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.

Microglial TNFR2 signaling regulates the inflammatory response after CNS injury in a sex-specific fashion.

Microglia, the resident immune cells of the central nervous system (CNS), play a major role in damage progression and tissue remodeling after acute CNS injury, including ischemic stroke (IS) and spinal cord injury (SCI). Understanding the molecular mechanisms regulating microglial responses to injury may thus reveal novel therapeutic targets to promote CNS repair. Here, we investigated the role of microglial tumor necrosis factor receptor 2 (TNFR2), a transmembrane receptor previously associated with pro-survival and neuroprotective responses, in shaping the neuroinflammatory environment after CNS injury. By inducing experimental IS and SCI in Cx3cr1CreER:Tnfrsf1bfl/fl mice, selectively lacking TNFR2 in microglia, and corresponding Tnfrsf1bfl/fl littermate controls, we found that ablation of microglial TNFR2 significantly reduces lesion size and pro-inflammatory cytokine levels, and favors infiltration of leukocytes after injury. Interestingly, these effects were paralleled by opposite sex-specific modifications of microglial reactivity, which was found to be limited in female TNFR2-ablated mice compared to controls, whereas it was enhanced in males. In addition, we show that TNFR2 protein levels in the cerebrospinal fluid (CSF) of human subjects affected by IS and SCI, as well as healthy donors, significantly correlate with disease stage and severity, representing a valuable tool to monitor the inflammatory response after acute CNS injury. Hence, these results advance our understanding of the mechanisms regulating microglia reactivity after acute CNS injury, aiding the development of sex- and microglia-specific, personalized neuroregenerative strategies.

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.

Distribution of cholinergic nerve terminals in the aged human brain measured with [18F]FEOBV PET and its correlation with histological data.

INTRODUCTION: [18F]fluoroetoxybenzovesamicol ([18F]FEOBV) is a positron emission topography (PET) tracer for the vesicular acetylcholine transporter (VAChT), a protein located predominantly in synaptic vesicles in cholinergic nerve terminals. We aimed to use [18F]FEOBV PET to study the cholinergic topography of the healthy human brain. MATERIALS AND METHODS: [18F]FEOBV PET brain data volumes of healthy elderly humans were normalized to standard space and intensity-normalized to the white matter. Stereotactic atlases of regions of interest were superimposed to describe and quantify tracer distribution. The spatial distribution of [18F]FEOBV PET uptake was compared with histological and gene expression data. RESULTS: Twenty participants of both sexes and a mean age of 73.9 ± 6.0 years, age-range [64; 86], were recruited. Highest tracer binding was present in the striatum, some thalamic nuclei, and the basal forebrain. Intermediate binding was found in most nuclei of the brainstem, thalamus, and hypothalamus; the vermis and flocculonodular lobe; and the hippocampus, amygdala, insula, cingulate, olfactory cortex, and Heschl's gyrus. Lowest binding was present in most areas of the cerebral cortex, and in the cerebellar nuclei and hemispheres. The spatial distribution of tracer correlated with immunohistochemical post-mortem data, as well as with regional expression levels of SLC18A3, the VAChT coding gene. DISCUSSION: Our in vivo findings confirm the regional cholinergic distribution in specific brain structures as described post-mortem. A positive spatial correlation between tracer distribution and regional gene expression levels further corroborates [18F]FEOBV PET as a validated tool for in vivo cholinergic imaging. The study represents an advancement in the continued efforts to delineate the spatial topography of the human cholinergic system in vivo.

Synaptic Density and Glucose Consumption in Patients with Lewy Body Diseases: An [11 C]UCB-J and [18 F]FDG PET Study.

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

Neuropathological evidence of body-first vs. brain-first Lewy body disease.

Aggregation of alpha-synuclein into inclusion bodies, termed Lewy pathology, is a defining feature of Parkinson's disease (PD) and Dementia with Lewy bodies (DLB). In the majority of post mortem cases, the distribution of Lewy pathology seems to follow two overarching patterns: a caudo-rostral pattern with relatively more pathology in the brainstem than in the telencephalon, and an amygdala-centered pattern with the most abundant pathology in the "center of the brain", including the amygdala, entorhinal cortex, and substantia nigra, and relatively less pathology in the lower brainstem and spinal autonomic nuclei. The recent body-first versus brain-first model of Lewy Body Disorders proposes that the initial pathogenic alpha-synuclein in some patients originates in the enteric nervous system with secondary spreading to the brain; and in other patients originates inside the CNS with secondary spreading to the lower brainstem and peripheral autonomic nervous system. Here, we use two existing post mortem datasets to explore the possibility that clinical body-first and brain-first subtypes are equivalent to the caudo-rostral and amygdala-centered patterns of Lewy pathology seen at post mortem.

Reduced Synaptic Density in Patients with Lewy Body Dementia: An [11 C]UCB-J PET Imaging Study.

BACKGROUND: Patients with Parkinson's disease (PD) often develop dementia, but the underlying substrate is incompletely understood. Generalized synaptic degeneration may contribute to dysfunction and cognitive decline in Lewy body dementias, but in vivo evidence is lacking. OBJECTIVE: The objective of this study was to assess the density of synapses in non-demented PD (nPD) subjects (N = 21), patients with PD-dementia or Dementia with Lewy bodies (DLB) (N = 13), and age-matched healthy controls (N = 15). METHOD: Using in vivo PET imaging and the novel synaptic-vesicle-glycoprotein 2A (SV2A) radioligand [11C]UCB-J, SUVR-1 values were obtained for 12 pre-defined regions. Volumes-of-interest were defined on MRI T1 scans. Voxel-level between-group comparisons of [11C]UCB-J SUVR-1 were performed. All subjects underwent neuropsychological assessment. Correlations between [11C]UCB- J PET and domain-specific cognitive functioning were examined. RESULTS: nPD patients only demonstrated significantly reduced SUVR-1 values in the substantia nigra (SN) compared to HC. DLB/PDD patients demonstrated reduced SUVR-1 values in SN and all cortical VOIs except for the hippocampus and amygdala. The voxel-based analysis supported the VOI results. Significant correlation was seen between middle frontal gyrus [11C]UCB-J SUVR-1 and performance on tests of executive function. CONCLUSION: Widespread cortical reduction of synaptic density was documented in a cohort of DLB/PDD subjects using in vivo [11C]UCB-J PET. Our study confirms previously reported synaptic loss in SN of nPD patients. [11C]UCB-J binding in selected cortical VOIs of the DLB/PDD patients correlated with their levels of cognitive function across relevant neuropsychological domains. These findings suggest that the loss of synaptic density contributes to cognitive impairment in nPD and DLB/PDD. © 2021 International Parkinson and Movement Disorder Society.

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.

Premature mortality in persons with epilepsy and schizophrenia: A population-based nationwide cohort study.

OBJECTIVE: To determine the mortality for persons with epilepsy and schizophrenia by absolute and relative measures. METHODS: This is a population-based nationwide cohort study of persons born in Denmark from 1960 to 1987 who were alive and residing in Denmark on their 25th birthday. We identified persons diagnosed with epilepsy and schizophrenia prior to their 25th birthday and followed them to death, emigration, or December 31, 2012, whichever came first. The primary outcome was overall mortality. Data were analyzed using Cox regressions. RESULTS: Persons were followed for 24 167 573 person years; the median was 15 years. The mortality rate ratio was 4.4 (95% confidence interval [CI] = 4.1-4.7) for persons with epilepsy, 6.6 (95% CI = 6.1-7.1) for persons with schizophrenia, and 12.8 (95% CI = 9.1-18.1) for persons with both disorders, compared with persons without these disorders. The estimated cumulative mortality at the age of 50 years was 3.1% (95% CI = 3.0-3.1) for persons without epilepsy and schizophrenia, 10.7% (95% CI = 9.7-11.8) for persons with epilepsy, 17.4% (95% CI = 16.0-18.8) for persons with schizophrenia, and 27.2% (95% CI = 15.7-40.1) for persons with both disorders. SIGNIFICANCE: Persons with epilepsy and schizophrenia have very high mortality; more than one in four persons with both disorders died between the age of 25 and 50 years, indicating that these patients need special clinical attention.

The sorting receptor SorCS3 is a stronger regulator of glutamate receptor functions compared to GABAergic mechanisms in the hippocampus.

Correct function of glutamate receptors in the postsynaptic density is crucial to synaptic function and plasticity. SorCS3 (sortilin-related receptor CNS expressed 3) is a sorting receptor which previously has been shown to interact with the key postsynaptic proteins; PSD-95 and PICK1. In this study, we employed electrophysiological analyses of acute brain slices combined with immunohistochemistry to define the role of SorCS3 in hippocampal synapses in CA1 and the dentate gyrus. We analyzed a juvenile (P17-21) and a young adult (P55-65) group of animals from a Sorcs3 knockout mouse model. We show that the basal synaptic transmission is severely affected in SorCS3-deficient neurons in CA1, while only slightly reduced in the dentate gyrus. Specifically, input/output curves of CA1 synapses revealed a 20% reduction of fEPSP (field excitatory postsynaptic potential) slopes at the highest stimulation intensity in knockouts of the juvenile group, which developed to a 33% decrease in young adult animals. These impairments may be a result of changes in the postsynaptic AMPA receptors. Interestingly, repetitive afferent stimulation demonstrated that SorCS3-deficient slices respond with an enhanced synaptic facilitation and reduced synaptic depression. These changes also developed with age. A molecular mechanism underlying this relative increase during repetitive stimulations is compatible with enhanced mobility of postsynaptic AMPA receptors resulting in faster exchange of desensitized receptors in the postsynaptic density. The altered response during repetitive stimulation was characteristic for CA1 but not the dentate gyrus. Immunohistochemical analyses of parvalbumin positive neurons combined with paired-pulse tests of network inhibition and patch-clamp recordings only showed minute inhibitory changes in SorCS3-deficient slices. Our results suggest that SorCS3 serves an important role in the postsynaptic protein network, which is more pronounced in CA1 compared to the dentate gyrus. These data support a role for SorCS3 in controlling proper positioning and mobility of glutamate receptors in the postsynaptic density. © 2016 Wiley Periodicals, Inc.

Sibling relatedness and pubertal development in girls and boys: A population-based cohort study.

PURPOSE: To investigate the association between sibling relatedness and pubertal development in girls and boys. METHODS: This cohort study consisted of 10,657 children from the Puberty Cohort, Denmark. Information on sibling relatedness was obtained by self-report. Information on pubertal markers was obtained half yearly from age 11 and throughout puberty. Mean age difference at attaining pubertal markers was estimated using interval-censored regression models according to sibling relatedness (full, half and/or step siblings; half and/or step siblings; no siblings; relative to full siblings). RESULTS: Girls with both full, half and/or step siblings (-1.2 (CI 95 %: -2.5; 0.1) months), only half- and/or stepsiblings (-2.2 (CI 95 %: -3.7; -0.7) months), and no siblings (-5.5 (CI 95 %: -8.5; -2.5) months) entered puberty earlier than girls with full siblings. Boys with full, half and/or step siblings (-1.4 (CI 95 %: -2.7; -0.1) months), only half and/or step siblings (-1.2 (CI 95 %: -3.0; 0.6) months), and no siblings (-4.5 (CI 95 %: -8.8; -0.3) months) entered puberty earlier than boys with full siblings. CONCLUSIONS: Children with sibling relatedness other than full siblings entered puberty earlier than their peers with full siblings even after adjustment for parental cohabitation status, childhood body mass index and childhood internalizing and externalizing symptoms.

Correlation between dopaminergic and metabolic asymmetry in Lewy body disease - A dual-imaging study.

INTRODUCTION: The a-Synuclein Origin and Connectome (SOC) model of Lewy body diseases postulates that a-syuclein will be asymmetrically distributed in some patients with Lewy body diseases, potentially leading to asymmetric neuronal dysfunction and symptoms. METHODS: We included two patient groups: 19 non-demented Parkinson's disease (nPD) patients with [18F]FDG PET and motor symptoms assessed by UPDRS-III, and 65 Lewy body dementia (LBD) patients with [18F]FDG PET and dopamine radioisotope imaging. Asymmetry indices were calculated for [18F]FDG PET by including the cortex for each hemisphere, for dopamine radioisotope imaging by including the putamen and caudate separately, and for motor symptoms by using the difference between right-left UPDRS-III score. Correlations between these asymmetry indices were explored to test the predictions of the SOC model. To identify cases with a more typical LBD imaging profile, we calculated a Cingulate Island Sign (CIS) index on the [18F]FDG PET image. RESULTS: We found a significant correlation between cortical interhemispheric [18F]FDG asymmetry and motor-symptom asymmetry in nPD patients (r = 0.62, P = 0.004). In patients with LBD, we found a significant correlation between cortical interhemispheric [18F]FDG asymmetry and dopamine transporter asymmetry in the caudate (r = 0.37, P = 0.0019), but not in the putamen (r = 0.15, P = 0.22). We observed that the correlation in the caudate was stronger in LBD subjects with the highest CIS index, i.e., with more typical LBD imaging profiles. CONCLUSION: Our study partly supports the SOC model, but further investigations are needed - ideally of de novo, non-demented PD patients.

Cerebral microvascular changes in healthy carriers of the APOE-ɛ4 Alzheimer's disease risk gene.

APOE-ɛ4 is a genetic risk factor for Alzheimer's disease (AD). AD is associated with reduced cerebral blood flow (CBF) and with microvascular changes that limit the transport of oxygen from blood into brain tissue: reduced microvascular cerebral blood volume and high relative transit time heterogeneity (RTH). Healthy APOE-ɛ4 carriers reveal brain regions with elevated CBF compared with carriers of the common ɛ3 allele. Such asymptomatic hyperemia may reflect microvascular dysfunction: a vascular disease entity characterized by suboptimal tissue oxygen uptake, rather than limited blood flow per se. Here, we used perfusion MRI to show that elevated regional CBF is accompanied by reduced capillary blood volume in healthy APOE-ɛ4 carriers (carriers) aged 30-70 years compared with similarly aged APOE-ɛ3 carriers (noncarriers). Younger carriers have elevated hippocampal RTH and more extreme RTH values throughout both white matter (WM) and cortical gray matter (GM) compared with noncarriers. Older carriers have reduced WM CBF and more extreme GM RTH values than noncarriers. Across all groups, lower WM and hippocampal RTH correlate with higher educational attainment, which is associated with lower AD risk. Three days of dietary nitrate supplementation increased carriers' WM CBF but caused older carriers to score worse on two of six aggregate neuropsychological scores. The intervention improved late recall in younger carriers and in noncarriers. The APOE-ɛ4 gene is associated with microvascular changes that may impair tissue oxygen extraction. We speculate that vascular risk factor control is particularly important for APOE-ɛ4 carriers' healthy aging.

Healthy brain aging assessed with [18F]FDG and [11C]UCB-J PET.

BACKGROUND: The average human lifespan has increased dramatically over the past century. However, molecular and physiological alterations of the healthy brain during aging remain incompletely understood. Generalized synaptic restructuring may contribute to healthy aging and the reduced metabolism observed in the aged brain. The aim of this study was to assess healthy brain aging using [18F]FDG as a measure of cerebral glucose consumption and [11C]UCB-J PET as an indicator of synaptic density. METHOD: Using in vivo PET imaging and the novel synaptic-vesicle-glycoprotein 2A (SV2A) radioligand [11C]UCB-J alongside with the fluorodeoxyglucose radioligand [18F]FDG, we obtained SUVR-1 values for 14 pre-defined volume-of-interest brain regions defined on MRI T1 scans. Regional differences in relative [18F]FDG and [11C]UCB-J uptake were investigated using a voxel-wise approach. Finally, correlations between [11C]UCB-J, [18F]FDG PET, and age were examined. RESULTS: We found widespread cortical reduction of synaptic density in a cohort of older HC subjects (N = 15) compared with young HC subjects (N = 11). However, no reduction persisted after partial volume correction and corrections for multiple comparison. Our study confirms previously reported synaptic stability during aging. Regional differences in relative [18F]FDG and [11C]UCB-J uptake were observed with up to 20 % higher [11C]UCB-J uptake in the amygdala and temporal lobe and up to 34 % higher glucose metabolism in thalamus, striatum, occipital, parietal and frontal cortex. CONCLUSION: In vivo PET using [11C]UCB-J does not support declining synaptic density levels during aging. Thus, loss of synaptic density may be unrelated to aging and does not seem to be a sufficient explanation for the recognized reduction in brain metabolism during aging. Our study also demonstrates that the relationship between glucose consumption and synaptic density is not uniform throughout the human brain with implications for our understanding of neuroenergetics.

Imaging progressive peripheral and central dysfunction in isolated REM sleep behaviour disorder after 3 years of follow-up.

INTRODUCTION: Most patients with isolated rapid eye movement sleep behaviour disorder (iRBD) convert to Parkinson's disease (PD), dementia with Lewy bodies, or multiple system atrophy within 15 years of diagnosis. Furthermore, iRBD patients develop non-motor symptoms similar to those of manifest PD patients and display dysfunction of the sympathetic and parasympathetic nervous system, comparable to that seen in PD. However, progression rates of autonomic dysfunction in iRBD have not been studied with objective measures in detail, which is the aim of this study. METHODS: Twenty-two iRBD patients were included at baseline and 14 participated in follow-up after 3 years. Colonic transit time (CTT) was examined using radio opaque markers, colonic volume was defined on abdominal computed tomography (CT) scans, Iodine-123-metaiodobenzylguanidine ([123I]MIBG) scintigraphy was performed to assess cardiac sympathetic innervation, and 3,4-dihydroxy-6-(18F) fluoro-l-phenylalanine ([18F]FDOPA) positron emission tomography (PET) scan determined nigrostriatal dopamine storage capacity. All examinations were performed at baseline and after 3 years. RESULTS: iRBD patients displayed increased CTT (p = 0.001) and colonic volume (p = 0.01) at follow-up compared to baseline. Furthermore, [123I]MIBG uptake and [18F]FDOPA uptake showed progressive reductions at follow-up (p = 0.02 and p = 0.002, respectively). No correlations were seen between changes in intestinal or cardiac measurements and dopaminergic function. CONCLUSION: Using objective markers, the present study documented that intestinal dysfunction and cardiac sympathetic degeneration worsen in the majority of iRBD patients over a 3-year period. The absent correlation between these markers and nigrostriatal dopaminergic dysfunction suggests that progressive gastrointestinal and cardiac dysfunction in iRBD is caused mainly by non-dopaminergic mechanisms.

Mapping Cholinergic Synaptic Loss in Parkinson's Disease: An [18F]FEOBV PET Case-Control Study.

BACKGROUND: Cholinergic degeneration is strongly associated with cognitive decline in patients with Parkinson's disease (PD) but may also cause motor symptoms and olfactory dysfunction. Regional differences are striking and may reflect different PD related symptoms and disease progression patterns. OBJECTIVE: To map and quantify the regional cerebral cholinergic alterations in non-demented PD patients. METHODS: We included 15 non-demented PD patients in early-moderate disease stage and 15 age- and sex-matched healthy controls for [18F]FEOBV positron emission tomography imaging. We quantitated regional variations using VOI-based analyses which were supported by a vertex-wise cluster analysis. Correlations between imaging data and clinical and neuropsychological data were explored. RESULTS: We found significantly decreased [18F]FEOBV uptake in global neocortex (38%, p = 0.0002). The most severe reductions were seen in occipital and posterior temporo-parietal regions (p < 0.0001). The vertex-wise cluster analysis corroborated these findings. All subcortical structures showed modest non-significant reductions. Motor symptoms (postural instability and gait difficulty) and cognition (executive function and composite z-score) correlated with regional [18F]FEOBV uptake (thalamus and cingulate cortex/insula/hippocampus, respectively), but the correlations were not statistically significant after multiple comparison correction. A strong correlation was found between interhemispheric [18F]FEOBV asymmetry, and motor symptom asymmetry of the extremities (r = 0.84, p = 0.0001). CONCLUSION: Cortical cholinergic degeneration is prominent in non-demented PD patients, but more subtle in subcortical structures. Regional differences suggest uneven involvement of cholinergic nuclei in the brain and may represent a window to follow disease progression. The correlation between asymmetric motor symptoms and neocortical [18F]FEOBV asymmetry indicates that unilateral cholinergic degeneration parallels ipsilateral dopaminergic degeneration.

Asymmetric Dopaminergic Dysfunction in Brain-First versus Body-First Parkinson's Disease Subtypes.

BACKGROUND: We have hypothesized that Parkinson's disease (PD) comprises two subtypes. Brain-first, where pathogenic α-synuclein initially forms unilaterally in one hemisphere leading to asymmetric nigrostriatal degeneration, and body-first with initial enteric pathology, which spreads through overlapping vagal innervation leading to more symmetric brainstem involvement and hence more symmetric nigrostriatal degeneration. Isolated REM sleep behaviour disorder has been identified as a strong marker of the body-first type. OBJECTIVE: To analyse striatal asymmetry in [18F]FDOPA PET and [123I]FP-CIT DaT SPECT data from iRBD patients, de novo PD patients with RBD (PD+RBD) and de novo PD patients without RBD (PD-RBD). These groups were defined as prodromal body-first, de novo body-first, and de novo brain-first, respectively. METHODS: We included [18F]FDOPA PET scans from 21 iRBD patients, 11 de novo PD+RBD, 22 de novo PD-RBD, and 18 controls subjects. Also, [123I]FP-CIT DaT SPECT data from iRBD and de novo PD patients with unknown RBD status from the PPPMI dataset was analysed. Lowest putamen specific binding ratio and putamen asymmetry index (AI) was defined. RESULTS: Nigrostriatal degeneration was significantly more symmetric in patients with RBD versus patients without RBD or with unknown RBD status in both FDOPA (p = 0.001) and DaT SPECT (p = 0.001) datasets. CONCLUSION: iRBD subjects and de novo PD+RBD patients present with significantly more symmetric nigrostriatal dopaminergic degeneration compared to de novo PD-RBD patients. The results support the hypothesis that body-first PD is characterized by more symmetric distribution most likely due to more symmetric propagation of pathogenic α-synuclein compared to brain-first PD.

Vagus Nerve Cross-Sectional Area in Patients With Parkinson's Disease-An Ultrasound Case-Control Study.

Background: Vagal parasympathetic neurons are prone to degeneration in Parkinson's disease (PD). High-resolution ultrasound can precisely estimate the cross-sectional (CSA) area of peripheral nerves. Here, we tested the hypothesis that vagus CSA is reduced in PD. Methods: We included 56 healthy controls (HCs) and 63 patients with PD. Using a high-end ultrasound system equipped with a high-frequency transducer, five images were obtained of each nerve. The hypoechoic neuronal tissue was delineated offline with dedicated software and the CSA extracted. Results: In the initial PD vs. HC comparison, no statistically significant differences were observed in mean left vagus CSA (HC: 1.97 mm2, PD: 1.89 mm2, P = 0.36) nor in mean right vagus CSA (HC: 2.37 mm2, PD: 2.23 mm2, P = 0.17). The right vagus CSA was significantly larger than the left vagus CSA in both groups (P < 0.0001). Females were overrepresented in the HC group and presented with generally smaller vagus CSAs. Consequently, sex-adjusted CSA was significantly smaller for the right vagus nerve of the PD group (P = 0.041), but not for the left. Conclusion: A small but significant reduction in sex-adjusted right vagus CSA was observed in patients with PD. The left vagus CSA was not significantly reduced in patients with PD. Ultrasound may not be a suitable method to detecting vagal axonal loss in individual patients.

Altered sensorimotor cortex noradrenergic function in idiopathic REM sleep behaviour disorder - A PET study.

INTRODUCTION: Noradrenergic denervation is thought to aggravate motor dysfunction in Parkinson's disease (PD). In a previous PET study with the norepinephrine transporter (NART) ligand 11C-MeNER, we detected reduced NART binding in primary sensorimotor cortex (M1S1) of PD patients. Idiopathic rapid-eye-movement sleep behaviour disorder (iRBD) is a phenotype of prodromal PD. Using 11C-MeNER PET, we investigated whether iRBD patients showed similar NART binding reductions in M1S1 cortex as PD patients. Additionally, we investigated whether 11C-MeNER binding and loss of nigrostriatal dopamine storage capacity measured with 18F-DOPA PET were correlated. METHODS: 17 iRBD patients, 16 PD patients with (PDRBD+) and 14 without RBD (PDRBD-), and 25 control subjects underwent 11C-MeNER PET. iRBD patients also had 18F-DOPA PET. Volume-of-interest analyses and voxel-level statistical parametric mapping were performed. RESULTS: Partial-volume corrected 11C-MeNER binding potential (BPND) values in M1S1 differed across the groups (P = 0.022) with the iRBD and PDRBD+ groups showing significant reductions (controls vs. iRBD P = 0.007; control vs. PDRBD+P = 0.008). Voxel-wise comparisons confirmed reductions of M1S1 11C-MeNER binding in PD and iRBD patients. Significant correlation was seen between putaminal 18F-DOPA uptake and thalamic 11C-MeNER binding in iRBD patients (r2 = 0.343, P = 0.013). CONCLUSIONS: This study found altered noradrenergic neurotransmission in the M1S1 cortex of iRBD patients. The observed reduction of M1S1 11C-MeNER binding in iRBD may represent noradrenergic terminal degeneration or physiological down-regulation of NARTs in this prodromal phenotype of PD. The correlation between thalamic 11C-MeNER binding and putaminal 18F-DOPA binding suggests that these neurotransmitter systems degenerate in parallel in the iRBD phenotype of prodromal PD.

Normative values for region-specific colonic and gastrointestinal transit times in 111 healthy volunteers using the 3D-Transit electromagnet tracking system: Influence of age, gender, and body mass index.

BACKGROUND: The 3D-Transit electromagnet tracking system (Motilis Medica, SA, Lausanne, Switzerland) is an emerging tool for the ambulatory assessment of gastrointestinal (GI) transit and motility. Using this tool, we aimed to derive normative values for region-specific colonic and GI transit times and to assess the influence of age, gender, and body mass index (BMI). METHODS: Regional and total colonic transit times (CTT), gastric emptying (GET), small intestinal (SITT), and whole gut (WGTT) transit times were extracted from 111 healthy volunteers from the United Kingdom and Denmark (58 female; median age: 40 years [range: 21-88]). The effects of age, gender, and BMI were assessed using standard statistical methods. KEY RESULTS: The ascending, transverse, descending, and rectosigmoid colon transit times accounted for 32%, 34%, 17%, and 17% of total CTT in females, and 33%, 25%, 14%, and 28% of total CTT in males. CTT and WGTT were seen to cluster at intervals separated by approximately 24 hours, providing further evidence of the non-continuous nature of these measurements. Increasing age was associated with longer CTT (P = .021), WGTT (P < .001) ascending (P = .004), transverse (P < .001), and total right (P < .001) colon transit times, but shorter rectosigmoid (P = .004) transit time. Female gender was significantly associated with longer transverse (P = .049) and descending (P < .001) colon transit times, but shorter rectosigmoid (P < .001) transit time. Increasing BMI was significantly associated with shorter WGTT (P = .012). CONCLUSIONS AND INFERENCES: For the first time, normative reference values for region-specific colonic transit have been presented. Age, gender, and BMI were seen to have an effect on transit times.