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Background Although Dementia with Lewy bodies (DLB) is the second most common form of dementia in elderly patients, it remains underdiagnosed compared with Alzheimer's (AD) and Parkinson's diseases (PD). This may be explained by overlapping clinical symptoms, e.g. Parkinsonism. While current MRI research focuses primarily on atrophy patterns of the frontal and temporal lobes, we focus on brainstem characteristics of DLB. In particular, we focused on brainstem atrophy patterns distinguishing DLB from Progressive Supranuclear Palsy (PSP) and PD based as the most common differential diagnoses. Methods We identified patients diagnosed with DLB, PD, PSP, and a control group (CTRL) in our psychiatric and neurological archives. All patients with competing diagnoses and without a high-quality T1 MPRAGE 3D dataset were excluded. We assessed atrophy patterns in all patients (1) manually and (2) using FastSurfer’s segmentation algorithm in combination with FreeSurfer’s brainstem volumetric calculations. We compared classical measurement methods and ratios with automated volumetric approaches. Results One hundred two patients were enrolled and evaluated in this study. Patients with DLB (n = 37) showed on average less atrophy of the brainstem than patients with PSP (n = 21), but a significantly more pronounced atrophy than patients with PD (n = 36) and the control group (CTRL, n = 8). The mean measured sagittal diameters of the midbrain were 8.17 ± 1.06 mm (mean ± standard deviation) for PSP, 9.45 ± 0.95 mm for DLB, 10.37 ± 0.99 mm for PD and 10.74 ± 0.70 for CTRL. The mean measured areas of the midbrain were 81 ± 18 mm2 for PSP, 105 ± 17 mm2 for DLB, 130 ± 26 mm2 for PD and 135 ± 23 mm2 for CTRL. The mean segmented volumes of the midbrain were 5595 ± 680 mm3 for PSP, 6051 ± 566 mm3 for DLB, 6646 ± 802 mm3 for PD and 6882 ± 844 mm3 for CTRL. The calculated midbrain pons ratios did not show superiority over the absolute measurements of the midbrain for distinguishing PSP from DLB. Because of the relatively uniform atrophy throughout the brainstem, the ratios were not suitable for distinguishing DLB from PD. Conclusions DLB patients exhibit homogenous atrophy of the brainstem and can be distinguished from patients with PSP and PD by both manual measurement methods and automated volume segmentation using absolute values or ratios.

Purpose Development and performance measurement of a fully automated pipeline that localizes and segments the locus coeruleus in so-called neuromelanin-sensitive magnetic resonance imaging data for the derivation of quantitative biomarkers of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Methods We propose a pipeline composed of several 3D-Unet-based convolutional neural networks for iterative multi-scale localization and multi-rater segmentation and non-deep learning-based components for automated biomarker extraction. We trained on the healthy aging cohort and did not carry out any adaption or fine-tuning prior to the application to Parkinson’s disease subjects. Results The localization and segmentation pipeline demonstrated sufficient performance as measured by Euclidean distance (on average around 1.3mm on healthy aging subjects and 2.2mm in Parkinson’s disease subjects) and Dice similarity coefficient (overall around $$71\%$$ 71 % on healthy aging subjects and $$60\%$$ 60 % for subjects with Parkinson’s disease) as well as promising agreement with respect to contrast ratios in terms of intraclass correlation coefficient of $$\ge 0.80$$ ≥ 0.80 for healthy aging subjects compared to a manual segmentation procedure. Lower values ($$\ge 0.48$$ ≥ 0.48 ) for Parkinson’s disease subjects indicate the need for further investigation and tests before the application to clinical samples. Conclusion These promising results suggest the usability of the proposed algorithm for data of healthy aging subjects and pave the way for further investigations using this approach on different clinical datasets to validate its practical usability more conclusively.

BackgroundImpaired self-awareness of cognitive deficits (ISAcog) has rarely been investigated in Parkinson's disease (PD). ISAcog is associated with poorer long-term outcome in other diseases. This study examines ISAcog in PD with and without mild cognitive impairment (PD-MCI), compared to healthy controls, and its clinical-behavioral and neuroimaging correlates.MethodsWe examined 63 PD patients and 30 age- and education-matched healthy controls. Cognitive state was examined following the Movement Disorder Society Level II criteria. ISAcog was determined by subtracting z-scores (based on controls' scores) of objective tests and subjective questionnaires. Neural correlates were assessed by structural magnetic resonance imaging (MRI) and 2-[fluorine-18]fluoro-2-deoxy-d-glucose-positron emission tomography (FDG-PET) in 47 patients (43 with MRI) and 11 controls. We analyzed whole-brain glucose metabolism and cortical thickness in regions where FDG-uptake correlated with ISAcog.ResultsPD-MCI patients (N = 23) showed significantly more ISAcog than controls and patients without MCI (N = 40). When all patients who underwent FDG-PET were examined, metabolism in the bilateral superior medial frontal gyrus, anterior and midcingulate cortex negatively correlated with ISAcog (FWE-corrected p < 0.001). In PD-MCI, ISAcog was related to decreased metabolism in the right superior temporal lobe and insula (N = 13; FWE-corrected p = 0.023) as well as the midcingulate cortex (FWE-corrected p = 0.002). Cortical thickness was not associated with ISAcog in these regions. No significant correlations were found between ISAcog and glucose metabolism in controls and patients without MCI.ConclusionsSimilar to Alzheimer's disease, the cingulate cortex seems to be relevant in ISAcog in PD. In PD-MCI patients, ISAcog might result from a disrupted network that regulates awareness of cognition and error processes.

Background Alterations in the GBA gene (NM_000157.3) are the most important genetic risk factor for Parkinson's disease (PD). Biallelic GBA mutations cause the lysosomal storage disorder Gaucher's disease. The GBA variants p.E365K and p.T408M are associated with PD but not with Gaucher's disease. The pathophysiological role of these variants needs to be further explored. Objective This study analyzed clinical, neuropsychological, metabolic, and neuroimaging phenotypes of patients with PD carrying the GBA variants p.E365K and p.T408M. Methods GBA was sequenced in 56 patients with mid-stage PD. Carriers of GBA variants were compared with noncarriers regarding clinical history and symptoms, neuropsychological features, metabolomics, and multimodal neuroimaging. Blood plasma gas chromatography coupled to mass spectrometry, 6-[18 F]fluoro-L-Dopa positron emission tomography (PET), [18 F]fluorodeoxyglucose PET, and resting-state functional magnetic resonance imaging were performed. Results Sequence analysis detected 13 heterozygous GBA variant carriers (7 with p.E365K, 6 with p.T408M). One patient carried a GBA mutation (p.N409S) and was excluded. Clinical history and symptoms were not significantly different between groups. Global cognitive performance was lower in variant carriers. Metabolomic group differences were suggestive of more severe PD-related alterations in carriers versus noncarriers. Both PET scans showed signs of a more advanced disease; [18 F]fluorodeoxyglucose PET and functional magnetic resonance imaging showed similarities with Lewy body dementia and PD dementia in carriers. Conclusions This is the first study to comprehensively assess (neuro-)biological phenotypes of GBA variants in PD. Metabolomics and neuroimaging detected more significant group differences than clinical and behavioral evaluation. These alterations could be promising to monitor effects of disease-modifying treatments targeting glucocerebrosidase metabolism. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

INTRODUCTION Subthalamic DBS in Parkinson's disease has been associated with cognitive decline in few cases. Volume reduction of the nucleus basalis of Meynert (NBM) seems to precede cognitive impairment in Parkinson's disease. In this retrospective study, we evaluated NBM volume as a predictor of cognitive outcome 1 year after subthalamic DBS. METHODS NBM volumes were calculated from preoperative MRIs using voxel-based morphometry. Cognitive outcome was defined as the relative change of MMSE or DemTect scores from pre-to 1 year postoperatively. A multiple linear regression analysis adjusted for the number of cognitive domains affected in the preoperative neuropsychological testing and UPDRS III was conducted. To account for other variables and potential non-linear effects, an additional machine learning analysis using random forests was applied. RESULTS 55 patients with Parkinson's disease (39 male, age 61.4 ± 7.5 years, disease duration 10.8 ± 4.7 years) who received bilateral subthalamic DBS electrodes at our center were included. Although overall cognition did not change significantly, individual change in cognitive abilities was variable. Cognitive outcome could be predicted based on NBM size (B = 208.98, p = 0.022*) in the regression model (F(3,49) = 2.869; R2 of 0.149; p = 0.046*). Using random forests with more variables, cognitive outcome could also be predicted (average root mean squared error between predicted and true cognitive change 11.28 ± 9.51, p = 0.039*). Also in this model, NBM volume was the most predictive variable. CONCLUSION NBM volume can be used as a simple non-invasive predictor for cognitive outcome after DBS in Parkinson's disease, especially when combined with other clinical parameters that are prognostically relevant.

Background Subjective cognitive decline (SCD) may occur very early in the course of Parkinson’s disease (PD) before the onset of objective cognitive decline. Data on neural correlates and determinants of SCD in PD are rare. Objective The aim of the present study was to identify neural correlates as well as sociodemographic, clinical, and neuropsychological predictors of SCD in patients with PD. Methods We retrospectively analyzed 30 patients with PD without cognitive impairment (23% female, 66.90 ± 7.20 years, UPDRS-III: 19.83 ± 9.29), of which n = 12 patients were classified as having no SCD (control group, PD-CG) and n = 18 as having SCD (PD-SCD). Neuropsychological testing and 18-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) were conducted. SCD was assessed using a questionnaire covering multiple cognitive domains. Results SCD subscores differed significantly between PD-CG and PD-SCD and correlated significantly with other scales measuring related concepts. FDG-PET whole-brain voxel-wise regression analysis revealed hypometabolism in middle frontal, middle temporal, and occipital areas, and the angular gyrus as neural correlates of SCD in PD. Next to this hypometabolism, depressive symptoms were an independent significant determinant of SCD in a stepwise regression analysis (adjusted R2 = 50.3%). Conclusion This study strengthens the hypothesis of SCD being an early manifestation of future cognitive decline in PD and, more generally, early pathological changes in PD. The early identification of the vulnerability for future cognitive decline constitutes the basis for successful prevention and delay of this non-motor symptom.

BACKGROUND AND OBJECTIVE Cognitive impairment is among the most burdensome non-motor symptoms in Parkinson's disease (PD) and has been associated with hippocampal atrophy. Exercise has been reported to enhance neuroplasticity in the hippocampus in correlation with an improvement of cognitive function. We present data from the Training-PD study, which was designed to evaluate effects of an "" training protocol on neuronal plasticity in PD. METHODS We initiated a 6-week exergaming training program, combining visually stimulating computer games with physical exercise in 17 PD patients and 18 matched healthy controls. Volumetric segmentation of hippocampal subfields on T1- and T2-weighted magnetic resonance imaging and brain-derived neurotrophic factor (BDNF) serum levels were analyzed before and after the training protocol. RESULTS The PD group showed a group-dependent significant volume increase of the left hippocampal subfields CA1, CA4/dentate gyrus (DG) and subiculum after the 6-week training protocol. The effect was most pronounced in the left DG of PD patients, who showed a significantly smaller percentage volume compared to healthy controls at baseline, but not at follow-up. Both groups had a significant increase in serum BDNF levels after training. CONCLUSIONS The results of the present study indicate that exergaming might be a suitable approach to induce hippocampal volume changes in PD patients. Further and larger studies are needed to verify our findings.

Ultra-high-field (UHF) magnetic resonance (MR) scanners, that is, equipment operating at static magnetic field of 7 tesla (7 T) and above, enable the acquisition of data with greatly improved signal-to-noise ratio with respect to conventional MR systems (e.g., scanners operating at 1.5 T and 3 T). The change in tissue relaxation times at UHF offers the opportunity to improve tissue contrast and depict features that were previously inaccessible. These potential advantages come, however, at a cost: in the majority of UHF-MR clinical protocols, potential drawbacks may include signal inhomogeneity, geometrical distortions, artifacts introduced by patient respiration, cardiac cycle, and motion. This article reviews the 7 T MR literature reporting the recent studies on the most widespread neurodegenerative diseases: Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis.

Visuospatial impairment in Parkinson's disease (PD) heralds the onset of a progressive dementia syndrome and might be associated with cholinergic dysfunction. It remains unclear however, whether degeneration of the cholinergic basal forebrain is directly related to cognitive decline, or whether relationships between this region and cognitive function are mediated by closely related brain structures such as those in the medial temporal lobe. To evaluate relationships between structure of the cholinergic basal forebrain, medial temporal lobe and cognition, 27 PD patients without dementia and 20 controls underwent neuropsychological assessment and MRI. Volumes of the cholinergic basal forebrain nuclei, the entorhinal cortex, the hippocampus and its subfields were measured. Regression models utilised basal forebrain and hippocampal volumetric measures to predict cognitive performance. In PD, visuospatial memory (but not verbal memory or executive function) was correlated with hippocampal volume, particularly CA2-3, and basal forebrain subregion Ch1-2, but not Ch4. In addition, hippocampal volume was correlated with Ch1-2 in PD. The relationship between Ch1-2 and visuospatial memory was mediated by CA2-3 integrity. There were no correlations between cognitive and volumetric measures in controls. Our data imply that the integrity of the cholinergic basal forebrain is associated with subregional hippocampal volume. Additionally, a relationship between visuospatial function and cholinergic nuclei does exist, but is fully mediated by variations in hippocampal structure. These findings are consistent with the recent hypothesis that forebrain cholinergic system degeneration results in cognitive deficits via cholinergic denervation, and subsequent structural degeneration, of its target regions., This work was supported by the Slovenian Research Agency (principal investigator ZP, Research Grant No. L3-4255). MJG is supported by the "Miguel Servet" program [CP19/00031] of the Spanish Instituto de Salud Carlos III (ISCIIIFEDER). NJR received funding from the Wellcome Trust and the Eleanor Countess Peel Trust.

Substantia nigra (SN) hyper-echogenicity (SN+) describes an enlargement (>90th percentile) of the area of echogenicity at the anatomic site of the SN in the midbrain detected by transcranial sonography. This ultrasound sign has proven to be a valuable marker supporting the clinical diagnosis of Parkinson's disease (PD). Although there is considerable variation in the extent of echogenic signals at the anatomic site of the SN among PD patients, previous work suggests that SN+ is a stable marker throughout the course of the disease. The present study focused on two aspects: (i) determining whether SN+ values differ between the sides, mirroring the asymmetric character of the disease; and (ii) determining whether age has an influence on SN echogenicity. This cross-sectional study included 300 PD patients and 200 healthy controls. SN+ was measured planimetrically by transcranial sonography. Echogenicity was analyzed separately for onset and non-onset sides, with onset side defined as the SN contralateral to the side of the body that first manifested PD-related motor impairment. Age of the patients and healthy controls at study time was used for correlation. We found that the onset SN+ contralateral to the side of initial motor symptoms was on average 17.6% larger than its counterpart. However, we also found that contrary to the control group, where an increase in age was associated with an increase in size of SN+, age of PD patients was associated with a decline in size of the onset SN+. Furthermore, SN measured at the onset side of PD patients correlated significantly with patient age and Hoehn and Yahr stage, a scale that grades PD severity, although this was not the case for the non-onset side. The present study indicates that changes in SN echogenicity have a different dynamic depending on the onset side of the disease. The age at study time had a significantly negative effect on the size of onset SN+, the effect on the non-onset side was non-significant. We conclude that for appropriate PD analysis, onset SN+ is a more important marker than the average of both sides of SN. Furthermore, we found that among healthy controls, the size of SN+ increases with age.

Previous studies have reported substantial involvement of the noradrenergic system in Parkinson’s disease. Neuromelanin-sensitive MRI sequences and PET tracers have become available to visualize the cell bodies in the locus coeruleus and the density of noradrenergic terminal transporters. Combining these methods, we investigated the relationship of neurodegeneration in these distinct compartments in Parkinson’s disease. We examined 93 subjects (40 healthy controls and 53 Parkinson’s disease patients) with neuromelanin-sensitive turbo spin-echo MRI and calculated locus coeruleus-to-pons signal contrasts. Voxels with the highest intensities were extracted from published locus coeruleus coordinates transformed to individual MRI. To also investigate a potential spatial pattern of locus coeruleus degeneration, we extracted the highest signal intensities from the rostral, middle, and caudal third of the locus coeruleus. Additionally, a study-specific probabilistic map of the locus coeruleus was created and used to extract mean MRI contrast from the entire locus coeruleus and each rostro-caudal subdivision. Locus coeruleus volumes were measured using manual segmentations. A subset of 73 subjects had 11C-MeNER PET to determine noradrenaline transporter density, and distribution volume ratios of noradrenaline transporter-rich regions were computed. Patients with Parkinson’s disease showed reduced locus coeruleus MRI contrast independently of the selected method (voxel approaches: P The data shed first light on the interaction between the axonal and cell body compartments and their differential susceptibility to neurodegeneration in Parkinson’s disease, which may eventually direct research towards potential novel treatment approaches.

The subthalamic nucleus is part of a global stopping network that also includes the presupplementary motor area and inferior frontal gyrus of the right hemisphere. In Parkinson’s disease, subthalamic deep brain stimulation improves movement initiation and velocity, but its effect on stopping of ongoing movement is unknown. Here, we examine the relation between movement stopping and connectivity of stimulation volumes to the stopping network. Stop and go times were collected in 17 patients with Parkinson’s disease on and off subthalamic stimulation during visually cued initiation and termination of continuous, rotational movements. Deep brain stimulation contacts were localized; the stimulation volume computed and connectivity profiles estimated using an openly available, normative structural connectome. Subthalamic stimulation significantly increased stop times, which correlated with the connectivity of the stimulation volume to presupplementary motor area and inferior frontal gyrus of the right hemisphere. The robustness of this finding was validated using three separate analysis streams: voxel-wise whole-brain connectivity, region of interest connectivity and a tract-centred method. Our study sheds light on the role of the fronto-subthalamic inhibitory triangle in stopping of ongoing movements and may inspire circuit based adaptive stimulation strategies for control of stopping impairment, possibly reflected in stimulation-induced dyskinesia.

Graphical abstract, Highlights • Freezers exhibited a dopaminergic deficit in the left caudate. • The dopamine depleted caudate shows altered striatocortical functional connectivity. • Ventral tegmental area displays increased coupling with regions of the DMN. • Molecular connectivity revealed a specific impairment in mesocorticolimbic pathways., Freezing of gait is a common phenomenon of advanced Parkinson’s disease. Besides locomotor function per se, a role of cognitive deficits has been suggested. Limited evidence of associated dopaminergic deficits points to caudatal denervation. Further, altered functional connectivity within resting-state networks with importance for cognitive functions has been described in freezers. A potential pathophysiological link between both imaging findings has not yet been addressed. The current study sought to investigate the association between dopaminergic pathway dysintegrity and functional dysconnectivity in relation to FOG severity and cognitive performance in a well-characterized PD cohort undergoing high-resolution 6-[18F]fluoro-L-Dopa PET and functional MRI. The freezing of gait questionnaire was applied to categorize patients (n = 59) into freezers and non-freezers. A voxel-wise group comparison of 6-[18F]fluoro-L-Dopa PET scans with focus on striatum was performed between both well-matched and neuropsychologically characterized patient groups. Seed-to-voxel resting-state functional connectivity maps of the resulting dopamine depleted structures and dopaminergic midbrain regions were created and compared between both groups. For a direct between-group comparison of dopaminergic pathway integrity, a molecular connectivity approach was conducted on 6-[18F]fluoro-L-Dopa scans. With respect to striatal regions, freezers showed significant dopaminergic deficits in the left caudate nucleus, which exhibited altered functional connectivity with regions of the visual network. Regarding midbrain structures, the bilateral ventral tegmental area showed altered functional coupling to regions of the default mode network. An explorative examination of the integrity of dopaminergic pathways by molecular connectivity analysis revealed freezing-associated impairments in mesolimbic and mesocortical pathways. This study represents the first characterization of a link between dopaminergic pathway dysintegrity and altered functional connectivity in Parkinson’s disease with freezing of gait and hints at a specific involvement of striatocortical and mesocorticolimbic pathways in freezers.

Involvement of the default mode network (DMN) in cognitive symptoms of Parkinson's disease (PD) has been reported by resting-state functional MRI (rsfMRI) studies. However, the relation to metabolic measures obtained by [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) is largely unknown. We applied multimodal resting-state network analysis to clarify the association between intrinsic metabolic and functional connectivity abnormalities within the DMN and their significance for cognitive symptoms in PD. PD patients were classified into normal cognition (n = 36) and mild cognitive impairment (MCI; n = 12). The DMN was identified by applying an independent component analysis to FDG-PET and rsfMRI data of a matched subset (16 controls and 16 PD patients) of the total cohort. Besides metabolic activity, metabolic and functional connectivity within the DMN were compared between the patients' groups and healthy controls (n = 16). Glucose metabolism was significantly reduced in all DMN nodes in both patient groups compared to controls, with the lowest uptake in PD-MCI (p < .05). Increased metabolic and functional connectivity along fronto-parietal connections was identified in PD-MCI patients compared to controls and unimpaired patients. Functional connectivity negatively correlated with cognitive composite z-scores in patients (r = -.43, p = .005). The current study clarifies the commonalities of metabolic and hemodynamic measures of brain network activity and their individual significance for cognitive symptoms in PD, highlighting the added value of multimodal resting-state network approaches for identifying prospective biomarkers.Keywords: Parkinson's disease; [18F]-FDG-PET; default mode network; metabolic covariance; mild cognitive impairment; resting-state fMRI.

[Background] There is an urgent need to identify individuals at risk of postural instability and gait difficulties, and the resulting propensity for falls, in Parkinson's disease., [Objectives] Given known relationships between posture and gait and degeneration of the cholinergic pedunculopontine nucleus, we investigated whether metrics of pedunculopontine nucleus microstructural integrity hold independent utility for predicting future postural instability and gait difficulties and whether they could be combined with other candidate biomarkers to improve prognostication of these symptoms., [Methods] We used stereotactic mapping of the pedunculopontine nucleus and diffusion tensor imaging to extract baseline pedunculopontine nucleus diffusivity metrics in 147 participants with Parkinson's disease and 65 controls enrolled in the Parkinson's Progression Markers Initiative. We also recorded known candidate markers of posture and gait changes: loss of caudate dopamine and CSF β‐amyloid 1‐42 levels at baseline; as well as longitudinal progression motor symptoms over 72‐months., [Results] Survival analyses revealed that reduced dopamine in the caudate and increased axial diffusivity in the pedunculopontine nucleus incurred independent risk of postural instability and gait difficulties. Binary logistic regression and receiver operating characteristics analysis in 117 participants with complete follow‐up data at 60 months revealed that only pedunculopontine nucleus microstructure provided more accurate discriminative ability for predicting future postural instability and gait difficulties than clinical and demographic variables alone., [Conclusion] Dopaminergic and cholinergic loss incur independent risk for future postural instability and gait difficulties, and pedunculopontine nucleus microstructure can be used to prognosticate these symptoms from early Parkinson's disease stages. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society., The Parkinson's Progression Markers Initiative is sponsored and partially funded by the Michael J. Fox Foundation for Parkinson's Research. Other funding partners include a consortium of industry players, nonprofit organizations, and private individuals. Additional funding to support the current analysis was provided by the Wellcome Trust.

Although olfactory dysfunction is one of the most well-established prodromal symptoms in Parkinson's disease (PD), its correlation with clinical disease progression or dopaminergic dysfunction still remains unclear. We here evaluated the association of striatal dopamine metabolism and olfactory function in a homogenous cohort of 30 patients with early untreated de novo PD. Striatal dopamine metabolism was assessed by the extended 18Fluorodopa PET scanning protocol to measure 18Fluorodopa uptake (Kocc) and the effective dopamine distribution volume ratio (EDVR) as the inverse of dopamine turnover. Olfactory function was estimated by the 'Sniffin' Sticks' test including odor threshold (T), discrimination (D) and identification (I) assessment. We detected moderate correlations of the EDVR in the posterior putamen with the TDI composite score (r = 0.412; p = 0.024; Pearson's correlation test) and the odor identification score (r = 0.444; p = 0.014). These correlations were confirmed by multivariate regression analyses using age, sex, symptom duration and disease severity as measured by UPDRSIII motor score as candidate covariates. No other associations were observed between olfaction measures and Kocc and EDVR in all striatal regions. Together, olfactory dysfunction in early PD is not correlated with striatal 18Fluorodopa uptake as a measure for dopaminergic degeneration, but with putaminal dopamine turnover as a marker for dopaminergic presynaptic compensatory processes in early PD. These results should be treated as hypothesis generating and require confirmation by larger multicenter studies.

This cross-sectional study investigates the potential of novel tau radiotracer 18F-PI-2620 as a biomarker in patients with clinically diagnosed progressive supranuclear palsy., Key Points Question Can tau–positron emission tomography imaging with the novel tau radiotracer 18F-PI-2620 differentiate patients with progressive supranuclear palsy (PSP) from healthy controls and controls with disease? Findings In this cross-sectional study of 60 patients with PSP, 10 healthy controls, and 20 controls with disease, there was significantly higher 18F-PI-2620 binding in target regions of patients with PSP compared with controls regardless of disease severity. Individual patients with PSP with Richardson syndrome were separated with high sensitivity and specificity. Meaning 18F-PI-2620 tau–positron emission tomography differentiates patients with PSP from controls at the single-patient level, potentially facilitating a more reliable diagnosis., Importance Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy. Region-specific tau aggregates establish the neuropathologic diagnosis of definite PSP post mortem. Future interventional trials against tau in PSP would strongly benefit from biomarkers that support diagnosis. Objective To investigate the potential of the novel tau radiotracer 18F-PI-2620 as a biomarker in patients with clinically diagnosed PSP. Design, Setting, and Participants In this cross-sectional study, participants underwent dynamic 18F-PI-2620 positron emission tomography (PET) from 0 to 60 minutes after injection at 5 different centers (3 in Germany, 1 in the US, and 1 in Australia). Patients with PSP (including those with Richardson syndrome [RS]) according to Movement Disorder Society PSP criteria were examined together with healthy controls and controls with disease. Four additionally referred individuals with PSP-RS and 2 with PSP–non-RS were excluded from final data analysis owing to incomplete dynamic PET scans. Data were collected from December 2016 to October 2019 and were analyzed from December 2018 to December 2019. Main Outcomes and Measures Postmortem autoradiography was performed in independent PSP-RS and healthy control samples. By in vivo PET imaging, 18F-PI-2620 distribution volume ratios were obtained in globus pallidus internus and externus, putamen, subthalamic nucleus, substantia nigra, dorsal midbrain, dentate nucleus, dorsolateral, and medial prefrontal cortex. PET data were compared between patients with PSP and control groups and were corrected for center, age, and sex. Results Of 60 patients with PSP, 40 (66.7%) had RS (22 men [55.0%]; mean [SD] age, 71 [6] years; mean [SD] PSP rating scale score, 38 [15]; score range, 13-71) and 20 (33.3%) had PSP–non-RS (11 men [55.0%]; mean [SD] age, 71 [9] years; mean [SD] PSP rating scale score, 24 [11]; score range, 11-41). Ten healthy controls (2 men; mean [SD] age, 67 [7] years) and 20 controls with disease (of 10 [50.0%] with Parkinson disease and multiple system atrophy, 7 were men; mean [SD] age, 61 [8] years; of 10 [50.0%] with Alzheimer disease, 5 were men; mean [SD] age, 69 [10] years). Postmortem autoradiography showed blockable 18F-PI-2620 binding in patients with PSP and no binding in healthy controls. The in vivo findings from the first large-scale observational study in PSP with 18F-PI-2620 indicated significant elevation of tracer binding in PSP target regions with strongest differences in PSP vs control groups in the globus pallidus internus (mean [SD] distribution volume ratios: PSP-RS, 1.21 [0.10]; PSP–non-RS, 1.12 [0.11]; healthy controls, 1.00 [0.08]; Parkinson disease/multiple system atrophy, 1.03 [0.05]; Alzheimer disease, 1.08 [0.06]). Sensitivity and specificity for detection of PSP-RS vs any control group were 85% and 77%, respectively, when using classification by at least 1 positive target region. Conclusions and Relevance This multicenter evaluation indicates a value of 18F-PI-2620 to differentiate suspected patients with PSP, potentially facilitating more reliable diagnosis of PSP.

BACKGROUND: Falls are common among people with idiopathic Parkinson's disease (IPD) and are suggested to be associated with white matter hyperintensities (WMH) of the brain.OBJECTIVE: To investigate the contribution of brain area-specific WMH to the risk of falls in IPD.METHODS: In fifty participants with IPD, occurrence and severity of WMH in specific brain areas were determined using Scheltens (without lateralization) and Age-related white matter changes (ARWMC) (with lateralization) scores. Falls were evaluated with the fall item of the Unified PD Rating Scale (UPDRS). Correlations between area-specific WMH and falls were tested with stepwise backward regression and multivariate regression analyses.RESULTS: In this cohort of participants with IPD, left temporal WMH were associated with occurrence of falls. Frontal WMH of both hemispheres showed tendencies towards significance for the association with falls.CONCLUSION: According to our study, WMH in the left temporal area are significantly associated with falls in IPD. Potential reasons for this association could be deficits in memory, navigation, orientation, auditory processing, and fear conditioning, which are all associated with pathologies of the left temporal lobe.

Purpose: There are no comprehensive guidelines for the use of FDG PET in the following three clinical scenarios: (1) diagnostic work-up of patients with idiopathic Parkinson’s disease (PD) at risk of future cognitive decline, (2) discriminating idiopathic PD from progressive supranuclear palsy, and (3) identifying the underlying neuropathology in corticobasal syndrome. Methods: We therefore performed three literature searches and evaluated the selected studies for quality of design, risk of bias, inconsistency, imprecision, indirectness and effect size. Critical outcomes were the sensitivity, specificity, accuracy, positive/negative predictive value, area under the receiving operating characteristic curve, and positive/negative likelihood ratio of FDG PET in detecting the target condition. Using the Delphi method, a panel of seven experts voted for or against the use of FDG PET based on published evidence and expert opinion. Results: Of 91 studies selected from the three literature searches, only four included an adequate quantitative assessment of the performance of FDG PET. The majority of studies lacked robust methodology due to lack of critical outcomes, inadequate gold standard and no head-to-head comparison with an appropriate reference standard. The panel recommended the use of FDG PET for all three clinical scenarios based on nonquantitative evidence of clinical utility. Conclusion: Despite widespread use of FDG PET in clinical practice and extensive research, there is still very limited good quality evidence for the use of FDG PET. However, in the opinion of the majority of the panellists, FDG PET is a clinically useful imaging biomarker for idiopathic PD and atypical parkinsonism associated with dementia.

Background Both the cerebello-thalamo-cortical circuit and the basal ganglia/cortical motor loop have been postulated to be generators of tremor in PD. The recent suggestion that the basal ganglia trigger tremor episodes and the cerebello-thalamo-cortical circuitry modulates tremor amplitude combines both competing hypotheses. However, the role of the STN in tremor generation and the impact of proprioceptive feedback on tremor suppression during voluntary movements have not been considered in this model yet. Objectives The objective of this study was to evaluate the role of the STN and proprioceptive feedback in PD tremor generation during movement execution. Methods Local-field potentials of the STN as well as electromyographical and electroencephalographical rhythms were recorded in tremor-dominant and nontremor PD patients while performing voluntary movements of the contralateral hand during DBS surgery. Effective connectivity between these electrophysiological signals were analyzed and compared to electromyographical tremor activity. Results There was an intensified information flow between the STN and the muscle in the tremor frequencies (5-8 Hz) for tremor-dominant, in comparison to nontremor, patients. In both subtypes, active movement was associated with an increase of afferent interaction between the muscle and the cortex in the β- and γ-frequencies. The γ-frequency (30-40 Hz) of this communication between muscle and cortex correlated inversely with electromyographical tremor activity. Conclusions Our results indicate an involvement of the STN in propagation of tremor-related activity to the muscle. Furthermore, we provide evidence that increased proprioceptive information flow during voluntary movement interferes with central tremor generation. © 2018 International Parkinson and Movement Disorder Society.

Background Several MRI studies have demonstrated hippocampal atrophy in Parkinson's disease (PD), a structure considered a key element in spatial learning. Despite this, no study has been undertaken to investigate spatial navigation in PD using a virtual version of the Morris water maze, which is the gold standard for testing hippocampal function in rodents. Methods We studied 17 cognitively unimpaired PD patients, 12 PD patients with mild cognitive impairment (MCI) and 15 controls in a virtual water maze procedure. Results Measured by the main outcome parameters latency to locate the target and heading error (average difference between direction of movement toward anticipated target and real direction toward the target), controls performed significantly better on the virtual water maze task than cognitively unimpaired PD patients or PD patients with MCI, while there was no significant difference between latter two groups. Conclusions The virtual water maze test differentiates PD patients from controls, but does not distinguish between cognitively normal and cognitively impaired PD patients, indicating a possible dopamine dependent component in spatial learning. Spatial performance deficits might thus constitute very early signs of dopamine depletion independent of the presence of MCI in Parkinson's disease.

In Parkinson's disease (PD) and related disorders pathological alpha-synuclein has been discussed to propagate via a prion-like mechanism in the CNS. The application of exogenous alpha-synuclein fibrils via injection to animal models of PD has been shown to be a useful method to study prion-like propagation of pathological alpha-synuclein and of transmission pathways that play a critical role in recapitulating characteristics of synucleinopathies. Using bigenic mice expressing mutant human alpha-synuclein in neurons and firefly luciferase in astrocytes we showed that transmission via the tongue and the peritoneum represent entrance points for pathological alpha-synuclein to invade the CNS. Here we present a method to quantify astrogliosis by bioluminescence imaging in an animal model of PD. This method allows noninvasive tracking of the neuroinflammatory process that often precedes neurological signs of disease and represents an alternative to behavioral or histological and biochemical analysis to detect disease.

Cognitive impairment and dementia are common in PD; however, no stable marker of cognitive dysfunction is available. Transcranial sonography can evaluate global and focal brain atrophy and has been widely used in the differential diagnosis of parkinsonism.225 consecutive PD patients were recruited in a two-center cross sectional study and underwent a standardized sonographic protocol assessing the third ventricle's width and substantia nigra hyperechogenicity. All subjects were evaluated with an extensive motor and cognitive battery.222 PD patients were included and classified as PD with normal cognition (PDNC; n = 130), mild cognitive impairment (PD-MCI; n = 61) and dementia (PDD; n = 31). Ventricular width correlated strongly with cognitive performance in all cognitive domains (p 0.001) while SN size did not. PDD patients had significantly wider ventricles than PD patients without dementia (p 0.001) while differences between PD-MCI and PDNC or PDD were less strong (p 0.05). There were no group differences in SN size. ROC analyses resulted in age-related cut-offs of third ventricular diameter for the prediction of PDD (6.0 and 7.5 mm for subjects and ≥70 years of age, respectively). These cut-offs significantly differentiated PDD from PDNC (p 0.001) and from all patients without dementia (PDNC + PD-MCI; p 0.001).The third ventricular diameter correlated with cognitive performance in all domains and was able to differentiate PDD patients from those without dementia. Longitudinal studies are warranted to evaluate whether transcranial sonography could identify PD patients at risk for a rapid cognitive decline.

We investigated the brain atrophy distribution pattern and rate of regional atrophy change in Parkinson's disease (PD) in association with the cognitive status to identify the morphological characteristics of conversion to mild cognitive impairment (MCI) and dementia (PDD). T1-weighted longitudinal 3T MRI data (up to four follow-up assessments) from neuropsychologically well-characterized advanced PD patients (n = 172, 8.9 years disease duration) and healthy elderly controls (n = 85) enrolled in the LANDSCAPE study were longitudinally analyzed using a linear mixed effect model and atlas-based volumetry and cortical thickness measures. At baseline, PD patients presented with cerebral atrophy and cortical thinning including striatum, temporoparietal regions, and primary/premotor cortex. The atrophy was already observed in “cognitively normal” PD patients (PD-N) and was considerably more pronounced in cognitively impaired PD patients. Linear mixed effect modeling revealed almost similar rates of atrophy change in PD and controls. The group comparison at baseline between those PD-N whose cognitive performance remained stable (n = 42) and those PD-N patients who converted to MCI/PDD (“converter” cPD-N, n = 26) indicated suggested cortical thinning in the anterior cingulate cortex in cPD-N patients which was correlated with cognitive performance. Our results suggest that cortical brain atrophy has been already expanded in advanced PD patients without overt cognitive deficits while atrophy progression in late disease did not differ from “normal” aging regardless of the cognitive status. It appears that cortical atrophy begins early and progresses already in the initial disease stages emphasizing the need for therapeutic interventions already at disease onset. CA extern

Introduction Executive dysfunction is a common and early cognitive symptom in Parkinson's disease (PD) with a detrimental effect on quality of life of patients and their care givers. Thus, a number of neuroimaging studies investigated the underlying neural correlates of such an impairment. Results of individual studies, however, are not univocal in terms of location and directionality of associated functional brain changes. Objective To assess convergence of abnormal brain activation in patients with PD during the performance of tasks probing executive functions (EF). Methods We screened the functional imaging literature on EF in PD using the PubMed database, extracted reported stereotactic data and tested for convergence of deviant neural activation in patients with PD when compared to healthy controls (HC) using a coordinate-based activation likelihood estimation approach. Results We identified 22 eligible papers from which the main proportion was targeted at the investigation of working memory encompassing 354 patients and 306 HC. Surprisingly, no significant converging aberrant activation between HC and patients (ON, OFF or ON + OFF medication, respectively) could be observed when controlling for multiple comparisons using family-wise error correction on cluster-level. Conclusion We conclude that there is currently not enough available evidence to pinpoint a specific neural correlate associated with executive dysfunction in PD. This might be due to the small number of studies performed and their methodical inconsistency. Therefore, it is important to conduct more research regarding functional brain changes associated with EF in these patients using more consistent frameworks and bigger samples.

Objective: To investigate the predictive value of striatal dopamine turnover in patients with de novo Parkinson disease (PD) for the onset of later motor complications. Methods: This retrospective, observer-blinded cohort study followed up 31 patients with early PD who completed quantitative 18 F-dopa PET imaging to measure striatal 18 F-dopa uptake (K occ ) and effective distribution volume ratio (EDVR) as the inverse of dopamine turnover prior to antiparkinsonian treatment. The onset of wearing-off and dyskinesias was determined based on blinded clinical assessments and patient records. The predictive value of baseline PET measures for motor complications was evaluated using Cox proportional hazard models. Results: During a mean follow-up time of 6.8 years, 18 (58.1%) patients developed wearing-off, 11 (35.5%) dyskinesia, and 20 (64.5%) any motor complication. Patients with dyskinesia and any motor complication showed lower baseline EDVR (higher dopamine turnover) in the putamen than those without dyskinesias and any motor complication, with differences most markedly present in the posterior putamen. Baseline EDVR in the whole and the posterior putamen predicted development of motor complications with an increasing risk with lower EDVR (higher dopamine turnover), whereas EDVR in other regions and K occ did not correlate with motor complications. Correspondingly, Kaplan-Meier curves showed reduced survival from motor complications in patients with lower baseline EDVR (higher dopamine turnover) in the posterior putamen with ongoing levodopa treatment and disease duration. Conclusions: Elevated putaminal dopamine turnover in de novo PD is associated with an increased risk for later motor complications and comprises a disease-intrinsic predisposing factor for their development.

Background. Hypokinetic dysarthria is highly prevalent in idiopathic Parkinson disease (PD), and effectiveness of high-intensity voice treatment is well established. However, the neural correlates remain largely unknown. Objective. We aimed to specify cerebral pathophysiology of hypokinetic dysarthria and treatment-induced changes using functional magnetic resonance imaging (fMRI). Methods. We used fMRI to investigate healthy controls (HCs) and patients with idiopathic PD–associated dysarthria before and after treatment according to the Lee Silverman Voice Treatment LOUD (LSVT). During fMRI, participants covertly read sentences with normal (eg, conversation in a quiet room) or high (eg, shouting on a windy beach) intensity. In addition, we tested LSVT effects on intelligibility and different speech features (intensity, pitch, articulation). Results. LSVT effectively improved intelligibility, articulation, and pitch in patients. Covert high-intensity speech compared with covert normal-intensity speech led to increased activation of mainly secondary motor areas and bilateral superior and medial temporal regions. Prior to LSVT, patients showed less activity in several speech-associated areas compared with HCs. As a neural correlate of effective LSVT, increased right-sided superior temporal activity correlated with improved intelligibility. Conclusion. This is the first brain imaging study using a covert speech paradigm in PD, which revealed cortical hypoactivation as correlate of hypokinetic dysarthria. Furthermore, cortical correlates of effective LSVT treatment colocalized with the neuronal network, showing increased activation during high- versus normal-intensity speech generation.

Cognitive impairment (CI) in Parkinson’s disease (PD) is associated with a widespread reduction in cortical glucose metabolism and relative increases in the cerebellum and brainstem as measured using 18F-fluorodesoxyglucose (FDG) PET. We separately analysed CI-related hypermetabolism and hypometabolism in comparison with neuropsychological test performance and investigated whether increased FDG uptake is a true feature of the disease or a normalization effect. The study included 29 subjects (12 patients with PD, 10 patients with PD dementia and 7 healthy controls") who underwent FDG PET and comprehensive neuropsychological testing. Test performance across various cognitive domains was summarized in a cognitive staging score. Metabolic indices reflecting associated changes in regional cerebral glucose metabolism (rCGM) were calculated: index(−) for CI-related hypometabolism, and index(+) for CI-related hypermetabolism. We tested whether index(+) offered additional value in predicting the severity of CI in multiple regression analysis. At higher stages of CI, increased rCGM was found in the posterior cerebellar vermis and pons, associated with impaired attention, executive function and memory. Reduced rCGM was found in various cortical regions in agreement with the literature. In multiple regression analysis, both indices independently predicted the severity of CI with a whole-model R2 of 0.68 (index(−), p = 0.0006; index(+), p = 0.013), confirmed by alternative analyses combining different reference tissues in the multiple regression. We found CI-related hypermetabolism in cerebellar regions that are known to be involved in several cognitive functions and in the pons. These alterations may represent compensatory activation of cognitive networks including cerebropontocerebellar tracts.

Item does not contain fulltext BACKGROUND: The clinical diagnosis of idiopathic Parkinson's disease (iPD) can be challenging. In these cases, additional diagnostic methods are available that can help to improve diagnostic accuracy. OBJECTIVES, MATERIAL AND METHODS: This article provides an overview of currently available and promising novel ancillary methods for the early and differential diagnosis of iPD. RESULTS: Imaging tools, such as 1.5 Tesla magnetic resonance imaging (MRI) and computed tomography (CT) are mainly used for the differentiation between iPD and symptomatic parkinsonian syndromes (PS). High-resolution diffusion tensor imaging and iron and neuromelanin-sensitive high-field MRI sequences can become important in the future, particularly for earlier diagnosis. Transcranial Bmode sonography of the substantia nigra and basal ganglia is established for early and differential diagnostics, especially in the combination of diagnostic markers but necessitates an adequately trained investigator and the use of validated digital image analysis instruments. DATScan can discriminate iPD from essential tremor, medication-induced parkinsonism and psychogenic movement disorder but not iPD from atypical PS. For the latter differential diagnosis, fluorodeoxyglucose positron emission tomography and myocardial metaiodobenzylguanidine scintigraphy can be helpful. Olfactory testing should preferably be used in combination with other diagnostic tests. Genetic, biochemical and histopathological tests are currently not recommended for routine use. Novel sensor-based techniques have a high potential to support clinical diagnosis of iPD but have not yet reached a developmental stage that is sufficient for clinical use. Novel sensor-based techniques have high potential to support clinical diagnosis of iPD, but have not yet reached a development stage that is sufficient for clinical use. CONCLUSION: Ancillary diagnostic methods can support the early and differential diagnosis of iPD.

Although iron-mediated oxidative stress has been proposed as a potential pathomechanism in Parkinson's disease, the global distribution of iron accumulation in Parkinson's disease has not yet been elucidated. This study used a new magnetic resonance imaging contrast, quantitative susceptibility mapping, and state-of-the-art methods to map for the first time the whole-brain landscape of magnetostatic alterations as a surrogate for iron level changes in n = 25 patients with idiopathic Parkinson's disease versus n = 50 matched controls. In addition to whole-brain analysis, a regional study including sub-segmentation of the substantia nigra into dorsal and ventral regions and qualitative assessment of susceptibility maps in single subjects were also performed. The most remarkable basal ganglia effect was an apparent magnetic susceptibility increase-consistent with iron deposition-in the dorsal substantia nigra, though an effect was also observed in ventral regions. Increased bulk susceptibility, additionally, was detected in rostral pontine areas and in a cortical pattern tightly concordant with known Parkinson's disease distributions of α-synuclein pathology. In contrast, the normally iron-rich cerebellar dentate nucleus returned a susceptibility reduction suggesting decreased iron content. These results are in agreement with previous post-mortem studies in which iron content was evaluated in specific regions of interest; however, extensive neocortical and cerebellar changes constitute a far more complex pattern of iron dysregulation than was anticipated. Such findings also stand in stark contrast to the lack of statistically significant group change using conventional magnetic resonance imaging methods namely voxel-based morphometry, cortical thickness analysis, subcortical volumetry and tract-based diffusion tensor analysis; confirming the potential of whole-brain quantitative susceptibility mapping as an in vivo biomarker in Parkinson's disease.

Despite advances in diagnostics and clinical recognition, depressive symptoms in Parkinson's disease (PD) exceeding normal limits remain effectively untreated. In this study, we report on the prevalence and severity of depressive symptoms as well as their association with brainstem raphe echogenicity in patients with PD and non-PD controls. The study included 266 Estonian PD patients and 168 age- and education-matched controls. Demographic and clinical data was documented. Brainstem raphe (BR) was visualized by transcranial sonography (TCS). The prevalence of depressive symptoms in the patient sample was found to be significantly higher than in controls. BR echogenicity in both patients and controls was directly related to their total BDI score, although we found a significantly greater reduction of BR echogenicity in patients with PD and depressive symptoms compared to depressed non-PD controls. The present results corroborate the hypothesis that morphological alteration of the BR is involved in the pathogenesis of depressive disorders. TCS of BR could be used as a non-invasive biomarker to improve detection of depressive symptoms in early PD stages where clinicians may not recognize affective disturbances in the context of PD phenomena.

Manual MRI morphometry in Parkinsonian syndromes.

Many studies have used functional magnetic resonance imaging to unravel the neuronal underpinnings of motor system abnormalities in Parkinson's disease, indicating functional inhibition at the level of basal ganglia-thalamo-cortical motor networks. The study aim was to extend the characterization of functional motor changes in Parkinson's Disease by dissociating between two phases of action (i.e. motor planning and motor execution) during an automated unilateral finger movement sequence with the left and right hand, separately. In essence, we wished to identify neuronal dysfunction and potential neuronal compensation before (planning) and during (execution) automated sequential motor behavior in unmedicated early stage Parkinson's Disease patients. Twenty-two Parkinson's Disease patients (14 males; 53 ± 11 years; Hoehn and Yahr score 1.4 ± 0.6; UPDRS (part 3) motor score 16 ± 6) and 22 healthy controls (14 males; 49 ± 12 years) performed a pre-learnt four finger sequence (index, ring, middle and little finger, in order), either self-initiated (FREE) or externally triggered (REACT), within an 8-second time window. Findings were most pronounced during FREE with the clinically most affected side, where motor execution revealed significant underactivity of contralateral primary motor cortex, contralateral posterior putamen (sensorimotor territory), ipsilateral anterior cerebellum / cerebellar vermis, along with underactivity in supplementary motor area (based on ROI analyses only), corroborating previous findings in Parkinson's Disease. During motor planning, Parkinson's Disease patients showed a significant relative overactivity in dorsolateral prefrontal cortex (DLPFC), suggesting a compensatory overactivity. To a variable extent this relative overactivity in the DLPFC went along with a relative overactivity in the precuneus and the ipsilateral anterior cerebellum/cerebellar vermis Our study illustrates that a refined view of disturbances in motor function and compensatory processes can be gained from experimental designs that try to dissociate motor planning from motor execution, emphasizing that compensatory mechanisms are triggered in Parkinson's Disease when voluntary movements are conceptualized for action., Highlights • Dissociated activations in early stage PD for motor planning and motor execution • PD patients show frontal-parietal network compensation during self-initiated movement. • Compensation for an impaired basal ganglia-premotor circuit occurs during planning.

Deep brain stimulation of the subthalamic nucleus is an established treatment for the motor symptoms of Parkinson’s disease. Given the frequent occurrence of stimulation- induced affective and cognitive adverse effects, a better understanding about the role of the subthalamic nucleus in non-motor functions is needed. The main goal of this study is to characterize anatomical circuits modulated by subthalamic deep brain stimulation, and infer about the inner organization of the nucleus in terms of motor and non-motor areas. Given its small size and anatomical intersubject variability, functional organization of the subthalamic nucleus is difficult to investigate in vivo with current methods. Here, we used local field potential recordings obtained from 10 patients with Parkinson’s disease to identify a subthalamic area with an analogous electrophysiological signature, namely a predominant beta oscillatory activity. The spatial accuracy was improved by identifying a single contact per macroelectrode for its vicinity to the electrophysiological source of the beta oscillation. We then conducted whole brain probabilistic tractography seeding from the previously identified contacts, and further described connectivity modifications along the macroelectrode’s main axis. The designated subthalamic ‘beta’ area projected predominantly to motor and premotor cortical regions additional to connections to limbic and associative areas. More ventral subthalamic areas showed predominant connectivity to medial temporal regions including amygdala and hippocampus. We interpret our findings as evidence for the convergence of different functional circuits within subthalamic nucleus’ portions deemed to be appropriate as deep brain stimulation target to treat motor symptoms in Parkinson’s disease. Potential clinical implications of our study are illustrated by an index case where deep brain stimulation of estimated predominant non-motor subthalamic nucleus induced hypomanic behaviour.

α-Synucleinopathies, such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB), are characterized by α-synuclein accumulation from brainstem structures to the neocortex. PD and DLB are clinically distinguishable, while discrimination between Parkinson Disease Dementia (PDD) and DLB can be subtle and based on the temporal relationship between motor and cognitive symptoms. To explore patterns of subcortical atrophy in PD, PDD and DLB, and assess specific differences between PD and PDD, and between DLB and PDD. 16 PD, 11 PDD and 16 DLB patients were recruited and underwent 1.5 Tesla structural MRI scanning. Segmentation of subcortical structures was performed with a well-validated, fully-automated tool, and volume and shape for each structure were compared between groups. PDD and DLB patients showed global subcortical atrophy compared to PD patients. Greater hippocampal atrophy was the specific trait that distinguished PDD from PD, while greater atrophy of the pallidi discriminated DLB from PDD. Vertex analysis revealed specific shape differences in both structures. Our results suggest that automated, time-sparing, subcortical volumetry may provide diagnostically useful information in α-synucleinopathies. Future studies on larger samples and with iron-sensitive MRI contrasts are needed.

Objectives Substantia nigra hyperechogenicity is a promising biomarker for Parkinson disease (PD). Substantia nigra hyperechogenicity has previously been established as a useful diagnostic criterion in several European and Asian patient cohorts. However, diagnostic cutoff values for substantia nigra hyperechogenicity remain unknown for most patient populations. This study validated the diagnostic accuracy of substantia nigra hyperechogenicity in a large cohort of patients with PD in Estonia. Methods The study included 300 patients with PD from Estonia, representing 10% of the national PD patient population, and 200 healthy control participants. To define the optimal cutoff value in the PD cohort, data from a single assessment versus repetitive assessments by transcranial sonography were compared. With the use of 3 repetitive assessments, the diagnostic accuracy of the data was measured. In addition, calculations for percentile values were used to define substantia nigra hyperechogenicity among controls. Results Our data showed that the multiassessment approach yielded higher diagnostic accuracy than a single assessment (P = .021). The highest diagnostic accuracy was achieved by using the measurement mean to define substantia nigra hyperechogenicity, which was 0.23 cm2 (sensitivity, 88.7%; specificity, 92.2%), whereas single measurements detected PD with higher sensitivity (sensitivity, 93.2%; specificity, 85.1%). No significant difference was found between mean and median measurements (P= .18). Conclusions This study indicates the diagnostic merit of transcranial sonography in PD diagnosis in an additional population and demonstrates that transcranial sonography of the substantia nigra is a relevant and useful diagnostic tool for patients with PD.

In Brazil there is no systematic study on Transcranial Sonography (TCS), a neuroimaging method that depicts echogenic deep brain structures using ultrasound. Objective: To establish the percentage of subjects with permissive temporal windows and to address the ability of TCS of the substantia nigra (SN) to distinguish parkinsonian patients in a Brazilian sample. Method: We performed TCS using the Acuson X300 (Siemens, Germany) in 37 individuals: 23 with Parkinson’s disease (PD) and 14 healthy controls. Results: 10.8% of subjects had insufficient temporal acoustic bone windows. SN echogenic areas were larger in patients (mean±SD, 0.31±0.08cm 2 ) compared to controls (mean±SD, 0.17±0.02cm 2 ). TCS accurately identified 88.2% of PD patients. Conclusion: A large proportion of Brazilians seem to be eligible for TCS. An expressive number of PD patients could be diagnosed by TCS based on an expanded SN echogenic area. However, the current data is preliminary and must be corroborated by larger studies.

Objective: To evaluate whether there exists distinct characteristics in glucocerebrosidase ( GBA )–associated Parkinson disease (PD) with regard to motor and nonmotor symptoms as well as imaging characteristics assessed by transcranial sonography (TCS). Methods: Twenty patients with PD with heterozygous GBA mutations (N370S, L444P) (GBA-PD) in comparison to 20 patients with sporadic PD negative for GBA mutations (sPD) were included. We assessed motor impairment with the Unified Parkinson’s Disease Rating Scale–III. Nonmotor symptoms were evaluated using the Montreal Cognitive Assessment, Neuropsychiatric Inventory, revised form of the Beck Depression Inventory, Parkinson Disease Sleep Scale, Sniffin’ Sticks, and Unified Multiple System Atrophy Rating Scale items 9–12. TCS imaging was used to detect morphologic characteristics. Results: Patients with GBA-PD more often had a variety of nonmotor symptoms, namely dementia, neuropsychiatric disturbances, and autonomic dysfunction, and had more severe cases, than patients with sPD. They also demonstrated a higher prevalence of a reduced echogenicity of the brainstem raphe assessed by TCS. Conclusions: Especially nonmotor symptoms seem to be very common in GBA-PD. Further studies are needed to validate these observations in order to better understand the pathogenesis of GBA-PD and develop specific therapeutic concepts.

As there is increasing evidence that the neurodegenerative process in Parkinson's disease (PD) starts years to decades before clinical symptoms allow diagnosis, markers for the identification of subjects at risk are eagerly sought after in order to allow an earlier, disease modulating or even neuroprotective therapy. In recent years, transcranial sonography (TCS) has evolved as a useful instrument in the differential diagnosis and also very early diagnosis of PD. The typical hallmark for PD, hyperechogenicity at the anatomical site of the substantia nigra (SN), can also be found in about 10% of healthy subjects. There is accumulating evidence that SN hyperechogenicity discloses a vulnerability of the nigrostriatal system in at least some of these persons. Moreover, an association of the ultrasound sign with a number of risk and premotor markers has been shown. However, the most striking argument for a relevance of SN hyperechogenicity in healthy subjects can be derived from the observation that some initially healthy subjects with SN hyperechogenicity developed PD in the long run, an observation which has led to longitudinal studies on the predictive value of the ultrasound sign for the development of PD. A first follow up after 3 years of a large cohort of at baseline extrapyramidally healthy individuals revealed a relative risk for incident PD 17.37 times higher in subjects with SN hyperechogenicity at baseline compared to those without this echomarker. Taken together, there is encouraging evidence to implement TCS in a screening battery to identify subjects at risk for the development of PD.

Hyperechogenicity of the substantia nigra (SN) is a sensitive marker for Parkinson's disease (PD). Previously, a relation between SN echogenicity and iron as well as neuromelanin content could be described in 60 human brains. In the present study on a subset of 33 brains, SN echogenicity was found to be correlated with microglia activation (ρ = 0.46, p = 0.008) after correction for iron and neuromelanin content. These findings strengthen the hypothesis of a close pathophysiological connection between SN hyperechogenicity and PD pathology.

During the last decade, substantia nigra (SN) hyperechogenicity has been established as a valuable supplementary diagnostic marker for Parkinson's disease. As an increasing number of studies indicate that this ultrasound feature may even be evident before motor symptoms of Parkinson's disease occur, longitudinal studies revealing its value as a screening instrument for subjects at risk are awaited with great expectancy. At the same time, other studies have shown that SN hyperechogenicity is not only found in Parkinson's disease but also in other disease entities. Limitations and pitfalls of the method need to be considered to evaluate and compare these studies. Taking these into account, it is important to realize that in some other neurodegenerative diseases as well as in disorders associated with an increased risk for Parkinson's disease hyperechogenicity can be found--usually, however, less prevalent. Interestingly, even in subgroups of patients with non-neurodegenerative disorders, SN hyperechogenicity can be detected. This holds, for example, true for multiple sclerosis patients with a higher rate of disease progression. In this disorder, microglia activation is known to occur, which is also evident in Parkinson's disease. This pathomechanism as well as increased iron content is known to contribute to SN hyperechogenicity. From the studies published so far it can be concluded that, although SN hyperechogenicity is not only found in Parkinson's disease, assessment of the echogenicity of the SN and other ultrasound features is valuable in the differential diagnosis of Parkinsonian syndromes and most probably in subjects at risk. Further elucidation of the cause of the echosignal will not only contribute to the understanding of the pathophysiology of some neurodegenerative diseases but also to an even better implementation in the clinical routine and for scientific studies.

Identification of risk factors and prodromal markers for Parkinson's disease (PD) and the understanding of the point in time of first occurrence is essential for the early detection of incident PD. In this three-center longitudinal, observational study, we evaluated the specific risk for PD associated with single or combinations of risk factors and prodromal markers. In addition, we evaluated which risk factors and prodromal markers emerge at which time before the diagnosis of PD. Of the 1,847 at-baseline PD-free individuals ≥ 50 years, 1,260 underwent the 5-year follow-up assessment. There were 21 cases of incident PD during the study period. Enlarged hyperechogenic substantia nigra was the most frequent baseline sign in individuals developing PD after 3 years (80.0 %) and 5 years (85.7 %) compared to healthy controls (17.5 %) followed by the occurrence of mild parkinsonian signs and hyposmia. Evaluation of the signs at the first follow-up assessment showed that individuals developing PD after two additional years showed the same pattern of signs as individuals who developed PD 3 years after baseline assessment.

Abnormal substantia nigra morphology in healthy individuals, viewed with transcranial ultrasound, is a significant risk factor for Parkinson's disease. However, little is known about the functional consequences of this abnormality (termed 'hyperechogenicity') on movement. The aim of the current study was to investigate hand function in healthy older adults with (SN?) and without (SN-) substantia nigra hyperechogenicity during object manipulation. We hypothesised that SN? subjects would exhibit increased grip force and a slower rate of force application compared to SN- subjects. Twenty-six healthy older adults (8 SN? aged 58 ± 8 years, 18 SN- aged 57 ± 6 years) were asked to grip and lift a light-weight object with the dominant hand. Horizontal grip force, vertical lift force, acceleration, and first dorsal interosseus EMG were recorded during three trials. During the first trial, SN? subjects exhibited a longer period between grip onset and lift onset (i.e. preload duration; 0.27 ± 0.25 s) than SN- subjects (0.13 ± 0.08 s; P = 0.046). They also exerted a greater downward force prior to lift off (-0.54 ± 0.42 N vs. -0.21 ± 0.12 N; P = 0.005) and used a greater grip force to lift the object (19.5 ± 7.0 N vs. 14.0 ± 4.3 N; P = 0.022) than SNsubjects. No between group differences were observed in subsequent trials. SN? subjects exhibit impaired planning for manipulation of new objects. SN? individuals overestimate the grip force required, despite a longer contact period prior to lifting the object. The pattern of impairment observed in SN? subjects shares similarities with de novo Parkinson's disease patients. Refereed/Peer-reviewed

Clinical and neuroimaging data suggest impairment of the nigrostriatal system in amyotrophic lateral sclerosis (ALS). We thus hypothesized whether Parkinson's disease (PD)-like midbrain sonography findings are also present in ALS. Eighty-six patients with the diagnosis of possible or definite ALS according to revised El Escorial criteria were examined by transcranial B-mode sonography compared to 76 age- and gender-matched controls and 33 PD patients. Hyperechogenic areas of the midbrain representing the substantia nigra were measured planimetrically using standard protocols. In subjects with sufficient temporal acoustic bone windows, mean midbrain hyperechogenic areas were significantly higher in ALS (0.251 ± 0.104 cm(2)) and PD patients (0.286 ± 0.078 cm(2)) compared to controls (0.091 ± 0.054 cm(2)) with no significant difference between ALS and PD patients (one-way ANOVA: F value = 94.3; P0.0001). Sixty-seven percent (95 % CI 57-78 %) of ALS patients and 84 % (95 % CI 71-97 %) of PD patients displayed abnormal midbrain hyperechogenic areas (P = 0.383 for group comparison, χ(2) test). No correlations of hyperechogenic area sizes in ALS patients were found in regard to age, gender, ALS subtype (bulbar versus spinal form) or ALS-FRS-R score. In summary, we observed hyperechogenicity of the substantia nigra in patients with sporadic ALS with a frequency similar to that in PD and higher than in all other movement disorders. These findings are important for the diagnosis and differential diagnosis of PD and ALS alike.

Homozygous or compound heterozygous mutations in the glucocerebrosidase gene cause Gaucher disease. Moreover, heterozygous glucocerebrosidase gene mutations represent the most common genetic risk factor for Parkinson’s disease (PD) known so far. Substantia nigra (SN) hyperechogenicity, a sonographic feature thought to reflect iron accumulation, has been described in both PD and Gaucher disease patients. Here we studied how clinical, genetic, and brain sonographic findings relate to the occurrence of PD in Gaucher disease. Sixteen Gaucher disease patients, 12 PD patients, and 32 control subjects were enrolled. The glucocerebrosidase genotypes were identified by DNA sequencing. All subjects underwent transcranial ultrasound, and eight Gaucher disease patients additionally MRI for comparison with SN ultrasound findings. SN hyperechogenicity and reduced echogenicity of brainstem raphe were more frequent in Gaucher disease patients (62, 37 %) than in controls (12, 12 %; p < 0.001, p < 0.05). SN hyperechogenicity in Gaucher disease patients was unrelated to type or severity of glucocerebrosidase gene mutation, but correlated with iron-sensitive MRI-T2 hypointensity of SN pars compacta, and with age at start of enzyme replacement therapy. While none of the five Gaucher disease patients with signs of PD (definite PD, n = 4; early PD, n = 1) had severe glucocerebrosidase gene mutations known to cause neuronopathic Gaucher disease, all carried a N370S allele, previously reported to predict non-neuronopathic Gaucher disease. Hyposmia, higher non-motor symptoms score (constipation, depression, executive dysfunction), and SN hyperechogenicity were characteristic features of Gaucher disease-related PD. We conclude that the combined clinical, genetic, and transcranial sonographic assessment may improve the PD risk evaluation in Gaucher disease.

Background We hypothesized that postural instability and cognitive decline in patients with Richardson’s syndrome could be a consequence of reduced thalamic and frontal metabolism. Severe Parkinsonian signs in patients with progressive supranuclear palsy-parkinsonism may be reflected by alterations in putaminal metabolism. Methods Eleven patients with Richardson’s syndrome, 8 patients with progressive supranuclear palsy-parkinsonism, 12 with Parkinson’s disease, and 10 controls underwent clinical assessment and fluorodeoxyglucose positron emission tomography (PET). Results Richardson’s syndrome patients showed pronounced thalamic hypometabolism, and patients with progressive supranuclear palsy-parkinsonism pronounced putaminal hypometabolism, compared to all other investigated groups. The putamen/thalamus uptake ratio differentiated progressive supranuclear palsy-parkinsonism from Richardson’s syndrome (area under the curve 5 0.86) and from Parkinson’s disease (area under the curve 5 0.80) with acceptable accuracy. Frontal hypometabolism was predominantly found in Richardson’s syndrome patients. Conclusions Richardson’s syndrome, progressive supranuclear palsy-parkinsonism and Parkinson’s disease showed different metabolic patterns in fluorodeoxyglucose PET.

We reviewed eight studies on transcranial sonography (TCS) as a tool for differentiating idiopathic Parkinson's disease (IPD) from atypical parkinsonian syndromes (APS) and included some first data on TCS findings in the subforms of PSP. Changes of specific structures on TCS like the substantia nigra (SN), lenticular nucleus (LN), and the third ventricle are discussed as well as how they can contribute to differentiate between IPD, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), Lewy body disease (LBD), and corticobasal degeneration (CBD). We finish with an algorithm that may be used to employ TCS as a diagnostic instrument delineating IPD from the APS and discerning among the APS themselves. As TCS is at present the most promising tool for this particular diagnostic problem, this algorithm might be a suitable hypothesis to study in future research.

Transcranial B-mode sonography (TCS) is a relatively new method which has been proven to be helpful in the diagnosis of Parkinson’s disease (PD). Due to the underlying physical principles, supplementary information to other neuroimaging methods can be derived. Substantia nigra (SN) hyperechogenicity is the characteristic feature of idiopathic PD, which can help in the differentiation of atypical parkinsonian syndromes like multiple system atrophy or progressive supranuclear palsy. Besides, the quick ‘look into the brain’ can easily visualize an enlargement of the ventricular system, alterations of the basal ganglia like increased contents of calcium or trace metals, or a missing brain stem raphe, typically seen in depressive disorders, and can therefore give further diagnostic hints for symptomatic parkinsonian syndromes. Many studies indicate that SN hyperechogenicity constitutes a stable marker, irrespective of the disease stage. In a prospective study of patients with very first signs of yet unclear parkinsonism, a high predictive value of TCS for the diagnosis of PD could be proven. Moreover, there is accumulating evidence that SN hyperechogenicity could play a role in the premotor diagnosis of PD. In this review, the additional diagnostic value of TCS in the early diagnosis of PD as well as limitations of the method are being discussed.

During the past two decades, transcranial sonography (TCS) has developed to an increasingly used brain imaging method that visualizes characteristic patterns of basal ganglia alterations in distinct movement disorders. Since the discovery of a characteristic abnormal hyperechogenic appearance of substantia nigra (SN) on TCS in Parkinson’s disease (PD), which is stable during the course of the disease and probably present already in preclinical disease stages, the results of several studies have promoted the idea that this TCS finding in healthy subjects might be a risk marker of PD. The present view summarizes current scientific evidence favouring the idea that the TCS finding of SN hyperechogenicity alone may not be a (strong) risk marker of PD. Especially, it is discussed how reliable this TCS finding is, whether this TCS finding can be regarded as a progression marker or a risk marker of PD, how strongly it may indicate a risk of PD, what else if not an increased risk of PD could be indicated, and which role TCS of SN may finally play in the detection of subjects at risk of PD.

During the last decade, mutations in a growing number of genes have been found to cause monogenic forms of Parkinson's disease (PD). Moreover, many studies shed light on their contribution to sporadic variants of PD. Since hyperechogenicity of the substantia nigra (SN) represents a characteristic hallmark of sporadic PD questions arise concerning the echo pattern of monogenic forms of this disorder on TCS.