Autonomic dysfunction and white matter microstructural changes in drug-naïve patients with Parkinson’s disease

Background Autonomic dysfunction (AD) is one of the non-motor features of Parkinson’s disease (PD). Some symptoms tend to occur in the early stages of PD. AD also has a great impact on patient’s quality of life. In this study, we aimed to discover the association between AD (Scales for Outcomes in Parkinson’s disease-Autonomic, SCOPA-AUT) and microstructural changes in white matter tracts in drug-naïve early PD patients to elucidate the central effects of autonomic nervous system impairments. Method In total, this study included 85 subjects with PD recruited from the Parkinson’s Progression Markers Initiative (PPMI) database. Among the 85 PD patients, 38 were in Hoehn & Yahr stage 1 (HY1PD) and 47 were in stage 2 (HY2PD). Diffusion magnetic resonance imaging (DMRI) data were reconstructed in the MNI space using q-space diffeomorphic reconstruction to obtain the spin distribution function. The spin distribution function (SDF) values were used in DMRI connectometry analysis. We investigated through diffusion MRI connectometry the structural correlates of white matter tracts with SCOPA-AUT subscores and total score. Results Connectometry analysis also revealed positive association with white matter density in bilateral corticospinal tract in HY1PD patients and negative association in genu of corpus callosum (CC) and, bilateral cingulum in both groups. In addition, there were associations between gastrointestinal, sexual, thermoregulatory and urinary items and structural brain connectivity in PD. Conclusion Our study reveals positive correlation, suggesting neural compensations in early PD. Cingulum and CC tracts have well-known roles in PD pathology, compatible with our findings that bring new insights to specific areas of AD and its role in central nervous system (CNS) neurodegeneration, paving the way for using prodromal makers in the diagnosis and treatment of PD

Longitudinal Alterations of Alpha-Synuclein, Amyloid Beta, Total, and Phosphorylated Tau in Cerebrospinal Fluid and Correlations Between Their Changes in Parkinson's Disease

Background: Parkinson's disease (PD) is characterized by proteinopathies and these proteinopathies seem to interact synergistically and lead to protein aggregations and changes in protein cerebrospinal fluid (CSF) levels. In this study, we aimed to explore the longitudinal changes of CSF a lpha-synuclein (α-syn), total tau (t-tau), phosphorylated tau (p-tau), and beta-amyloid (Aβ1−42) and their relationships with each other and with baseline clinical entities like REM sleep behavior disorder (RBD), cognitive impairment, motor symptoms, and olfaction dysfunction.Method: One hundred and twelve non-demented PD patients and 110 controls were recruited from Parkinson's Progression Markers Initiative (PPMI).We used a linear mixed model within groups to assess longitudinal protein changes over 6 and 12 months and a random regression coefficient within the linear mixed model to investigate the correlation between proteins and their baseline clinical characteristics.Results: P-tau was lower in PDs only at baseline, but during a year, p-tau increased more rapidly in PDs than controls. Aβ1−42 was not significantly different between groups at any separate timepoint; however, when assessed longitudinally, Aβ1−42 showed significant changes in both groups. Conversely, t-tau and α-syn differed significantly between groups, but their longitudinal changes were not significant in either of the groups. Moreover, all proteins' baseline levels, except p-tau, could determine estimated longitudinal tau changes. Baseline RBDSQ scores but not UPDRS III, MoCA, or UPSIT scores were predictive of longitudinal increase in α-syn levels.Conclusion: Longitudinal changes in levels of CSF proteins are related to each other and could help researchers further understand PD pathology. In addition, RBD seems to be a potential prognostic factor for PD progression. However, in order to reach a consensus, longer follow-up times are required

Serum Insulin-Like Growth Factor-1 in Parkinson's Disease; Study of Cerebrospinal Fluid Biomarkers and White Matter Microstructure

Background: Growing evidence shows that impaired signaling of Insulin-like Growth Factor-1 (IGF-1) is associated with neurodegenerative disorders, such as Parkinson's disease (PD). However, there is still controversy regarding its proinflammatory or neuroprotective function. In an attempt to elucidate the contribution of IGF-1 in PD, we aimed to discover the relation between serum IGF-1 levels in drug-naïve early PD patients and cerebrospinal fluid (CSF) biomarkers as well as microstructural changes in brain white matter.Methods: The association between quartiles of serum IGF-1 levels and CSF biomarkers (α-synuclein, dopamine, amyloid-β1−42, total tau, and phosphorylated tau) was investigated using adjusted regression models in 404 drug-naïve early PD patients with only mild motor manifestations and 188 age- and sex-matched healthy controls (HC) enrolled in the Parkinson's Progression Markers Initiative (PPMI). By using region of interest analysis and connectometry approach, we tracked the white matter microstructural integrity and diffusivity patterns in a subgroup of study participants with available diffusion MRI data to investigate the association between subcomponents of neural pathways with serum IGF-1 levels.Results: PD patients had higher levels of IGF-1 compared to HC, although not statistically significant (mean difference: 3.60, P = 0.44). However, after adjustment for possible confounders and correction for False Discovery Rate (FDR), IGF-1 was negatively correlated with CSF α-synuclein, total and phosphorylated tau levels only in PD subjects. The imaging analysis proved a significant negative correlation (FDR corrected P-value = 0.013) between continuous levels of serum IGF-1 in patients with PD and the connectivity, but not integrity, in following fibers while controlling for age, sex, body mass index, depressive symptoms, education years, cognitive status and disease duration: middle cerebellar peduncle, cingulum, genu and splenium of the corpus callosum. No significant association was found between brain white matter microstructral measures or CSF markers of healthy controls and levels of IGF-1.Conclusion: Altered connectivity in specific white matter structures, mainly involved in cognitive and motor deterioration, in association with higher serum IGF-1 levels might propose IGF-1 as a potential associate of worse outcome in response to higher burden of α-synucleinopathy and tauopathy in PD

Use of multidimensional item response theory methods for dementia prevalence prediction : an example using the Health and Retirement Survey and the Aging, Demographics, and Memory Study

Background Data sparsity is a major limitation to estimating national and global dementia burden. Surveys with full diagnostic evaluations of dementia prevalence are prohibitively resource-intensive in many settings. However, validation samples from nationally representative surveys allow for the development of algorithms for the prediction of dementia prevalence nationally. Methods Using cognitive testing data and data on functional limitations from Wave A (2001-2003) of the ADAMS study (n = 744) and the 2000 wave of the HRS study (n = 6358) we estimated a two-dimensional item response theory model to calculate cognition and function scores for all individuals over 70. Based on diagnostic information from the formal clinical adjudication in ADAMS, we fit a logistic regression model for the classification of dementia status using cognition and function scores and applied this algorithm to the full HRS sample to calculate dementia prevalence by age and sex. Results Our algorithm had a cross-validated predictive accuracy of 88% (86-90), and an area under the curve of 0.97 (0.97-0.98) in ADAMS. Prevalence was higher in females than males and increased over age, with a prevalence of 4% (3-4) in individuals 70-79, 11% (9-12) in individuals 80-89 years old, and 28% (22-35) in those 90 and older. Conclusions Our model had similar or better accuracy as compared to previously reviewed algorithms for the prediction of dementia prevalence in HRS, while utilizing more flexible methods. These methods could be more easily generalized and utilized to estimate dementia prevalence in other national surveys

Mapping 123 million neonatal, infant and child deaths between 2000 and 2017

Since 2000, many countries have achieved considerable success in improving child survival, but localized progress remains unclear. To inform efforts towards United Nations Sustainable Development Goal 3.2—to end preventable child deaths by 2030—we need consistently estimated data at the subnational level regarding child mortality rates and trends. Here we quantified, for the period 2000–2017, the subnational variation in mortality rates and number of deaths of neonates, infants and children under 5 years of age within 99 low- and middle-income countries using a geostatistical survival model. We estimated that 32% of children under 5 in these countries lived in districts that had attained rates of 25 or fewer child deaths per 1,000 live births by 2017, and that 58% of child deaths between 2000 and 2017 in these countries could have been averted in the absence of geographical inequality. This study enables the identification of high-mortality clusters, patterns of progress and geographical inequalities to inform appropriate investments and implementations that will help to improve the health of all populations

White Matter Tract Alterations in Drug-Naïve Parkinson’s Disease Patients With Impulse Control Disorders

Impulse control disorders (ICDs) are relatively frequent in patients with Parkinson’s disease (PD), although it is still unclear whether an underlying pathological process plays a significant role in the development of ICD in PD apart from dopaminergic replacement therapy. In this study, we have investigated alterations of white matter tract in drug-naïve PD patients with ICDs via diffusion MRI connectometry. Our results showed that disrupted connectivity in the complex network of dynamic connections between cerebellum, basal ganglia, cortex, and its spinal projections serves as the underlying neuropathology of ICD in PD not interfered with the contribution of dopaminergic replacement therapy. These findings provide the first evidence on involved white matter tracts in the neuropathogenesis of ICD in drug-naïve PD population, supporting the hypothesis that neural disturbances intrinsic to PD may confer an increased risk for ICDs. Future studies are needed to validate the attribution of the impaired corticocerebellar network to impulsivity in PD

Association Between Peripheral Inflammation and DATSCAN Data of the Striatal Nuclei in Different Motor Subtypes of Parkinson Disease

The interplay between peripheral and central inflammation has a significant role in dopaminergic neural death in nigrostriatal pathway, although no direct assessment of inflammation has been performed in relation to dopaminergic neuronal loss in striatal nuclei. In this study, the correlation of neutrophil to lymphocyte ratio (NLR) as a marker of peripheral inflammation to striatal binding ratios (SBRs) of DAT SPECT images in bilateral caudate and putamen nuclei was calculated in 388 drug-naïve early PD patients [288 tremor dominant (TD), 73 postural instability and gait difficulty (PIGD), and 27 indeterminate] and 148 controls. NLR was significantly higher in PD patients than in age- and sex-matched healthy controls, and showed a negative correlation to SBR in bilateral putamen and ipsilateral caudate in all PD subjects. Among our three subgroups, only TD patients showed remarkable results. A positive association between NLR and motor severity was observed in TD subgroup. Besides, NLR could negatively predict the SBR in ipsilateral and contralateral putamen and caudate nuclei in tremulous phenotype. Nonetheless, we found no significant association between NLR and other clinical and imaging findings in PIGD and indeterminate subgroups, supporting the presence of distinct underlying pathologic mechanisms between tremor and non-tremor predominant PD at early stages of the disease

Microstructural Changes in Patients With Parkinson's Disease Comorbid With REM Sleep Behaviour Disorder and Depressive Symptoms

The diagnosis of Parkinson's disease (PD) is currently anchored on clinical motor symptoms, which appear more than 20 years after initiation of the neurotoxicity. Extra-nigral involvement in the onset of PD with probable nonmotor manifestations before the development of motor signs, lead us to the preclinical (asymptomatic) or prodromal stages of the disease (various nonmotor or subtle motor signs). REM sleep behavior disorder (RBD) and depression are established prodromal clinical markers of PD and predict worse motor and cognitive outcomes. Nevertheless, taken by themselves, these markers are not yet claimed to be practical in identifying high-risk individuals. Combining promising markers may be helpful in a reliable diagnosis of early PD. Therefore, we aimed to detect neural correlates of RBD and depression in 93 treatment-naïve and non-demented early PD by means of diffusion MRI connectometry. Comparing four groups of PD patients with or without comorbid RBD and/or depressive symptoms with each other and with 31 healthy controls, we found that these two non-motor symptoms are associated with lower connectivity in several white matter tracts including the cerebellar peduncles, corpus callosum and long association fibers such as cingulum, fornix, and inferior longitudinal fasciculus. For the first time, we were able to detect the involvement of short association fibers (U-fibers) in PD neurodegenerative process. Longitudinal studies on larger sample groups are needed to further investigate the reported associations