14 subjects with Tourette syndrome. We found reduced microsaccade amplitude but increased time between adjacent microsaccades (intersaccadic interval). Hence, the rate of microsaccades was reduced in subjects with TS compared to controls. Measure of ocular stability during intersaccadic intervals revealed increased drift velocity and increased variance in eye position. We hypothesize that increased activity of the direct fronto-striatal pathway and the resulting reduction in basal ganglia outflow targeting the superior colliculus fixation zone affect the rate and amplitude of microsaccades in subjects with TS. The resulting impairment in frontal eye field fixation leads to increased drifts during intersaccadic interval in subjects with TS. Possible clinical implication for these results is that fixational eye movements can be objective biological markers of TS.

Background: Previous studies have demonstrated both clinical and neurochemical similarities between Parkinson’s disease (PD) and narcolepsy. The intrusion of REM sleep into the daytime remains a cardinal feature of narcolepsy, but the importance of these intrusions in PD remains unclear. In this study we examined REM sleep during daytime Maintenance of Wakefulness Testing (MWT) in PD patients. Methods: Patients spent 2 consecutive nights and days in the sleep laboratory. During the daytime, we employed a modified MWT procedure in which each daytime nap opportunity (4 per day) was extended to 40 minutes, regardless of whether the patient was able to sleep or how much the patient slept. We examined each nap opportunity for the presence of REM sleep and time to fall asleep. Results: Eleven of 63 PD patients studied showed 2 or more REM episodes and 10 showed 1 REM episode on their daytime MWTs. Nocturnal sleep characteristics and sleep disorders were unrelated to the presence of daytime REM sleep, however, patients with daytime REM were significantly sleepier during the daytime than those patients without REM. Demographic and clinical variables, including Unified Parkinson’s Disease Rating Scale motor scores and levodopa dose equivalents, were unrelated to the presence of REM sleep. Conclusions: A sizeable proportion of PD patients demonstrated REM sleep and daytime sleep tendency during daytime nap testing. These data confirm similarities in REM intrusions between narcolepsy and PD, perhaps suggesting parallel neurodegenerative conditions of hypocretin deficiency.

Background Many patients with idiopathic Parkinson’s disease experience difficulties maintaining daytime alertness. Controversy exists regarding whether this reflects effects of anti-Parkinsonian medications, the disease itself or other factors such as nocturnal sleep disturbances. In this study we examined the phenomenon by evaluating medicated and unmedicated Parkinson’s patients with objective polysomnographic measurements of nocturnal sleep and daytime alertness. Methods Patients (n = 63) underwent a 48-hour laboratory-based study incorporating 2 consecutive nights of overnight polysomnography and 2 days of Maintenance of Wakefulness Testing. We examined correlates of individual differences in alertness, including demographics, clinical features, nocturnal sleep variables and class and dosage of anti-Parkinson’s medications. Results Results indicated that: 1) relative to unmediated patients, all classes of dopaminergic medications were associated with reduced daytime alertness and this effect was not mediated by disease duration or disease severity; 2) increasing dosages of dopamine agonists were associated with less daytime alertness, whereas higher levels of levodopa were associated with higher levels of alertness. Variables unrelated to Maintenance of Wakefulness Test defined daytime alertness included age, sex, years with diagnosis, motor impairment score and most nocturnal sleep variables. Conclusions Deficits in objectively assessed daytime alertness in Parkinson’s disease appear to be a function of both the disease and the medications and their doses utilized. The apparent divergent dose-dependent effects of drug class in Parkinson’s disease are anticipated by basic science studies of the sleep/wake cycle under different pharmacological agents.

Background: Age and gender specific prevalence rates for parkinsonism and Parkinson's disease (PD) are important to guide research, clinical practice, and public health planning; however, prevalence estimates in Latin America (LatAm) are limited. We aimed to estimate the prevalence of parkinsonism and PD and examine related risk factors in a cohort of elderly individuals from Latin America (LatAm). Methods: Data from 11,613 adults (65+ years) who participated in a baseline assessment of the 10/66 study and lived in six LatAm countries were analyzed to estimate parkinsonism and PD prevalence. Crude and age-adjusted prevalence were determined by sex and country. Diagnosis of PD was established using the UK Parkinson's Disease Society Brain Bank's clinical criteria. Findings: In this cohort, the prevalence of parkinsonism was 8.0% (95% CI 7.6%–8.5%), and the prevalence of PD was 2.0% (95% CI 1.7%–2.3%). PD prevalence increased with age from 1.0 to 3.5 (65–69vs. 80 years or older, p < 0.001). Age-adjusted prevalence rates were lower for women than for men. No significant differences were found across countries, except for lower prevalence in urban areas of Peru. PD was positively associated with depression (adjusted prevalence ratio [aPR] 2.06, 95% CI 1.40–3.01, I2 = 56.0%), dementia (aPR 1.57, 95% CI 1.07- 2.32, I2 = 0.0%) and educational level (aPR 1.14, 95% CI 1.01– 1.29, I2 = 58.6%). Interpretation: The reported prevalence of PD in LatAm is similar to reports from high-income countries (HIC). A significant proportion of cases with PD did not have a previous diagnosis, nor did they seek any medical or neurological attention. These findings underscore the need to improve public health programs for populations currently undergoing rapid demographic aging and epidemiological transition. Funding: The funding source 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.