Non-motor Features Research Articles

Proposal for a Biologic Staging System of Parkinson's Disease.

The Parkinson's disease (PD) research field has seen the advent of several promising biomarkers and a deeper understanding of the clinical features of the disease from the earliest stages of pathology to manifest disease. Despite progress, a biologically based PD staging system does not exist. Such staging would be a useful framework within which to model the disease, develop and validate biomarkers, guide therapeutic development, and inform clinical trials design. We propose that the presence of aggregated neuronal α-synuclein, dopaminergic neuron dysfunction/degeneration, and clinical signs and symptoms identifies a group of individuals that have Lewy body pathology, which in early stages manifests with what is now referred to as prodromal non-motor features and later stages with the manifestations of PD and related Lewy body diseases as defined by clinical diagnostic criteria. Based on the state of the field, we herein propose a definition and staging of PD based on biology. We present the biologic basis for such a staging system and review key assumptions and evidence that support the proposed approach. We identify gaps in knowledge and delineate crucial research priorities that will inform the ultimate integrated biologic staging system for PD.

The Impact of microRNAs on Mitochondrial Function and Immunity: Relevance to Parkinson's Disease.

Parkinson's Disease (PD), the second most common neurodegenerative disorder, is characterised by the severe loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc) and by the presence of Lewy bodies. PD is diagnosed upon the onset of motor symptoms, such as bradykinesia, resting tremor, rigidity, and postural instability. It is currently accepted that motor symptoms are preceded by non-motor features, such as gastrointestinal dysfunction. In fact, it has been proposed that PD might start in the gut and spread to the central nervous system. Growing evidence reports that the gut microbiota, which has been found to be altered in PD patients, influences the function of the central and enteric nervous systems. Altered expression of microRNAs (miRNAs) in PD patients has also been reported, many of which regulate key pathological mechanisms involved in PD pathogenesis, such as mitochondrial dysfunction and immunity. It remains unknown how gut microbiota regulates brain function; however, miRNAs have been highlighted as important players. Remarkably, numerous studies have depicted the ability of miRNAs to modulate and be regulated by the host's gut microbiota. In this review, we summarize the experimental and clinical studies implicating mitochondrial dysfunction and immunity in PD. Moreover, we gather recent data on miRNA involvement in these two processes. Ultimately, we discuss the reciprocal crosstalk between gut microbiota and miRNAs. Studying the bidirectional interaction of gut microbiome-miRNA might elucidate the aetiology and pathogenesis of gut-first PD, which could lead to the application of miRNAs as potential biomarkers or therapeutical targets for PD.

Periaqueductal grey and spinal cord pathology contribute to pain in Parkinson’s disease

Pain is a key non-motor feature of Parkinson’s disease (PD) that significantly impacts on life quality. The mechanisms underlying chronic pain in PD are poorly understood, hence the lack of effective treatments. Using the 6-hydroxydopamine (6-OHDA) lesioned rat model of PD, we identified reductions in dopaminergic neurons in the periaqueductal grey (PAG) and Met-enkephalin in the dorsal horn of the spinal cord that were validated in human PD tissue samples. Pharmacological activation of D1-like receptors in the PAG, identified as the DRD5+ phenotype located on glutamatergic neurons, alleviated the mechanical hypersensitivity seen in the Parkinsonian model. Downstream activity in serotonergic neurons in the Raphé magnus (RMg) was also reduced in 6-OHDA lesioned rats, as detected by diminished c-FOS positivity. Furthermore, we identified increased pre-aggregate α-synuclein, coupled with elevated activated microglia in the dorsal horn of the spinal cord in those people that experienced PD-related pain in life. Our findings have outlined pathological pathways involved in the manifestation of pain in PD that may present targets for improved analgesia in people with PD.

A comprehensive cognitive profile of patients with cervical dystonia (P5-12.006)

<h3>Objective:</h3> To conduct a comprehensive analysis of cognition in cervical dystonia (CD). <h3>Background:</h3> Cervical dystonia is the most prevalent phenotype of the adult onset idiopathic focal dystonias (AOIFD), a group of hyperkinetic disorders. Patients with AOIFD have been shown to have varying abnormalities in cognition. This non-motor feature is underrecognised and may influence QoL. Studies into cognition in CD have been limited by inconsistent psychological assessment tools making generalisations difficult. We selected wide ranging neuropsychological tests to create a comprehensive cognitive profile. <h3>Design/Methods:</h3> 13 adult patients (5 male, 8 female) with idiopathic focal CD completed an extensive neuropsychological battery. Participants were screened for presence of mood disorders (HADS). All patients were receiving 3 monthly botulinum toxin treatment and were not on any medications that could influence cognition. Cognitive domains assessed: premorbid functioning, general intellectual functioning, language, information processing speed, attention, memory, executive function and social cognition using reliable and valid standardized neuropsychological assessments. <h3>Results:</h3> Mean age was 60-years. Mean HADS-A= 6 and mean HADS-D=5. CD patients showed clear evidence of cognitive dysfunction compared to normative data. The most significant impairments were noted in social cognitive measures [emotional prosody to emotional face, FAB (mean Z score: −1.75); naming emotional prosody, FAB (mean Z score: −0.81)], executive function [SWMBE468, CANTAB (mean Z score: −0.73)] and, memory [LM2, WMS (mean Z score: −0.82)]. Moderate impairments were seen in information processing speed [WAIS coding (mean Z score: −0.51)], language [Boston Naming Test (mean Z score: −0.51)] and attention and working memory [RVPA, CANTAB (mean Z score: −0.61)]. Patients performed better than controls in another aspect of social cognition [conflicting emotional prosody, FAB (Z score: 1.67)]. <h3>Conclusions:</h3> There is mounting evidence of cognitive deficits in CD, implicating cognitive pathways in disease pathogenesis. This non-motor aspect may influence QoL and patient satisfaction. Early recognition and neuropsychological input could improve outcomes. <b>Disclosure:</b> Ms. Diepman has nothing to disclose. Dr. Rafee has nothing to disclose. Ruth Monaghan has nothing to disclose. Miss McCormack has nothing to disclose. Dr. Hutchinson has nothing to disclose. Dr. O’Keeffe has nothing to disclose.

Data-driven phenotypic clustering of Parkinson’s disease patients seeking deep brain stimulation (P6-11.008)

<h3>Objective:</h3> To identify unique phenotypic clusters amongst participants in RAD-PD (Registry for the Advancement of Deep Brain Stimulation in Parkinson’s Disease). <h3>Background:</h3> RAD-PD is a longitudinal quality improvement registry that systematically characterizes participants through patient reported outcome measures and clinician administered scales, with the overarching goal of improving outcomes from deep brain stimulation (DBS) in PD. Multiple investigations demonstrate that DBS improves motor function and quality of life (QoL). Less is understood about non-motor outcomes and determinants. <h3>Design/Methods:</h3> A variety of demographic/social, disease-related, motor, non-motor, quality of life, and treatment-related datapoints are captured in RAD-PD. Continuous data variables from participants with complete pre-operative assessments were analyzed using R software. A pairs plot correlation analysis, principal component analysis (PCA) and hierarchical clustering analysis (HCA) with normalized data were conducted. <h3>Results:</h3> Data from 133 subjects were included. Amongst 32 categories of RAD-PD data covering demographic/disease (n=5), non-motor (n=18), motor (n=3), cognitive (n=3) and QoL (n=3) variables, all 3 QoL scale scores were strongly correlated with each other (r=0.47–0.64, p&lt;0.0001), and were otherwise most highly correlated (r&gt;0.4) with measures of depression, anxiety, sleep/fatigue, NMSS total, mood/cognition, IADLs, and MDS-UPDRS part 2. Motor and disease-related variables did not strongly correlate with other variables. PCA revealed two dimensions that together explain 38.7% of the variance in the data, driven mainly by quality of life, NMSS domain/total scores, and QUIP-RS subscores/total scores. HCA classified individuals into two groups that were differentiated based on non-motor (NMSS and ICD scores), cognitive, and QoL features. <h3>Conclusions:</h3> While recommendations for DBS in PD are often driven by motor disease features, QoL and non-motor symptoms are prominent features that are closely related and can be combined to classify phenotypic clusters. Such data-driven classifications can be used in the RAD-PD cohort for novel outcomes analyses and predictive modeling. <b>Disclosure:</b> Dr. Jimenez Shahed has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Bracket Global LLC. Dr. Jimenez Shahed has received personal compensation in the range of $500-$4,999 for serving as a Consultant for St. Jude Medical, Inc. Dr. Jimenez Shahed has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Teva. Dr. Jimenez Shahed has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Revance. Dr. Jimenez Shahed has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Medtronic. Dr. Jimenez Shahed has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Spark Therapeutics. Dr. Jimenez Shahed has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbvie. Dr. Jimenez Shahed has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alpha Omega. Dr. Jimenez Shahed has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BlueRock Therapeutics. Dr. Jimenez Shahed has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for PhotoPharmics. The institution of Dr. Jimenez Shahed has received research support from Michael J Fox Foundation. The institution of Dr. Jimenez Shahed has received research support from Amneal. Dr. Jimenez Shahed has received personal compensation in the range of $500-$4,999 for serving as a Faculty with Movement Disorders Society. Dr. Jimenez Shahed has received personal compensation in the range of $500-$4,999 for serving as a Faculty with American Academy of Neurology. Dr. Jimenez Shahed has received personal compensation in the range of $500-$4,999 for serving as a Grant Reviewer with Parkinson Foundation. Dr. Jimenez Shahed has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant on Research Grant with Florida Atlantic University. Dr. Jimenez Shahed has received personal compensation in the range of $0-$499 for serving as a Speaker with Tourette Association of America. Dr. Jimenez Shahed has received personal compensation in the range of $10,000-$49,999 for serving as a Speaker with NACCME. The institution of Arthur Berg has received research support from U.S. Army Medical Research and Development Command

A novel ANO3 variant in two siblings with different phenotypes

IntroductionDystonia type 24 is due to the mutation of the ANO3 gene. It generally consists of craniocervical dystonia associated with tremor; however, other neurological manifestations may also occur. Scientific literature has been expanding on its phenotype over the past few years. CaseHere we present two siblings affected by dystonia 24 associated to a novel missense mutation of the ANO3 gene. Description of their phenotype, with regard to motor and non-motor features, may improve the knowledge on DYT 24. Consistent with previous reports, our patients presented with cranio-cervical involvement, and they also exhibited different severity and phenotypes. However non-motor symptoms were present too. ConclusionDystonia 24 spectrum is continuously expanding. This case suggests that the ANO3 missense mutation should be sought in all cases of dystonia and isolated tremor and that non-motor symptoms are an integral part of dystonic syndromes. It also shows that clinical and treatment features may vary from patient to patient, even if they may present the same mutation.

The strength, hope and resourcefulness program for people with Parkinson’s disease: a qualitative investigation of group members’ experiences

ABSTRACT Parkinson’s Disease (PD) is a neurodegenerative disease characterized by motor and non-motor features. Many people with PD struggle with mental health issues such as depression. Evidence shows that people with PD may have trouble adopting a hopeful or positive orientation given their diagnosis and symptoms. Psychological treatments for PD are scarce and even more scarce are treatments that specifically focus on promoting hope and well-being. The Strengths, Hope, and Resourcefulness Program for People with Parkinson’s Disease was developed to begin to address this treatment gap. This qualitative study identifies seven processes group members found helpful during treatment: Accessing Hope, Comparing, Drawing Together, Reaching Out Beyond Self, Releasing Emotion, Sharing Skills and Picking Up Resources, and Self-Reflecting Leading to Personal Insight. The unique contributions of an intentional and explicit hope, strengths, and resources intervention are discussed with specific attention to therapeutic process and practice.

Mood disturbances in Parkinson's disease: From prodromal origins to application of animal models

Parkinson's disease (PD) is a complex illness with a constellation of environmental insults and genetic vulnerabilities being implicated. Strikingly, many studies only focus on the cardinal motor symptoms of the disease and fail to appreciate the major non-motor features which typically occur early in the disease process and are debilitating. Common comorbid psychiatric features, notably clinical depression, as well as anxiety and sleep disorders are thought to emerge before the onset of prominent motor deficits. In this review, we will delve into the prodromal stage of PD and how early neuropsychiatric pathology might unfold, followed by later motor disturbances. It is also of interest to discuss how animal models of PD capture the complexity of the illness, including depressive-like characteristics along with motor impairment. It remains to be determined how the underlying PD disease processes contributes to such comorbidity. But some of the environmental toxicants and microbial pathogens implicated in PD might instigate pro-inflammatory effects favoring α-synuclein accumulation and damage to brainstem neurons fueling the evolution of mood disturbances. We posit that comprehensive animal-based research approaches are needed to capture the complexity and time-dependent nature of the primary and co-morbid symptoms. This will allow for the possibility of early intervention with more novel and targeted treatments that fit with not only individual patient variability, but also with changes that occur over time with the evolution of the disease.

Associations of striatal dopamine transporter binding with motor and non-motor symptoms in early Parkinson's disease.

Dopamine transporter (DAT) imaging is an in vivo tool to assess presynaptic dopaminergic function in the clinical practices of Parkinson's disease (PD). Current clinical practices focused on qualitatively visual interpretation of DAT imaging, whereas quantitative analyses are potentially more helpful when monitoring the progression of PD. Previous cross-sectional studies indicated certain motor and non-motor features were associated with striatal DAT binding, whereas limited data were reported in terms of the longitudinal correlation between clinical features of PD with striatal DAT binding. The purpose of our study is to clarify current and longitudinal correlations between striatal DAT binding and clinical measures. A total of 352 untreated PD individuals and 167 healthy controls with complete baseline clinical measures and neuroimaging data were identified from the Parkinson's Progression and Markers Initiative (PPMI) database. Patients with PD underwent DAT imaging at the screening visit and following months 12, 24, and 48. Multiple linear regression models and linear mixed-effect models were respectively conducted to investigate the cross-sectional and longitudinal correlation between clinical characteristics and DAT binding. Associations between changes in clinical characteristics and changes in DAT binding were further evaluated and the Spearman rank correlation coefficients were reported. In the cross-sectional analysis, baseline striatal DAT binding was significantly associated with the Hoehn and Yahr scale, the Movement Disorder Society-Sponsored Revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS) scores, the rigidity scores, and the axial scores in PD individuals (false discovery rate [FDR]-adjusted p=0.0017 for all above). Patients who developed freezing of gait had lower striatal DAT binding (FDR-adjusted p=0.0161). Healthy controls who had higher tremor scores and suffered more severe olfactory dysfunction had lower striatal DAT binding (FDR-adjusted p=0.0257 for all above). Longitudinal analysis indicated that baseline severity of rapid-eye-movement sleep behavior disorder was significantly associated with longitudinal striatal DAT binding in patients with PD (FDR-adjusted p=0.0120). Furthermore, changes in MDS-UPDRS scores and the State-Trait Anxiety Inventory (STAI) scores demonstrated significant correlations with changes in striatal DAT binding over 4 years (p=0.005 and p=0.032, respectively). Our findings clarified quantitative associations between certain motor and non-motor features with current and future striatal dopamine binding, suggesting the feasibility of using DAT images as a progression predictive marker for PD. Further studies are needed to investigate correlations between different regional dopamine binding with specific clinical features.

The Influence of GBA and LRRK2 on Mood Disorders in Parkinson's Disease.

Mood disorders have emerged as major non-motor comorbidities in Parkinson's disease (PD) even at the prodromal stage of the disease. Mutations in the LRRK2 and GBA genes are common among Ashkenazi Jews, with more severe phenotype reported for GBA-PD. To explore the association between genetic status and mood related disorders before and after diagnosis of PD and the association between mood-related medications, phenotype, and genetic status. Participants were genotyped for mutations in the LRRK2 and GBA genes. State of depression, anxiety and non-motor features were evaluated using validated questionnaires. History of mood disorders prior to diagnosis of PD and use of mood-related medications were assessed. The study included 105 idiopathic PD (iPD), 55 LRRK2-PD and 94 GBA-PD. Scores on mood related questionnaires and frequency of depression and anxiety before diagnosis were similar between the groups (p>0.05). However, more GBA-PD patients used mood related medications before PD diagnosis than LRRK2-PD and iPD (16.5% vs 7.1% and 8.2%, p=0.044). LRRK2-PD and GBA-PD receiving mood-related medications at time of assessment had worse motor and non-motor phenotype compared to those that did not (p<0.05). LRRK2-PD receiving mood related-medications at time of assessment, scored higher on mood-related questionnaires compared to LRRK2-PD not receiving such medications (p<0.04). Prodromal GBA-PD are more frequently treated with mood related-medications despite equal rates of reported mood-related disorders, while LRRK2-PD with mood-related disorders experience high rates of anxiety and depression despite treatment, attesting to the need of more precise assessment and treatment of these genetic subgroups.

Eye movement study in essential tremor patients and its clinical correlates.

Essential tremor (ET) encompasses a wide spectrum of motor and non-motor features. Eye movement abnormalities were first reported two decades ago as an atypical finding in ET. Today, a growing number of publications about eye movement abnormalities in neurodegenerative diseases have helped understand their pathophysiology and the basis of their phenotypic variability. Thus, addressing such aspect in ET may disentangle, based on the oculomotor network abnormalities, the dysfunctional brain pathways in ET. In this study, we aimed to describe neurophysiological eye movement abnormalities in ET and their clinical correlates in terms of cognition and other associated clinical signs. We conducted a cross-sectional study in a tertiary neurology referral center including consecutive ET patients and cognitively normal healthy controls (HC) matched for age and sex. The study protocol included the assessment of voluntary horizontal saccades, smooth pursuit, anti-saccades and saccadic intrusions. We assessed the associated motor signs, cognitive functions and the presence of rapid eye movement disorder (RBD). Sixty-two ET patients and 66 HC were enrolled in the study. Eye movement examination showed significant abnormalities in comparison with HC (46.7% vs 20%, p = 0.002). Prolonged saccadic latency (38.7%, p = 0.033) and altered smooth pursuit (38.7%, p = 0.033) were the most common abnormalities in ET patients. Anti-saccadic errors (16% vs 0% in HC, p = 0.034) correlated with the presence of rigidity (p = 0.046), bradykinesia (p = 0.001), cognitive dysfunction (p = 0.006), executive dysfunction (p = 0.0002), apraxia (p = 0.0001), altered verbal fluency (p = 0.013) and altered backward digit span (p = 0.045) along with the presence of RBD (p = 0.035). Square-wave jerks (11.5% vs 0% in HC, p = 0.0024) correlated with rest tremor. A distinctive phenotype of ET could emerge out of this study characterized by anti-saccadic errors and a sub-cortical cognitive profile, consecutive to the disruption of the cerebello-thalamo-cortical loop. Patients with anti-saccadic errors could be cognitively vulnerable and in need of a close monitoring of their cognitive efficiency during the disease's progression. They may as well convert to Parkinson disease if they present with parkinsonism, RBD and square-wave jerks and require, consequently, a close observation of their motor progression.

Effects of mutant huntingtin in oxytocin neurons on non-motor features of Huntington's disease.

Early non-motor features including anxiety, depression and altered social cognition are present in Huntington's disease (HD). The underlying neurobiological mechanisms are not known. Oxytocin (OXT) is involved in the regulation of emotion, social cognition and metabolism, and our previous work showed that the OXT system is affected early in HD. The aim of the study was to investigate the potential causal relationship between the selective expression of mutant huntingtin (mHTT) in OXT neurons and the development of non-motor features and neuropathology. To express mHTT only in OXT neurons, we used a novel flex-switch adeno-associated viral vector design to selectively express either mHTT or wild-type HTT in the paraventricular nucleus of the hypothalamus using OXT-Cre-recombinase mice. We also performed a mirror experiment to selectively delete mHTT in OXT neurons using the BACHD mouse model. Mice underwent a battery of behavioural tests to assess psychiatric and social behaviours 3months post-injection or at 2 months of age, respectively. Post-mortem analyses were performed to assess the effects on the OXT system. Our results show that selective expression of mHTT in OXT neurons was associated with the formation of mHTT inclusions and a 26% reduction of OXT-immunopositive neurons as well as increased anxiety-like behaviours compared with uninjected mice. However, selective deletion of mHTT from OXT neurons alone was not sufficient to alter the metabolic and psychiatric phenotype of the BACHD mice at this early time point. Our results indicate that mHTT expression can exert cell-autonomous toxic effects on OXT neurons without affecting the non-motor phenotype at early time points in mice.

Premorbid performances determine the deleterious effects of nigrostriatal degeneration and pramipexole on behavioural flexibility

Subtle cognitive impairment can occur early in the course of Parkinson’s disease (PD) and may manifest under different forms of executive dysfunction such as impaired cognitive flexibility. The precise contribution of nigrostriatal dopaminergic neurodegeneration to these non-motor features of the disease is poorly known. Whether such cognitive impairment associated with the disease process may also predate and contribute to the development of neuropsychiatric side-effects following dopamine replacement therapy remains largely unknown. To address these issues, we investigated the respective contributions of nigrostriatal degeneration and chronic treatment with the dopamine D3-preferring agonist pramipexole on behavioral flexibility in a rat model of PD. Flexible, intermediate and inflexible rats were identified based on baseline assessment of behavioral flexibility using an operant set-shifting task. Nigrostriatal degeneration was induced by bilateral viral-mediated expression of A53T mutated human α-synuclein in the substantia nigra pars compacta and behavioral flexibility was assessed after induction of nigrostriatal degeneration, and during chronic pramipexole treatment. Nigrostriatal degeneration impaired behavioral flexibility in flexible but not in inflexible rats. Pramipexole induced a decrease of behavioral flexibility that was exacerbated in lesioned rats and in the most flexible individuals. Furthermore, the deficits induced by pramipexole in lesioned rats affected different components of the task between flexible and inflexible individuals. This study demonstrates that nigrostriatal degeneration and pramipexole unequally impair behavioral flexibility, suggesting that the susceptibility to develop non-motor impairments upon treatment initiation could primarily depend on premorbid differences in behavioral flexibility.

Beyond shallow feelings of complex affect: Non-motor correlates of subjective emotional experience in Parkinson's disease.

Affective disorders in Parkinson's disease (PD) concern several components of emotion. However, research on subjective feeling in PD is scarce and has produced overall varying results. Therefore, in this study, we aimed to evaluate the subjective emotional experience and its relationship with autonomic symptoms and other non-motor features in PD patients. We used a battery of film excerpts to elicit Amusement, Anger, Disgust, Fear, Sadness, Tenderness, and Neutral State, in 28 PD patients and 17 healthy controls. Self-report scores of emotion category, intensity, and valence were analyzed. In the PD group, we explored the association between emotional self-reported scores and clinical scales assessing autonomic dysregulation, depression, REM sleep behavior disorder, and cognitive impairment. Patient clustering was assessed by considering relevant associations. Tenderness occurrence and intensity of Tenderness and Amusement were reduced in the PD patients. Tenderness occurrence was mainly associated with the overall cognitive status and the prevalence of gastrointestinal symptoms. In contrast, the intensity and valence reported for the experience of Amusement correlated with the prevalence of urinary symptoms. We identified five patient clusters, which differed significantly in their profile of non-motor symptoms and subjective feeling. Our findings further suggest the possible existence of a PD phenotype with more significant changes in subjective emotional experience. We concluded that the subjective experience of complex emotions is impaired in PD. Non-motor feature grouping suggests the existence of disease phenotypes profiled according to specific deficits in subjective emotional experience, with potential clinical implications for the adoption of precision medicine in PD. Further research on larger sample sizes, combining subjective and physiological measures of emotion with additional clinical features, is needed to extend our findings.

Brain Degeneration in Synucleinopathies Based on Analysis of Cognition and Other Nonmotor Features: A Multimodal Imaging Study.

We aimed to characterize subtypes of synucleinopathies using a clustering approach based on cognitive and other nonmotor data and to explore structural and functional magnetic resonance imaging (MRI) brain differences between identified clusters. Sixty-two patients (n = 6 E46K-SNCA, n = 8 dementia with Lewy bodies (DLB) and n = 48 idiopathic Parkinson's disease (PD)) and 37 normal controls underwent nonmotor evaluation with extensive cognitive assessment. Hierarchical cluster analysis (HCA) was performed on patients' samples based on nonmotor variables. T1, diffusion-weighted, and resting-state functional MRI data were acquired. Whole-brain comparisons were performed. HCA revealed two subtypes, the mild subtype (n = 29) and the severe subtype (n = 33). The mild subtype patients were slightly impaired in some nonmotor domains (fatigue, depression, olfaction, and orthostatic hypotension) with no detectable cognitive impairment; the severe subtype patients (PD patients, all DLB, and the symptomatic E46K-SNCA carriers) were severely impaired in motor and nonmotor domains with marked cognitive, visual and bradykinesia alterations. Multimodal MRI analyses suggested that the severe subtype exhibits widespread brain alterations in both structure and function, whereas the mild subtype shows relatively mild disruptions in occipital brain structure and function. These findings support the potential value of incorporating an extensive nonmotor evaluation to characterize specific clinical patterns and brain degeneration patterns of synucleinopathies.

A machine learning approach to predict quality of life changes in patients with Parkinson's Disease.

Parkinson disease (PD) is a progressive neurodegenerative disorder with an annual incidence of approximately 0.1%. While primarily considered a motor disorder, increasing emphasis is being placed on its non-motor features. Both manifestations of the disease affect quality of life (QoL), which is captured in part II of the Unified Parkinson's Disease Rating Scale (UPDRS-II). While useful in the management of patients, it remains challenging to predict how QoL will change over time in PD. The goal of this work is to explore the feasibility of a machine learning algorithm to predict QoL changes in PD patients. In this retrospective cohort study, patients with at least 12 months of follow-up were identified from the Parkinson's Progression Markers Initiative database (N = 630) and divided into two groups: those with and without clinically significant worsening in UPDRS-II (n = 404 and n = 226, respectively). We developed an artificial neural network using only UPDRS-II scores, to predict whether a patient would clinically worsen or not at 12 months from follow-up. Using UPDRS-II at baseline, at 2 months, and at 4 months, the algorithm achieved 90% specificity and 56% sensitivity. A learning model has the potential to rule in patients who may exhibit clinically significant worsening in QoL at 12 months. These patients may require further testing and increased focus.

How should future clinical trials be designed in the search for disease-modifying therapies for Parkinson’s disease?

ABSTRACT Introduction Although there has been substantial progress in research and innovations in symptomatic treatments, similar success has not been achieved in disease-modifying therapy (DMT) for Parkinson’s disease (PD). Considering the enormous motor, psychosocial and financial burden associated with PD, safe and effective DMT is of paramount importance. Areas covered One of the reasons for the lack of progress in DMT for PD is poor or inappropriate design of clinical trials. In the first part of the article, the authors focus on the plausible reasons why the previous trials have failed and in the latter part, they provide their perspectives on future DMT trials. Expert opinion There are several potential reasons why previous trials have failed, including broad clinical and etiopathogenic heterogeneity of PD, poor definition and documentation of target engagement, lack of appropriate biomarkers and outcome measures, and short duration of follow-up. To address these deficiencies, future trials may consider- (i) a more customized approach to select the most suitable participants and therapeutic approaches, (ii) explore combination therapies that would target multiple pathogenetic mechanisms, and (iii) moving beyond targeting only motor symptoms to also assessing non-motor features of PD in well-designed longitudinal studies.

Ethnicity and Parkinson's Disease: Motor and Nonmotor Features and Disease Progression in Latino Patients Living in Rural California.

Parkinson's disease (PD) is the second most common neurodegenerative disorder among older adults worldwide. Currently, studies of PD progression rely primarily on White non-Latino (WNL) patients. Here, we compare clinical profiles and PD progression in Latino and WNL patients enrolled in a community-based study in rural Central California. PD patients within 5years of diagnosis were identified from 3 counties between 2001 and 2015. During up to 3 visits, participants were examined by movement disorders specialists and interviewed. We analyzed cross-sectional differences in PD clinical features severity at each study visit and used linear mixed models and Cox proportional hazards models to compare motor, nonmotor, and disability progression longitudinally and to assess time to death in Latinos compared to WNL patients. Of 775 patients included, 138 (18%) self-identified as Latino and presented with earlier age at diagnosis (63.6 vs 68.9) and death (78.6 vs 81.5) than WNL. Motor (hazard ratio [HR]=1.17 [0.71, 1.94]) and nonmotor symptoms did not progress faster in Latino versus WNL patients after accounting for differences in baseline symptom severity. However, Latino patients progressed to disability stages according to Hoehn and Yahr faster than WNL (HR=1.81 [1.11, 2.96]). Motor and nonmotor symptoms in Latino patients were also medically managed less well than in WNL. Our PD study with a large proportion of Latino enrollees and progression data reveals disparities in clinical features and progression by ethnicity that may reflect healthcare access and structural socioeconomic disadvantages in Latino patients with PD.

Quality of life implications for elevated trait impulsivity in people with Parkinson’s disease

BackgroundSeveral non-motor features of Parkinson’s disease (PD) are known to adversely affect patient health-related quality of life (HRQL). However, the specific impact of neuropsychiatric complications, such as impulsive behaviour, is yet to be elucidated.ObjectivesThe present cross-sectional, observational study aimed to investigate the effects of heightened trait impulsivity on HRQL in individuals with PD.MethodsA total of 322 people with idiopathic PD were sequentially recruited from Movement Disorder clinics across Australia. Trait impulsivity in patients was determined by Barratt’s Impulsiveness Scale Version 11 (BIS-11), and grouped into tertiles (low, medium, and high). Patient HRQL was determined by the 39-item Parkinson’s Disease Questionnaire (PDQ-39), complemented by the Cambridge Behavioural Inventory-Revised (CBI-R) indicating caregivers’ perception of patient HRQL.ResultsWhen total BIS-11 scores were grouped into tertiles, patient perceived and caregiver-perceived HRQL were 1.7-fold (p < .001) and 2.2-fold (p < .001) worse in the high BIS-11 group when compared to patients in the low group. Univariate analysis revealed significant associations between second-order attentional (p < .001) and non-planning (p < .001) impulsivity domains with PDQ-39 scores. When controlling for confounding demographic and clinical variables, a multivariate linear regression model revealed second-order attentional impulsivity was independently predictive of poor patient perceived HRQL (p < .001).ConclusionThese findings suggest that increasing trait impulsivity is significantly associated with patient perceived HRQL in PD. Improved knowledge and recognition of subclinical impulsivity may guide clinicians’ treatment and reduce disease burden for patients experiencing PD symptoms.

The characteristic of nonmotor symptoms with different phenotypes and onsets in multiple system atrophy patients

ObjectivesThe characteristic of nonmotor symptoms in patients with multiple system atrophy (MSA) has varied among previous studies. The objective was to investigatethe nonmotor characteristics in MSA patients with different phenotypes, sex and different onset patterns. MethodsWe performed a retrospective review of 1492 MSA patients. All cases were evaluatedby neurologists and assessed with motormanifestations, nonmotor symptoms, auxiliary examinationand brain MRI scans. ResultsMultiple system atrophy–cerebellar ataxia (MSA-C) was the predominant phenotype in 998 patients. Average age of onset (56.8 ± 9.2 years) was earlier, the disease duration (2.4 ± 2.2 year) was shorter and brain MRI abnormalities (49.2 %) were more frequently in MSA-C (P < 0.001). Multiple system atrophy–parkinsonism (MSA-P) patients were more likely to have nonmotor symptoms. After adjusted significant parameters, urinary dysfunction (OR 1.441, 95 %CI = 1.067–1.946, P = 0.017), constipation (OR 1.482, 95 %CI = 1.113–1.973, P = 0.007), cognitive impairment (OR 1.509, 95 %CI = 1.074–2.121, P = 0.018) and drooling (OR 2.095, 95 %CI = 1.248–3.518, P = 0.005) were associated with the MSA-P phenotype. Males were more likely to have orthostatic hypotension, urinary dysfunction, sexual dysfunction, drooling and females in constipation and probable RBD. In different onset patterns, constipation (59.2 %) and probable RBD (28.4 %) were more frequently in autonomiconset pattern. ConclusionsMSA-C is the predominant phenotype in Chinese patients, while many nonmotor symptoms are more common in MSA-P phenotype. Patients with different sex and onset patterns have different nonmotor characteristics. The different clinical features identified could help the physician counseling of MSA patients more easily and more accurately.