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Background: Using 11C‐(R)‐PK11195‐PET, we found increased microglia activation in isolated REM sleep behavior disorder (iRBD) patients. Their role remains to be clarified. Objectives: The objective is to assess relationships between activated microglia and progression of nigrostriatal dysfunction in iRBD. Methods: Fifteen iRBD patients previously scanned with 11C‐(R)‐PK11195 and 18F‐DOPA‐PET underwent repeat 18F‐DOPA‐PET after 3 years. 18F‐DOPA Ki changes from baseline were evaluated with volumes‐of‐interest and voxel‐based analyses. Results: Significant 18F‐DOPA Ki reductions were found in putamen and caudate. Reductions were larger and more widespread in patients with increased nigral microglia activation at baseline. Left nigral 11C‐(R)‐PK11195 binding at baseline was a predictor of 18F‐DOPA Ki reduction in left caudate (coef = −0.0426, P = 0.016). Conclusions: Subjects with increased baseline 11C‐(R)‐PK11195 binding have greater changes in nigrostriatal function, suggesting a detrimental rather than protective effect of microglial activation. Alternatively, both phenomena occur in patients with prominent nigrostriatal dysfunction without a causative link. The clinical and therapeutic implications of these findings need further elucidation. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Patients with Lewy body diseases exhibit variable degrees of cortical and subcortical hypometabolism. However, the underlying causes behind this progressive hypometabolism remain unresolved. Generalized synaptic degeneration may be one key contributor. Objective: The objective of this study was to investigate whether local cortical synaptic loss is proportionally linked to the magnitude of hypometabolism in Lewy body disease. Method: Using in vivo positron emission tomography (PET) we investigated cerebral glucose metabolism and quantified the density of cerebral synapses, as measured with [18F]fluorodeoxyglucose ([18F]FDG) PET and [11C]UCB‐J, respectively. Volumes‐of‐interest were defined on magnetic resonance T1 scans and regional standard uptake value ratios‐1 values were obtained for 14 pre‐selected brain regions. Between‐group comparisons were conducted at voxel‐level. Results: We observed regional differences in both synaptic density and cerebral glucose consumption in our cohorts of non‐demented and demented patients with Parkinson's disease or dementia with Lewy bodies compared to healthy subjects. Additionally, voxel‐wise comparisons showed a clear difference in cortical regions between demented patients and controls for both tracers. Importantly, our findings strongly suggested that the magnitude of reduced glucose uptake exceeded the magnitude of reduced cortical synaptic density. Conclusion: Here, we investigated the relationship between in vivo glucose uptake and the magnitude of synaptic density as measured using [18F]FDG PET and [11C]UCB‐J PET in Lewy body patients. The magnitude of reduced [18F]FDG uptake was greater than the corresponding decline in [11C]UCB‐J binding. Therefore, the progressive hypometabolism seen in Lewy body disorders cannot be fully explained by generalized synaptic degeneration. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Gait impairments are characteristic motor manifestations and significant predictors of poor quality of life in Parkinson's disease (PD). Neuroimaging biomarkers for gait impairments in PD could facilitate effective interventions to improve these symptoms and are highly warranted. Objective: The aim of this study was to identify neural networks of discrete gait impairments in PD. Methods: Fifty‐five participants with early‐stage PD and 20 age‐matched healthy volunteers underwent quantitative gait assessment deriving 12 discrete spatiotemporal gait characteristics and [18F]‐2‐fluoro‐2‐deoxyglucose‐positron emission tomography measuring resting cerebral glucose metabolism. A multivariate spatial covariance approach was used to identify metabolic brain networks that were related to discrete gait characteristics in PD. Results: In PD, we identified two metabolic gait‐related covariance networks. The first correlated with mean step velocity and mean step length (pace gait network), which involved relatively increased and decreased metabolism in frontal cortices, including the dorsolateral prefrontal and orbital frontal, insula, supplementary motor area, ventrolateral thalamus, cerebellum, and cuneus. The second correlated with swing time variability and step time variability (temporal variability gait network), which included relatively increased and decreased metabolism in sensorimotor, superior parietal cortex, basal ganglia, insula, hippocampus, red nucleus, and mediodorsal thalamus. Expression of both networks was significantly elevated in participants with PD relative to healthy volunteers and were not related to levodopa dosage or motor severity. Conclusions: We have identified two novel gait‐related brain networks of altered glucose metabolism at rest. These gait networks could serve as a potential neuroimaging biomarker of gait impairments in PD and facilitate development of therapeutic strategies for these disabling symptoms. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Glucocerebrosidase gene mutations are a common genetic risk factor for Parkinson's disease. They exhibit incomplete penetrance. The objective of the present study was to measure microglial activation and dopamine integrity in glucocerebrosidase gene mutation carriers without Parkinson's disease compared to controls. Methods: We performed PET scans on 9 glucocerebrosidase gene mutation carriers without Parkinson's disease and 29 age‐matched controls. We measured microglial activation as 11C‐(R)‐PK11195 binding potentials, and dopamine terminal integrity with 18F‐dopa influx constants. Results: The 11C‐(R)‐PK11195 binding potential was increased in the substantia nigra of glucocerebrosidase gene carriers compared with controls (Student t test; right, t = −4.45, P = 0.0001). Statistical parametric mapping also localized significantly increased 11C‐(R)‐PK11195 binding potential in the occipital and temporal lobes, cerebellum, hippocampus, and mesencephalon. The degree of hyposmia correlated with nigral 11C‐(R)‐PK11195 regional binding potentials (Spearman's rank, P = 0.0066). Mean striatal 18F‐dopa uptake was similar to healthy controls. Conclusions: In vivo 11C‐(R)‐PK11195 PET imaging detects neuroinflammation in brain regions susceptible to Lewy pathology in glucocerebrosidase gene mutation carriers without Parkinson's. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Reduced noradrenaline levels have been reported to occur in the motor cortices of PD patients postmortem. Imaging techniques have recently become available to specifically study noradrenergic terminal function in vivo using PET. The objective of this study was to evaluate cortical 11 C-MeNER binding in PD patients. Thirty PD patients and 12 healthy control subjects comparable in age, sex, and cognitive performance underwent PET imaging with 11 C-MeNER, a specific ligand of the noradrenaline transporter. Cortical noradrenaline transporter binding was compared at a voxel level using Statistical Parametric Mapping, whereas cortical thickness was assessed using FreeSurfer software with MRI. PD patients showed reduced 11 C-MeNER binding in the primary motor cortex unrelated to cortical thickness; other cortical regions did not differ between groups. In a subgroup analysis, patients with higher Hoehn & Yahr stage exhibited more pronounced 11 C-MeNER binding reductions. Loss of cortical noradrenergic projections to the primary motor cortex occurs in PD associated with disease stage. © 2018 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Despite enormous advances in our current understanding of PD since James Parkinson described the "shaking palsy" 200 years ago, l-dopa, in clinical use since the 1960s, remains the gold standard of treatment. Virtually every patient with PD requires varying doses of l-dopa to manage motor and some nonmotor symptoms and retain an acceptable quality of life. However, after a period of treatment with l-dopa, a number of problems emerge; the key ones are motor and nonmotor fluctuations, a range of dyskinesias, and a combination of both. Nonmotor complications can range from behavioral problems to sensory, autonomic, and cognitive issues. Even with a wealth of data, both in animal models and in vivo imaging that address the pathophysiology of l-dopa-related motor and nonmotor complications, the treatment remains challenging and is an unmet need. Although refinement in types of dopamine replacement therapy and delivery systems have improved the management of l-dopa-related complications, the search for the ideal treatment continues. © 2018 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease copathology is common in PD at autopsy. In non-PD subjects with mild cognitive impairment, tau depositions can be detected using 18F-AV-1451 PET. We hypothesized that 18F-AV-1451 PET would show tau aggregation in PD with mild cognitive impairment and correlate with cognitive dysfunction.Objectives: To describe tau aggregation in PD patients.Methods: Twenty-six PD patients and 23 controls had 18F-AV-1451 PET and neuropsychological assessment to detect mild cognitive impairment.Results: Nine PD patients (35%) were identified with mild cognitive impairment. Regional analyses showed no significant differences between groups. Voxel-wise analyses showed no correlation with cognitive domain z-scores within patients. One patient with mild cognitive impairment was estimated Braak tau stage 5; all other patients were stage 0.Conclusion: Our results indicate that tau pathology, as detected by 18F-AV-1451, is uncommon in PD with mild cognitive impairment and shows no significant correlation with cognitive dysfunction at this stage. © 2017 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to investigate in vivo the ability of levodopa/carbidopa intestinal gel infusions to produce sustained striatal dopamine levels and to improve clinical outcomes in Parkinson's disease patients.Methods: Six advanced Parkinson's disease patients had serial [11 C]raclopride PET to assess levodopa/carbidopa intestinal gel infusion-induced rises in striatal dopamine as reflected by a fall in dopamine-D2/3 receptor availability. Parkinson's disease patients had baseline scan OFF-dopaminergic stimulation and 2 scans following initiation of levodopa/carbidopa intestinal gel infusions. Striatal D2/3 binding was measured in striatal subregions corresponding to sensorimotor, limbic, and cognitive/associative function.Results: Mean striatal [11 C]raclopride nondisplaceable binding potential decreased by 14.0% to 16.7% in sensorimotor, 12.0%-14.4% in limbic, and 8.7%-11.6% in cognitive/associative function subregions at 1- to 10-hour points (P < 0.01). Sensorimotor subregion [11 C]raclopride nondisplaceable binding potential reductions correlated with reductions in Unified Parkinson's Disease Rating Scale Part III scores over the course of the infusion (r = 0.81; P < 0.05).Conclusions: Levodopa/carbidopa intestinal gel infusions generate a stable rise in striatal dopamine levels and are associated with improvements in motor manifestations. © 2016 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Recent studies have suggested that melatonin-a hormone produced by the pineal gland under circadian control-contributes to PD-related sleep dysfunction. We hypothesized that degenerative changes to the neural structures controlling pineal function (especially the suprachiasmatic nuclei of the anterior hypothalamus) may be responsible for reduced melatonin output in these patients. We compared hypothalamic volumes in PD patients with matched controls and determined whether volume loss correlated with reduced melatonin output in the PD group.Methods: A total of 12 PD patients and 12 matched controls underwent magnetic resonance imaging to determine hypothalamic volume. In addition, PD patients underwent 24-hour blood sampling in a controlled environment to determine serum melatonin concentrations using enzyme-linked immunosorbent assays.Results: PD patients had significantly reduced hypothalamic gray matter volume when compared with matched controls. Melatonin levels were significantly associated with hypothalamic gray matter volume and disease severity in PD patients.Conclusion: Melatonin levels are associated with hypothalamic gray matter volume loss and disease severity in PD patients. This provides anatomical and physiological support for an intrinsic sleep and circadian phenotype in PD. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Ten to fifteen percent of Parkinson's disease (PD) patients recruited to clinical trials have scans without evidence of dopaminergic deficit, whose presence represents a heterogeneous patient population.Methods: A cohort of 41 patients with parkinsonism and scans without evidence of dopaminergic deficit at baseline, were subdivided into groups according to their final clinical diagnoses and nigrostriatal dopamine function assessed after 2 years of study. At follow up, 23 patients had clinically probable PD or unclassified parkinsonism with normal nigrostriatal dopamine imaging ("true" scans without evidence of dopaminergic deficit), nine were diagnosed with another tremulous condition, five had psychogenic parkinsonism, and four had phenoconverted to PD with reduced nigrostriatal dopamine function. We analyzed nonmotor symptoms at baseline and follow-up in subgroups of patients with scans without evidence of dopaminergic deficit in comparison with a random sample of 62 PD patients and 195 healthy controls (HCs). All patients were enrolled in the Parkinson's Progressive Marker's Initiative.Results: Patients who had true scans without evidence of dopaminergic deficit had more severe rapid eye movement sleep disorder, depression, anxiety, and autonomic dysfunction than HCs in addition to more frequent depressive symptoms and worse cardiovascular dysfunction than patients with PD (P = 0.038, P = 0.047, respectively). Patients with true scans without evidence of dopaminergic deficit had normal olfaction that was significantly better than that of patients with PD (P < 0.001). Subgroup analysis of the cohort with scans without evidence of dopaminergic deficit revealed that all patients shared similar nonmotor features irrespective of their final clinical diagnoses. Follow-up of subject groups showed stable nonmotor symptoms over 2 years of study.Conclusions: At an early symptomatic stage, patients with scans without evidence of dopaminergic deficit and long-standing parkinsonism exhibit nonmotor features that differ from those of patients with PD on mood and cardiovascular and olfactory function, but remain similar to patients with scans without evidence of dopaminergic deficit with alternative final diagnoses. [ABSTRACT FROM AUTHOR]

Background: The aim of this work was to investigate the cortical and white matter changes that underlie cognitive impairment in patients with incident Parkinson's disease (PD) disease using voxel-based morphometry and diffusion tensor imaging.Methods: Newly diagnosed nondemented PD (n = 125) and control subjects (n = 50) were recruited from the Incidence of Cognitive Impairment in Cohorts with Longitudinal Evaluation in Parkinson's Disease Study and completed cognitive assessments and 3T structural and diffusion tensor MR imaging. Voxel-based morphometry was performed to investigate the relationship between gray matter volume and cognitive ability. Microstructural white matter changes were assessed with diffusion tensor imaging measures of fractional anisotropy and mean diffusivity using tract-based spatial statistics.Results: Increased mean diffusivity was observed bilaterally in subjects with PD, relative to controls (P = 0.019). Increased mean diffusivity was associated with performance on the semantic fluency and Tower of London tasks in frontal and parietal white matter tracts, including the cingulum, superior longitudinal fasciculus, inferior longitudinal fasciculus, and inferior fronto-occipital fasciculus. There was no difference in total gray matter volume between groups; however, bilateral reductions in frontal and parietal gray matter volume were associated with reduced performance on measures of executive function in PD subjects.Conclusions: At the earliest stages of PD, regionally specific increases in central white matter mean diffusivity are present and suggest early axonal damage. Such changes are not accompanied by significant gray matter volume loss and are consistent with proposed models of pathological progression of the disease. Structural MRI, especially diffusion tensor imaging analysis, offers potential as a noninvasive biomarker reflecting cognitive impairment in PD. [ABSTRACT FROM AUTHOR]

ABSTRACT Cognitive decline is common in Parkinson's disease (PD), even in the early motor stage, and this non-motor feature impacts quality of life and prognosis tremendously. In this article, we discuss marker candidates for cognitive decline in PD from different angles, including functional and structural imaging techniques, biological fluid markers in cerebrospinal fluid, and blood genetic predictors, as well as gait as a surrogate marker of cognitive decline. Specifically, imaging-based markers of cognitive impairment in PD include cortical atrophy, reduced cortical metabolism, loss of cortical cholinergic and frontal dopaminergic function, as well as an increased cortical amyloid load. Reduced β-amyloid(1-42) in cerebrospinal fluid and lower plasma levels of epidermal growth factor are predictors for cognitive decline in PD. In addition, genetic variation in the apolipoprotein E ( APOE), catechol-O-methyltransferase ( COMT), microtubule-associated protein tau ( MAPT), and glucocerebrosidase ( GBA) genes may confer risk for cognitive impairment in PD; and gait disturbance may also indicate an increased risk for dementia. Other marker candidates have been proposed and are discussed. All of the current studies are hampered by gaps in our knowledge about the molecular causes of cognitive decline, which will have to be considered in future biomarker studies. © 2014 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

ABSTRACT Nonmotor symptoms (NMS) are common in patients with established Parkinson's disease (PD) and have a major impact upon quality of life. We investigated the significance of NMS in relation to health-related quality of life (HRQoL) in patients with newly diagnosed PD. Patients and healthy controls were recruited as part of the Incidence of Cognitive Impairment in Cohorts with Longitudinal Evaluation in Parkinson's Disease Study. Prevalence of NMS was determined with the Non-Motor Symptom Questionnaire. HRQoL was recorded with the 39-item Parkinson's Disease Quality of Life Questionnaire (PDQ-39). Further assessments included measures of motor disability, depression, sleep, and cognition. One hundred and fifty-eight patients with newly diagnosed PD and 99 controls participated in this cross-sectional study. Patients reported greater numbers of NMS than controls (mean 8.3 ± 4.3 versus 2.8 ± 2.5 symptoms; P < 0.001). Patients reported lowest HRQoL in the domains assessing bodily discomfort, mobility, and activities of daily living. Motor and nonmotor symptoms impacted negatively upon HRQoL scores. Patients with the postural instability and gait difficulty motor subtype reported worse HRQoL, compared with those with tremor-dominant disease. Depression ( P < 0.001), incomplete bowel emptying ( P < 0.001), anxiety ( P < 0.001), impaired concentration ( P < 0.001), memory complaints ( P < 0.001), and insomnia ( P = 0.001) had the greatest negative impact upon HRQoL. NMS are common in patients with early PD and represent a significant cause of poorer health-related quality of life. Cognitive, neuropsychiatric, and sleep disturbances are particularly associated with reduced well-being. Screening and management of these symptoms should be prioritized at the time of diagnosis. © 2013 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]