Abnormal topological organization of structural covariance networks in early-stage Parkinson’s disease patients with autonomic dysfunction

Purpose Autonomic dysfunction is a common nonmotor feature and early manifestation of Parkinsons disease (PD). Autonomic dysfunction in PD is associated with a worse prognosis. We sought to characterize autonomic dysfunction and identify associated factors in patients with early PD. Methods An observational, cross-sectional, descriptive, and analytical study was conducted to evaluate patients with early PD from the Parkinsons Progression Markers Initiative. We utilized the Scales for Outcomes in Parkinsons Disease-Autonomic dysfunction questionnaire to determine the prevalence and frequencies of autonomic symptomatology. The cohort was grouped into high and low dysautonomic scores. A regression model identified variables that independently explained dysautonomic scores in our early PD cohort. Results 414 PD patients had a mean age of 61.1 (SD 9.7) years at diagnosis and mean disease duration of 6.7 (SD 6.6) months. Among all patients, 43.7% (181/414) had high dysautonomic scores. Urinary and gastrointestinal symptoms were the most prevalent and frequently reported dysautonomic symptoms. Patients with fatigue (beta = 4.28, p < 0.001), probable rapid eye movement sleep behavior disorder (beta = 2.71, p < 0.001), excessive daytime sleepiness (beta = 1.88,p=0.039), impulsivity and compulsivity (beta = 2.42, p < 0.001), and increasing age (beta = 1.05, p < 0.001) were more likely to have high dysautonomic scores. Conclusion Lower urinary tract and gastrointestinal symptoms are prevalent and frequent in early PD patients. Fatigue, sleep disorders, impulsivity and compulsivity, and age are predictors of autonomic dysfunction. Autonomic symptoms predominated in this group of early PD patients in the disease course and were associated with more severe disease.

ABSTRACTCognitive impairment (CI) is among the most common non-motor symptoms of Parkinson’s disease (PD), with a substantially negative impact on patient management and outcome. The development and progression of CI exhibits high interindividual variability, which requires better diagnostic and monitoring strategies. PD patients often display sweating disorders resulting from autonomic dysfunction, which has been associated with CI. Because the axillary microbiota is known to change with humidity level and sweat composition, we hypothesized that the axillary microbiota of PD patients shifts in association with CI progression, and thus can be used as a proxy for classification of CI stages in PD. We compared the axillary microbiota compositions of 103 PD patients (55 PD patients with dementia [PDD] and 48 PD patients with mild cognitive impairment [PD-MCI]) and 26 cognitively normal healthy controls (HC). We found that axillary microbiota profiles differentiate HC, PD-MCI, and PDD groups based on differential ranking analysis, and detected an increasing trend in the log ratio of Corynebacterium to Anaerococcus in progression from HC to PDD. In addition, phylogenetic factorization revealed that the depletion of the Anaerococcus, Peptoniphilus, and W5053 genera is associated with PD-MCI and PDD. Moreover, functional predictions suggested significant increases in myo-inositol degradation, ergothioneine biosynthesis, propionate biosynthesis, menaquinone biosynthesis, and the proportion of aerobic bacteria and biofilm formation capacity, in parallel to increasing CI. Our results suggest that alterations in axillary microbiota are associated with CI in PD. Thus, axillary microbiota has the potential to be exploited as a noninvasive tool in the development of novel strategies.IMPORTANCE Parkinson's disease (PD) is the second most common neurodegenerative disease. Cognitive impairment (CI) in PD has significant negative impacts on life quality of patients. The emergence and progression of cognitive impairment shows high variability among PD patients, and thus requires better diagnostic and monitoring strategies. Recent findings indicate a close link between autonomic dysfunction and cognitive impairment. Since thermoregulatory dysfunction and skin changes are among the main manifestations of autonomic dysfunction in PD, we hypothesized that alterations in the axillary microbiota may be useful for tracking cognitive impairment stages in PD. To our knowledge, this the first study characterizing the axillary microbiota of PD patients and exploring its association with cognitive impairment stages in PD. Future studies should include larger cohorts and multicenter studies to validate our results and investigate potential biological mechanisms.

Objective To assess the value of detecting sympathetic skin response (SSR) in the diagnosis of autonomic dysfunction in patients with Parkinson disease (PD). Methods SSR measurement was performed in 47 PD patients and 20 healthy control subjects and the results were compared. The SSR was also comparatively analyzed between patients with and those without autonomic dysfimction. Results Compared with the healthy controls, the PD patients showed significantly lowered mean amplitude (2.56±1.47 vs 1.87±0.26, P<0.05) and prolonged latency (1.42±0.29 vs 1.55± 0.18, P<0.05) of the SSR in the upper limbs, with also lowered mean amplitude (0.76±0.39 vs 0.49±0.21, P<0.05) and prolonged latency (2.04±0.27 vs 2.13±0.16, P<0.05) in the lower limbs. Compared with the PD patients without autonomic dysfunction, those having autonomic dysfunction showed significantly lowered mean amplitude (1.89±0.33 vs 1.75±0.21, P<0.05) and prolonged latency (1.53±0.15 vs 1.56±0.17, P<0.05) of SSR in the upper limbs and lowered mean amplitude (0.51±0.17 vs 0.46±0.20,P<0.05) and prolonged latency (2.08±0.24 vs 2.17±0.18, P<0.05) in the lower limbs. Conclusion The results of SSR measurements are consistent with the clinical manifestations of the PD patients. SSR can be of value in the diagnosis of autonomic nerve dysfunction in PD. Key words: Parkinson's diease; Sympathetic skin response; Autonomic nerve dysfunction

Patients with Parkinson's disease (PD) present with a broad spectrum of nonmotor features including autonomic disorders. More severe autonomic dysfunction in PD is associated with increased cognitive deficits. The presence of cerebral small-vessel disease, measured by T2-weighted magnetic resonance imaging white matter hyperintensity (WMH) burden, is also observed in patients with PD with faster cognitive decline. To investigate whether baseline orthostatic hypotension and autonomic dysfunction in early-stage PD affect later cognitive decline via mediation through cerebral small-vessel disease. De novo PD patients (N = 365) and age-matched controls (N = 174) with baseline T2-weighted/ fluid-attenuated inversion recovery scans were selected from the Parkinson's Progression Markers Initiative. WMHs were automatically segmented. Mediation analysis was used to assess whether WMH load mediates the effect of orthostatic hypotension and autonomic dysfunction (measured by Scales for Outcomes in Parkinson's Disease-Autonomic) on future cognitive decline (measured by Montreal Cognitive Assessment) in an average of 4 years of follow-up. Mediation analysis supported the existence of a full mediation of WMHs on the effect of diastolic orthostatic hypotension in patients with PD and future cognitive decline (average causal mediation effect: ab = -0.032, 95% confidence interval = -0.064 to -0.01, P = 0.01). There was also a partial mediation for overall autonomic dysfunction (ab = -0.027, 95% confidence interval = -0.054 to 0.00, P = 0.02). WMHs fully mediate the effect of diastolic orthostatic hypotension and partially mediate the effect of autonomic dysregulation on future cognitive decline in patients with PD. Our findings support the hypothesis that autonomic dysfunction in early clinical stages predisposes the brain to WMHs through dysregulation of the blood flow in the small vessels. This in turn increases the risk of future cognitive impairment in early PD.

Cardiovascular dysautonomia in de novo Parkinson's disease

Parkinson disease has traditionally been classified as a movement disorder, despite patients' accounts of diverse symptoms stemming from impairments in numerous body systems. Today, Parkinson disease is increasingly recognized by clinicians and scientists as a complex neurodegenerative disorder featuring both motor and nonmotor manifestations concomitant with pathology throughout all major branches of the nervous system. Dysfunction of the autonomic nervous system, or dysautonomia, is a common feature of Parkinson disease. It produces signs and symptoms that severely affect patients' quality of life, such as blood pressure dysregulation, hyperhidrosis, and constipation. Treatment options for dysautonomia are limited to symptom alleviation because the cause of these symptoms and Parkinson disease overall are still unknown. Animal models provide a platform to interrogate mechanisms of Parkinson disease-related autonomic nervous system dysfunction and test novel treatment strategies. Several animal models of Parkinson disease are available, each with different effects on the autonomic nervous system. This review critically analyses key dysautonomia signs and symptoms and associated pathology in Parkinson disease patients and relevant findings in animal models. We focus on the cardiovascular system, adrenal medulla, skin/thermoregulation, bladder, pupils, and gastrointestinal tract, to assess the contribution of animal models to the understanding of Parkinson disease autonomic dysfunction.

Differentiation of Parkinson’s disease and multiple system atrophy in early disease stages by means of I-123-MIBG–SPECT

Dysautonomia is common in patients with Parkinson disease (PD) since disease early phase. Scales for Outcomes in Parkinson's disease – Autonomic (SCOPA-AUT) is a well-designed scale assessing the autonomic dysfunctions of PD patients. Our objectives were to examine the autonomic dysfunction in PD and scan without evidence of dopaminergic deficit (SWEDD) patients and to assess the correlation of autonomic dysfunctions with cerebrospinal fluid (CSF) biomarkers.An analysis of the Parkinson's Progression Markers Initiative (PPMI) data including 414 PD patients, 60 SWEDD patients, and 170 healthy controls (HCs) with baseline CSF biomarker measurements and SCOPA-AUT assessments was presented. Autonomic symptoms including gastrointestinal, urinary, cardiovascular, pupillomotor, thermoregulatory and sexual dysfunctions were assessed by SCOPA-AUT scales. Spearman correlation test was used to examine the correlations between CSF measurements and each section of SCOPA-AUT scales in HCs and subjects with PD or SWEDD.More severe autonomic dysfunctions were observed in patients with SWEDD than those with PD (P < .001). Specifically, patients with PD have lower scores on the urinary scale [4 (0–17) vs 5 (1–18)], pupillomotor scale [0 (0–3) vs 0 (0–3)], thermoregulatory scale [0 (0–4) vs 1.5 (0–10)] and sexual scale [1 (0–6) vs 2 (0–6)] compared with SWEDD patients. Thermoregulatory dysfunction scores were found correlated with CSF α-syn levels in SWEDD group, and gastrointestinal dysfunction scores were correlated with CSF Abeta1–42 in PD group. Additionally, urinary dysfunction scores were correlated with CSF total tau and tau phosphorylated at threonine 181(p-tau181) levels in both HCs and PD patients.

Specific MR sequences have been able to identify the loss of neuromelanin in the substantia nigra (SN) of early stage Parkinson's disease (PD) patients. Since this technique may have a significant impact in clinical patient management, easy and widely available imaging analysis is needed for routine use. In this study we compared a quantitative analysis with a visual assessment of SN neuromelanin-sensitive MR images in early stage PD patients, in terms of pattern changes recognition and diagnostic accuracy. The inclusion criteria were untreated "de novo" PD patients or a 2-5 year PD duration; in addition, age matched controls were enrolled. These were studied with a high-resolution T1-weighted MR imaging sequence at 3.0 Tesla to visualize neuromelanin. The primary outcome was the comparison of quantitative width measurement with visual assessment by experienced neuroradiologists of SN neuromelanin sensitive MR images for PD diagnosis. A total of 12 "de novo" PD patients, 10 PD patients with 2-5 year disease duration and 10 healthy controls were evaluated. We obtained a good accuracy in discriminating early-stage PD patients from controls using either a quantitative width measurement of the T1 high signal or a simple visual image inspection of the SN region. Visual inspection of neuromelanin-sensitive MR images by experienced neuroradiologists provides comparable results to quantitative width measurement in the detection of early stage PD SN changes and may become a useful tool in clinical practice.

Neurodegenerative change in the central nervous system has been suggested as one of the pathophysiological mechanisms of autonomic nervous system dysfunction in Parkinson’s disease (PD). We analyzed gray matter (GM) volume changes and clinical parameters in patients with PD to investigate any involvement in the brain structures responsible for autonomic control in patients with PD having orthostatic hypotension (OH). Voxel-based morphometry was applied to compare regional GM volumes between PD patients with and without OH. Multivariate logistic regression analysis using a hierarchical model was carried out to identify clinical factors independently contributing to the regional GM volume changes in PD patients with OH. The Sobel test was used to analyze mediation effects between the independent contributing factors to the GM volume changes. PD patients with OH had more severe autonomic dysfunction and reduction in volume in the right inferior temporal cortex than those without OH. The right inferior temporal volume was positively correlated with the Qualitative Scoring MMSE Pentagon Test (QSPT) score, reflecting visuospatial/visuoperceptual function, and negatively correlated with the Composite Autonomic Severity Score (CASS). The CASS and QSPT scores were found to be factors independently contributing to regional volume changes in the right inferior temporal cortex. The QSPT score was identified as a mediator in which regional GM volume predicts the CASS. Our findings suggest that a decrease in the visuospatial/visuoperceptual process may be involved in the presentation of autonomic nervous system dysfunction in PD patients.

Chapter 43 - Thermoregulation in Parkinson disease

Although literature suggests that exercise can improve symptoms in Parkinson's Disease (PD) patients, research on the effects of aerobic exercise and resistance training (AE&RT) in early-stage PD remains limited. Understanding the synergistic effects of these exercise modalities can provide valuable insights for optimizing exercise interventions for PD patients, particularly in the early stages of the disease, where interventions may have the greatest impact on long-term functional outcomes. This study aimed to investigate the effects of a combined AE&RT program on motor function, postural stability, and cognitive processing speed in early stage PD patients. A total of 236 participants with early-stage PD were assigned to either the Aerobic Exercise Group (AE group) (n= 112) or the AE&RT Group (n= 124) inthis controlled randomized trial. The study employed a one-year supervised exercise program, with the AE Group participating in aerobic activities and the AE&RT Group engaging in combined AE&RT. Outcome measures included symptom improvement, motor function, postural stability, cognitive processing speed, peak oxygen consumption, quality of life evaluation, and the incidence of adverse events. The AE&RT Group demonstrated greater improvements in tremor, muscle rigidity, gait instability, sleep problems, and hyposmia compared to the AE Group. Additionally, the combined exercise group exhibited better cognitive processing speed, as well as enhanced motor function and postural stability. Peak oxygen consumption was significantly higher in the AE&RT Group. However, the quality of life evaluation indicated a statistically higher quality of life in the AE Group. There was no significant difference in the incidence of adverse events between the two groups. The findings suggest that the integration of AE&RT in early-stage PD patients leads to more comprehensive improvements in motor symptoms, cognitive function, postural stability, and cardiovascular fitness compared to aerobic exercise alone. These results have important implications for developing tailored exercise interventions to enhance the physical and cognitive well-being of individuals with early-stage PD.

Parkinson’s disease (PD) is a neurodegenerative disease with heterogeneous pathological and clinical features. Cognitive dysfunction, a frequent non-motor complication, is a risk factor for poor prognosis and shows inter-individual variation in its progression. Of the clinical studies performed to identify biomarkers of PD progression, the Parkinson’s Progression Markers Initiative (PPMI) study is the largest study that enrolled drug-naïve and very early stage PD patients. The baseline characteristics of the PPMI cohort were recently published. The diagnostic utility of cerebrospinal fluid (CSF) biomarkers, including alpha-synuclein (α-syn), total tau, phosphorylated tau at Thr181, and amyloid β1-42, was not satisfactory. However, the baseline data on CSF biomarkers in the PPMI study suggested that the measurement of the CSF biomarkers enables the prediction of future cognitive decline in PD patients, which was consistent with previous studies. To prove the hypothesis that the interaction between Alzheimer’s pathology and α-syn pathology is important to the progression of cognitive dysfunction in PD, longitudinal observational studies must be followed. In this review, the neuropathological nature of heterogeneous cognitive decline in PD is briefly discussed, followed by a summarized interpretation of baseline CSF biomarkers derived from the data in the PPMI study. The combination of clinical, biochemical, genetic and imaging biomarkers of PD constitutes a feasible strategy to predict the heterogeneous progression of PD.

Insulin-like growth factor in Parkinson’s disease is related to nonmotor symptoms and the volume of specific brain areas

Over the past two decades, the development of functional imaging methods has greatly promoted our understanding on the changes of neurons following neurodegenerative disorders, such as Parkinson's disease (PD). The application of a spatial covariance analysis on 18F-FDG PET imaging has led to the identification of a distinctive disease-related metabolic pattern. This pattern has proven to be useful in clinical diagnosis, disease progression monitoring as well as assessment of the neuronal changes before and after clinical treatment. It may potentially serve as an objective biomarker on disease progression monitoring, assessment, histological and functional evaluation of related diseases. PD is one of the most common neurodegenerative disorders in the elderly. It is characterized by progressive loss of dopamine neurons in the substantia nigra pars compacta. Throughout the course of disease, the most obvious symptoms are movement-related, such as resting tremor, muscle rigidity, hypokinesia and postural instability (Worth, 2013). Currently, a definite diagnosis of PD is made by clinical evaluation with at least 2 years of follow-up (Hughes et al., 2002; Bhidayasiri and Reichmann, 2013), due to the overlap of motor symptoms between early PD and atypical parkinsonism including multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). However, this classic diagnostic criterion does not benefit the early diagnosis of disease. The prognostic outcome and treatment option are substantially different between PD and atypical parkinsonism. Thus it is critical to develop biomarkers for earlier and more accurate diagnosis of PD. Generally, appropriate diagnostic biomarker for PD ought to cover several key characteristics: (i) minimal invasiveness to detect the biomarker in easily accessible body tissue or fluids, (ii) excellent sensitivity to explore the patients with PD, (iii) high specificity to prevent false-positive results in PD-free individuals, and (iv) robustness against potential affecting factors. A PD-related spatial covariance pattern (PDRP) with quantifiable expression on 18F-FDG PET imaging has been gradually detected using a spatial covariance method during the last two decades and it has been demonstrated to be the right diagnostic biomarker for PD (Eidelberg et al., 1994). PDRP has proven not only to be effective in early discrimination of PD from atypical parkinsonian disorders, but also to be able to assess the disease progression and treatment response. Thus it is considered as a multifunctional biomarker. In this review, we aim to provide an overview of the development in pattern-based biomarker for PD.