Chenodeoxycholic acid (CDCA) treatment during pregnancy in women with cerebrotendinous xanthomatosis (CTX): Lessons learned from 19 pregnancies.

PURPOSE: Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive bile acid synthesis disorder. Biallelic pathogenic variants in CYP27A1, encoding for sterol 27-hydroxylase, impair cholic acid (CA) and chenodeoxycholic acid (CDCA) synthesis and lead to accumulation of cholestanol and C27 bile alcohols. Treatment with CDCA decreases the accumulation of these harmful metabolites and slows disease progression. Currently, CDCA is contraindicated for use during pregnancy based on animal studies that showed that high-dose CDCA may cause fetal harm when administered to pregnant animals. Data regarding the safety of CDCA treatment in humans are lacking. METHODS: We present a case series of 19 pregnancies in 9 women with CTX who either received CDCA treatment throughout pregnancy or did not. RESULTS: In 11 pregnancies where mothers continued CDCA treatment, no complications were reported, and newborns were born at or near full term, with normal birth weight and Apgar scores. In 8 pregnancies where mothers did not receive CDCA, 2 newborns experienced elevated bilirubin soon after birth. One woman who stopped treatment during her pregnancy deteriorated neurologically while off treatment. CONCLUSION: The data we present support the benefit of continued CDCA treatment in pregnant women with CTX for both the affected women and their offspring.

GALC variants affect galactosylceramidase enzymatic activity and risk of Parkinson's disease.

The association between glucocerebrosidase, encoded by GBA, and Parkinson's disease (PD) highlights the role of the lysosome in PD pathogenesis. Genome-wide association studies in PD have revealed multiple associated loci, including the GALC locus on chromosome 14. GALC encodes the lysosomal enzyme galactosylceramidase, which plays a pivotal role in the glycosphingolipid metabolism pathway. It is still unclear whether GALC is the gene driving the association in the chromosome 14 locus and, if so, by which mechanism. We first aimed to examine whether variants in the GALC locus and across the genome are associated with galactosylceramidase activity. We performed a genome-wide association study in two independent cohorts from (i) Columbia University; and (ii) the Parkinson's Progression Markers Initiative study, followed by a meta-analysis with a total of 976 PD patients and 478 controls with available data on galactosylceramidase activity. We further analysed the effects of common GALC variants on expression and galactosylceramidase activity using genomic colocalization methods. Mendelian randomization was used to study whether galactosylceramidase activity may be causal in PD. To study the role of rare GALC variants, we analysed sequencing data from 5028 PD patients and 5422 controls. Additionally, we studied the functional impact of GALC knockout on alpha-synuclein accumulation and on glucocerebrosidase activity in neuronal cell models and performed in silico structural analysis of common GALC variants associated with altered galactosylceramidase activity. The top hit in PD genome-wide association study in the GALC locus, rs979812, is associated with increased galactosylceramidase activity (b = 1.2; SE = 0.06; P = 5.10 × 10-95). No other variants outside the GALC locus were associated with galactosylceramidase activity. Colocalization analysis demonstrated that rs979812 was also associated with increased galactosylceramidase expression. Mendelian randomization suggested that increased galactosylceramidase activity may be causally associated with PD (b = 0.025, SE = 0.007, P = 0.0008). We did not find an association between rare GALC variants and PD. GALC knockout using CRISPR-Cas9 did not lead to alpha-synuclein accumulation, further supporting that increased rather than reduced galactosylceramidase levels may be associated with PD. The structural analysis demonstrated that the common variant p.I562T may lead to improper maturation of galactosylceramidase affecting its activity. Our results nominate GALC as the gene associated with PD in this locus and suggest that the association of variants in the GALC locus may be driven by their effect of increasing galactosylceramidase expression and activity. Whether altering galactosylceramidase activity could be considered as a therapeutic target should be further studied.

Quantifying Changes in Dexterity as a Result of Piano Training in People with Parkinson's Disease.

People with Parkinson's disease often show deficits in dexterity, which, in turn, can lead to limitations in performing activities of daily life. Previous studies have suggested that training in playing the piano may improve or prevent a decline in dexterity in this population. In this pilot study, we tested three participants on a six-week, custom, piano-based training protocol, and quantified dexterity before and after the intervention using a sensor-enabled version of the nine-hole peg test, the box and block test, a test of finger synergies using unidimensional force sensors, and the Quantitative Digitography test using a digital piano, as well as selected relevant items from the motor parts of the MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and the Parkinson's Disease Questionnaire (PDQ-39) quality of life questionnaire. The participants showed improved dexterity following the training program in several of the measures used. This pilot study proposes measures that can track changes in dexterity as a result of practice in people with Parkinson's disease and describes a potential protocol that needs to be tested in a larger cohort.

GBA1-Associated Parkinson's Disease Is a Distinct Entity.

GBA1-associated Parkinson's disease (GBA1-PD) is increasingly recognized as a distinct entity within the spectrum of parkinsonian disorders. This review explores the unique pathophysiological features, clinical progression, and genetic underpinnings that differentiate GBA1-PD from idiopathic Parkinson's disease (iPD). GBA1-PD typically presents with earlier onset and more rapid progression, with a poor response to standard PD medications. It is marked by pronounced cognitive impairment and a higher burden of non-motor symptoms compared to iPD. Additionally, patients with GBA1-PD often exhibit a broader distribution of Lewy bodies within the brain, accentuating neurodegenerative processes. The pathogenesis of GBA1-PD is closely associated with mutations in the GBA1 gene, which encodes the lysosomal enzyme beta-glucocerebrosidase (GCase). In this review, we discuss two mechanisms by which GBA1 mutations contribute to disease development: 'haploinsufficiency,' where a single functional gene copy fails to produce a sufficient amount of GCase, and 'gain of function,' where the mutated GCase acquires harmful properties that directly impact cellular mechanisms for alpha-synuclein degradation, leading to alpha-synuclein aggregation and neuronal cell damage. Continued research is advancing our understanding of how these mechanisms contribute to the development and progression of GBA1-PD, with the 'gain of function' mechanism appearing to be the most plausible. This review also explores the implications of GBA1 mutations for therapeutic strategies, highlighting the need for early diagnosis and targeted interventions. Currently, small molecular chaperones have shown the most promising clinical results compared to other agents. This synthesis of clinical, pathological, and molecular aspects underscores the assertion that GBA1-PD is a distinct clinical and pathobiological PD phenotype, necessitating specific management and research approaches to better understand and treat this debilitating condition.

Adult-onset Alexander disease among patients of Jewish Syrian descent.

Alexander disease (AxD) is a rare autosomal dominant leukodystrophy caused by heterozygous mutations in the glial fibrillary acid protein (GFAP) gene. The age of symptoms onset ranges from infancy to adulthood, with variable clinical and radiological manifestations. Adult-onset AxD manifests as a chronic and progressive condition, characterized by bulbar, motor, cerebellar, and other clinical signs and symptoms. Neuroradiological findings typically involve the brainstem and cervical spinal cord. Adult-onset AxD has been described in diverse populations but is rare in Israel. We present a series of patients diagnosed with adult-onset AxD from three families, all of Jewish Syrian descent. Five patients (4 females) were diagnosed with adult-onset AxD due to the heterozygous mutation c.219G > A, p.Met73Ile in GFAP. Age at symptoms onset ranged from 48 to 61 years. Clinical characteristics were typical and involved progressive bulbar and gait disturbance, followed by pyramidal and cerebellar impairment, dysautonomia, and cognitive decline. Imaging findings included medullary and cervical spinal atrophy and mostly infratentorial white matter hyperintensities. A newly recognized cluster of adult-onset AxD in Jews of Syrian origin is presented. This disorder should be considered in differential diagnosis in appropriate circumstances. Genetic counselling for family members is required in order to discuss options for future family planning.

Association of Rare Variants in ARSA with Parkinson's Disease.

BACKGROUND: Several lysosomal genes are associated with Parkinson's disease (PD), yet the association between PD and ARSA remains unclear. OBJECTIVES: To study rare ARSA variants in PD. METHODS: To study rare ARSA variants (minor allele frequency < 0.01) in PD, we performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by a meta-analysis. RESULTS: We found evidence for associations between functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each) and in the meta-analysis (P = 0.042). We also found an association between loss-of-function variants and PD in the United Kingdom Biobank cohort (P = 0.005) and in the meta-analysis (P = 0.049). These results should be interpreted with caution as no association survived multiple comparisons correction. Additionally, we describe two families with potential co-segregation of ARSA p.E382K and PD. CONCLUSIONS: Rare functional and loss-of-function ARSA variants may be associated with PD. Further replications in large case-control/familial cohorts are required. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Differential gait adaptation patterns in Parkinson's disease - a split belt treadmill pilot study.

BACKGROUND: Interventions using split belt treadmills (SBTM) aim to improve gait symmetry (GA) in Parkinson's disease (PD). Comparative effects in conjugated SBTM conditions were not studied systematically despite potentially affecting intervention outcomes. We compared gait adaptation effects instigated by SBTM walking with respect to the type (increased\decreased speed) and the side (more/less affected) of the manipulated belt in PD. METHODS: Eight individuals with PD performed four trials of SBTM walking, each consisted of baseline tied belt configuration, followed by split belt setting - either WS or BS belt's speed increased or decreased by 50% from baseline, and final tied belt configuration. Based on the disease's motor symptoms, a 'worst' side (WS) and a 'best' side (BS) were defined for each participant. RESULTS: SB initial change in GA was significant regardless of condition (p ≤ 0.02). This change was however more pronounced for BS-decrease compared with its matching condition WS-increase (p = 0.016). Similarly, the same was observed for WS-decrease compared to BS-increase (p = 0.013). Upon returning to tied belt condition, both BS-decrease and WS-increased resulted in a significant change in GA (p = 0.04). Upper limb asymmetry followed a similar trend of GA reversal, although non-significant. CONCLUSIONS: Stronger effects on GA were obtained by decreasing the BS belt's speed of the best side, rather than increasing the speed of the worst side. Albeit a small sample size, which limits the generalisability of these results, we propose that future clinical studies would benefit from considering such methodological planning of SBTM intervention, for maximising of intervention outcomes. Larger samples may reveal arm swinging asymmetries alterations to match SBTM adaptation patterns. Finally, further research is warranted to study post-adaption effects in order to define optimal adaptation schemes to maximise the therapeutic effect of SBTM based interventions.

Targeted sequencing of Parkinson's disease loci genes highlights SYT11, FGF20 and other associations.

Genome-wide association studies (GWAS) have identified numerous loci associated with Parkinson's disease. The specific genes and variants that drive the associations within the vast majority of these loci are unknown. We aimed to perform a comprehensive analysis of selected genes to determine the potential role of rare and common genetic variants within these loci. We fully sequenced 32 genes from 25 loci previously associated with Parkinson's disease in 2657 patients and 3647 controls from three cohorts. Capture was done using molecular inversion probes targeting the exons, exon-intron boundaries and untranslated regions (UTRs) of the genes of interest, followed by sequencing. Quality control was performed to include only high-quality variants. We examined the role of rare variants (minor allele frequency < 0.01) using optimized sequence Kernel association tests. The association of common variants was estimated using regression models adjusted for age, sex and ethnicity as required in each cohort, followed by a meta-analysis. After Bonferroni correction, we identified a burden of rare variants in SYT11, FGF20 and GCH1 associated with Parkinson's disease. Nominal associations were identified in 21 additional genes. Previous reports suggested that the SYT11 GWAS association is driven by variants in the nearby GBA gene. However, the association of SYT11 was mainly driven by a rare 3' UTR variant (rs945006601) and was independent of GBA variants (P = 5.23 × 10-5 after exclusion of all GBA variant carriers). The association of FGF20 was driven by a rare 5' UTR variant (rs1034608171) located in the promoter region. The previously reported association of GCH1 with Parkinson's disease is driven by rare non-synonymous variants, some of which are known to cause dopamine-responsive dystonia. We also identified two LRRK2 variants, p.Arg793Met and p.Gln1353Lys, in 10 and eight controls, respectively, but not in patients. We identified common variants associated with Parkinson's disease in MAPT, TMEM175, BST1, SNCA and GPNMB, which are all in strong linkage disequilibrium with known GWAS hits in their respective loci. A common coding PM20D1 variant, p.Ile149Val, was nominally associated with reduced risk of Parkinson's disease (odds ratio 0.73, 95% confidence interval 0.60-0.89, P = 1.161 × 10-3). This variant is not in linkage disequilibrium with the top GWAS hits within this locus and may represent a novel association. These results further demonstrate the importance of fine mapping of GWAS loci, and suggest that SYT11, FGF20, and potentially PM20D1, BST1 and GPNMB should be considered for future studies as possible Parkinson's disease-related genes.

Neuro-Ophthalmic Phenotype of OPA3.

BACKGROUND: Type III 3-methylglutaconic aciduria (OPA 3) is a neuro-ophthalmologic syndrome consisting of early-onset bilateral optic atrophy. Since Costeff described the phenotype of 19 patients in 1989, several reports described approximately 50 patients, but most of them lack details about neuro-ophthalmic phenotype. Our aim was to characterize the clinical neuro-ophthalmic phenotype of this syndrome. METHODS: Nine patients underwent meticulous visual function history and medical documents' review. Results of best-corrected visual acuity (VA), color vision, visual field (VF), ocular motility, pupillary reaction, slit-lamp, and dilated fundus examinations were recorded. Optical coherence tomography (OCT) was performed whenever possible. RESULTS: The average VA was 1.4 ± 0.8 logarithm of the minimum angle of resolution. Poor vision was the presenting symptom in 5 patients. Six patients had decreased VA and variable degrees of optic atrophy. Humphrey VF testing of 7 patients revealed generalized depression in 5 and a cecocentral defect in 2. All patients demonstrated dysmetric saccades. Four patients had strabismus, 3 with exotropia, and one with esotropia. Seven patients had nystagmus. Ocular motility abnormality is possibly the result of cerebellar atrophy that was found in MRI studies of our patients. OCT of the retina was possible in 6 patients and revealed retinal nerve fiber layer (RNFL) thinning as well as average retinal thinning. Three patients, in whom ganglion cell layer-inner plexiform layer (IPL) measurement was possible, also showed diffused thinning. CONCLUSIONS: This study compiled data regarding neuro-ophthalmic manifestation of OPA 3 Type III patients. Contrary to established literature, poor vision was the presenting symptom in only 50% of our patients. This is the first report of OCT findings in 3MGA patients. The results demonstrated diffused thinning of the RNFL and ganglion cell complex-IPL with correlation to VA, which is in contrast to OPA1 patients in whom the most severe thinning is at the level of the papillomacular bundle. Average retinal thinning was identified at second and third decades of life, possibly resulting from early ganglion cell loss. These results may contribute to visual prognosis, and OCT may help monitor experimental therapies.

Patients' Self-Report and Handwriting Performance Features as Indicators for Suspected Mild Cognitive Impairment in Parkinson's Disease.

Early identification of mild cognitive impairment (MCI) in Parkinson's disease (PD) patients can lessen emotional and physical complications. In this study, a cognitive functional (CF) feature using cognitive and daily living items of the Unified Parkinson's Disease Rating Scale served to define PD patients as suspected or not for MCI. The study aimed to compare objective handwriting performance measures with the perceived general functional abilities (PGF) of both groups, analyze correlations between handwriting performance measures and PGF for each group, and find out whether participants' general functional abilities, depression levels, and digitized handwriting measures predicted this CF feature. Seventy-eight participants diagnosed with PD by a neurologist (25 suspected for MCI based on the CF feature) completed the PGF as part of the Daily Living Questionnaire and wrote on a digitizer-affixed paper in the Computerized Penmanship Handwriting Evaluation Test. Results indicated significant group differences in PGF scores and handwriting stroke width, and significant medium correlations between PGF score, pen-stroke width, and the CF feature. Regression analyses indicated that PGF scores and mean stroke width accounted for 28% of the CF feature variance above age. Nuances of perceived daily functional abilities validated by objective measures may contribute to the early identification of suspected PD-MCI.

Overconfidence in visual perception in parkinson's disease.

Increased dependence on visual cues in Parkinson's disease (PD) can unbalance the perception-action loop, impair multisensory integration, and affect everyday function of PD patients. It is currently unknown why PD patients seem to be more reliant on their visual cues. We hypothesized that PD patients may be overconfident in the reliability (precision) of their visual cues. In this study we tested coherent visual motion perception in PD, and probed subjective (self-reported) confidence in their visual motion perception. Twenty patients with idiopathic PD, 21 healthy aged-matched controls and 20 healthy young adult participants were presented with visual stimuli of moving dots (random dot kinematograms). They were asked to report: (1) whether the aggregate motion of dots was to the left or to the right, and (2) how confident they were that their perceptual discrimination was correct. Visual motion discrimination thresholds were similar (unimpaired) in PD compared to the other groups. By contrast, PD patients were significantly overconfident in their visual perceptual decisions (p = .002 and p < .001 vs. the age-matched and young adult groups, respectively). These results suggest intact visual motion perception, but overestimation of visual cue reliability, in PD. Overconfidence in visual (vs. other, e.g., somatosensory) cues could underlie increased visual dependence and impaired multisensory/sensorimotor integration in PD. It could thereby contribute to gait and balance impairments, and affect everyday activities, such as driving. Future work should investigate and compare PD confidence in somatosensory function. A better understanding of altered sensory reliance might open up new avenues to treat debilitating PD symptoms.

Self-motion perception in Parkinson's disease.

Parkinson's disease (PD), best characterized by its classic motor symptoms, also manifests non-motor symptoms including perceptual impairments. Normal motor and perceptual brain functions interact continuously in an action-perception loop; hence, perceptual and motor dysfunction in PD are likely also intertwined. A vital skill in order to maintain balance, and to move around in the environment is the ability to perceive one's own motion in space (self-motion perception). Self-motion perception is a complex brain process, that requires the integration of information from visual (optic flow), vestibular (gravito-inertial), and somatosensory senses. Yet, not much is known about self-motion perception or multisensory integration in PD. In this review, we highlight the need to better study these important functions in PD. We review perceptual deficits in underlying functions required for adept self-motion perception (visual, vestibular and somatosensory, as well as multisensory integration) and address how these might affect self-motion perception and motor function in PD. We propose that dysfunction of central brain mechanisms, implicated in impaired visual, vestibular and somatosensory function, likely impact self-motion perception in PD. Recent evidence suggests that visual and multisensory integration mechanisms of self-motion perception are indeed impaired in PD. This can affect motor control, gait and balance. Future research is needed to better investigate this important topic. A better understanding of self-motion perception and multisensory integration in PD may aid diagnosis and subtyping and may open new avenues for novel therapies to treat debilitating motor symptoms, including gait and balance impairment, using sensory augmentation devices or sensory retraining.

Genetic, Structural, and Functional Evidence Link TMEM175 to Synucleinopathies.

OBJECTIVE: The TMEM175/GAK/DGKQ locus is the 3rd strongest risk locus in genome-wide association studies of Parkinson disease (PD). We aimed to identify the specific disease-associated variants in this locus, and their potential implications. METHODS: Full sequencing of TMEM175/GAK/DGKQ followed by genotyping of specific associated variants was performed in PD (n = 1,575) and rapid eye movement sleep behavior disorder (RBD) patients (n = 533) and in controls (n = 1,583). Adjusted regression models and a meta-analysis were performed. Association between variants and glucocerebrosidase (GCase) activity was analyzed in 715 individuals with available data. Homology modeling, molecular dynamics simulations, and lysosomal localization experiments were performed on TMEM175 variants to determine their potential effects on structure and function. RESULTS: Two coding variants, TMEM175 p.M393T (odds ratio [OR] = 1.37, p = 0.0003) and p.Q65P (OR = 0.72, p = 0.005), were associated with PD, and p.M393T was also associated with RBD (OR = 1.59, p = 0.001). TMEM175 p.M393T was associated with reduced GCase activity. Homology modeling and normal mode analysis demonstrated that TMEM175 p.M393T creates a polar side-chain in the hydrophobic core of the transmembrane, which could destabilize the domain and thus impair either its assembly, maturation, or trafficking. Molecular dynamics simulations demonstrated that the p.Q65P variant may increase stability and ion conductance of the transmembrane protein, and lysosomal localization was not affected by these variants. INTERPRETATION: Coding variants in TMEM175 are likely to be responsible for the association in the TMEM175/GAK/DGKQ locus, which could be mediated by affecting GCase activity. ANN NEUROL 2020;87:139-153.

Analysis of Heterozygous PRKN Variants and Copy-Number Variations in Parkinson's Disease.

BACKGROUND: Biallelic PRKN mutation carriers with Parkinson's disease (PD) typically have an earlier disease onset, slow disease progression, and, often, different neuropathology compared to sporadic PD patients. However, the role of heterozygous PRKN variants in the risk of PD is controversial. OBJECTIVES: Our aim was to examine the association between heterozygous PRKN variants, including single-nucleotide variants and copy-number variations (CNVs), and PD. METHODS: We fully sequenced PRKN in 2809 PD patients and 3629 healthy controls, including 1965 late-onset (63.97 ± 7.79 years, 63% men) and 553 early-onset PD patients (43.33 ± 6.59 years, 68% men). PRKN was sequenced using targeted next-generation sequencing with molecular inversion probes. CNVs were identified using a combination of multiplex ligation-dependent probe amplification and ExomeDepth. To examine whether rare heterozygous single-nucleotide variants and CNVs in PRKN are associated with PD risk and onset, we used optimized sequence kernel association tests and regression models. RESULTS: We did not find any associations between all types of PRKN variants and risk of PD. Pathogenic and likely-pathogenic heterozygous single-nucleotide variants and CNVs were less common among PD patients (1.52%) than among controls (1.8%, false discovery rate-corrected P = 0.55). No associations with age at onset and in stratified analyses were found. CONCLUSIONS: Heterozygous single-nucleotide variants and CNVs in PRKN are not associated with PD. Molecular inversion probes allow for rapid and cost-effective detection of all types of PRKN variants, which may be useful for pretrial screening and for clinical and basic science studies targeting specifically PRKN patients. © 2020 International Parkinson and Movement Disorder Society.

Genetic modifiers of risk and age at onset in GBA associated Parkinson's disease and Lewy body dementia.

Parkinson's disease is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of Parkinson's disease, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as Parkinson's disease and Lewy body dementia. These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known Parkinson's disease risk variants. Using multiple, large case-control datasets, totalling 217 165 individuals (22 757 Parkinson's disease cases, 13 431 Parkinson's disease proxy cases, 622 Lewy body dementia cases and 180 355 controls), we identified 1691 Parkinson's disease cases, 81 Lewy body dementia cases, 711 proxy cases and 7624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent Parkinson's disease-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall Parkinson's disease genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S induced pluripotent cell-derived neurons were shown to have decreased cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated Parkinson's disease risk and age at onset, although the total contribution of common genetics variants is not large. We further demonstrate that common variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have implications for selection of GBA carriers for therapeutic interventions.

Implicit sequence learning in individuals with Parkinson's disease: The added value of using an ocular version of the serial reaction time (O-SRT) task.

INTRODUCTION: Though the majority of studies reported impaired sequence learning in individuals with Parkinson's disease (PD) tested with the Serial Reaction Time (SRT) task, findings are inconclusive. To elucidate this point, we used an eye tracker in an ocular SRT task version (O-SRT) that in addition to RT, enables extraction of two measures reflecting different cognitive processes, namely, Correct Anticipation (CA) and number of Stucks. METHODS: Individuals with PD (n = 29) and matched controls (n = 31) were tested with the O-SRT task, consisting of a repeated sequence of six blocks, then a block with an interference sequence followed by an original sequence block. RESULTS: Unlike controls, patients with PD did not improve in CA rate across learning trials, did not show an increase in RT when presented with the interference sequence, and showed a significantly higher rate of Stucks. CONCLUSIONS: Low CA rate and high Stucks rate emerge as the cardinal deficits leading to impaired sequence learning following PD. These are viewed as reflecting difficulty in exploration for an efficient learning strategy. This study highlights the advantage in using the O-SRT task, which enables the generation of several informative measures of learning, allowing better characterization of the PD effect on sequence learning.

DailyCog: A Real-World Functional Cognitive Mobile Application for Evaluating Mild Cognitive Impairment (MCI) in Parkinson's Disease.

Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder affecting patient functioning and quality of life. Aside from the motor symptoms of PD, cognitive impairment may occur at early stages of PD and has a substantial impact on patient emotional and physical health. Detecting these early signs through actual daily functioning while the patient is still functionally independent is challenging. We developed DailyCog-a smartphone application for the detection of mild cognitive impairment. DailyCog includes an environment that simulates daily tasks, such as making a drink and shopping, as well as a self-report questionnaire related to daily events performed at home requiring executive functions and visual-spatial abilities, and psychomotor speed. We present the detailed design of DailyCog and discuss various considerations that influenced the design. We tested DailyCog on patients with mild cognitive impairment in PD. Our case study demonstrates how the markers we used coincide with the cognitive levels of the users. We present the outcome of our usability study that found that most users were able to use our app with ease, and provide details on how various features were used, along with some of the difficulties that were identified.

A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders.

Genetic ataxias are associated with mutations in hundreds of genes with high phenotypic overlap complicating the clinical diagnosis. Whole-exome sequencing (WES) has increased the overall diagnostic rate considerably. However, the upper limit of this method remains ill-defined, hindering efforts to address the remaining diagnostic gap. To further assess the role of rare coding variation in ataxic disorders, we reanalyzed our previously published exome cohort of 76 predominantly adult and sporadic-onset patients, expanded the total number of cases to 260, and introduced analyses for copy number variation and repeat expansion in a representative subset. For new cases (n = 184), our resulting clinically relevant detection rate remained stable at 47% with 24% classified as pathogenic. Reanalysis of the previously sequenced 76 patients modestly improved the pathogenic rate by 7%. For the combined cohort (n = 260), the total observed clinical detection rate was 52% with 25% classified as pathogenic. Published studies of similar neurological phenotypes report comparable rates. This consistency across multiple cohorts suggests that, despite continued technical and analytical advancements, an approximately 50% diagnostic rate marks a relative ceiling for current WES-based methods and a more comprehensive genome-wide assessment is needed to identify the missing causative genetic etiologies for cerebellar ataxia and related neurodegenerative diseases.

Evolution of echovirus 11 in a chronically infected immunodeficient patient.

Deep sequencing was used to determine complete nucleotide sequences of echovirus 11 (EV11) strains isolated from a chronically infected patient with CVID as well as from cases of acute enterovirus infection. Phylogenetic analysis showed that EV11 strains that circulated in Israel in 1980-90s could be divided into four clades. EV11 strains isolated from a chronically infected individual belonged to one of the four clades and over a period of 4 years accumulated mutations at a relatively constant rate. Extrapolation of mutations accumulation curve into the past suggested that the individual was infected with circulating EV11 in the first half of 1990s. Genomic regions coding for individual viral proteins did not appear to be under strong selective pressure except for protease 3C that was remarkably conserved. This may suggest its important role in maintaining persistent infection.

Smartphone Based Timed Up and Go Test Can Identify Postural Instability in Parkinson's Disease.

BACKGROUND: There is a need for standardized and objective methods to measure postural instability (PI) and gait dysfunction in Parkinson's disease (PD) patients. Recent technological advances in wearable devices, including standard smartphones, may provide such measurements. OBJECTIVES: To test the feasibility of smartphones to detect PI during the Timed Up and Go (TUG) test. METHODS: Ambulatory PD patients, divided by item 30 (postural stability) of the motor Unified Parkinson's Disease Rating Scale (UPDRS) to those with a normal (score = 0, PD-NPT) and an abnormal (score ≥ 1, PD-APT) test and a group of healthy controls (HC) performed a 10-meter TUG while motion sensor data was recorded from a smartphone attached to their sternum using the EncephaLog application. RESULTS: In this observational study, 44 PD patients (21 PD-NPT and 23 PD-APT) and 22 HC similar in age and gender distribution were assessed. PD-APT differed significantly in all gait parameters when compared to PD-NPT and HC. Significant difference between PD-NPT and HC included only turning time (P < 0.006) and step-to-step correlation (P < 0.05). CONCLUSIONS: While high correlations were found between EncephaLog gait parameters and axial UPDRS items, the pull test was least correlated with EncephaLog measures. Motion sensor data from a smartphone can detect differences in gait and balance measures between PD with and without PI and HC.