Severity Of Non-motor Symptoms Research Articles

ON/OFF non-motor evaluation: a new way to evaluate non-motor fluctuations in Parkinson’s disease

BackgroundNMF are currently poorly evaluated in therapeutic decisions. A quantification of their severity would facilitate their integration. The objective of this study was to validate an autoquestionnaire evaluating the severity...

Impact of ataxia aetiology on self-reported mental health, fatigue, cognition and ataxia symptom severity

IntroductionIt has been increasingly recognised that the impact of Ataxia extends beyond physical and motor symptomology. However, it is less known whether self-reported non-motor and ataxia symptom severity varies across ataxias of differing aetiology, which would have important implications for providing more targeted treatment.AimThis study aimed to investigate the impact of ataxia aetiology (hereditary, acquired or idiopathic) on self-reported depression, anxiety, fatigue, cognitive deficits, and ataxia symptom severity. Comparisons were also made between the ataxia sample as a whole and a neurologically healthy control group.MethodResponses were collected using a cross-sectional online survey to recruit a national UK sample of people with ataxia.ResultsThe study recruited 110 participants with ataxia (hereditary = 51, acquired = 16, idiopathic = 43) and 32 healthy controls. No significant differences were found across study variables for different causes of ataxia. However, participants with ataxia did report significantly higher levels of depression, anxiety, fatigue, cognitive deficits, and ataxia symptom severity compared to healthy controls.ConclusionThis study found that participants with ataxia self-reported increased non-motor symptoms compared to healthy controls, which was a generally homogenous experience across different causes of ataxia. There was also considerable comorbidity of symptoms which requires further exploration. This study highlights the need for early assessment and intervention to address these non-motor symptoms in ataxia populations.

Variant-specific effects of GBA1 mutations on dopaminergic neuron proteostasis.

Glucocerebrosidase 1 (GBA1) mutations are the most important genetic risk factors for Parkinson's disease (PD). Clinically, mild (e.g., p.N370S) and severe (e.g., p.L444P and p.D409H) GBA1 mutations have different PD phenotypes, with differences in age at disease onset, progression, and the severity of motor and non-motor symptoms. We hypothesize that GBA1 mutations cause the accumulation of α-synuclein by affecting the cross-talk between cellular protein degradation mechanisms, leading to neurodegeneration. Accordingly, we tested whether mild and severe GBA1 mutations differentially affect the degradation of α-synuclein via the ubiquitin-proteasome system (UPS), chaperone-mediated autophagy (CMA), and macroautophagy and differentially cause accumulation and/or release of α-synuclein. Our results demonstrate that endoplasmic reticulum (ER) stress and total ubiquitination rates were significantly increased in cells with severe GBA1 mutations. CMA was found to be defective in induced pluripotent stem cell (iPSC)-derived dopaminergic neurons with mild GBA1 mutations, but not in those with severe GBA1 mutations. When examining macroautophagy, we observed reduced formation of autophagosomes in cells with the N370S and D409H GBA1 mutations and impairments in autophagosome-lysosome fusion in cells with the L444P GBA1 mutation. Accordingly, severe GBA1 mutations were found to trigger the accumulation and release of oligomeric α-synuclein in iPSC-derived dopaminergic neurons, primarily as a result of increased ER stress and defective macroautophagy, while mild GBA1 mutations affected CMA, which is mainly responsible for the degradation of the monomeric form of α-synuclein. Overall, our findings provide new insight into the molecular basis of the clinical variability in PD associated with different GBA1 mutations.

Predictors of stress resilience in Parkinson’s disease and associations with symptom progression

People with Parkinson’s disease (PD) are sensitive to effects of long-term stress, but might differ in stress resilience, i.e. the ability to maintain mental health despite adversity. It is unclear whether stress resilience in PD is predominantly determined by dopamine deficiency, psychosocial factors, or both. In PD animal models, chronic stressors accelerate disease progression, but evidence in humans is lacking. Our objectives were to (1) distinguish stressor-reactive from resilient PD patients, (2) identify resilience factors, and (3) compare symptom progression between stressor-reactive and resilient patients. We conducted a longitudinal survey in Personalized Parkinson Project participants (N = 350 PD). We used the COVID-19 pandemic as a model of a stressor, aligned in time for the entire cohort. COVID-19-related stressors, perceived stress, and PD symptoms were assessed at 11 timepoints (April-October 2020). Both pre-COVID and in-COVID clinical assessments were available. We quantified stressor-reactivity as the residual between actual and predicted perceived stress relative to COVID-19-related stressors, and modeled trajectories of stressor-reactivity across timepoints. We explored pre-COVID predictors of 6-month average stressor-reactivity, and tested whether stressor-reactivity was prospectively associated with one-year clinical progression rates. Latent class trajectory models distinguished patients with high (N = 123) or low (N = 227) stressor-reactivity. Pre-existing anxiety, rumination and non-motor symptom severity predicted high stressor-reactivity (risk factors), whereas quality of life, social support, positive appraisal style and cognitive abilities predicted low stressor-reactivity (resilience factors). PD-specific factors, e.g. disease duration, motor severity, and levodopa use, did not predict stressor-reactivity. The COVID-19 pandemic did not accelerate disease progression, but worsened depressive symptoms in stressor-reactive PD patients.

A randomized feasibility trial of medium chain triglyceride-supplemented ketogenic diet in people with Parkinson's disease

BackgroundA ketogenic diet (KD) may benefit people with neurodegenerative disorders marked by mitochondrial depolarization/insufficiency, including Parkinson’s disease (PD).ObjectiveEvaluate whether a KD supplemented by medium chain triglyceride (MCT-KD) oil is feasible and acceptable for PD patients. Furthermore, we explored the effects of MCT-KD on blood ketone levels, metabolic parameters, levodopa absorption, mobility, nonmotor symptoms, simple motor and cognitive tests, autonomic function, and resting-state electroencephalography (rsEEG).MethodsA one-week in-hospital, double-blind, randomized, placebo-controlled diet (MCT-KD vs. standard diet (SD)), followed by an at-home two-week open-label extension. The primary outcome was KD feasibility and acceptability. The secondary outcome was the change in Timed Up & Go (TUG) on day 7 of the diet intervention. Additional exploratory outcomes included the N-Back task, Unified Parkinson’s Disease Rating Scale, Non-Motor Symptom Scale, and rsEEG connectivity.ResultsA total of 15/16 subjects completed the study. The mean acceptability was 2.3/3, indicating willingness to continue the KD. Day 7 TUG time was not significantly different between the SD and KD groups. The nonmotor symptom severity score was reduced at the week 3 visit and to a greater extent in the KD group. UPDRS, 3-back, and rsEEG measures were not significantly different between groups. Blood ketosis was attained by day 4 in the KD group and to a greater extent at week 3 than in the SD group. The plasma levodopa metabolites DOPAC and dopamine both showed nonsignificant increasing trends over 3 days in the KD vs. SD groups.ConclusionsAn MCT-supplemented KD is feasible and acceptable to PD patients but requires further study to understand its effects on symptoms and disease.Trial RegistrationTrial Registration Number NCT04584346, registration dates were Oct 14, 2020 – Sept 13, 2022.

Relationship between increased serum neurofilament light chain and glial fibrillary acidic protein levels with non-motor symptoms in patients with Parkinson's disease.

This study set out to investigate the relationship between serum neurofilament light chain (NFL), glial fibrillary acidic protein (GFAP), and various non-motor symptoms (NMSs) in patients with Parkinson's disease (PD). The study included 37 healthy controls (HCs) and 51 PD patients. Clinical assessments of PD symptoms were conducted for all PD patients. The NMSS was utilised to evaluate the NMS burden (NMSB) in individuals. Based on the severity of NMSB, we further categorised the PD group into two subgroups: mild-moderate NMSB group and severe-very severe NMSB group. The amounts of NFL and GFAP in the serum were measured using an extremely sensitive single molecule array (Simoa) method. Statistical analyses were performed on the collected data using SPSS 26.0 and R (version 3.6.3). Serum GFAP and NFL levels in the PD group with severe-very severe NMSB were significantly higher than those in the mild-moderate NMSB group (GFAP: P < 0.007; NFL: P < 0.009). Serum NFL and GFAP levels had positive correlations with NMSS total scores (GFAP: r = 0.326, P = 0.020; NFL: r = 0.318, P = 0.023) and multiple subdomains. The relationship between the attention/memory domains of NMSS and NFL levels is significantly positive (r = 0.283, P = 0.044). Similarly, the mood/apathy domains of NMSS are also significantly positively correlated with GFAP levels (r = 0.441, P = 0.001). Patients with emotional problems or cognitive impairment had higher GFAP or NFL levels, respectively. Furthermore, it has been demonstrated that NMSs play a mediating role in the quality of life of patients with PD. Moreover, the combination of NFL and GFAP has proven to be more effective than using a single component in identifying PD patients with severe-very severe NMSB. The severity of NMSs in PD patients, particularly cognitive and emotional symptoms, was found to be associated with the levels of serum NFL and GFAP. This study marks the first attempt to examine the connection between NMSs of PD and the simultaneous identification of NFL and GFAP levels.

Preoperative Attention/Memory Problem Affects the Quality of Life of Parkinson's Disease Patients after Deep Brain Stimulation: A Cohort Study.

The aim of this study was to investigate the impact of nonmotor symptoms (NMS) on the quality of life (QoL) outcome after subthalamic nucleus deep brain stimulation (STN-DBS) at the 1-year follow-up. Ninety-three patients diagnosed with Parkinson's disease (PD), who underwent subthalamic nucleus deep brain stimulation (STN-DBS) between April 2020 and August 2021, were included in this study. Demographic information was gathered through a self-designed questionnaire. The severity of both motor and non-motor symptoms, along with the quality of life (QoL), was assessed using the Unified Parkinson's Disease Rating Scale-III (UPDRS-III), Nonmotor Symptoms Scale (NMSS), and 8-item Parkinson's Disease Questionnaire (PDQ-8), respectively. Significant differences were observed in the UPDRS-III score, NMSS summary index (SI), and subscores of six domains (sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, urinary, and sexual function) between the baseline and the 6- and 12-month follow-ups. The correlation analysis revealed positive correlations between the preoperative NMSS SI and subscores of seven domains (cardiovascular, sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, gastrointestinal, and urinary) and ΔPDQ-8. Moreover, the preoperative PDQ-8 SI (β = 0.869, P < 0.001) and the preoperative attention/memory subscore (β = -0.154, P = 0.026) were predictive of the postsurgery improvement in quality of life (QoL). Deep brain stimulation (DBS) led to an improvement in the patients' nonmotor symptoms (NMS) at the 1-year follow-up, along with a correlation observed between NMS and the patients' quality of life (QoL). Notably, the severity of preoperative attention/memory problems emerged as the most significant predictor of NMS influencing the QoL outcome after STN-DBS at the 1-year follow-up.

Age and gender differences in non-motor symptoms in people with Parkinson's disease.

Non-motor symptoms of Parkinson's disease (PD) are highly prevalent and heterogenic. Previous studies aimed to gain more insight on this heterogeneity by investigating age and gender differences in non-motor symptom severity, but findings were inconsistent. Furthermore, besides examining the single effects of age and gender, the interaction between them in relation to non-motor functioning has -as far as we know- not been investigated before. To investigate the association of age and gender identity -as well as the interaction between age and gender identity- with non-motor symptoms and their impact on quality of life. We combined three large and independent studies. This approach resulted in a total number of unique participants of 1,509. We used linear regression models to assess the association of age and gender identity, and their interaction, with non-motor symptoms and their impact on quality of life. Older people with PD generally had worse cognitive functioning, worse autonomic functioning and worse quality of life. Women with PD generally experienced more anxiety, worse autonomic functioning and worse quality of life compared to men with PD, whereas men with PD generally had worse cognitive functioning. In interaction analyses by age and gender identity, depressive symptoms and anxiety were disproportionally worse with increasing age in women compared to men. Our findings indicate that both age and gender -as well as their interaction- are differentially associated with non-motor symptoms of PD. Both research and clinical practice should pay more attention to demographic subgroups differences and possible different treatment approaches with respect to age and gender. We showed how combining datasets is of added value in this kind of analyses and encourage others to use similar approaches.

Associations of serum neuromarkers with clinical features of Parkinson's disease

To evaluate the clinical and laboratory correlation of biomarkers with anti- and pro-apoptotic activity with the severity of motor and non-motor symptoms depending on the progression rate of Parkinson's disease (PD). A wide range of non-motor symptoms (emotional-affective, cognitive, psychotic and behavioral disorders, fatigue, sleep disorders and autonomic disorders) was evaluated using validated scales and a number of serum neuromarkers responsible for neuroplasticity and neuronal survival processes (BDNF, PDGF, cathepsin D) in 71 patients with PD (mean age 65 (55; 70) years, disease duration 7 (4; 9) years, age of onset 57 (49; 62) years). The concentration of biomarkers (BDNF, PDGF and cathepsin D) was the lowest in the group of patients with a rapid PD progression rate (p<0.001, p=0.001 and p=0.031, respectively), the severity of motor and most non-motor symptoms was higher (p=0.023 and p=0.001, respectively) compared to middle and slow progression rate. There were correlations between BDNF concentration and the severity of depression (r=-0.63, p<0.001), apathy (r=-0.48, p<0.001), impulsive behavioral disorders (r=0.500, p<0.001), level of cognitive functions (r=0.54, p<0.001), motor symptoms (r=-0.43, p<0.001); between PDGF level and the severity of motor manifestations of PD (r=-0.30, p=0.011), depression (r=-0.70, p<0.001), apathy (r=-0.460, p<0.001), the degree of severity of behavioral disorders (r=0.742, p<0.001). No significant correlations were observed between the level of cathepsin D and the severity of clinical manifestations of PD, which indicates the connection of cathepsin D with the general pathogenesis of PD. The possibility of using serum proteins of the neurotrophin subfamily and the protein associated with autophagy, cathepsin D, as biomarkers that determine the prognosis of PD, is considered.

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.

Minor hallucinations in Parkinson's disease with probable rapid eye movement sleep behavior disorder.

Rapid eye movement sleep behavior disorder (RBD) and minor hallucinations (MHs) are prevalent nonmotor symptoms in Parkinson's disease (PD). The purpose of this study was to explore the association of MHs in PD patients with probable RBD (pRBD). This cross-sectional study included 291 patients diagnosed with PD. Patients who scored 6 or higher on the Rapid Eye Movement Behavior Disorder (RBD) Screening Questionnaire were defined as pRBD. A comprehensive evaluation was performed for all patients, including the collection of demographic information, clinical assessment, and MH features. Among the 291 PD patients, 69 (23.7%) had pRBD. MHs were observed in 35 (50.7%) patients with pRBD, significantly higher than 29.7% in patients without RBD (p = 0.015). The main type of MHs in pRBD was presence hallucinations with variable content. Patients with pRBD and MHs tended to be older, had a longer disease duration, and were more likely to take levodopa or dopamine-receptor agonists. Besides, the pRBD with MHs group had higher scores on the Nonmotor Symptoms Questionnaire (NMS-Quest) and Hamilton Anxiety Scale (HAMA). Binary logistic regression analysis revealed that longer disease duration and higher NMS-Quest scores were associated with MHs in PD patients with pRBD. A high prevalence of MHs was observed in PD patients with pRBD. The main type of MHs in pRBD was presence hallucinations. MHs in PD with RBD are mainly associated with disease duration and severity of nonmotor symptoms. These findings provide new insights into the interaction between MHs and RBD.

Associations of Nonmotor Symptom Burden, Activities of Daily Living, and Fear of Falling in Parkinson Disease.

BACKGROUND: Parkinson disease (PD), a neurodegenerative disease characterized by motor and nonmotor symptoms, can affect the daily activities of individuals. This study was conducted to determine nonmotor symptom burden in patients with PD and to reveal the relationship of nonmotor symptom burden with activities of daily living and fear of falling. METHODS: This cross-sectional and correlational study was carried out with 309 patients given a diagnosis of PD. The data were collected using a personal information form, the Non-Motor Symptoms Scale, the Katz Activities of Daily Living Scale, and the Fear of Falling Questionnaire. RESULTS: Whereas 70.2% of the patients had very high nonmotor symptom severity levels, 33.7% were semidependent or dependent in terms of performing their activities of daily living. The fear of falling was experienced by 32.7% of the patients. A statistically significant inverse relationship was found between the mean Non-Motor Symptoms Scale scores of the patients and their mean Katz Activities of Daily Living Scale and Fear of Falling Questionnaire scores (P < .05). Nonmotor symptom burden independently explained 66% of the total variance in the performance of activities of daily living and 69% of the total variance in fear of falling (P < .01). CONCLUSION: Nonmotor symptom burden in PD patients is a significant determinant for participation in activities of daily living and fear of falling. Nurses should approach patients with PD with a focus not only on assessing motor symptoms but also on assessing nonmotor symptoms.

Spirituality in Parkinson's Disease within a Sample from the USA.

Spirituality and religious beliefs are important for coping with medical conditions. The dopaminergic system is involved in reward behavior, and its dysfunction in Parkinson Disease (PD) raises questions about religiosity and spirituality in people with PD. This study examines the association between levels of spirituality and religiosity and the severity of PD motor and non-motor symptoms. The secondary aim investigates the perceived impact of PD diagnosis on spirituality and religiosity. This was a cross-sectional analysis of demographic, physical, mental, and spirituality and religiosity status in patients with PD recruited for the Health Outcomes Measurement (HOME) Study at the University of Maryland Parkinson Disease and Movement Disorders Center, Baltimore, USA. Spirituality and religiosity were assessed using the Spiritual Well-being Scale, and the World Health Organization Quality of Life Spiritual Religious and Personal Belief field-test instrument. The sample size was 85 PD patients. The mean age (standard deviation) was 65.5 (9.4) years and 67.1% were male. Higher levels of spirituality and religiosity were associated with younger age, sex (female), less education, religious affiliation (Christian), and mental health status. After adjusting for age, education, gender, race, marital status, religion, physical health, mental health, and comorbidity, only anxiety was associated with all of the spirituality/religiosity assessments. The majority of patients reported no change in their religious or spiritual beliefs following diagnosis. Greater spirituality and religiosity were associated with less anxiety. Also, younger women with PD showed higher levels of spirituality and religiosity. Longitudinal studies on more diverse populations are needed.

Salivary gland immunohistochemistry vs substantia nigra sonography: comparative analysis of diagnostic significance

Introduction. Parkinson's disease (PD) urges for new instrumental methods of diagnosis. Transcranial sonography of the substantia nigra (SN TCS) is an established method for early PD diagnosis but its application is limited. Recently, biopsies (primarily that of salivary gland) and test for abnormal α-synuclein are suggested to verify PD.&#x0D; Materials and methods. We assessed 12 individuals with PD, Hoehn–Yahr 2.3 ± 0.4. The assessments included: UPDRS, NMSQ, NMSS, RBDSQ, PDQ-8, MoCA, and HADS scoring; SN TCS; and sublingual gland immunohistochemistry for phosphorylated α-synuclein (PS-129) with automated morphometric analysis.&#x0D; Results. Substantia nigra hyperechogenicity was shown in 75% of patients whereas biopsy revealed PS-129 in 100% of patients. Echogenic area of the substantia nigra was 0.24 [0.21; 0.3] cm2. PS-129 inclusion area varied from 28.47 [27.55; 96.26] to 238.77 [234.13; 272.49] μm2, and PS-129 proportion varied from 13.4% to 93.4% of the nervous fiber area across the patients. We found relations between PS-129 and NMSQ (r = 0.8; p 0.001), NMSS (r = 0.9; p 0.001), PDQ-8 (r = 0.7; p = 0.003), UPDRS-I (r = 0.7; p = 0.009), UPDRS-II (r = 0.6; p = 0.03), and HADS (anxiety r = 0.8; p = 0.002; depression r = 0.6; p = 0.04) scores.&#x0D; Conclusion. The results demonstrate a higher biopsy sensitivity as compared to SN TCS. Automated morphometric analysis has been newly applied to assess PS-129 occurrence. Immunohistochemistry results are directly related to non-motor symptom severity, which may indicate high probability of PS-129 presence and diagnosis confirmation in early disease.

A descriptive study on symptoms of Parkinson’s disease in an Indian cohort from Karnataka

Introduction and Aim: Parkinson’s Disease (PD) is a multifactorial neurodegenerative disorder with ever-changing motor and nonmotor symptoms. Disease treatment is modified accordingly with the progression of the disease. The present study was carried out to understand the symptoms reported by PD subjects in different phases of the disease.&#x0D; &#x0D; Materials and Methods: Demographic and clinical details were obtained using questionnaires to evaluate the frequency and severity of various motor and nonmotor symptoms experienced by the PD subjects.&#x0D; &#x0D; Results: Ageing was strongly associated with the onset of disease, whereas the BMI category adversely correlated with other motor symptoms (OMS), nonmotor symptoms (NMS), and specifically gastrointestinal symptoms. Tremors were the most troublesome cardinal motor symptoms, followed by stiffness and bradykinesia. The most common NMS were fatigue/tiredness, anxiety/depression, insomnia, constipation, and cognitive impairment. Anxiety and depression were positively associated with other NMS symptoms such as insomnia, fatigue and exhaustion, apathy, and gastrointestinal problems. More than half of our patients reported gastrointestinal discomfort, early satiety, appetite decrease, and bloating. In our present investigation, the most common gastrointestinal symptoms linked with constipation were straining evacuation, lumpy hard stool, and incomplete evacuation.&#x0D; &#x0D; Conclusion: We have analysed the frequency and trend of various symptoms associated with PD in an Indian population from Karnataka. A significant correlation exists between motor and nonmotor symptoms, which impacts the quality of life in PD during the course of the disease.

Seasonal variations of nonmotor symptoms in patients with Parkinson's disease in Southeast China.

Studies suggest seasonal fluctuations of symptoms in Parkinson's disease (PD) patients in Western countries. However, the association between seasonal change and variation in nonmotor symptoms (NMS) in Chinese PD patients is unclear. Here, we studied whether there is a change rule with annual cycle with severity of NMS for patients with PD in Southeast China. We studied 1005 PD patients between April 2008 and October 2020. Patients were classified into four seasons according to the 24 Chinese solar terms, based on assessment date. We compared comprehensive NMS scales and polysomnography parameters among groups and conducted further analysis of disease severity. Among the 1005 patients studied, the mean age was 64.2 ± 9.7 years and 569 (56.6%) of them were men. Relative to the summer group, patients assessed during winter had higher Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction (SCOPA-AUT) scores ( P = 0.045). The sleep efficiency factor scores of Pittsburgh Sleep Quality Index in patients were higher during spring than summer ( P = 0.009). Among patients who completed polysomnography during the same period ( n = 135), compared with summer follow-ups, we observed a higher percentage of NREMS1 in winter and spring follow-ups ( P = 0.042, P = 0.011), a higher NREMS1 time in spring follow-ups ( P = 0.0024), a lower NREMS2 time in winter follow-ups ( P = 0.007), and a higher percentage of phasic RSWA in autumn and winter follow-ups ( P = 0.026 and P = 0.020, respectively). In a subset of patients with PD and REM sleep behavior disorder (RBD; n = 182), those visited during winter had higher scores for RBD questionnaire- Hong Kong and its factor 1 (dream-related sub-score) than those visited during summer ( P = 0.034, P = 0.020). We observed similar findings for SCOPA-AUT and sleep efficiency factor scores in early stage patients in subgroup analysis. PD patients assessed for follow-up during summer showed less severe symptoms of autonomic dysfunction and RBD symptoms than those assessed in winter, and less sleep disturbance than those in spring and winter, suggesting that seasonal change and NMS fluctuation are related, especially in patients with early stage PD.

White and gray matter alterations in de novo PD patients: which matter most?

This paper aimed to identify white matter (WM) and gray matter (GM) abnormalities in a sample of early PD patients, and their correlations with motor and non-motor symptom severity. We enrolled 62 de novo PD patients and 31 healthy subjects. Disease severity and non-motor symptom burden were assessed by the Unified Parkinson's Disease Rating Scale part III and the Non-Motor Symptoms Scale, respectively. Cognitive performance was assessed using Montreal Cognitive Assessment and Frontal Assessment Battery. All subjects underwent a 3-Tesla MRI protocol. MRI analyses included tract-based spatial statistics, cortical thickness, and subcortical and cerebellar volumetry. In comparison to control subjects, PD patients exhibited lower fractional anisotropy and higher mean, axial, and radial diffusivity in most WM bundles, including corticospinal tracts, the internal and external capsule, the anterior and posterior thalamic radiations, the genu and body of the corpus callosum, cerebellar peduncles, and superior and inferior longitudinal and fronto-occipital fasciculi. Correlations between Montreal Cognitive Assessment scores and fractional anisotropy values in the right posterior thalamic radiation, left superior corona radiata, right inferior-fronto-occipital fasciculus, left inferior longitudinal fasciculus, bilateral anterior thalamic radiations, and bilateral superior longitudinal fasciculi were found. Smaller cerebellar volumes in early PD patients in the left and right crus I were also found. No GM changes were present in subcortical or cortical regions. The combined evaluation of WM and GM in the same patient sample demonstrates that WM microstructural abnormalities precede GM structural changes in early PD patients.

A Combined Panel of Salivary Biomarkers in de novo Parkinson's Disease.

To investigate molecular biomarkers of a-synuclein and tau aggregation, autophagy, and inflammation in the saliva of de novo Parkinson's disease (PD) patients in comparison to healthy subjects (HS), and to correlate molecular data with clinical features of PD patients, in order to establish whether abnormalities of these parameters are associated with specific clusters of de novo PD patients, and their potential diagnostic power in differentiating PD patients from HS. We measured total and oligomeric a-synuclein, total-tau and phosphorylated-tau, microtubule-associated protein light chain 3 beta (MAP-LC3beta), and tumor necrosis factor alpha (TNFalpha) in the saliva of 80 de novo PD patients and 62 HS, using quantitative enzyme-linked immunosorbent Assay analysis. Oligomeric a-synuclein, total-tau, MAP-LC3beta, and TNFalpha levels resulted significantly higher in patients with respect to HS, while no significant differences were detected for total a-synuclein or phosphorylated-tau. Phosphorylated-tau directly correlated with MAP-LC3beta, whereas it inversely correlated with TNFalpha in PD patients. An inverse correlation was detected between MAP-LC3beta and non-motor symptoms severity. Principal Component Analysis showed that molecular and clinical parameters were independent of each other in de novo PD patients. Receiver operating characteristic curve analysis reported an accurate diagnostic performance of oligomeric a-synuclein and MAP-LC3beta. The diagnostic accuracy of total a-synuclein increased when it was combined with other salivary biomarkers targeting different molecular pathways. Our study proposes a novel biomarker panel using saliva, a non-invasive biofluid, in de novo PD patients, with implications in understanding the molecular pathways involved in PD pathogenesis and the relevance of different molecular pathways in determining clinical PD subtypes. ANN NEUROL 2023;93:446-459.

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.

The effect of regional white matter hyperintensities on essential tremor subtypes and severity.

To investigate the effect of regional white matter hyperintensities (WMHs) on Essential tremor (ET) subtypes and to explore the association between WMHs load and the severity of motor and non-motor symptoms in patients with ET. A cohort of 176 patients with ET (including 86 patients with pure ET and 90 patients with ET plus) and 91 normal controls (NC) was consecutively recruited. Demographic, clinical, and imaging characteristics were compared between individuals with pure ET, ET plus, and NC. The cross-sectional association among regional WMHs and the severity of tremor and non-motor symptoms were assessed within each group. Compared with the pure ET subgroup, the ET plus subgroup demonstrated higher TETRAS scores, NMSS scores, and lower MMSE scores (all P < 0.05). Periventricular and lobar WMHs' loads of pure ET subgroup intermediated between NC subjects and ET plus subgroup. WMHs in the frontal horn independently increased the odds of ET (OR = 1.784, P < 0.001). The age (P = 0.021), WMHs in the frontal lobe (P = 0.014), and WMHs in the occipital lobe (P = 0.020) showed a significant impact on TETRAS part II scores in the ET plus subgroup. However, only the disease duration was positively associated with TETRAS part II scores in patients with pure ET (P = 0.028). In terms of non-motor symptoms, NMSS scores of total patients with ET were associated with disease duration (P = 0.029), TETRAS part I scores (P = 0.017), and WMH scores in the frontal lobe (P = 0.033). MMSE scores were associated with age (P = 0.027), body mass index (P = 0.006), education level (P < 0.001), and WMHs in the body of the lateral ventricle (P = 0.005). Our results indicated that the WMHs in the frontal horn could lead to an increased risk of developing ET. WMHs may be used to differentiate pure ET and ET plus. Furthermore, WMHs in the frontal and occipital lobes are strong predictors of worse tremor severity in the ET plus subgroup. Regional WMHs are associated with cognitive impairment in patients with ET.