A 24-Year-Old Man With Spastic Ataxia and Hypodontia.

A 24-year-old man presented with progressive gait instability, marked spinal cord atrophy, and dental radiography showing the absence of several elements, microdontia, and taurodontia. What is your diagnosis?

Pupil light reflex dynamics in Parkinson's disease.

Introduction: Visual disturbance is common symptom in Parkinson's disease (PD), and defective pupil light reflex (PLR) is an anticipated contributing factor that may be associated to the presence of autonomic dysfunction, which is a common non-motor feature of PD. Studies investigating the intercorrelation between PLR and dysautonomia in PD are limited. Methods: The aim of this study was to investigate differences of PLR parameters, measured by eye-tracker, between patients with PD, with and without signs of dysautonomia, and healthy controls (HC). In total, 43 HC and 50 patients with PD were recruited and PLR parameters were measured with Tobii Pro Spectrum, during a long (1,000 ms) and a short (100 ms) light stimulus. Presence of orthostatic hypotension (OH) was used as proxy marker of dysautonomia. Linear mixed-effects model and non-parametric comparative statistics were applied to investigate differences among groups. Results: Peak constriction velocity was slower in PD compared with HC, after adjustment for age and sex in the mixed model, and the difference was greater in the subgroup of PD with OH (unadjusted). Dilation amplitude and velocity were also gradually slower in HC vs. PD without OH vs. PD with OH (unadjusted for confounders). In the mixed model, age was significant predictor of dilation response. Discussion: Our results support previous observations on defective PLR in PD, evaluated with eye-tracker, and show a possible association with autonomic dysfunction. Further studies with more patients and rigorous evaluation of autonomic dysfunction are needed to validate these findings.

Reading Alterations in Parkinson's Disease Indicate Worse Cognitive Status.

Background: Reading difficulties are commonly reported in Parkinson's disease (PD). So far, only a few studies have assessed reading in PD, most of them confirming a different pattern in patients compared with healthy populations. Impaired oculomotor control is an early feature of PD. Cognitive deficits, on the other hand, may appear early, but they are most prominent at later stages. Although these two factors are thought to be responsible for the alterations in reading performance, it is unclear how each factor contributes to them. Objectives: To evaluate eye movements during reading in PD and healthy controls (HCs). Methods: Data from 42 HCs (36% men) and 48 patients with PD (67% men) at Hoehn and Yahr stages ≤3 were analyzed. PD participants were further divided into 2 groups based on their Montreal Cognitive Assessment (MoCA) score using a cutoff of ≥26. Eye movements were recorded with Tobii Pro Spectrum, a screen-based eye tracker with a sampling rate of 1200 Hz. Results: PD participants performed fewer fixations per second (P = 0.033), with a longer mean (P = 0.037) and standard deviation fixation duration (P = 0.033) than HC, and further analysis showed that only patients with a lower MoCA score performed worse than HCs. Reading parameters were weakly associated with MoCA scores, irrespective of age and education. Conclusion: Changes in the reading pattern of PD patients are probably attributed to cognitive rather than pure oculomotor alterations.

Complement system changes in blood in Parkinson's disease and progressive Supranuclear Palsy/Corticobasal Syndrome.

Parkinson's Disease (PD) is diagnosed clinically, and early PD is often challenging to differentiate from atypical parkinsonian disorders such as the Four-repeat (4R-) Tauopathies Progressive Supranuclear Palsy and Corticobasal Syndrome. Diagnostic biomarkers are needed, and proteomic studies have suggested that the plasma complement system is altered in PD, but validation studies are lacking. In this study, plasma from 148 individuals (PD, 4R-Tauopathies, and healthy controls (HC)) were used to quantify 12 complement proteins with immunoassays, and CH50 classical pathway complement activity was quantified in sera from further 78 individuals (PD and HC). Complement factors C1q and C3 in plasma were lower in individuals with 4R-Tauopathies (ANOVA, p = 0.0041, p = 0.0057 respectively) compared to both PD and HC. None of the complement proteins were altered between PD and HC, however a few proteins correlated with clinical parameters within the PD group. Notably, levels of C3 correlated with non-motor symptoms in female patients. Classical pathway complement activity was not altered in PD serum, but did correlate with mental fatigue. In conclusion, individuals with 4R-Tauopathies showed lower plasma C1q and C3 compared PD and HC. Neither complement levels nor CH50 activity were significantly altered in PD versus HC but may associate with PD symptom severity.

Glycosphingolipid Changes in Plasma in Parkinson's Disease Independent of Glucosylceramide Levels.

BACKGROUND: Alteration in glycosphingolipids (GSLs) in Parkinson's disease (PD) still needs to be determined. OBJECTIVES: We evaluated if PD subjects show abnormal GSLs levels compared to healthy controls (HC) and if GSLs correlate with clinical features. METHODS: We analyzed GSLs and glucosylceramide (GlcCer) in plasma using two normal-phase high-performance liquid chromatography assays; clinico-demographic data were extracted. RESULTS: Eighty PD subjects and 25 HCs were analyzed. Levels of GlcCer, GD1b, Gb4, GalNAcGA1, and b-series were higher in PD patients than in HCs; total GSLs, GT1b, GM1a, GM3, GM2, and a-series levels were lower in PD patients than in HCs. Changes in GSLs were present in PD subjects, with GlcCer levels similar to those in HCs. The results were similar after excluding certain GBA1 mutation carriers. Movement Disorder Society Unified Parkinson's Disease Rating Scale, Part III, correlated with Gb4 and Montreal Cognitive Assessment with GD1b levels. CONCLUSIONS: Multiple GSL abnormalities in plasma were detected in patients with and without GlcCer changes, indicating a broader shift in lipid homeostasis. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Changes in emotion processing in early Parkinson's disease reflect disease progression.

OBJECTIVE: Parkinson's disease (PD) is a neurodegenerative disorder which can substantially affect nonmotor functions related to emotional processing. We aimed to examine the underlying differences in emotional processing in PD by comparing how early-stage PD patients recognize, rate, and react to facial, bodily, and vocal emotional stimuli to that of healthy controls (HC). METHOD: We compared emotion recognition, emotional rating bias, and emotional response range between a PD patient group (n = 33) and a HC group (n = 29). Pearson's correlations were conducted to evaluate the relationship between emotion processing measures and clinical outcome measures in each group. RESULTS: PD patients showed an enhanced emotion processing as compared to HC. They were overall more accurate than HC's at identifying correct emotions and furthermore showed an increase in emotional ratings and reactions to both positive and negative stimuli that scaled with increased symptom severity, thereby yielding significant correlations between clinical outcomes and emotional range in the PD patient group. CONCLUSION: Our results suggest that alterations in emotional processing reflect disease progression in early PD. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Neurocognitive profile of adults with the Norrbottnian type of Gaucher disease.

INTRODUCTION: Gaucher disease (GD) is a monogenic, lysosomal storage disorder, classified according to the presence of acute (type 2), chronic (type 3), or no (type 1) neurological manifestations. The Norrbottnian subtype of neuronopathic GD type 3 (GD3) is relatively frequent in the northern part of Sweden. It exhibits a wide range of neurological symptoms but is characterized by extended life expectancy compared to GD3 in other countries. The aim of our study was to describe the cognitive profile of adult patients with Norrbottnian GD3. MATERIALS AND METHODS: Ten patients with GD3 (five males and five females) underwent neurocognitive testing with the Repeatable Battery for Assessment of Neuropsychological Status (RBANS). RBANS consists of different short tests that assess Immediate Memory, Visuospatial and Constructional function, Language, Attention, and Delayed Memory. General neurological symptoms of the patients were assessed with the modified severity scoring tool. RESULTS: Patients (median age 41.5 range 24-57) performed lower than average in all cognitive domains. The overall index score was low (median 58.5, Interquartile range [IQR] 25.5), with the most profound deficit in attention (median 57, IQR 32.5) and immediate memory (median 76.5, IQR 13). Higher scores were found in language (median 83, IQR 21.5), delayed memory (median 81, IQR 41), and visuospatial/constructional function (median 86, IQR 32.35). CONCLUSION: Norrbottnian GD3 patients showed a unique neurocognitive profile with low overall performance, mostly derived from low scores in attention and memory domains whereas language and visuospatial/constructional ability were relatively spared.

Fixation Duration and Pupil Size as Diagnostic Tools in Parkinson's Disease.

BACKGROUND: Visual and oculomotor problems are very common in Parkinson's disease (PD) and by using eye-tracking such problems could be characterized in more detail. However, eye-tracking is not part of the routine clinical investigation of parkinsonism. OBJECTIVE: To evaluate gaze stability and pupil size in stable light conditions, as well as eye movements during sustained fixation in a population of PD patients and healthy controls (HC). METHODS: In total, 50 PD patients (66% males) with unilateral to mild-to-moderate disease (Hoehn & Yahr 1-3, Schwab and England 70-90%) and 43 HC (37% males) were included in the study. Eye movements were recorded with Tobii Pro Spectrum, a screen-based eye tracker with a sampling rate of 1200 Hz. Logistic regression analysis was applied to investigate the strength of association of eye-movement measures with diagnosis. RESULTS: Median pupil size (OR 0.811; 95% CI 0.666-0.987; p = 0.037) and longest fixation period (OR 0.798; 95% CI 0.691-0.921; p = 0.002), were the eye-movement parameters that were independently associated with diagnosis, after adjustment for sex (OR 4.35; 95% CI 1.516-12.483; p = 0.006) and visuospatial/executive score in Montreal Cognitive Assessment (OR 0.422; 95% CI 0.233-0.764; p = 0.004). The area under the ROC curve was determined to 0.817; 95% (CI) 0.732-0.901. CONCLUSION: Eye-tracking based measurements of gaze fixation and pupil reaction may be useful biomarkers of PD diagnosis. However, larger studies of eye-tracking parameters integrated into the screening of patients with suspected PD are necessary, to further investigate and confirm their diagnostic value.

Cerebrospinal Fluid Levels of Kininogen-1 Indicate Early Cognitive Impairment in Parkinson's Disease.

BACKGROUND: Cognitive impairment is common in patients with PD. Core markers of Alzheimer's dementia have been related also to PD dementia, but no disease-specific signature to predict PD dementia exists to date. OBJECTIVES: The aim of this study was to investigate CSF markers associated with cognition in early PD. METHODS: A high-throughput suspension bead array examined 216 proteins in CSF of 74 PD patients in the AETIONOMY project. Cognitive function was assessed with Repeatable Battery for the Assessment of the Neuropsychological Status, Montreal Cognitive Assessment, and Mini-Mental State Examination. RESULTS: Of 69 patients with complete data, 34 had high (≥90) and 35 had low Repeatable Battery for the Assessment of the Neuropsychological Status total score (<90). Of 14 proteins in CSF that differed in levels between groups, increased kininogen-1, validated with several antibodies, was independently associated with lower Repeatable Battery for the Assessment of the Neuropsychological Status and Montreal Cognitive Assessment scores after adjustment for confounders. CONCLUSIONS: Kininogen-1 levels in CSF may serve as a marker of cognitive impairment in PD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Reduction of spontaneous cortical beta bursts in Parkinson's disease is linked to symptom severity.

Parkinson's disease is characterized by a gradual loss of dopaminergic neurons, which is associated with altered neuronal activity in the beta-band (13-30 Hz). Assessing beta-band activity typically involves transforming the time-series to get the power of the signal in the frequency domain. Such transformation assumes that the time-series can be reduced to a combination of steady-state sine- and cosine waves. However, recent studies have suggested that this approach masks relevant biophysical features in the beta-band-for example, that the beta-band exhibits transient bursts of high-amplitude activity. In an exploratory study, we used magnetoencephalography to record beta-band activity from the sensorimotor cortex, to characterize how spontaneous cortical beta bursts manifest in Parkinson's patients on and off dopaminergic medication, and compare this to matched healthy controls. We extracted the time-course of beta-band activity from the sensorimotor cortex and characterized bursts in the signal. We then compared the burst rate, duration, inter-burst interval and peak amplitude between the Parkinson's patients and healthy controls. Our results show that Parkinson's patients off medication had a 5-17% lower beta bursts rate compared to healthy controls, while both the duration and the amplitude of the bursts were the same for healthy controls and medicated state of the Parkinson's patients. These data thus support the view that beta bursts are fundamental underlying features of beta-band activity, and show that changes in cortical beta-band power in Parkinson's disease can be explained-primarily by changes in the underlying burst rate. Importantly, our results also revealed a relationship between beta burst rate and motor symptom severity in Parkinson's disease: a lower burst rate scaled with increased severity of bradykinesia and postural/kinetic tremor. Beta burst rate might thus serve as a neuromarker for Parkinson's disease that can help in the assessment of symptom severity in Parkinson's disease or in the evaluation of treatment effectiveness.

A Phase 2a Trial Investigating the Safety and Tolerability of the Novel Cortical Enhancer IRL752 in Parkinson's Disease Dementia.

BACKGROUND: IRL752 is a novel small-molecule compound that acts to regioselectively enhance norepinephrine, dopamine, and acetylcholine neurotransmission in the cerebral cortex. OBJECTIVE: The primary objective of the trial was to investigate the safety and tolerability of IRL752 in patients with Parkinson's disease and dementia. METHODS: Patients with Parkinson's disease and dementia were randomized to IRL752 or placebo treatment (3:1 ratio) for 28 days. The study drug was given as an adjunct treatment to the patients' regular stable antiparkinsonian medication. Dosing was individually titrated for 14 days after which the dose was kept stable for an additional 14 days. RESULTS: A total of 32 patients were randomized to treatment, and 29 patients completed the 4-week treatment. Adverse events were generally mild and transient and were mostly reported during the dose titration phase. There were 2 serious adverse events, and none of them were related to the experimental treatment. The average dose achieved in the stable dose phase was 600 mg daily, yielding a 2-hour postdose plasma concentration of about 4 µM on day 28. Exploratory assessment of secondary outcomes indicated efficacy for symptoms and signs known to be poorly responsive to levodopa. CONCLUSIONS: IRL752 appears to be safe and well tolerated for a 4-week treatment in patients with Parkinson's disease and dementia. © 2020 International Parkinson and Movement Disorder Society.

Vertical saccades and antisaccades: complementary markers for motor and cognitive impairment in Parkinson's disease.

Previous studies provide partly contradictory results about the characteristics of saccades in PD and the possible effects of levodopa, which may be attributed to different study design regarding disease stages, medication state or cognitive functioning. We studied horizontal and vertical visually guided saccades (VGS) and antisaccades (AS) in 40 patients with PD with and without postural instability in On and Off medication state as well as in 20 healthy controls (HC). Motor and cognitive performance were assessed using UPDRS, Montreal Cognitive Assessment (MoCA) and Frontal Assessment Battery (FAB). The PD group showed decreased VGS amplitudes and increased vertical VGS and AS latencies. Only relatively few studies had assessed vertical saccades in PD so far. However, our results indicate that vertical saccadic amplitude may be a supportive marker in diagnosing PD since upwards gain demonstrated an AUC of 0.85 for the discrimination of PD and HC. Only more advanced patients in Hoehn & Yahr stage 3 executed higher numbers of AS errors than HC. Since the AS error rate correlated with FAB and MoCA scores, AS performance seems to reflect cognitive ability in PD. Furthermore, the correlation of AS latency with the UPDRS axial subscore promotes the recently highlighted connection between postural control and executive function in PD. Levodopa did not alter saccade amplitudes and had opposing effects on the initiation of VGS and AS: Levodopa intake prolonged VGS latency, but decreased AS latency. Possible mechanisms by which levodopa may be capable of partially reversing the impaired balance between voluntary and reflexive cortical saccade initiation of PD are discussed.

The role of C9orf72 in neurodegenerative disorders: a systematic review, an updated meta-analysis, and the creation of an online database.

A pathologic expansion of a noncoding GGGGCC hexanucleotide repeat of the C9orf72 gene has been strongly associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) cases predominantly in Caucasian populations. In the last decade, scientific interest had been drawn to this gene and many studies conducted have shown a possible correlation with other neurodegenerative diseases as well. We performed an extensive literature search for C9orf72 mutation and its frequency in various neurological and psychiatric diseases. In addition, we performed a meta-analysis of the data related to ALS and familial ALS. An online cloud-based database and an interactive map were developed. The overall mutation frequency of C9orf72 is 20% for familial FTD, 16% for familial ALS and around 6%-8% for sporadic ALS and FTD. The updated meta-analysis that we performed showed that the pooled frequency of C9orf72 repeat expansion in patients with familial ALS was 23% (CI: 18%-28%) and in patients with sporadic ALS 3% (CI: 3%-4%). The subgroup analysis regarding the origin of the population revealed significant differences between Caucasian and Asian patients. Our analysis supports the direct causal relation of the C9orf72 expansion in ALS and FTD. On the contrary, the role of C9orf72 in other neurodegenerative disorders remains controversial. The system that we developed-the online database and the interactive map-is hopefully a stepping stone for an ever-growing platform that will aid scientists from all over the world in contributing to the meta-analysis of C9orf72-related publications.

Attenuated beta rebound to proprioceptive afferent feedback in Parkinson's disease.

Motor symptoms are defining traits in the diagnosis of Parkinson's disease (PD). A crucial component in motor function is the integration of afferent proprioceptive sensory feedback. Previous studies have indicated abnormal movement-related cortical oscillatory activity in PD, but the role of the proprioceptive afference on abnormal oscillatory activity in PD has not been elucidated. We examine the cortical oscillations in the mu/beta-band (8-30 Hz) in the processing of proprioceptive stimulation in PD patients, ON/OFF levodopa medication, as compared to that of healthy controls (HC). We used a proprioceptive stimulator that generated precisely controlled passive movements of the index finger and measured the induced cortical oscillatory responses following the proprioceptive stimulation using magnetoencephalography. Both PD patients and HC showed a typical beta-band desynchronization during the passive movement. However, the subsequent beta rebound after the passive movement that was almost absent in PD patients compared to HC. Furthermore, we found no difference in the degree of beta rebound attenuation between patients ON and OFF levodopa medication. The results demonstrate a disease-related deterioration in cortical processing of proprioceptive afference in PD.

Novel Treatment Opportunities Against Cognitive Impairment in Parkinson's Disease with an Emphasis on Diabetes-Related Pathways.

Cognitive impairment is highly prevalent in patients with Parkinson's disease (PD) and causes adverse health outcomes. Novel procognitive therapies are needed to address this unmet need. It is now established that there is an increased risk of dementia in patients with type 2 diabetes mellitus (T2DM) and, moreover, T2DM and PD may have common underlying biological mechanisms. As such, T2DM medications are emerging as potential therapies in the context of PD dementia (PDD). In this review, we provide an update on pathophysiological mechanisms underlying cognitive impairments and PDD, focusing on diabetes-related pathways. Finally, we have conducted a review of ongoing clinical trials in PD patients with dementia, highlighting the multiple pharmacological mechanisms that are targeted to achieve cognitive enhancement.

Safety and tolerability of IRL790 in Parkinson's disease with levodopa-induced dyskinesia-a phase 1b trial.

IRL790 is a novel compound with psychomotor stabilizing properties primarily targeting the dopamine D3 receptor. IRL790 is developed as an experimental treatment for levodopa-induced dyskinesia (LID), impulse control disorder, and psychosis in Parkinson's disease (PD). The primary objective was to investigate the safety and tolerability of IRL790 in PD patients with LID in a randomized controlled trial. PD patients with peak-dose dyskinesia were randomized to placebo or IRL790 treatment (1:3 ratio) for 4 weeks. Study drug was given as an adjunct treatment to the patients' regular stable antiparkinsonian medication. Dosing was individually titrated for 14 days, whereafter dosing was kept stable for an additional 14 days. Fifteen patients were randomized to treatment and 13 patients completed the 4-week treatment. Adverse events were mostly reported during the titration phase of the trial. They were mainly central nervous system related and could be mitigated by dose adjustments. There were no serious adverse events. There were no clinically significant changes in vital signs, electrocardiogram, and laboratory parameters due to the treatment. The average dose in the stable dose phase was 18 mg daily, yielding a 2-h post-dose plasma concentration of average 229 nM on day 28. Assessments for motor function showed a numeric reduction in dyskinesia. It is concluded that IRL790 can be safely administered to patients with advanced PD. The results will be of guidance for the design of phase 2 studies.

Synaptic proteins in CSF relate to Parkinson's disease stage markers.

Recent findings of morphological and functional changes in Parkinson's disease brains have shown altered synapse formation, but their role in cognitive decline is still an area under exploration. Here we measured the concentration of three key synaptic proteins, Rab3A, SNAP25 and neurogranin by enzyme-linked immunosorbent assay, in cerebrospinal fluid from a total of 139 participants (87 controls and 52 Parkinson's disease patients out of which 30 were drug-naïve) and explored their associations with motor and cognitive symptoms. Associations with motor disease stage (assessed by Hoehn and Yahr scale) and cognitive performance (assessed by the Montreal Cognitive Assessment scores) were explored. An overall increase in the concentration of SNAP25 was found in Parkinson's disease patients (p = 0.032). Increased neurogranin levels were found in the drug naïve patients subgroup (p = 0.023). Significant associations were observed between increased concentration of neurogranin and cognitive impairment in total Parkinson's disease group (p = 0.017), as well as in the drug naïve (p = 0.021) and with motor disease stage (p = 0.041). There were no significant disease-driven changes observed in the concentration of Rab3a. Concentrations SNAP25 and neurogranin were increased in cerebrospinal fluid of Parkinson's disease patients in a disease specific manner and related to cognitive and motor symptom severity. Future longitudinal studies should explore whether cerebrospinal fluid synaptic proteins can predict cognitive decline in Parkinson's disease.