Onset Of Motor Symptoms Research Articles

Predictors of the Rapid Progression in Prodromal Parkinson’s Disease: A Longitudinal Follow-Up Study

Introduction: Parkinson’s disease (PD) is characterized by a prodromal phase preceding the onset of classic motor symptoms. The duration and clinical manifestations of prodromal PD vary widely, indicating underlying heterogeneity within this stage. This discrepancy prompts the question of whether specific factors contribute to the divergent rates of progression in prodromal PD. Methods: This study included prodromal PD patients from the Parkinson’s progression marker initiative. They were followed up to assess the disease progression. The data collected during the follow-up period were analyzed to identify potential predictors of rapid disease progression in prodromal PD. Results: In this study, 61 individuals with prodromal PD were enrolled. Among them, 43 patients presented with both RBD and hyposmia, 17 had hyposmia alone, and 1 had RBD alone at baseline. 13 (21.3%) prodromal PD participants exhibited rapid disease progression, with two of these cases advancing to non-neurological diseases. Significant differences were observed between the rapid progression group and no rapid progression group in terms of MDS-UPDRS II score and UPSIT score. Longitudinal analysis showed a significant increase in the MDS-UPDRS III score and MDS-UPDRS total score in the rapid progression group. Regression analyses identified the MDS-UPDRS II score and UPSIT score as predictors of rapid disease progression in prodromal PD. Conclusion: Our study findings suggest that the MDS-UPDRS II score and UPSIT score may serve as clinical markers associated with rapid disease progression. Further research and development of precise biomarkers and advanced assessment methods are needed to enhance our understanding of prodromal PD and its progression patterns.

Social cognition in Parkinson's disease and functional movement disorders.

Functional movement disorders (FMD) can overlap with Parkinson's disease (PD), and distinguishing between the two clinical conditions can be complex. Framing social cognition (theory of mind) (TOM) disorder, attention deficit, and psychodynamic features of FMD and PD may improve diagnosis. Subjects with FMD and PD and healthy controls (HC) were administered tasks assessing TOM abilities and attention. The psychodynamic hypothesis of conversion disorder was explored by a questionnaire assessing dissociative symptoms. A comprehensive battery of neuropsychological tasks was also administered to FMD and PD. Although both FMD and PD scored lower than HC on all TOM tests, significant correlations between TOM and neuropsychological tasks were found only in PD but not in FMD. Only PD showed a reduction in attentional control. Dissociative symptoms occurred only in FMD. Cognitive-affective disturbances are real in FMD, whereas they are largely dependent on cognitive impairment in PD. Attentional control is preserved in FMD compared to PD, consistent with the hypothesis that overload of voluntary attentional orientation may be at the basis of the onset of functional motor symptoms. On a psychodynamic level, the confirmation of dissociative symptoms in FMD supports the conversion disorder hypothesis. FMD and PD can be distinguished on an affective and cognitive level. At the same time, however, the objective difficulty often encountered in distinguishing between the two pathologies draws attention to how blurred the boundary between 'organic' and 'functional' can be.

Predictive Modelling for Parkinson's Disease Diagnosis using Biomedical Voice Measurements

INTRODUCTION: Parkinson's Disease (PD), a progressively debilitating neurological disorder impacting a substantial global population, stands as a significant challenge in modern healthcare. The gradual onset of motor and non-motor symptoms underscores the criticality of early detection for optimal treatment outcomes. In response to this urgency, novel avenues for early diagnosis are being explored, where the amalgamation of biomedical voice analysis and advanced machine learning techniques holds immense promise. Individuals afflicted by PD experience a nuanced deterioration of bodily functions, necessitating interventions that are most effective when initiated at an early stage. The potential of biomedical voice measurements to encode subtle health indicators presents an enticing opportunity. The human voice, an intricate interplay of frequencies and patterns, might offer insights into the underlying health condition.
 OBJECTIVES: This research embarks on a comprehensive journey to delve into the intricate connections between voice attributes and the presence of PD, with the aim of expediting its detection and treatment.
 METHODS: At the heart of this exploration is the Support Vector Machine (SVM) model, a versatile machine learning tool [1-2]. Functioning as a virtual detective, the SVM model learns from historical data to decipher the intricate patterns that differentiate healthy individuals from those with PD [3-4].
 RESULTS: Through the power of pattern recognition, the SVM becomes a predictive instrument, a potential catalyst in unravelling the latent manifestations of PD using the unique patterns harbored within the human voice. Embedded within this research are the practical demonstrations showcased through code snippets [5-7]. By synergizing the intricate voice measurements with the SVM model, we envision the emergence of a diagnostic paradigm where early PD detection becomes both accessible and efficient. This study not only epitomizes the synergy of voice and machine interactions but also attests to the transformative potential of technology within the domain of healthcare. .
 CONCLUSION: Ultimately, this research strives to harness the intricate layers of voice data, as exemplified through the provided model code [8-11], to contribute to the evolution of an advanced tool for PD prediction. By amalgamating the principles of machine learning and biomedical analysis, we aspire to expedite early PD diagnosis, thereby catalyzing more efficacious treatment strategies. In traversing this multidimensional exploration, we aspire to pave the path toward a future where technology plays an instrumental role in enhancing healthcare outcomes for individuals navigating the challenges of PD, ultimately advancing the pursuit of early diagnosis and intervention.

Cortical-sparing chronic traumatic encephalopathy (CSCTE): a distinct subtype of CTE.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease caused by repetitive head impacts (RHI) and pathologically defined as neuronal phosphorylated tau aggregates around small blood vessels and concentrated at sulcal depths. Cross-sectional studies suggest that tau inclusions follow a stereotyped pattern that begins in the neocortex in low stage disease, followed by involvement of the medial temporal lobe and subcortical regions with significant neocortical burden in high stage CTE. Here, we define a subset of brain donors with high stage CTE and with a low overall cortical burden of tau inclusions (mean semiquantitative value ≤1) and classify them as cortical-sparing CTE (CSCTE). Of 620 brain donors with pathologically diagnosed CTE, 66 (11%) met criteria for CSCTE. Compared to typical high stage CTE, those with CSCTE had a similar age at death and years of contact sports participation and were less likely to carry apolipoprotein ε4 (p<0.05). CSCTE had less overall tau pathology severity, but a proportional increase of disease burden in medial temporal lobe and brainstem regions compared to the neocortex (p's<0.001). CSCTE also had lower prevalence of comorbid neurodegenerative disease. Clinically, CSCTE participants were less likely to have dementia (p= 0.023) and had less severe cognitive difficulties (as reported by informants using the Functional Activities Questionnaire (FAQ); p<0.001, meta-cognitional index T score; p=0.002 and Cognitive Difficulties Scale (CDS); p<0.001,) but had an earlier onset age of behavioral (p=0.006) and Parkinsonian motor (p=0.013) symptoms when compared to typical high stage CTE. Other comorbid tauopathies likely contributed in part to these differences: when cases with concurrent Alzheimer dementia or frontal temporal lobar degeneration with tau pathology were excluded, differences were largely retained, but only remained significant for FAQ (p=0.042), meta-cognition index T score (p=0.014) and age of Parkinsonian motor symptom onset (p=0.046). Overall, CSCTE appears to be a distinct subtype of high stage CTE with relatively greater involvement of subcortical and brainstem regions and less severe cognitive symptoms.

Spectrum and frequency of non-motor disorders in Parkinson’s patients in the Kursk Region

Introduction. Parkinson's disease (PD) is characterized by a long period of latent neurodegenerative process. Some patients experience non-motor manifestations in the form of autonomic (constipation, dizziness, fainting, and sleep, smell, and urination disorders), mental (anxiety and depression), and cognitive disorders that occur several years before the onset of motor symptoms [1]. Purpose of the study: to determine the spectrum and frequency of non-motor disorders in patients with Parkinson’s disease in the Kursk Region, as well as to assess the degree of their severit y. Materials and method. We examined 32 patients (18 women and 14 men) with an established diagnosis of PD (mixed type), who were treated at the Kursk Regional Multidisciplinary Clinical Hospital. The age of the patients ranged from 59 to 76 years. The mean age was 69.03±5.71 years, and the duration of the disease was 6.93±8.08 years. Non-motor symptoms and their severity were assessed using the UPDRS (Part I) and the NMSS-PD. Sleep disturbances were assessed according to the Epworth Sleepiness Scale (ESS). The Hospital Anxiety and Depression Scale (HADS) was used to study the neuropsychological status of the patients. Cognitive status was assessed according to the MMSE, Frontal Assessment Battery, and the clock drawing test. Results. Non-motor symptoms occurred in 87.5 % of the patients in the study population and are an equally significant part of the PD clinical picture. These manifestations are most often represented by autonomic (87.5 %), mental (68.7 %), and cognitive (72 %) disorders, which have a different spectrum and frequency in this group of patients. Conclusion. Non-motor manifestations of PD require special attention from a neurologist. The clinical picture of such disorders is varied. Early detection and adequate correction of non-motor disorders contributes to the main goal of PD therapy — to improve the qualit y of life of patients.

Linalool, a Fragrance Compound in Plants, Protects Dopaminergic Neurons and Improves Motor Function and Skeletal Muscle Strength in Experimental Models of Parkinson's Disease.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in reduced dopamine levels in the striatum and eventual onset of motor symptoms. Linalool (3,7-dimethyl-1,6-octadien-3-ol) is a monoterpene in aromatic plants exhibiting antioxidant, antidepressant, and anti-anxiety properties. The objective of this study is to evaluate the neuroprotective impacts of linalool on dopaminergic SH-SY5Y cells, primary mesencephalic and cortical neurons treated with 1-methyl-4-phenylpyridinium ion (MPP+), as well as in PD-like mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Cell viability, α-tubulin staining, western blotting, immunohistochemistry and behavioral experiments were performed. In MPP+-treated SH-SY5Y cells, linalool increased cell viability, reduced neurite retraction, enhanced antioxidant defense by downregulation of apoptosis signaling (B-cell lymphoma 2 (Bcl-2), cleaved caspase-3 and poly ADP-ribose polymerase (PARP)) and phagocyte NADPH oxidase (gp91phox), as well as upregulation of neurotrophic signaling (brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF)) and nuclear factor-erythroid 2 related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. In MPP+-treated primary mesencephalic neurons, linalool enhanced the expressions of tyrosine hydroxylase (TH), Sirtuin 1 (SirT1), and parkin. In MPP+-treated primary cortical neurons, linalool upregulated protein expression of SirT1, γ-Aminobutyric acid type A-α1 (GABAA-α1), and γ-Aminobutyric acid type B (GABAB). In PD-like mice, linalool attenuated the loss of dopamine neurons in SNpc. Linalool improved the motor and nonmotor behavioral deficits and muscle strength of PD-like mice. These findings suggest that linalool potentially protects dopaminergic neurons and improves the impairment symptoms of PD.

Dopamine Synthesis in the Nigrostriatal Dopaminergic System in Patients at Risk of Developing Parkinson’s Disease at the Prodromal Stage

Parkinson’s disease (PD) is diagnosed by the onset of motor symptoms and treated long after its onset. Therefore, the development of the early diagnosis of PD is a priority for neurology. Advanced methodologies for this include (1) searching for patients at risk of developing prodromal PD based on premotor symptoms; (2) searching for changes in the body fluids in these patients as diagnostic biomarkers; (3) verifying the diagnosis of prodromal PD and diagnostic-value biomarkers using positron emission tomography (PET); (4) anticipating the development of motor symptoms. According to our data, the majority of patients (n = 14) at risk of developing PD selected in our previous study show pronounced interhemispheric asymmetry in the incorporation of 18F-DOPA into dopamine synthesis in the striatum. This was assessed for the caudate nucleus and putamen separately using the specific binding coefficient, asymmetry index, and putamen/caudate nucleus ratio. Interhemispheric asymmetry in the incorporation of 18F-DOPA into the striatum provides strong evidence for its dopaminergic denervation and the diagnostic value of previously identified blood biomarkers. Of the 17 patients at risk of developing prodromal PD studied using PET, 3 patients developed motor symptoms within a year. Thus, our study shows the promise of using the described methodology for the development of early diagnosis of PD.

Clinicopathological correlates in the frontotemporal lobar degeneration-motor neuron disease spectrum.

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease (MND) that shares a common clinical, genetic and pathologic spectrum with frontotemporal dementia (FTD). It is highly heterogeneous in its presentation and features. Up to 50% of patients with MND develop cognitive-behavioural symptoms during the course of the disease, meeting criteria for FTD in 10%-15% of cases. In the absence of a precise biomarker, neuropathology is still a valuable tool to understand disease nosology, reach a definite diagnostic confirmation and help define specific subgroups of patients with common phenotypic, genetic and biomarker profiles. However, few neuropathological series have been published, and the frequency of frontotemporal lobar degeneration (FTLD) in MND is difficult to estimate. In this work we describe a large clinicopathological series of MND patients, analysing the frequency of concurrent FTLD changes and trying to define specific subgroups of patients based on their clinical, genetic and pathological characteristics. We performed an observational, retrospective, multicentre case study. We included all cases meeting neuropathological criteria for MND from the Neurological Tissue Bank of the FRCB-IDIBAPS-Hospital Clínic Barcelona Biobank between 1994 and 2022, regardless of their last clinical diagnosis. While brain donation is encouraged in all patients, it is performed in very few, and representativeness of the cohort might not be precise for all patients with MND. We retrospectively reviewed clinical and neuropathological data and describe the main clinical, genetic and pathogenic features, comparing neuropathologic groups between MND with and without FTLD changes and aiming to define specific subgroups. We included brain samples from 124 patients, 44 of whom (35.5%) had FTLD neuropathologic features (i.e. FTLD-MND). Pathologic TDP-43 aggregates were present in 93.6% of the cohort and were more extensive (higher Brettschneider stage) in those with concurrent FTLD (P < 0.001). Motor symptom onset was more frequent in the bulbar region in FTLD-MND cases than in those with isolated MND (P = 0.023), with no differences in survival. We observed a better clinicopathological correlation in the MND group than in the FTLD-MND group (93.8% versus 61.4%; P < 0.001). Pathogenic genetic variants were more common in the FTLD-MND group, especially C9orf72. We describe a frequency of FTLD of 35.5% in our series of neuropathologically confirmed cases of MND. The FTLD-MND spectrum is highly heterogeneous in all aspects, especially in patients with FTLD, in whom it is particularly difficult to define specific subgroups. In the absence of definite biomarkers, neuropathology remains a valuable tool for a definite diagnosis, increasing our knowledge in disease nosology.

Gut microbiota dysbiosis contributes to α-synuclein-related pathology associated with C/EBPβ/AEP signaling activation in a mouse model of Parkinson's disease.

JOURNAL/nrgr/04.03/01300535-202409000-00042/figure1/v/2024-01-16T170235Z/r/image-tiff Parkinson's disease is a neurodegenerative disease characterized by motor and gastrointestinal dysfunction. Gastrointestinal dysfunction can precede the onset of motor symptoms by several years. Gut microbiota dysbiosis is involved in the pathogenesis of Parkinson's disease, whether it plays a causal role in motor dysfunction, and the mechanism underlying this potential effect, remain unknown. CCAAT/enhancer binding protein β/asparagine endopeptidase (C/EBPβ/AEP) signaling, activated by bacterial endotoxin, can promote α-synuclein transcription, thereby contributing to Parkinson's disease pathology. In this study, we aimed to investigate the role of the gut microbiota in C/EBPβ/AEP signaling, α-synuclein-related pathology, and motor symptoms using a rotenone-induced mouse model of Parkinson's disease combined with antibiotic-induced microbiome depletion and fecal microbiota transplantation. We found that rotenone administration resulted in gut microbiota dysbiosis and perturbation of the intestinal barrier, as well as activation of the C/EBP/AEP pathway, α-synuclein aggregation, and tyrosine hydroxylase-positive neuron loss in the substantia nigra in mice with motor deficits. However, treatment with rotenone did not have any of these adverse effects in mice whose gut microbiota was depleted by pretreatment with antibiotics. Importantly, we found that transplanting gut microbiota derived from mice treated with rotenone induced motor deficits, intestinal inflammation, and endotoxemia. Transplantation of fecal microbiota from healthy control mice alleviated rotenone-induced motor deficits, intestinal inflammation, endotoxemia, and intestinal barrier impairment. These results highlight the vital role that gut microbiota dysbiosis plays in inducing motor deficits, C/EBPβ/AEP signaling activation, and α-synuclein-related pathology in a rotenone-induced mouse model of Parkinson's disease. Additionally, our findings suggest that supplementing with healthy microbiota may be a safe and effective treatment that could help ameliorate the progression of motor deficits in patients with Parkinson's disease.

MAPT Locus in Parkinson's Disease Patients of Ashkenazi Origin: A Stratified Analysis.

Introduction: MAPT locus is associated with Parkinson's disease (PD), which is located within a large inversion region of high linkage disequilibrium (LD). We aimed to determine whether the H2-haplotype protective effect and its effect size depends on the GBA1 or LRRK2 risk allele carrier status, and to further characterize genetic alterations that might contribute to its effect. Methods: LD analysis was performed using whole-genome sequencing data of 202 unrelated Ashkenazi Jewish (AJ) PDs. A haplotype-divergent variant was genotyped in a cohort of 1200 consecutively recruited AJ-PDs. The odd ratios were calculated using AJ-non-neuro cases from the gnomAD database as the controls in an un-stratified and a stratified manner according to the mutation carrier status, and the effect on the Age at Motor Symptom Onset (AMSO) was examined. Expression and splicing quantitative trait locus (eQTL and sQTL) analyses were carried out using brain tissues from a database. Results: The H2 haplotype exhibited significant association with PD protection, with a similar effect size in GBA1 carriers, LRRK2-G2019S carriers, and non-carriers (OR = 0.77, 0.69, and 0.82, respectively), and there was no effect on AMSO. The LD interval was narrowed to approximately 1.2 Mb. The H2 haplotype carried potential variants in candidate genes (MAPT and SPPL2C); structural deletions and segmental duplication (KANSL1); and variants affecting gene expression and intron excision ratio in brain tissues (LRRC37A/2). Conclusions: Our results demonstrate that H2 is associated with PD and its protective effect is not influenced by the GBA1/LRRK2 risk allele carrier status. This effect may be genetically complex, resulting from different levels of variations such as missense mutations in relevant genes, structural variations, epigenetic modifications, and RNA expression changes, which may operate independently or in synergy.

The Role of Innovation Technology in the Rehabilitation of Patients Affected by Huntington's Disease: A Scoping Review.

Huntington's disease is an autosomal dominant neurodegenerative disease caused by the repetition of cytosine, adenine, and guanine trinucleotides on the short arm of chromosome 4p16.3 within the Huntingtin gene. In this study, we aim to examine and map the existing evidence on the use of innovations in the rehabilitation of Huntington's disease. A scoping review was conducted on innovative rehabilitative treatments performed on patients with Huntington's disease. A search was performed on PubMed, Embase, Web of Science, and Cochrane databases to screen references of included studies and review articles for additional citations. Of an initial 1117 articles, only 20 met the search criteria. These findings showed that available evidence is still limited and that studies generally had small sample sizes and a high risk of bias. Regarding cognitive rehabilitation, it has emerged that VR- and PC-based methods as well as NIBS techniques are feasible and may have promising effects in individuals with Huntington's disease. On the other hand, scarce evidence was found for cognitive and motor training that might have a slight impact on overall cognitive function in individuals with Huntington's disease. Data show that further investigation is needed to explore the effects of innovative rehabilitation tools on cognition, especially considering that cognitive and psychiatric symptoms can precede the onset of motor symptoms by many years.

Sleep Disorders in Early-Onset Parkinsonism: A Population-Based Study.

Sleep disturbances are common in parkinsonian disorders; however, whether sleep disorders affect individuals with early-onset parkinsonism and whether they differ from individuals with typical-onset parkinsonism is unknown. To compare the prevalence and incidence of sleep disorders before and after parkinsonian motor symptom onset between individuals with early onset parkinsonism (age ≤50 at motor symptom onset) and typical-onset parkinsonism (age >50 at motor symptom onset). We used a population-based, 1991 to 2015 incident-cohort study of parkinsonism including 38 patients with early-onset and 1,001 patients with typical-onset parkinsonism. Presence or absence and type of sleep disorder as well as the relationship between motor and sleep symptoms were abstracted from the medical records. Rates of sleep disorders before and after onset of parkinsonism were compared with logistic regression and Cox proportional hazards models. The prevalence of sleep disorders prior to the onset of parkinsonism in early vs. typical parkinsonism (24% vs. 16% p = 0.19) and incidence of sleep disorders after parkinsonism onset (5.85 cases per 100 person-years vs. 4.11 cases per 100 person-years; HR 1.15 95% CI: 0.74-1.77) were similar between the two groups. Early-onset parkinsonism had a higher risk for developing post-motor insomnia compared with typical-onset parkinsonism (HR 1.73, 95% CI: 1.02-2.93); the risk for developing all other sleep disorders considered was similar between groups. Sleep disorders are common in individuals with early-onset parkinsonism and occur with similar frequency to those with typical-onset parkinsonism, except for insomnia, which was more frequent in the early-onset group.

20 Laterality of Motor Symptom Onset is Not Associated with Cognitive Performance or Mood Symptoms in a Sample of 600 Individuals with Idiopathic Parkinson’s Disease”

Objective:Parkinson’s disease (PD) is typically characterized by unilateral onset of motor symptoms (i.e., tremors, rigidity) which is caused by dopaminergic degeneration of the substantia nigra that influences basal ganglia-prefrontal circuitry. Over time, motor symptoms become more bilateral, though continue to remain asymmetric. Many neuropsychological studies suggest that laterality of motor onset may be linked to hemispheric specific cognitive or mood changes. Namely, worse verbal/language performance may be present in individuals with right body (left hemisphere) onset and conversely for visuospatial performance, with depression symptoms relating more so to individuals with right body (left hemisphere) onset. To date, findings are often inconsistent, with some studies showing evidence for laterality effects and others not. The basis for this inconsistency is unclear, though one possibility relates to small sample sizes and varying methodologies. Thus, the goal of this study was to examine potential cognitive and mood laterality effects in a large clinical sample of individuals with PD.Participants and Methods:Participants included a convenience sample of 600 nondemented individuals with idiopathic PD from the University of Florida Fixel Institute Movement Disorders Center. As a group, participants were around 60 years of age (Mean Age=63.9+9.4), well educated (Mean years=14.9+2.7), predominantly male (70%), and white non-Hispanic (93%). Side of initial motor symptom onset was based on self-report: Right (N=337) and Left (N=263). Approximately 79% were tremor predominant. All received mood and neurocognitive measures as part of standard clinical care, including indices of executive function (Stroop Color-Word, Trails B, Letter Fluency), recent verbal memory (delayed recall: Hopkin’s Verbal Learning Test, WMS-III Logical Memory), language (Boston Naming Test, Animal fluency), visuospatial skills (Judgment of Line Orientation, Facial Recognition Test). Evaluation of emotion symptoms included: depression (Beck Depression Inventory-II), apathy (Apathy Scale), and anxiety (State-Trait Anxiety Inventory). Analyses used raw scores from these measures. Due to non-normality of most measures’ distributions, laterality effects were examined using bootstrapped multivariate methods (multivariate analysis of variance [MANOVA]). Separate MANOVA’s were run for each cognitive domain (i.e., EF, language, etc.) and mood measures.Results:The right and left sided onset groups did not significantly differ in demographic (age, education, sex) or disease characteristics (duration, PD subtype). Results of the MANOVA’s with cognitive variables were all nonsignificant broadly (all with F’s ranging from .33 to .94) and at the single test level. Similarly, the left and right onset groups did not significantly differ (a=0.05) across standard scales of depression (F=0.031), anxiety (Trait F=0.463; State F=3.29), and apathy (F=0.74).Conclusions:We found no evidence that laterality of initial motor symptoms influenced cognitive or mood symptoms in a large cohort of 600 individuals with PD. These findings raise questions about importance of motor onset laterality for cognitive and emotion related changes in PD. Future studies should move beyond self-report and behavioral motor scales for determining hemispheric contributions. In PD, use of refined metrics for determining the extent of asymmetric dopaminergic degeneration (e.g., DAT scan) at the hemispheric level coupled with sensitive neuropsychological measures may provide clearer understanding of potential neural circuitry relationships.

53 REM Sleep Behavior Disorder in Parkinson’s Disease : Longitudinal Effects on Brain Lateralization

Objective:Laterality of motor symptom onset in Parkinson’s disease (PD) is well-known and under-appreciated. It is still unclear though if this laterality might have an influence on other symptoms. Specifically, REM sleep behavior disorder has been shown to be a factor that has a high probability to be lined to PD. In this study we analyzed the longitudinal effect of REM symptomatology on brain lateralization in PD.Participants and Methods:We used the baseline and 3-year visit data of 116 participants (67 without REM (PD-non-REM), 49 with REM (PD-REM)) aged 37-81 years from the Parkinson’s Progression Markers Initiative (PPMI) dataset. Statistical 3T MRI data (cortical thicknesses, areas, foldings of cortical Desikan atlas and volumes of subcortical regions) were obtained via FreeSurfer 7.1.1. Lateralization was computed using the formula: (left-right)/(lef +right). Mixed ANOVAs were performed on each region of interest.Results:Our findings showed an increased right asymmetry of the paracentral lobule area and of the pars orbitalis area and volume in PD-REM. There was a reduced right asymmetry of the parietal inferior volume at baseline in PD-REM, whereas REM symptomatology had a stable effect at the 3 years visit. At baseline, there was an increased left asymmetry of the thickness of the caudal anterior cingulate, pars orbitalis and pars triangularis regions in PD-REM. After 3 years, there was an increased right asymmetry in those regions. The precentral, frontal superior and transversal temporal gyri showed inverse results: an increased right asymmetry of the thickness at baseline and an increased left asymmetry after 3 years. Finally, REM symptomatology is associated with more significant increases of the left asymmetry of the frontal superior gyrus volume and of the right asymmetry of the supramarginal gyrus volume after 3 years than at baseline.Conclusions:These results provide evidence of the modulating effect of the disease progression on the relationship between REM symptoms and brain lateralization in PD.

Factors influencing cognitive function in patients with Huntington's disease from China: A cross-sectional clinical study.

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder caused by CAG repeats expansion. Cognitive decline contributes to the loss of daily activity in manifest HD. We aimed to examine the cognition status in a Chinese HD cohort and explore factors influencing the diverse cognitive domains. A total of 205 participants were recruited in the study with the assessment by neuropsychological batteries, including the mini-mental state examination (MMSE), Stroop test, symbol digit modalities test (SDMT), trail making test (TMT), verbal fluency test (VFT), and Hopkins verbal learning test-revised, as well as motor and psychiatric assessment. Pearson correlation and multiple linear regression models were applied to investigate the correlation. Only 41.46% of patients had normal global function first come to our center. There was a significantly difference in MMSE, Stroop test, SDMT, TMT, and VFT across each stage of HD patients (p<.05). Apathy of PBA-s was correlated to MMSE, animal VFT and Stroop-interference tests performance. Severity of motor symptoms, functional capacity, age, and age of motor symptom onset were correlated to all neuropsychological scores, whereas education attainment and diagnostic delay were correlated to most neuropsychological scores except TMT. Severity of motor symptoms, functional capacity, and education attainment showed independent predicting effect (p<.05) in diverse cognitive domains. Cognitive impairment was very common in Chinese HD patients at the first visit and worse in the patients in advanced phase. The severity of motor symptoms and functional capacity were correlated to the diverse cognitive domains.

B - 43 Case Study: Native Hawaiian/Pacific Islander Female Veteran with Dementia with Lewy Bodies.

Recent research suggests there is a lack of consensus regarding current data on the racial/ethnic profiles of cognitively impaired persons with dementia with Lewy bodies (DLB) despite DLB being among the most common neurodegenerative dementias. This case study reviews a Native Hawaiian/Pacific Islander (NHPI) with probable DLB and discusses challenges encountered to emphasize the importance of appropriate normative data to help detect DLB in diverse populations. A 78-year-old NHPI female veteran presented for repeat neuropsychological evaluation to track her cognitive symptoms. Chief complaints included concurrent cognitive and motor difficulties, fully formed visual hallucinations, nighttime confusion, and reduplicative paramnesias which have significantly impacted her instrumental activities of daily living. Neuropsychological testing is suggestive of progressive decline in several cognitive domains, including visuospatial ability, executive functioning, semantic fluency, and verbal and visual learning and memory. Consistent with a DLB diagnosis, her cognitive symptoms emerged concurrently with motor symptom onset. There is also evidence of significant visuospatial and executive difficulties, as well as previously reported reduplicative paramnesia, confusion, and weekly fully-formed hallucinations. Additionally, there is evidence of concurrent parkinsonism's such as bradykinesia, rigidity, hypophonia, and tremor. The constellation of symptoms reported by the patient, combined with the results of neuropsychological assessment, was highly congruent with prototypical DLB; however, lack of proper normative data to accurately assess for decline in her scores led to significant caution in interpretation of her neuropsychological performance. This case demonstrates the importance of proper normative data in diverse populations and the role of neuropsychological evaluations in specific cultural contexts.

Neuroanatomical and cognitive biomarkers of alpha-synuclein propagation in a mouse model of synucleinopathy prior to onset of motor symptoms.

Significant evidence suggests that misfolded alpha-synuclein (aSyn), a major component of Lewy bodies, propagates in a prion-like manner contributing to disease progression in Parkinson's disease (PD) and other synucleinopathies. In fact, timed inoculation of M83 hemizygous mice with recombinant human aSyn preformed fibrils (PFF) has shown symptomatic deficits after substantial spreading of pathogenic alpha-synuclein, as detected by markers for the phosphorylation of S129 of aSyn. However, whether accumulated toxicity impact human-relevant cognitive and structural neuroanatomical measures is not fully understood. Here we performed a single unilateral striatal PFF injection in M83 hemizygous mice, and using two assays with translational potential, ex vivo magnetic resonance imaging (MRI) and touchscreen testing, we examined the combined neuroanatomical and behavioral impact of aSyn propagation. In PFF-injected mice, we observed widespread atrophy in bilateral regions that project to or receive input from the injection site using MRI. We also identified early deficits in reversal learning prior to the emergence of motor symptoms. Our findings highlight a network of regions with related cellular correlates of pathology that follow the progression of aSyn spreading, and that affect brain areas relevant for reversal learning. Our experiments suggest that M83 hemizygous mice injected with human PFF provides a model to understand how misfolded aSyn affects human-relevant pre-clinical measures and suggest that these pre-clinical biomarkers could be used to detect early toxicity of aSyn and provide better translational measures between mice and human disease.

Side of motor symptom onset predicts sustained attention deficits and motor improvements after attention training in Parkinson's disease

ObjectiveParkinson's disease (PD) side of motor symptom onset has been associated with distinct cognitive deficits; individuals with left-side onset (LPD) show more visuospatial impairments, whereas those with right-side onset (RPD) show more verbal impairments. Non-spatial attention is a critical cognitive ability associated with motor functioning that is right hemisphere lateralized but has not been characterized with regard to PD side of onset. We compared individuals with LPD and RPD on non-spatial attention tasks and examined differential responses to a 4-week sustained attention training program. MethodParticipants included 9 with LPD and 12 with RPD, who performed both brief and extended go/no-go continuous performance tasks and an attentional blink task. Participants also engaged in an at-home sustained attention training program, Tonic and Phasic Alertness Training (TAPAT), 5 days/week for 4 weeks. We assessed cognitive and motor symptoms before and after training, and after a 4-week no-contact period. ResultsAt baseline, participants with LPD exhibited worse performance than those with RPD on the extended continuous performance task, indicating specific deficits in sustaining attention. Poorer attention was associated with worse clinical motor scores. Notably, side of onset had a significant effect on clinical motor changes after sustained attention training, with only LPD participants improving after training, and 4/9 showing clinically meaningful improvements. ConclusionsCompared to RPD, participants with LPD had poorer sustained attention pre-training and were more likely to improve on clinical motor functioning after sustained attention training. These findings support mechanistic differences between LPD and RPD and suggest potential differential treatment approaches.

Multifactorial assessment of Parkinson's disease course and outcomes using trajectory modeling in a multiethnic, multisite cohort - extension of the LONG-PD study.

The severity, progression, and outcomes of motor and non-motor symptoms in Parkinson's disease (PD) are quite variable. Following PD cohorts holds promise for identifying predictors of disease severity and progression. PD patients (N = 871) were enrolled at five sites. Enrollment occurred within 5 years of initial motor symptom onset. Disease progression was assessed annually for 2-to-10 years after onset. Group-based trajectory modeling was used to identify groups differing in disease progression. Models were developed for UPDRS-III scores, UPDRS-III tremor and bradykinesia-rigidity subscores, Hoehn & Yahr (H&Y) stage, Mini-Mental Status Exam (MMSE) scores, and UPDRS-III, H&Y and MMSE scores considered together. Predictors of trajectory-group membership were modeled simultaneously with the trajectories. Kaplan-Meier survival analysis evaluated survival free of PD outcomes. The best fitting models identified three groups. One showed a relatively benign, slowly progressing trajectory (Group 1), a second showed a moderate, intermediately progressing trajectory (Group 2), and a third showed a more severe, rapidly progressing trajectory (Group 3). Stable trajectory-group membership occurred relatively early in the disease course, 5 years after initial motor symptom. Predictors of intermediate and more severe trajectory-group membership varied across the single variable models and the multivariable model jointly considering UPDRS-III, H&Y and MMSE scores. In the multivariable model, membership in Group 2 (28.4% of patients), relative to Group 1 (50.5%), was associated with male sex, younger age-at-onset, fewer education-years, pesticide exposure, absence of reported head injury, and akinetic/rigid subtype at initial presentation. Membership in Group 3 (21.3%), relative to Group 1, was associated with older age-at-onset, fewer education-years, pesticide exposure, and the absence of a tremor-predominant subtype at initial presentation. Persistent freezing, persistent falls, and cognitive impairment occurred earliest and more frequently in Group 3, later and less frequently in Group 2, and latest and least frequently in Group 1. Furthermore, autonomic complications, dysphagia, and psychosis occurred more frequently in Groups 2 and 3 than in Group 1. Modeling disease course using multiple objective assessments over an extended follow-up duration identified groups that more accurately reflect differences in PD course, prognosis, and outcomes than assessing single parameters over shorter intervals.

Caregiver Burden of Patients With Huntington's Disease in South Korea.

This is the first prospective cohort study of Huntington's disease (HD) in Korea. This study aimed to investigate the caregiver burden in relation to the characteristics of patients and caregivers. From August 2020 to February 2022, we enrolled patients with HD from 13 university hospitals in Korea. We used the 12-item Zarit Burden Interview (ZBI-12) to evaluate the caregiver burden. We evaluated the clinical associations of the ZBI-12 scores by linear regression analysis and investigated the differences between the low- and high-burden groups. Sixty-five patients with HD and 45 caregivers were enrolled in this cohort study. The average age at onset of motor symptoms was 49.3 ± 12.3 years, with an average cytosine-adenine-guanine (CAG)n of 42.9 ± 4.0 (38-65). The median ZBI-12 score among our caregivers was 17.6 ± 14.2. A higher caregiver burden was associated with a more severe Shoulson-Fahn stage (p = 0.038) of the patients. A higher ZBI-12 score was also associated with lower independence scale (B = -0.154, p = 0.006) and functional capacity (B = -1.082, p = 0.002) scores of patients. The caregiving duration was longer in the high- than in the low-burden group. Caregivers' demographics, blood relation, and marital and social status did not affect the burden significantly. HD patients' neurological status exerts an enormous impact on the caregiver burden regardless of the demographic or social status of the caregiver. This study emphasizes the need to establish an optimal support system for families dealing with HD in Korea. A future longitudinal analysis could help us understand how disease progression aggravates the caregiver burden throughout the entire disease course.