Progressive Motor Symptoms Research Articles

Clinical Phenotype Imprints on Brain Atrophy Progression in Parkinson’s Disease

There is much controversy about the link between motor symptom progression and the plethora of reported brain atrophy patterns in idiopathic Parkinson’s disease (PD). The main goal of this study is to provide empirical evidence for unique and common contributions of clinical phenotype characteristics on the dynamic changes of brain structure over time. We analyzed the behavioral and magnetic resonance imaging (MRI) data of PD patients (n = 22) and healthy individuals (n = 21) acquired two years apart through the computational anatomy framework of longitudinal voxel-based morphometry (VBM). This analysis revealed a symmetrical bi-hemispheric pattern of accelerated grey matter decrease in PD extending through the insula, parahippocampal gyrus, medial temporal lobes and the precuneus. We observed a hemisphere-specific correlation between the established scores for motor symptoms severity and the rate of atrophy within motor regions, which was further differentiated by the clinical phenotype characteristics of PD patients. Baseline cerebellum anatomy differences between the tremor-dominant and akineto-rigid PD remained stable over time and can be regarded as trait rather than state-associated features. We interpret the observed pattern of progressive brain anatomy changes as mainly linked to insular areas that determine together with basal ganglia the motor and non-motor phenotype in PD. Our findings provide empirical evidence for the sensitivity of computational anatomy to dynamic changes in PD, offering additional opportunities to establish reliable models of disease progression.

Proactive and Integrated Management and Empowerment in Parkinson’s Disease protocol for a randomised controlled trial (PRIME-UK) to evaluate a new model of care

BackgroundPeople living with Parkinson’s disease experience progressive motor and non-motor symptoms, which negatively impact on health-related quality of life and can lead to an increased risk of hospitalisation. It is increasingly recognised that the current care models are not suitable for the needs of people with parkinsonism whose care needs evolve and change as the disease progresses. This trial aims to evaluate whether a complex and innovative model of integrated care will increase an individual’s ability to achieve their personal goals, have a positive impact on health and symptom burden and be more cost-effective when compared with usual care.MethodsThis is a single-centre, randomised controlled trial where people with parkinsonism and their informal caregivers are randomised into one of two groups: either PRIME Parkinson multi-component model of care or usual care. Adults ≥18 years with a diagnosis of parkinsonism, able to provide informed consent or the availability of a close friend or relative to act as a personal consultee if capacity to do so is absent and living in the trial geographical area are eligible. Up to three caregivers per patient can also take part, must be ≥18 years, provide informal, unpaid care and able to give informed consent. The primary outcome measure is goal attainment, as measured using the Bangor Goal Setting Interview. The duration of enrolment is 24 months. The total recruitment target is n=214, and the main analyses will be intention to treat.DiscussionThis trial tests whether a novel model of care improves health and disease-related metrics including goal attainment and decreases hospitalisations whilst being more cost-effective than the current usual care. Subject to successful implementation of this intervention within one centre, the PRIME Parkinson model of care could then be evaluated within a cluster-randomised trial at multiple centres.

Metastatic Breast Cancer to the Spine: Incidence of Somatic Gene Alterations and Association of Targeted Therapies With Overall Survival.

The increase in use of targeted systemic therapies in cancer treatments has catalyzed the importance of identifying patient- and tumor-specific somatic mutations, especially regarding metastatic disease. Mutations found to be most prevalent in patients with metastatic breast cancer include TP53, PI3K, and CDH1. To determine the incidence of somatic mutations in patients with metastatic breast cancer to the spine (MBCS). To determine if a difference exists in overall survival (OS), progression-free survival, and progression of motor symptoms between patients who do or do not undergo targeted systemic therapy after treatment for MBCS. This is a retrospective study of patients with MBCS. Review of gene sequencing reports was conducted to calculate the prevalence of various somatic gene mutations within this population. Those patients who then underwent treatment (surgery/radiation) for their diagnosis of MBCS between 2010 and 2020 were subcategorized. The use of targeted systemic therapy in the post-treatment period was identified, and post-treatment OS, progression-free survival, and progression of motor deficits were calculated for this subpopulation. A total of 131 patients were included in the final analysis with 56% of patients found to have a PI3K mutation. Patients who received targeted systemic therapies were found to have a significantly longer OS compared with those who did not receive targeted systemic therapies. The results of this study demonstrate that there is an increased prevalence of PI3K mutations in patients with MBCS and there are a significant survival benefit and delay in progression of motor symptoms associated with using targeted systemic therapies for adjuvant treatment.

Abstract TP208: A Novel Rat Model Of Vascular Parkinsonism Using The Vasoconstrictor Endothelin-1

Background: Vascular parkinsonism (VP) results from one or more small strokes in the basal ganglia. Patients with vascular parkinsonism usually are unaware of the individual strokes that occur, until progressive motor symptoms gradually appear. While Parkinson’s Disease (PD) and VP share some common symptoms, patients with VP show clear evidence of cerebrovascular disease, are likely to be older, more likely to present with gait difficulty rather than tremor, and less likely to respond to the use of levodopa compared with patients with PD. There is currently no clinically effective treatment for this condition and no rodent model established in the field to study VP. Methods: To stimulate the onset of VP, male Sprague Dawley rats (10-12 mos) were injected with the vasoconstrictor endothelin-1 (ET-1) into the dorsolateral striatum (DLS) or sham operation. Adhesive-tape removal test (ART) was used to test sensory-motor function at 2- and 5- days post DLS stroke and brains were removed and stained with TTC to assess the location of the infarct. In another set, animals were tested for apomorphine-induced rotational behavior at 21-28 days, in conjunction with immunohistochemistry to assess dopamine loss in the substantia nigra pars compacta. Results: We observed a discrete infarct localized to the DLS in animals injected with ET-1. There was no difference in latency to remove the tape in ART outcomes of ET-1 injected animals at 2- and 5- day post ischemia when compared to sham, consistent the fact that these coordinates resulted in a discrete striatal infarction, rather than a cortico-striatal infarction, which is seen in the ET1-induced middle cerebral artery stroke model in rats. At 21- and 28- days post, there was minimal rotational behavior and minimal loss of tyrosine hydroxylase (TH)-positive cells in the lesioned hemisphere, unlike that of the 6-OHDA model of PD, where rapid changes are seen in rotational behavior and loss of TH-positive cells. Conclusions: These data suggest that ET-1-mediated ischemia into the DLS is a promising model for the slow progression of dopaminergic loss and motor deficits reminiscent to that seen in VP patients. Apomorphine induced rotations and TH immunohistochemistry will be evaluated at 30-, 60- and 90- day timepoints.

Age at Onset Influences Progression of Motor and Non-Motor Symptoms during the Early Stage of Parkinson's Disease: A Monocentric Retrospective Study.

The interactions between the age at onset with other pathogenic mechanisms and the interplays between the disease progression and the aging processes in Parkinson's disease (PD) remain undefined, particularly during the first years of illness. Here, we retrospectively investigated the clinical presentation and evolution of the motor and non-motor symptoms and treatment-related complications during the first 5 years of illness in subjects categorized according to age at onset. A total of 131 subjects were divided into "Early-Onset-PD" (EOPD; onset ≤49 years), "Middle-Onset-PD" (MOPD; onset 50-69 years) and "Late-Onset-PD" (LOPD; onset ≥70 years). The T0 visit was set at the time of the clinical diagnosis; the T1 visit was 5 years (±5 months) later. At T0, there were no significant differences in the motor features among the groups. At T1, the LOPD patients displayed a significantly higher frequency of gait disturbances and a higher frequency of postural instability. Moreover, at T1, the LOPD subjects reported a significantly higher frequency of non-motor symptoms; in particular, cardiovascular, cognitive and neuropsychiatric domains. The presented results showed a significantly different progression of motor and non-motor symptoms in the early course of PD according to the age at onset. These findings contribute to the definition of the role of age at onset on disease progression and may be useful for the pharmacological and non-pharmacological management of PD.

Cross-sectional proteomic expression in Parkinson's disease-related proteins in drug-naïve patients vs healthy controls with longitudinal clinical follow-up

There is an urgent need to find reliable and accessible blood-based biomarkers for early diagnosis of Parkinson's disease (PD) correlating with clinical symptoms and displaying predictive potential to improve future clinical trials. This led us to a conduct large-scale proteomics approach using an advanced high-throughput proteomics technology to create a proteomic profile for PD. Over 1300 proteins were measured in serum samples from a de novo Parkinson's (DeNoPa) cohort made up of 85 deep clinically phenotyped drug-naïve de novo PD patients and 93 matched healthy controls (HC) with longitudinal clinical follow-up available of up to 8 years. The analysis identified 73 differentially expressed proteins (DEPs) of which 14 proteins were confirmed as stable potential diagnostic markers using machine learning tools. Among the DEPs identified, eight proteins—ALCAM, contactin 1, CD36, DUS3, NEGR1, Notch1, TrkB, and BTK— significantly correlated with longitudinal clinical scores including motor and non-motor symptom scores, cognitive function and depression scales, indicating potential predictive values for progression in PD among various phenotypes. Known functions of these proteins and their possible relation to the pathophysiology or symptomatology of PD were discussed and presented with a particular emphasis on the potential biological mechanisms involved, such as cell adhesion, axonal guidance and neuroinflammation, and T-cell activation. In conclusion, with the use of advance multiplex proteomic technology, a blood-based protein signature profile was identified from serum samples of a well-characterized PD cohort capable of potentially differentiating PD from HC and predicting clinical disease progression of related motor and non-motor PD symptoms. We thereby highlight the need to validate and further investigate these markers in future prospective cohorts and assess their possible PD-related mechanisms.

Chapter 10 - Genetic mechanism vs genetic subtypes: The example of GBA

Genetic variants in GBA, encoding the lysosomal enzyme glucocerebrosidase (GCase), are common risk factors for Parkinson's disease (PD). Genotype-phenotype studies have demonstrated that different types of GBA variants have differential effects on the phenotype. Variants could be classified as mild or severe depending on the type of Gaucher disease they cause in the biallelic state. It was shown that severe GBA variants, as compared to mild variants, are associated with higher risk of PD, earlier age at onset, and faster progression of motor and nonmotor symptoms. The observed difference in phenotype might be caused by a diversity of cellular mechanisms related to the particular variants. The lysosomal function of GCase is thought to play a significant role in the development of GBA-associated PD, and other mechanisms such as endoplasmic reticulum retention, mitochondrial dysfunction, and neuroinflammation have also been suggested. Moreover, genetic modifiers such as LRRK2, TMEM175, SNCA, and CTSB can either affect GCase activity or modulate risk and age at onset of GBA-associated PD. To achieve ideal outcomes with precision medicine, therapies will have to be tailored to individuals with specific variants, potentially in combination with known modifiers.

Patients’ Perspective in Hereditary Ataxia

Hereditary ataxia represents a heterogeneous group of rare disorders with the chronic progression of motor symptoms that often become debilitating. Many forms include additional neurological, cognitive, or other symptoms. Most of these disorders lack specific treatment. We aimed to investigate aspects of patients’ quality of life, experiences, and expectations. Patients with a diagnosis of hereditary ataxia were identified from our center’s diagnostic register, direct referrals, and from a patient organization. We designed a questionnaire with 32 multiple-choice or open-ended questions on disability and impairment of daily life activities, the perceived effect of symptomatic and supportive therapies, coping strategies, and how they used and experienced various sources of information about their neurological disease. We also included the EQ-5D-3L quality-of-life instrument. Results were analyzed statistically for gender, age, and groups with and without a genetic diagnosis, and were compared to published data from the general population. Seventy-five patients returned the questionnaire. Patients reported considerable disease-related disability and impairment and had significantly lower quality-of-life scores than the general population. Physiotherapy and support from family or friends were important for patients’ overall well-being. Patients with a genetic diagnosis had a lower average age at onset and felt more well-informed about their disease than patients without a genetic diagnosis. Patients used internet sources but relied primarily on their doctors to obtain information about their disease. Our study provides insights into hereditary ataxia patients’ experiences that can lead to improvements in medical and nursing care for these patients.

Proximity to residential and workplace pesticides application and the risk of progression of Parkinson's diseases in Central California

BackgroundPesticide exposure has consistently been associated with Parkinson's disease (PD) onset. Yet, fewer epidemiologic studies have examined whether pesticides influence PD motor and non-motor symptom progression. ObjectivesUsing a geographic information system tool that integrates agricultural pesticide use reports and land use records to derive ambient exposures at residences and workplaces, we assessed associations between specific pesticides previously related to PD onset with PD symptom progression in two PD patient cohorts living in agricultural regions of California. MethodsWe calculated the pounds of pesticide applied agriculturally near each participant's residential or occupational addresses from 1974 to the year of PD diagnosis, using a geographic information system tool that links the California Pesticide Use Reports database to land use data. We examined 53 pesticides selected a priori as they have previously been associated with PD onset. We longitudinally followed two PD patient cohorts (PEG1 N = 242, PEG2 N = 259) for an average of 5.0 years (SD ± 3.5) and 2.7 years (SD ± 1.6) respectively and assessed PD symptoms using the movement disorder specialist-administered Unified Parkinson's disease Rating Scale part III (UPDRS), Mini-Mental State Examination (MMSE), and Geriatric Depression Scale (GDS). Weighted time-to-event regression models were implemented to estimate effects. ResultsTen agricultural pesticides, including copper sulfate (pentahydrate), 2-methyl-4-chlorophenoxyacetic acid (MCPA) dimethylamine salt, tribufos, sodium cacodylate, methamidophos, ethephon, propargite, bromoxynil octanoate, monosodium methanearsonate (MSMA), and dicamba, were associated with faster symptom progression. Among these pesticides, residential or workplace proximity to higher amounts of copper sulfate (pentahydrate) and MCPA (dimethylamine salt) was associated with all three progression endpoints (copper sulfate: HRs = 1.22–1.36, 95 % CIs = 1.03–1.73; MCPA: HRs = 1.27–1.35, 95 % CIs = 1.02–1.70). ConclusionsOur findings suggest that pesticide exposure may not only be relevant for PD onset but also PD progression phenotypes. We have implicated ten specific pesticide active ingredients in faster PD motor and non-motor decline.

Cerebrospinal Fluid Biomarkers of Synaptic Dysfunction are Altered in Parkinson's Disease and Related Disorders.

Synaptic dysfunction and degeneration are central contributors to the pathogenesis and progression of parkinsonian disorders. Therefore, identification and validation of biomarkers reflecting pathological synaptic alterations are greatly needed and could be used in prognostic assessment and to monitor treatment effects. To explore candidate biomarkers of synaptic dysfunction in Parkinson's disease (PD) and related disorders. Mass spectrometry was used to quantify 15 synaptic proteins in two clinical cerebrospinal fluid (CSF) cohorts, including PD (n1 =51, n2 =101), corticobasal degeneration (CBD) (n1 =11, n2 =3), progressive supranuclear palsy (PSP) (n1 =22, n2 =21), multiple system atrophy (MSA) (n1 =31, n2 =26), and healthy control (HC) (n1 =48, n2 =30) participants, as well as Alzheimer's disease (AD) (n2 =23) patients in the second cohort. Across both cohorts, lower levels of the neuronal pentraxins (NPTX; 1, 2, and receptor) were found in PD, MSA, and PSP, compared with HC. In MSA and PSP, lower neurogranin, AP2B1, and complexin-2 levels compared with HC were observed. In AD, levels of 14-3-3 zeta/delta, beta- and gamma-synuclein were higher compared with the parkinsonian disorders. Lower pentraxin levels in PD correlated with Mini-Mental State Exam scores and specific cognitive deficits (NPTX2; rho=0.25-0.32, P < 0.05) and reduced dopaminergic pre-synaptic integrity as measured by DaTSCAN (NPTX2; rho=0.29, P=0.023). Additionally, lower levels were associated with the progression of postural imbalance and gait difficulty symptoms (All NPTX; β-estimate=-0.025 to -0.038, P < 0.05) and cognitive decline (NPTX2; β-estimate=0.32, P=0.021). These novel findings show different alterations of synaptic proteins in parkinsonian disorders compared with AD and HC. The neuronal pentraxins may serve as prognostic CSF biomarkers for both cognitive and motor symptom progression in PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Longitudinal study of clinical and neurophysiological features in essential tremor.

Essential tremor (ET) is a common and heterogeneous disorder characterized by postural/kinetic tremor of the upper limbs and other body segments and by non-motor symptoms, including cognitive and psychiatric abnormalities. Only a limited number of longitudinal studies have comprehensively and simultaneously investigated motor and non-motor symptom progression in ET. Possible soft signs that configure the ET-plus diagnosis are also under-investigated in follow-up studies. We aimed to longitudinally investigate the progression of ET manifestations by means of clinical and neurophysiological evaluation. Thirty-seven ET patients underwent evaluation at baseline (T0) and at follow-up (T1; mean interval ± SD =39.89 ± 9.83 months). The assessment included the clinical and kinematic evaluation of tremor and voluntary movement execution, as well as the investigation of cognitive and psychiatric disorders. A higher percentage of patients showed tremor in multiple body segments and rest tremor at T1 as compared to T0 (all p-values < 0.01). At T1, the kinematic analysis revealed reduced finger-tapping movement amplitude and velocity as compared to T0 (both p-values < 0.001). The prevalence of cognitive and psychiatric disorders did not change between T0 and T1. Female sex, absence of family history, and rest tremor at baseline were identified as predictive factors of worse disease progression. ET progression is characterized by the spread of tremor in multiple body segments and by the emergence of soft signs. We also identified possible predictors of disease worsening. The results contribute to a better understanding of ET classification and pathophysiology.

Longitudinal evolution of motor and non-motor symptoms in early-stage multiple system atrophy: a 2-year prospective cohort study

BackgroundThe progression of motor and non-motor symptoms (NMS) and the sensitivity of each item of the Unified Multiple System Atrophy Rating Scale (UMSARS) to change remain unclear in Chinese patients with early-stage multiple system atrophy (MSA). We investigated the evolution of motor symptoms and NMS in early-stage MSA and the sensitivity of each item included in the UMSARS to change over a 2-year follow-up.MethodsMotor symptoms and NMS were recorded at baseline and at 1- and 2-year follow-ups based on the UMSARS and the NMS scale. Generalized estimating equation models were used. The sensitivity of an item included in the UMSARS to change was assessed by calculating a standardized effect using the mean annual change divided by the standard deviation of the change.ResultsWe enrolled 246 consecutive patients with MSA and 97 MSA completed the 2-year follow-up. The mean total UMSARS score increased by 11.90 and 22.54 points at the 1- and 2-year follow-ups, respectively. UMSARS-I items associated with motor functions were more sensitive to change and those associated with autonomic dysfunction showed less sensitivity to change. Items 4 (tremor at rest), 5 (action tremor), and 3 (ocular motor dysfunction) of the UMSARS-II were less sensitive to change. The prevalence and severity of NMS significantly increased over the 2-year follow-up.ConclusionsWe observed significant progression in motor symptoms and NMS in patients with early-stage MSA. Our results provide useful information to support the revision of the UMSARS.

Blood Markers of Inflammation, Neurodegeneration, and Cardiovascular Risk in Early Parkinson's Disease.

Recent studies point toward a significant impact of cardiovascular processes and inflammation on Parkinson's disease (PD) progression. The aim of this study was to assess established markers of neuronal function, inflammation, and cardiovascular risk by high-throughput sandwich immune multiplex panels in deeply phenotyped PD. Proximity Extension Assay technology on 273 markers was applied in plasma of 109 drug-naive at baseline (BL) patients with PD (BL, 2-, 4-, and 6-year follow-up [FU]) and 96 healthy control patients (HCs; 2- and 4-year FU) from the de novo Parkinson's cohort. BL plasma from 74 individuals (37 patients with PD, 37 healthy control patients) on the same platform from the Parkinson Progression Marker Initiative was used for independent validation. Correlation analysis of the identified markers and 6 years of clinical FU, including motor and cognitive progression, was evaluated. At BL, 35 plasma markers were differentially expressed in PD, showing downregulation of atherosclerotic risk markers, eg, E-selectin and ß2 -integrin. In contrast, we found a reduction of markers of the plasminogen activation system, eg, urokinase plasminogen activator. Neurospecific markers indicated increased levels of peripheral proteins of neurodegeneration and inflammation, such as fibroblast growth factor 21 and peptidase inhibitor 3. Several markers, including interleukin-6 and cystatin B, correlated with cognitive decline and progression of motor symptoms during FU. These findings were independently validated in the Parkinson Progression Marker Initiative. We identified and validated possible PD plasma biomarker candidates for state, fate, and disease progression, elucidating new molecular processes with reduced endothelial/atherosclerotic processes, increased thromboembolic risk, and neuroinflammation. Further investigations and validation in independent and larger longitudinal cohorts are needed. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Prolonged psychosis before onset of neurological symptoms; an atypical clinical manifestation of Huntington’s disease

Huntington's disease (HD) is a rare, autosomal dominant, progressive neurodegenerative disorder. HD manifests with a triad of progressive motor, cognitive, and psychiatric symptoms. Our patient, a 39-years-old married female with over a nine-year history of psychotic symptoms. The patient was diagnosed and treated for schizophrenia. Over the last 2-3 years, the patient had a progressive decline in her Activities of Daily Living, instrumental activities of daily living, and psychotic symptoms. She developed slurred speech, gait disturbances, frequent falls, involuntary movements of the trunk and distal extremities, bowel and bladder incontinence, and severe weight loss. Her genetic test for Huntington’s gene confirmed the diagnosis of HD. She was prescribed Olanzapine, fluoxetine, and clonazepam. Psychotic symptoms are rare in HD and usually appear well after the motor and cognitive symptoms. Our case highlights an unusual clinical presentation of HD, which can be diagnostically challenging and lead to diagnostic delays.&#x0D;

MAO-B Polymorphism Associated with Progression in a Chinese Parkinson's Disease Cohort but Not in the PPMI Cohort.

Introduction Genetic factors play an important role in Parkinson's disease (PD) risk. However, the genetic contribution to progression in Chinese PD patients has rarely been studied. This study investigated genetic associations with progression based on 30 PD risk loci common in a longitudinal cohort of Chinese PD patients and the Parkinson's Progression Markers Initiative (PPMI) cohort. Methods PD patients from the true world (TW) Chinese PD longitudinal cohort and the PPMI cohort with demographic information and assessment scales were assessed. A panel containing 30 PD risk single nucleotide polymorphisms was tested. Progression rates of each scale were derived from random-effect slope values of mixed-effects regression models. Progression rates of multiple assessments were combined by using principal component analysis (PCA) to derive scores for composite, motor, and nonmotor progression. The association of genetic polymorphism and separate scales or PCA progression was analysed via linear regression. Results In the Chinese PD cohort, MAOB rs1799836 was associated with progression based on the Montreal Cognitive Assessment, the top 3 principal components (PCs) of nonmotor PCA and PC1 of the composite PCA. In the PPMI cohort, both MDS-Unified Parkinson's Disease Rating Scale II and motor PC1 progression were associated with RIT2 rs12456492. The PARK16 haplotype was associated with Geriatric Depression Scale and the State-Trait Anxiety Inventory for Adults progression, and the SNCA haplotype was associated with the Hoehn-Yahr staging progression and motor PC1 progression. Ethnicity-stratified analysis showed that the association between MAOB rs1799836 and PD progression may be specific to Asian or Chinese patients. Conclusion MAOB rs1799836 was associated with the progression of nonmotor symptoms, especially cognitive impairment, and the composite progression of motor and nonmotor symptoms within our Chinese PD cohort. The RIT2 rs12456492 and SNCA haplotypes were associated with motor function decline, and the PARK16 haplotype was associated with progression in mood in the PPMI cohort.

A-2 Neuropsychological and Neuropsychiatric Symptoms Following Hypertrophic Olivary Degeneration

Abstract Objective: Hypertrophic Olivary Degeneration (HOD) is a rare neurological condition causing hypertrophy and eventual degeneration of the inferior olivary nucleus via transneuronal degeneration in the dentato-rubro-olivary pathway (DROP), or Guillain–Mollaret triangle. HOD is considered unique because the olive initially becomes hypertrophic rather than atrophic. Etiology is often cerebral vascular insult, cavernous malformation, surgical resection, and neurological disease, albeit cause may be unclear. While the neurologic and imaging findings have been well delineated in the literature, few studies investigate the neuropsychological impact. Methods: With consent, a review of the medical chart was conducted of a 39-year-old female with hypertension referred for assessment due to progressive cognitive, motor, and psychiatric symptoms. Results: Physical symptoms included progressive limb and trunk ataxia, palatal tremor, and opsoclonus myoclonus that plateaued within 4 years. Initial Magnetic Resonance Imaging (MRI) revealed bilateral, nonenhancing hyperintensity of the pontomedullary junction and enlargement of the inferior olive. Subsequent MRI displayed cerebellar atrophy. Cognitive assessment documented significant executive, language, spatial and fine motor dexterity deficits, alongside depression, anxiety, emotional blunting, and passive suicidality. She reported believing her neighbors were listening and following her in public. She remained semi-independent in daily living. Conclusions: This is the first case study that captures the neurocognitive profile associated with HOD and associated degeneration of DROP. This case highlights the potential for Cognitive Cerebellar Affective Syndrome (CCAS) to arise from damage to adjacent cerebellar pathways via transneuronal degeneration of brainstem circuits. It also provides evidence for the presence of delusions within CCAS as dysmetria of thought.

Gait alterations in Parkinson's disease at the stage of hemiparkinsonism-A longitudinal study.

Progressive gait impairment in Parkinson's disease (PD) leads to significant disability. Quantitative gait parameters analysis provides valuable information about fine gait alterations. To analyse change of gait parameters in patients with early PD at the stage of hemiparkinsonism and after 1 year of follow up, taking into account clinical asymmetry. Consecutive early PD outpatients with strictly unilateral motor features underwent clinical and neuropsychological assessment at the study entry and after 1 year of follow up. Gait was assessed with GAITRite walkway using dual-task methodology. Spatiotemporal gait parameters (step time and length, swing time and double support time) and their coefficients of variation (CV), gait velocity and heel-to-heel base support were evaluated. We included 42 PD patients with disease duration of 1.3 years (±1.13). Progression of motor and non-motor symptoms, without significant cognitive worsening, was observed after 1 year of follow up. Significant shortening of the swing time, prolongation of the double support and increase of their CVs were observed during all task conditions similarly for most parameters on symptomatic and asymptomatic bodysides, except for CV for the swing time under the combined task. Alterations of the swing time and double support time are already present even at the asymptomatic body side, and progress similarly, or even at faster pace, at this side, despite dopaminergic treatment These parameters deserve further investigation in larger, prospective studies to address their potential to serve as markers of progression in interventional disease modifying trials with early PD patients.

Visual and Brainstem Auditory-evoked Potentials Correlate with Specific Motor and Non-motor Symptoms in Parkinson's Disease

Parkinson’s disease (PD) is a common and complex neurodegenerative disease characterized by progressive motor and non-motor symptoms. The current study investigated the dysfunction of brain hemispheres and brainstem of PD patients and its relation to motor and non-motor symptoms using brainstem auditory evoked potentials (BAEP) and pattern reversal visual evoked potentials (p-VEP). We hypothesized that some motor and non-motor symptoms of PD due to specific dysfunctions of brainstem and brain hemispheres could be related to changes in p-VEP and BAEP. Accordingly, the aim of this study was to explore the abnormalities of BAEPs and p-VEPs in patients with PD and its correlation to the motor and non-motor symptoms of PD. Seventy-six nondemented PD patients took part in the p-VEP evaluations and 66 nondemented PD patients were included in BAEP evaluation. In order to compare the p-VEP performance of PD group, we included a control group comprising 32 age-matched participants. A BAEP substudy involved 29 age-matched healthy controls. All patients underwent a comprehensive motor and non-motor neuropsychological assessment. We found significant changes in all tested parameters of p-VEPs in PD patients compared to control subjects. In addition, these lower scores in p-VEP correlate with the results of some tests for cognition related to frontal-striatal dysfunction and contralateral rigidity, but not with the results of overall motor evaluation or other non-motor symptoms studied. In BAEP, PD patients have a significant prolongation of III and V wave latencies compared to controls. In addition, when examining the possible associations of BAEP with other non-motor manifestations of the disease, such association was observed only by the apathy scale. In conclusion, the current study confirms the visual and auditory abnormalities among PD patients thatreflect brain hemispheres and brainstem pathological changes. It also correlates these abnormalities to some motor and non-motor features of the disease, providing a localizing tool for associated brain hemispheres and brainstem dysfunctions. Furthermore, abnormal visual evoked potentials are associated with motor and non-motor symptoms due to the basal ganglia dysfunction. In contrast, abnormal auditory evoked potentials are connected with apathy, which is considered to be related with brainstem raphe nuclei dysfunction.

Novel inflammasome and oxidative modulators in Parkinson’s disease: A prospective study

IntroductionThe etiopathogenesis of Parkinson’s disease (PD) is not clear. Yet, it seems likely that inflammation as well as oxidative stress plays a major role in the disease pathogenesis. Based on our previous findings, we aimed to investigate prospective changes in peripheral inflammasome and oxidative modulators in relation to the progression of motor symptoms and severity of PD. MethodsLevels of inflammatory and oxidative markers in the serum of PD patients and healthy controls were estimated by quantitative ELISA and spectrophotometric methods at the baseline and at the end of one year. ResultsIn PD patients, serum NLRP3 inflammasome and IL-1β levels increased significantly over a year, compared to the baseline. The average enzymatic activity of serum SOD1 was also augmented at one-year follow-up. Alongside these serummarker changes, the mean motorseverity of this patient cohort worsened over the time period. ConclusionThis pioneering study identified a novel association of peripheral inflammatory and oxidative markers with the progression of PD. Correlation of these serum proteins with the central pathological changes in PD and disease severity in a prospective manner might be useful not only for prognostication, but for understanding disease mechanisms and for planning future therapeutic strategies.

Does Motor Symptoms Asymmetry Predict Motor Outcome of Subthalamic Deep Brain Stimulation in Parkinson's Disease Patients?

BackgroundIn Parkinson's disease (PD), the side of motor symptoms onset may influence disease progression, with a faster motor symptom progression in patients with left side lateralization. Moreover, worse neuropsychological outcomes after subthalamic nucleus deep brain stimulation (STN-DBS) have been described in patients with predominantly left-sided motor symptoms. The objective of this study was to evaluate if the body side of motor symptoms onset may predict motor outcome of bilateral STN-DBS.MethodsThis retrospective study included all consecutive PD patients treated with bilateral STN-DBS at Grenoble University Hospital from 1993 to 2015. Demographic, clinical and neuroimaging data were collected before (baseline condition) and 1 year after surgery (follow-up condition). The predictive factors of motor outcome at one-year follow-up, measured by the percentage change in the MDS-UPDRS-III score, were evaluated through univariate and multivariate linear regression analysis.ResultsA total of 233 patients were included with one-year follow-up after surgery [143 males (61.40%); 121 (51.90 %) right body onset; 112 (48.10%) left body onset; mean age at surgery, 55.31 ± 8.44 years; mean disease duration, 11.61 ± 3.87]. Multivariate linear regression analysis showed that the left side of motor symptoms onset did not predict motor outcome (β = 0.093, 95% CI = −1.967 to 11.497, p = 0.164).ConclusionsIn this retrospective study, the body side of motor symptoms onset did not significantly influence the one-year motor outcome in a large cohort of PD patients treated with bilateral STN-DBS.