Cholinergic changes in Lewy body disease: implications for presentation, progression and subtypes.

Cholinergic degeneration is significant in Lewy body disease, including Parkinson's disease, dementia with Lewy bodies, and isolated REM sleep behaviour disorder. Extensive research has demonstrated cholinergic alterations in the CNS of these disorders. More recently, studies have revealed cholinergic denervation in organs that receive parasympathetic denervation. This enables a comprehensive review of cholinergic changes in Lewy body disease, encompassing both central and peripheral regions, various disease stages and diagnostic categories. Across studies, brain regions affected in Lewy body dementia show equal or greater levels of cholinergic impairment compared to the brain regions affected in Lewy body disease without dementia. This observation suggests a continuum of cholinergic alterations between these disorders. Patients without dementia exhibit relative sparing of limbic regions, whereas occipital and superior temporal regions appear to be affected to a similar extent in patients with and without dementia. This implies that posterior cholinergic cell groups in the basal forebrain are affected in the early stages of Lewy body disorders, while more anterior regions are typically affected later in the disease progression. The topographical changes observed in patients affected by comorbid Alzheimer pathology may reflect a combination of changes seen in pure forms of Lewy body disease and those seen in Alzheimer's disease. This suggests that Alzheimer co-pathology is important to understand cholinergic degeneration in Lewy body disease. Thalamic cholinergic innervation is more affected in Lewy body patients with dementia compared to those without dementia, and this may contribute to the distinct clinical presentations observed in these groups. In patients with Alzheimer's disease, the thalamus is variably affected, suggesting a different sequential involvement of cholinergic cell groups in Alzheimer's disease compared to Lewy body disease. Patients with isolated REM sleep behaviour disorder demonstrate cholinergic denervation in abdominal organs that receive parasympathetic innervation from the dorsal motor nucleus of the vagus, similar to patients who experienced this sleep disorder in their prodrome. This implies that REM sleep behaviour disorder is important for understanding peripheral cholinergic changes in both prodromal and manifest phases of Lewy body disease. In conclusion, cholinergic changes in Lewy body disease carry implications for understanding phenotypes and the influence of Alzheimer co-pathology, delineating subtypes and pathological spreading routes, and for developing tailored treatments targeting the cholinergic system.

Impaired cholinergic integrity of the colon and pancreas in dementia with Lewy bodies.

Dementia with Lewy bodies is characterized by a high burden of autonomic dysfunction and Lewy pathology in peripheral organs and components of the sympathetic and parasympathetic nervous system. Parasympathetic terminals may be quantified with 18F-fluoroetoxybenzovesamicol, a PET tracer that binds to the vesicular acetylcholine transporter in cholinergic presynaptic terminals. Parasympathetic imaging may be useful for diagnostics, improving our understanding of autonomic dysfunction and for clarifying the spatiotemporal relationship of neuronal degeneration in prodromal disease. Therefore, we aimed to investigate the cholinergic parasympathetic integrity in peripheral organs and central autonomic regions of subjects with dementia with Lewy bodies and its association with subjective and objective measures of autonomic dysfunction. We hypothesized that organs with known parasympathetic innervation, especially the pancreas and colon, would have impaired cholinergic integrity. To achieve these aims, we conducted a cross-sectional comparison study including 23 newly diagnosed non-diabetic subjects with dementia with Lewy bodies (74 ± 6 years, 83% male) and 21 elderly control subjects (74 ± 6 years, 67% male). We obtained whole-body images to quantify PET uptake in peripheral organs and brain images to quantify PET uptake in regions of the brainstem and hypothalamus. Autonomic dysfunction was assessed with questionnaires and measurements of orthostatic blood pressure. Subjects with dementia with Lewy bodies displayed reduced cholinergic tracer uptake in the pancreas (32% reduction, P = 0.0003) and colon (19% reduction, P = 0.0048), but not in organs with little or no parasympathetic innervation. Tracer uptake in a region of the medulla oblongata overlapping the dorsal motor nucleus of the vagus correlated with autonomic symptoms (rs = -0.54, P = 0.0077) and changes in orthostatic blood pressure (rs = 0.76, P < 0.0001). Tracer uptake in the pedunculopontine region correlated with autonomic symptoms (rs = -0.52, P = 0.0104) and a measure of non-motor symptoms (rs = -0.47, P = 0.0230). In conclusion, our findings provide the first imaging-based evidence of impaired cholinergic integrity of the pancreas and colon in dementia with Lewy bodies. The observed changes may reflect parasympathetic denervation, implying that this process is initiated well before the point of diagnosis. The findings also support that cholinergic denervation in the brainstem contributes to dysautonomia.

Mitochondrial function-associated genes underlie cortical atrophy in prodromal synucleinopathies.

Isolated rapid eye movement sleep behaviour disorder (iRBD) is a sleep disorder characterized by the loss of rapid eye movement sleep muscle atonia and the appearance of abnormal movements and vocalizations during rapid eye movement sleep. It is a strong marker of incipient synucleinopathy such as dementia with Lewy bodies and Parkinson's disease. Patients with iRBD already show brain changes that are reminiscent of manifest synucleinopathies including brain atrophy. However, the mechanisms underlying the development of this atrophy remain poorly understood. In this study, we performed cutting-edge imaging transcriptomics and comprehensive spatial mapping analyses in a multicentric cohort of 171 polysomnography-confirmed iRBD patients [67.7 ± 6.6 (49-87) years; 83% men] and 238 healthy controls [66.6 ± 7.9 (41-88) years; 77% men] with T1-weighted MRI to investigate the gene expression and connectivity patterns associated with changes in cortical thickness and surface area in iRBD. Partial least squares regression was performed to identify the gene expression patterns underlying cortical changes in iRBD. Gene set enrichment analysis and virtual histology were then done to assess the biological processes, cellular components, human disease gene terms, and cell types enriched in these gene expression patterns. We then used structural and functional neighbourhood analyses to assess whether the atrophy patterns in iRBD were constrained by the brain's structural and functional connectome. Moreover, we used comprehensive spatial mapping analyses to assess the specific neurotransmitter systems, functional networks, cytoarchitectonic classes, and cognitive brain systems associated with cortical changes in iRBD. All comparisons were tested against null models that preserved spatial autocorrelation between brain regions and compared to Alzheimer's disease to assess the specificity of findings to synucleinopathies. We found that genes involved in mitochondrial function and macroautophagy were the strongest contributors to the cortical thinning occurring in iRBD. Moreover, we demonstrated that cortical thinning was constrained by the brain's structural and functional connectome and that it mapped onto specific networks involved in motor and planning functions. In contrast with cortical thickness, changes in cortical surface area were related to distinct genes, namely genes involved in the inflammatory response, and to different spatial mapping patterns. The gene expression and connectivity patterns associated with iRBD were all distinct from those observed in Alzheimer's disease. In summary, this study demonstrates that the development of brain atrophy in synucleinopathies is constrained by specific genes and networks.

Severe cholinergic terminal loss in newly diagnosed dementia with Lewy bodies.

Cholinergic changes play a fundamental role in the natural history of dementia with Lewy bodies and Lewy body disease in general. Despite important achievements in the field of cholinergic research, significant challenges remain. We conducted a study with four main objectives: (i) to examine the integrity of cholinergic terminals in newly diagnosed dementia with Lewy bodies; (ii) to disentangle the cholinergic contribution to dementia by comparing cholinergic changes in Lewy body patients with and without dementia; (iii) to investigate the in vivo relationship between cholinergic terminal loss and atrophy of cholinergic cell clusters in the basal forebrain at different stages of Lewy body disease; and (iv) to test whether any asymmetrical degeneration in cholinergic terminals would correlate with motor dysfunction and hypometabolism. To achieve these objectives, we conducted a comparative cross-sectional study of 25 newly diagnosed dementia with Lewy bodies patients (age 74 ± 5 years, 84% male), 15 healthy control subjects (age 75 ± 6 years, 67% male) and 15 Parkinson's disease patients without dementia (age 70 ± 7 years, 60% male). All participants underwent 18F-fluoroetoxybenzovesamicol PET and high-resolution structural MRI. In addition, we collected clinical 18F-fluorodeoxyglucose PET images. Brain images were normalized to standard space and regional tracer uptake and volumetric indices of basal forebrain degeneration were extracted. Patients with dementia showed spatially distinct reductions in cholinergic terminals across the cerebral cortex, limbic system, thalamus and brainstem. Also, cholinergic terminal binding in cortical and limbic regions correlated quantitatively and spatially with atrophy of the basal forebrain. In contrast, patients without dementia showed decreased cholinergic terminal binding in the cerebral cortex despite preserved basal forebrain volumes. In patients with dementia, cholinergic terminal reductions were most severe in limbic regions and least severe in occipital regions compared to those without dementia. Interhemispheric asymmetry of cholinergic terminals correlated with asymmetry of brain metabolism and lateralized motor function. In conclusion, this study provides robust evidence for severe cholinergic terminal loss in newly diagnosed dementia with Lewy bodies, which correlates with structural imaging measures of cholinergic basal forebrain degeneration. In patients without dementia, our findings suggest that loss of cholinergic terminal function occurs 'before' neuronal cell degeneration. Moreover, the study supports that degeneration of the cholinergic system is important for brain metabolism and may be linked with degeneration in other transmitter systems. Our findings have implications for understanding how cholinergic system pathology contributes to the clinical features of Lewy body disease, changes in brain metabolism and disease progression patterns.

Brain atrophy in prodromal synucleinopathy is shaped by structural connectivity and gene expression.

Isolated REM sleep behaviour disorder (iRBD) is a synucleinopathy characterized by abnormal behaviours and vocalizations during REM sleep. Most iRBD patients develop dementia with Lewy bodies, Parkinson's disease or multiple system atrophy over time. Patients with iRBD exhibit brain atrophy patterns that are reminiscent of those observed in overt synucleinopathies. However, the mechanisms linking brain atrophy to the underlying alpha-synuclein pathophysiology are poorly understood. Our objective was to investigate how the prion-like and regional vulnerability hypotheses of alpha-synuclein might explain brain atrophy in iRBD. Using a multicentric cohort of 182 polysomnography-confirmed iRBD patients who underwent T1-weighted MRI, we performed vertex-based cortical surface and deformation-based morphometry analyses to quantify brain atrophy in patients (67.8 years, 84% male) and 261 healthy controls (66.2 years, 75%) and investigated the morphological correlates of motor and cognitive functioning in iRBD. Next, we applied the agent-based Susceptible-Infected-Removed model (i.e. a computational model that simulates in silico the spread of pathologic alpha-synuclein based on structural connectivity and gene expression) and tested if it recreated atrophy in iRBD by statistically comparing simulated regional brain atrophy to the atrophy observed in patients. The impact of SNCA and GBA gene expression and brain connectivity was then evaluated by comparing the model fit to the one obtained in null models where either gene expression or connectivity was randomized. The results showed that iRBD patients present with cortical thinning and tissue deformation, which correlated with motor and cognitive functioning. Next, we found that the computational model recreated cortical thinning (r = 0.51, P = 0.0007) and tissue deformation (r = 0.52, P = 0.0005) in patients, and that the connectome's architecture along with SNCA and GBA gene expression contributed to shaping atrophy in iRBD. We further demonstrated that the full agent-based model performed better than network measures or gene expression alone in recreating the atrophy pattern in iRBD. In summary, atrophy in iRBD is extensive, correlates with motor and cognitive function and can be recreated using the dynamics of agent-based modelling, structural connectivity and gene expression. These findings support the concepts that both prion-like spread and regional susceptibility account for the atrophy observed in prodromal synucleinopathies. Therefore, the agent-based Susceptible-Infected-Removed model may be a useful tool for testing hypotheses underlying neurodegenerative diseases and new therapies aimed at slowing or stopping the spread of alpha-synuclein pathology.

Clinical and imaging evidence of brain-first and body-first Parkinson's disease.

Braak's hypothesis has been extremely influential over the last two decades. However, neuropathological and clinical evidence suggest that the model does not conform to all patients with Parkinson's disease (PD). To resolve this controversy, a new model was recently proposed; in brain-first PD, the initial α-synuclein pathology arise inside the central nervous system, likely rostral to the substantia nigra pars compacta, and spread via interconnected structures - eventually affecting the autonomic nervous system; in body-first PD, the initial pathological α-synuclein originates in the enteric nervous system with subsequent caudo-rostral propagation to the autonomic and central nervous system. By using REM-sleep behavior disorder (RBD) as a clinical identifier to distinguish between body-first PD (RBD-positive at motor symptom onset) and brain-first PD (RBD-negative at motor symptom onset), we explored the literature to evaluate clinical and imaging differences between these proposed subtypes. Body-first PD patients display: 1) a larger burden of autonomic symptoms - in particular orthostatic hypotension and constipation, 2) more frequent pathological α-synuclein in peripheral tissues, 3) more brainstem and autonomic nervous system involvement in imaging studies, 4) more symmetric striatal dopaminergic loss and motor symptoms, and 5) slightly more olfactory dysfunction. In contrast, only minor cortical metabolic alterations emerge before motor symptoms in body-first. Brain-first PD is characterized by the opposite clinical and imaging patterns. Patients with pathological LRRK2 genetic variants mostly resemble a brain-first PD profile whereas patients with GBA variants typically conform to a body-first profile. SNCA-variant carriers are equally distributed between both subtypes. Overall, the literature indicates that body-first and brain-first PD might be two distinguishable entities on some clinical and imaging markers.

Regional locus coeruleus degeneration is uncoupled from noradrenergic terminal loss in Parkinson's disease.

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 < 0.0001, P < 0.001; probabilistic map: P < 0.05), specifically on the clinically-defined most affected side (P < 0.05), and reduced locus coeruleus volume (P < 0.0001). Reduced MRI contrast was confined to the middle and caudal locus coeruleus (voxel approach, rostral: P = 0.48, middle: P < 0.0001, and caudal: P < 0.05; probabilistic map, rostral: P = 0.90, middle: P < 0.01, and caudal: P < 0.05). The noradrenaline transporter density was lower in patients with Parkinson's diseasein all examined regions (group effect P < 0.0001). No significant correlation was observed between locus coeruleus MRI contrast and noradrenaline transporter density. In contrast, the individual ratios of noradrenaline transporter density and locus coeruleus MRI contrast were lower in Parkinson's disease patients in all examined regions (group effect P < 0.001). Our multimodal imaging approach revealed pronounced noradrenergic terminal loss relative to cellular locus coeruleus degeneration in Parkinson's disease; the latter followed a distinct spatial pattern with the middle-caudal portion being more affected than the rostral part. 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.

Preserved noradrenergic function in Parkinson's disease patients with rest tremor.

Noradrenergic neurotransmission may play an important role in tremor modulation through its innervation of key structures of the central tremor circuits. Here, Parkinson's disease (PD) patients with (PDT+) or without (PDT-) rest tremor had 11C-methylreboxetine(11C-MeNER) positron emission tomography (PET) to test the hypothesis that noradrenaline terminal function was relatively preserved in PDT+ compared to PDT-. METHODS: Sixty-five PD patients and 28 healthy controls (HC) were scanned with 11C-MeNER PET. Patients were categorized as PDT+ if subscores in UPDRS-III item 3 or MDS-UPDRS-III item 17 was ≥2; remaining were categorized as PDT-. Simplified reference tissue model 2 distribution volume ratios (DVR) for 11C-MeNER were calculated for thalamus, dorsal and median raphe, locus coeruleus (LC) and red nucleus using time activity curves (TACs) obtained from volumes of interest (VOI). Data were statistically interrogated with a general linear mixed model using 'region', and 'group' as factors and the interaction of 'region x group' was examined. RESULTS: Tremor positive PD patients had a significantly higher mean 11C-MeNER DVR compared to PDT- in LC and thalamus. The PDT+ mean LC DVR was similar to that of HC. PDT+ mean 11C-MeNER DVRs were significantly lower than HC in the dorsal raphe while the PDT- group showed significantly lower mean 11C-MeNER DVR across all regions compared to HC. CONCLUSION: While both PD T+ and PD T- groups showed a significant loss of noradrenaline terminal function compared to controls, noradrenergic neurons were relatively preserved in PDT+ in LC and thalamus. The greater loss of noradrenergic transporters in PDT- in LC and thalamus compared with PDT+ is in line with earlier in-vitro studies and could potentially contribute to their tremor negative phenotype.

Brain-first versus body-first Parkinson's disease: a multimodal imaging case-control study.

Parkinson's disease is characterized by the presence of abnormal, intraneuronal α-synuclein aggregates, which may propagate from cell-to-cell in a prion-like manner. However, it remains uncertain where the initial α-synuclein aggregates originate. We have hypothesized that Parkinson's disease comprises two subtypes. A brain-first (top-down) type, where α-synuclein pathology initially arises in the brain with secondary spreading to the peripheral autonomic nervous system; and a body-first (bottom-up) type, where the pathology originates in the enteric or peripheral autonomic nervous system and then spreads to the brain. We also hypothesized that isolated REM sleep behaviour disorder (iRBD) is a prodromal phenotype for the body-first type. Using multimodal imaging, we tested the hypothesis by quantifying neuronal dysfunction in structures corresponding to Braak stages I, II and III involvement in three distinct patient groups. We included 37 consecutive de novo patients with Parkinson's disease into this case-control PET study. Patients with Parkinson's disease were divided into 24 RBD-negative (PDRBD-) and 13 RBD-positive cases (PDRBD+) and a comparator group of 22 iRBD patients. We used 11C-donepezil PET/CT to assess cholinergic (parasympathetic) innervation, 123I-metaiodobenzylguanidine (MIBG) scintigraphy to measure cardiac sympathetic innervation, neuromelanin-sensitive MRI to measure the integrity of locus coeruleus pigmented neurons, and 18F-dihydroxyphenylalanine (FDOPA) PET to assess putaminal dopamine storage capacity. Colon volume and transit times were assessed with CT scans and radiopaque markers. Imaging data from the three groups were interrogated with ANOVA and Kruskal-Wallis tests corrected for multiple comparisons. The PDRBD- and PDRBD+ groups showed similar marked reductions in putaminal FDOPA-specific uptake, whereas two-thirds of iRBD patients had normal scans (P < 10-13, ANOVA). When compared to the PDRBD- patients, the PDRBD+ and iRBD patients showed reduced mean MIBG heart:mediastinum ratios (P < 10-5, ANOVA) and colon 11C-donepezil standard uptake values (P = 0.008, ANOVA). The PDRBD+ group trended towards a reduced mean MRI locus coeruleus: pons ratio compared to PDRBD- (P = 0.07, t-test). In comparison to the other groups, the PDRBD+ group also had enlarged colon volumes (P < 0.001, ANOVA) and delayed colonic transit times (P = 0.01, Kruskal-Wallis). The combined iRBD and PDRBD+ patient data were compatible with a body-first trajectory, characterized by initial loss of cardiac MIBG signal and 11C-colonic donepezil signal followed by loss of putaminal FDOPA uptake. In contrast, the PDRBD- data were compatible with a brain-first trajectory, characterized by primary loss of putaminal FDOPA uptake followed by a secondary loss of cardiac MIBG signal and 11C-donepezil signal. These findings support the existence of brain-first and body-first subtypes of Parkinson's disease.

Evaluation of the noradrenergic system in Parkinson's disease: an 11C-MeNER PET and neuromelanin MRI study.

Pathological involvement of the noradrenergic locus coeruleus occurs early in Parkinson's disease, and widespread noradrenaline reductions are found at post-mortem. Rapid eye movement sleep behaviour disorder (RBD) accompanies Parkinson's disease and its presence predicts an unfavourable disease course with a higher propensity to cognitive impairment and orthostatic hypotension. MRI can detect neuromelanin in the locus coeruleus while 11C-MeNER PET is a marker of noradrenaline transporter availability. Here, we use both imaging modalities to study the association of RBD, cognition and autonomic dysfunction in Parkinson's disease with loss of noradrenergic function. Thirty non-demented Parkinson's disease patients [16 patients with RBD and 14 without RBD, comparable across age (66.6 ± 6.7 years), sex (22 males), and disease stage (Hoehn and Yahr, 2.3 ± 0.5)], had imaging of the locus coeruleus with neuromelanin sensitive MRI and brain noradrenaline transporter availability with 11C-MeNER PET. RBD was confirmed with polysomnography; cognitive function was assessed with a neuropsychological test battery, and blood pressure changes on tilting were documented; results were compared to 12 matched control subjects. We found that Parkinson's disease patients with RBD showed decreased locus coeruleus neuromelanin signal on MRI (P < 0.001) and widespread reduced binding of 11C-MeNER (P < 0.001), which correlated with amount of REM sleep without atonia. Parkinson's disease with RBD was also associated with a higher incidence of cognitive impairment, slowed EEG activity, and orthostatic hypotension. Reduced 11C-MeNER binding correlated with EEG slowing, cognitive performance, and orthostatic hypotension. In conclusion, reduced noradrenergic function in Parkinson's disease was linked to the presence of RBD and associated with cognitive deterioration and orthostatic hypotension. Noradrenergic impairment may contribute to the high prevalence of these non-motor symptoms in Parkinson's disease, and may be of relevance when treating these conditions in Parkinson's disease.

Decreased noradrenaline transporter density in the motor cortex of Parkinson's disease patients.

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.

Imaging the Autonomic Nervous System in Parkinson's Disease.

PURPOSE OF REVIEW: Patients with Parkinson's disease (PD) often display gastrointestinal and genitourinary autonomic symptoms years or even decades prior to diagnosis. These symptoms are thought to be caused in part by pathological α-synuclein inclusions in the peripheral autonomic and enteric nervous systems. It has been proposed that the initial α-synuclein aggregation may in some PD patients originate in peripheral nerve terminals and then spread centripetally to the spinal cord and brainstem. In vivo imaging methods can directly quantify the degeneration of the autonomic nervous system as well as the functional consequences such as perturbed motility. Here, we review the methodological principles of these imaging techniques and the major findings in patients with PD and atypical parkinsonism. RECENT FINDINGS: Loss of sympathetic and parasympathetic nerve terminals in PD can be visualized using radiotracer imaging, including 123I-MIBG scintigraphy, and 18F-dopamine and 11C-donepezil PET. Recently, ultrasonographical studies disclosed reduced diameter of the vagal nerves in PD patients. Radiological and radioisotope techniques have demonstrated dysmotility and prolonged transit time throughout all subdivisions of the gastrointestinal tract in PD. The prevalence of objective dysfunction as measured with these imaging methods is often considerably higher compared to the prevalence of subjective symptoms experienced by the patients. Degeneration of the autonomic nervous system may play a key role in the pathogenesis of PD. In vivo imaging techniques provide powerful and noninvasive tools to quantify the degree and extent of this degeneration and its functional consequences.

Cholinergic PET imaging in infections and inflammation using 11C-donepezil and 18F-FEOBV.

INTRODUCTION: Immune cells utilize acetylcholine as a paracrine-signaling molecule. Many white blood cells express components of the cholinergic signaling pathway, and these are up-regulated when immune cells are activated. However, in vivo molecular imaging of cholinergic signaling in the context of inflammation has not previously been investigated. METHODS: We performed positron emission tomography (PET) using the glucose analogue 18F-FDG, and 11C-donepezil and 18F-FEOBV, markers of acetylcholinesterase and the vesicular acetylcholine transporter, respectively. Mice were inoculated subcutaneously with Staphylococcus aureus, and PET scanned at 24, 72, 120, and 144 h post-inoculation. Four pigs with post-operative abscesses were also imaged. Finally, we present initial data from human patients with infections, inflammation, and renal and lung cancer. RESULTS: In mice, the FDG uptake in abscesses peaked at 24 h and remained stable. The 11C-donepezil and 18F-FEOBV uptake displayed progressive increase, and at 120-144 h was nearly at the FDG level. Moderate 11C-donepezil and slightly lower 18F-FEOBV uptake were seen in pig abscesses. PCR analyses suggested that the 11C-donepezil signal in inflammatory cells is derived from both acetylcholinesterase and sigma-1 receptors. In humans, very high 11C-donepezil uptake was seen in a lobar pneumonia and in peri-tumoral inflammation surrounding a non-small cell lung carcinoma, markedly superseding the 18F-FDG uptake in the inflammation. In a renal clear cell carcinoma no 11C-donepezil uptake was seen. DISCUSSION: The time course of cholinergic tracer accumulation in murine abscesses was considerably different from 18F-FDG, demonstrating in the 11C-donepezil and 18F-FEOBV image distinct aspects of immune modulation. Preliminary data in humans strongly suggest that 11C-donepezil can exhibit more intense accumulation than 18F-FDG at sites of chronic inflammation. Cholinergic PET imaging may therefore have potential applications for basic research into cholinergic mechanisms of immune modulation, but also clinical applications for diagnosing infections, inflammatory disorders, and cancer inflammation.

Constipation in parkinson's disease: Subjective symptoms, objective markers, and new perspectives.

Constipation is among the first nonmotor symptoms to develop in the prodromal phase of PD. Pathological alpha-synuclein deposition is present throughout the gastrointestinal tract up to 20 years preceding diagnosis. Nevertheless, constipation in the context of PD remains ill defined and poorly understood. In this review, we summarize current knowledge of subjective symptoms and objective measures of constipation in PD. More than 10 different definitions of constipation have been used in the PD literature, making generalizations difficult. When pooling results from the most homogeneous studies in PD, a median constipation prevalence of 40% to 50% emerges, but with large variation across individual studies. Also, constipation prevalence tends to increase with disease progression. A similar prevalence is observed among patients with idiopathic rapid eye movement sleep behavior disorder. Interestingly, we detected a correlation between constipation prevalence in PD patients and healthy control groups in individual studies, raising concerns about how various constipation questionnaires are implemented across study populations. More than 80% of PD patients exhibit prolonged colonic transit time, and the same is probably true for de novo PD patients. Thus, the prevalence of objective colonic dysfunction exceeds the prevalence of subjective constipation. Colonic transit time measures are simple, widely available, and hold promise as a useful biomarker in manifest PD. More research is needed to elucidate the role of gastrointestinal dysfunction in disease progression of PD. Moreover, colonic transit measures may have utility as a more accurate risk factor for predicting PD in the prodromal phase. © 2016 International Parkinson and Movement Disorder Society.

In Vivo cortical tau in Parkinson's disease using 18F-AV-1451 positron emission tomography.

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.

In vivo imaging of neuromelanin in Parkinson's disease using 18F-AV-1451 PET.

The tau tangle ligand (18)F-AV-1451 ((18)F-T807) binds to neuromelanin in the midbrain, and may therefore be a measure of the pigmented dopaminergic neuronal count in the substantia nigra. Parkinson's disease is characterized by progressive loss of dopaminergic neurons. Extrapolation of post-mortem data predicts that a ∼30% decline of nigral dopamine neurons is necessary to cause motor symptoms in Parkinson's disease. Putamen dopamine terminal loss at disease onset most likely exceeds that of the nigral cell bodies and has been estimated to be of the order of 50-70%. We investigated the utility of (18)F-AV-1451 positron emission tomography to visualize the concentration of nigral neuromelanin in Parkinson's disease and correlated the findings to dopamine transporter density, measured by (123)I-FP-CIT single photon emission computed tomography. A total of 17 patients with idiopathic Parkinson's disease and 16 age- and sex-matched control subjects had (18)F-AV-1451 positron emission tomography using a Siemens high-resolution research tomograph. Twelve patients with Parkinson's disease also received a standardized (123)I-FP-CIT single photon emission computed tomography scan at our imaging facility. Many of the patients with Parkinson's disease displayed visually apparent decreased (18)F-AV-1451 signal in the midbrain. On quantitation, patients showed a 30% mean decrease in total nigral (18)F-AV-1451 volume of distribution compared with controls (P = 0.004), but there was an overlap of the individual ranges. We saw no significant correlation between symptom dominant side and contralateral nigral volume of distribution. There was no correlation between nigral (18)F-AV-1451 volume of distribution and age or time since diagnosis. In the subset of 12 patients, who also had a (123)I-FP-CIT scan, the mean total striatal dopamine transporter signal was decreased by 45% and the mean total (18)F-AV-1451 substantia nigra volume of distribution was decreased by 33% after median disease duration of 4.7 years (0.5-12.4 years). (18)F-AV-1451 positron emission tomography may be the first radiotracer to reflect the loss of pigmented neurons in the substantia nigra of parkinsonian patients. The magnitude of the nigral signal loss was smaller than the decrease in striatal dopamine transporter signal measured by dopamine transporter single photon emission computed tomography. These findings suggest a more severe loss of striatal nerve terminal function compared with neuronal cell bodies, in accordance with the post-mortem literature.

Imaging Systemic Dysfunction in Parkinson's Disease.

Parkinson's disease is now widely recognized to be a multisystem disorder affecting the brain and peripheral autonomic nerves. Extensive pathology is present in both the sympathetic and parasympathetic nervous system and the intrinsic gastrointestinal plexuses in patients. Autonomic pathology and symptoms such as constipation can predate the clinical diagnosis by years or decades. Imaging studies have contributed greatly to our understanding of Parkinson's disease but focused primarily on imaging cerebral pathology. However, given the importance of understanding the nature, chronology, and functional consequences of peripheral pathology, there has been renewed interest in imaging peripheral organs in Parkinson's disease. Suitable imaging tools can be divided into two types: radiotracer studies that directly estimate loss of sympathetic or parasympathetic nerve terminals, and imaging modalities to quantitate dysphagia, gastric emptying, esophageal and intestinal transit times, and anorectal dyssynergia. In this review, we summarize current knowledge about peripheral imaging in Parkinson's disease.

Imaging acetylcholinesterase density in peripheral organs in Parkinson's disease with 11C-donepezil PET.

Parkinson's disease is associated with early parasympathetic dysfunction leading to constipation and gastroparesis. It has been suggested that pathological α-synuclein aggregations originate in the gut and ascend to the brainstem via the vagus. Our understanding of the pathogenesis and time course of parasympathetic denervation in Parkinson's disease is limited and would benefit from a validated imaging technique to visualize the integrity of parasympathetic function. The positron emission tomography tracer 5-[(11)C]-methoxy-donepezil was recently validated for imaging acetylcholinesterase density in the brain and peripheral organs. Donepezil is a high-affinity ligand for acetylcholinesterase-the enzyme that catabolizes acetylcholine in cholinergic synapses. Acetylcholinesterase histology has been used for many years for visualizing cholinergic neurons. Using 5-[(11)C]-methoxy-donepezil positron emission tomography, we studied 12 patients with early-to-moderate Parkinson's disease (three female; age 64 ± 9 years) and 12 age-matched control subjects (three female; age 62 ± 8 years). We collected clinical information about motor severity, constipation, gastroparesis, and other parameters. Heart rate variability measurements and gastric emptying scintigraphies were performed in all subjects to obtain objective measures of parasympathetic function. We detected significantly decreased (11)C-donepezil binding in the small intestine (-35%; P = 0.003) and pancreas (-22%; P = 0.001) of the patients. No correlations were found between the (11)C-donepezil signal and disease duration, severity of constipation, gastric emptying time, and heart rate variability. In Parkinson's disease, the dorsal motor nucleus of the vagus undergoes severe degeneration and pathological α-synuclein aggregations are also seen in nerve fibres innervating the gastro-intestinal tract. In contrast, the enteric nervous system displays little or no loss of cholinergic neurons. Decreases in (11)C-donepezil binding may, therefore, represent a marker of parasympathetic denervation of internal organs, but further validation studies are needed.

Functional and 123I-MIBG scintigraphy assessment of cardiac adrenergic dysfunction in diabetes.

OBJECTIVES: To assess the agreement between clinical cardiovascular adrenergic function and cardiac adrenergic innervation in type 2 diabetes patients (T2D). METHODS: Thirty-three patients with T2D were investigated bimodally through (1) a standardized clinical cardiovascular adrenergic assessment, evaluating adequacy of blood pressure responses to the Valsalva maneuver and (2) 123I-meta-iodobenzylguanidine (MIBG) scintigraphy assessing myocardial adrenergic innervation measured as early and delayed heart heart/mediastinum (H/M) ratio, and washout rate (WR). RESULTS: T2D patients had significantly lower early and delayed H/M-ratios, and lower WR, compared to laboratory specific reference values. Thirteen patients had an abnormal adrenergic composite autonomic severity score (CASS > 0). Patients with abnormal CASS scores had significantly higher early H/M ratios (1.76 [1.66-1.88] vs. 1.57 [1.49-1.63], p < 0.001), higher delayed H/M ratios (1.64 [1.51:1.73] vs. 1.51 [1.40:1.61] (p = 0.02)), and lower WR (-0.13(0.10) vs -0.05(0.07), p = 0.01). Lower Total Recovery and shorter Pressure Recovery Time responses from the Valsalva maneuver was significantly correlated to lower H/M early (r = 0.55, p = 0.001 and r = 0.5, p = 0.003, respectively) and lower WR for Total Recovery (r = -0.44, p = 0.01). CONCLUSION: The present study found impairment of sympathetic innervation in T2D patients based on parameters derived from MIBG cardiac scintigraphy (low early H/M, delayed H/M, and WR). These results confirm prior studies. We found a mechanistically inverted relationship with favourable adrenergic cardiovascular responses being significantly associated unfavourable MIBG indices for H/M early and delayed. This paradoxical relationship needs to be further explored but could indicate adrenergic hypersensitivity in cardiac sympathetic denervated T2D patients.

Dopaminergic Dysfunction Is More Symmetric in Dementia with Lewy Bodies Compared to Parkinson's Disease.

BACKGROUND: The α-syn Origin site and Connectome model (SOC) proposes that α-synucleinopathies can be divided into two categories: the asymmetrical brain-first, and more symmetrical body-first Lewy body disease. We have hypothesized that most patients with dementia with Lewy bodies (DLB) belong to the body-first subtype, whereas patients with Parkinson's disease (PD) more often belong to the brain-first subtype. OBJECTIVE: To compare asymmetry of striatal dopaminergic dysfunction in DLB and PD patients using [18F]-FE-PE2I positron emission tomography (PET). METHODS: We analyzed [18F]-FE-PE2I PET data from 29 DLB patients and 76 PD patients who were identified retrospectively during a 5-year period at Dept. of Neurology, Aarhus University Hospital. Additionally, imaging data from 34 healthy controls was used for age-correction and visual comparison. RESULTS: PD patients showed significantly more asymmetry in specific binding ratios between the most and least affected putamen (p < 0.0001) and caudate (p = 0.003) compared to DLB patients. PD patients also had more severe degeneration in the putamen compared to the caudate in comparison to DLB patients (p < 0.0001) who had a more universal pattern of striatal degeneration. CONCLUSION: Patients with DLB show significantly more symmetric striatal degeneration on average compared to PD patients. These results support the hypothesis that DLB patients may be more likely to conform to the body-first subtype characterized by a symmetrical spread of pathology, whereas PD patients may be more likely to conform to the brain-first subtype with more lateralized initial propagation of pathology.