In-vivo staging of pathology in REM sleep behaviour disorder: a multimodality imaging case-control study

Knudsen, Karen A.; Fedorova, Tatyana D.; Hansen, Allan K; Sommerauer, Michael; Otto, Marit; Svendsen, Kristina Bacher; Nahimi, Adjmal; Stokholm, Morten Gersel; Pavese, Nicola; Beier, Christoph P.; Brooks, David J.; Borghammer, Per

doi:10.1016/s1474-4422(18)30162-5

Cited by 258 publications

(298 citation statements)

References 49 publications

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“…Moreover, nearly all prodromal PD patients with REM sleep behavior disorder display fulminant cardiac denervation at an early time point, when their nigrostriatal dopamine system is still mostly intact [22, 28]. The etiology behind cardiac denervation is unknown, but it seems clear that the noradrenergic postganglionic neurons also constitute a particularly vulnerable cell population.…”

Section: Discussionmentioning

confidence: 99%

“…Asyn pathology can be detected in the gut of PD patients up to 20 years prior to diagnosis [18, 45, 48], and full truncal vagotomy seems to lower the risk of PD by 40–50% after 10–20 years of follow-up [23, 51]. Also, recent in vivo imaging data showed that prodromal PD patients display marked damage to the parasympathetic and sympathetic nervous system, while their nigrostriatal dopamine system is still relatively intact [22]. Moreover, recent studies support a bidirectional link between gastrointestinal inflammation and the initiation and progression of PD [39].…”

Section: Introductionmentioning

confidence: 99%

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Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats

et al. 2019

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The conversion of endogenous alpha-synuclein (asyn) to pathological asyn-enriched aggregates is a hallmark of Parkinson’s disease (PD). These inclusions can be detected in the central and enteric nervous system (ENS). Moreover, gastrointestinal symptoms can appear up to 20 years before the diagnosis of PD. The dual-hit hypothesis posits that pathological asyn aggregation starts in the ENS, and retrogradely spreads to the brain. In this study, we tested this hypothesis by directly injecting preformed asyn fibrils into the duodenum wall of wild-type rats and transgenic rats with excess levels of human asyn. We provide a meticulous characterization of the bacterial artificial chromosome (BAC) transgenic rat model with respect to initial propagation of pathological asyn along the parasympathetic and sympathetic pathways to the brainstem, by performing immunohistochemistry at early time points post-injection. Induced pathology was observed in all key structures along the sympathetic and parasympathetic pathways (ENS, autonomic ganglia, intermediolateral nucleus of the spinal cord (IML), heart, dorsal motor nucleus of the vagus, and locus coeruleus (LC)) and persisted for at least 4 months post-injection. In contrast, asyn propagation was not detected in wild-type rats, nor in vehicle-injected BAC rats. The presence of pathology in the IML, LC, and heart indicate trans-synaptic spread of the pathology. Additionally, the observed asyn inclusions in the stomach and heart may indicate secondary anterograde propagation after initial retrograde spreading. In summary, trans-synaptic propagation of asyn in the BAC rat model is fully compatible with the “body-first hypothesis” of PD etiopathogenesis. To our knowledge, this is the first animal model evidence of asyn propagation to the heart, and the first indication of bidirectional asyn propagation via the vagus nerve, i.e., duodenum-to-brainstem-to-stomach. The BAC rat model could be very valuable for detailed mechanistic studies of the dual-hit hypothesis, and for studies of disease modifying therapies targeting early pathology in the gastrointestinal tract.Electronic supplementary materialThe online version of this article (10.1007/s00401-019-02040-w) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats

et al. 2019

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“…The question of which neuroimaging marker is useful to identify the pre‐motor phase of PD/DLB has not been answered . A DAT scan can detect hyposmia, postural hypotension, RBD, and possibly constipation in situ in individuals with pre‐motor PD. An MIBG test can detect mild memory disorder, constipation, postural hypotension, and RBD in situ.…”

Section: Discussionmentioning

confidence: 99%

MIBG Myocardial Scintigraphy Identifies Premotor PD/DLB During a Negative DAT Scan Period: Second Report

Sakakibara

Tateno

Aiba

et al. 2018

Movement Disord Clin Pract

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Objectives Neuroimaging markers for Parkinson's disease (PD)/dementia with Lewy bodies (DLB) include dopamine transporter (DAT) scanning and metaiodobenzylguanidine (MIBG) myocardial scintigraphy. It is unknown which marker is useful to identify the premotor phase PD/DLB. We reported four patients who, during a negative DAT scan period, had a positive MIBG result that suggested premotor PD/DLB. Here we report 18 additional patients. Methods This study was a prospective cohort study. The recruiting period was five years; prospective follow‐up period, 5.5 ± 3.0 years; and a once a year (minimum) follow‐up visit. We recruited 745 referred subjects. The inclusion criteria were having at least one of the following known PD nonmotor features: (1) autonomic: postural hypotension (pure autonomic failure [PAF]), constipation, bladder dysfunction; (2) sleep: REM sleep behavior disorder (RBD); and (3) cognitive: mild cognitive impairment or psychiatric symptoms. Also, the patient had to have undergone both DAT and MIBG tests. Results Only 18 patients fulfilled these criteria. Their characteristics were: elderly (mean age 75.5 years), with long histories (onset 61.0 years; duration 14.5 years), and predominately male (14 men, four women). The patients' neurologic diagnoses were constipation/RBD in 10, constipation/RBD/PAF in six, and constipation/PAF in two. During the follow‐up period, seven patients developed PD or DLB. An abnormal MIBG result was noted in 94%, and an abnormal DAT result was noted in 56%. Conclusions MIBG has the potential to be a useful marker during the DAT scan negative period to identify premotor PD/DLB, but further studies are needed.

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“…[9][10][11][12][13][14] The initial aggregates of alpha-synuclein are postulated to begin in the olfactory bulb or the nerve endings surrounding the gastrointestinal tract before ascending via the autonomic nerves to the dorsal motor nucleus of vagus and subsequently moving upwards into the brain. [9][10][11][12][13][14] The initial aggregates of alpha-synuclein are postulated to begin in the olfactory bulb or the nerve endings surrounding the gastrointestinal tract before ascending via the autonomic nerves to the dorsal motor nucleus of vagus and subsequently moving upwards into the brain.…”

mentioning

confidence: 99%

“…[9][10][11][12][13][14] The initial aggregates of alpha-synuclein are postulated to begin in the olfactory bulb or the nerve endings surrounding the gastrointestinal tract before ascending via the autonomic nerves to the dorsal motor nucleus of vagus and subsequently moving upwards into the brain. 12 Our group has recently reported the presence of a dopaminergic deficit in 54% of a prodromal DLB cohort. However, the Braak model is insufficient to explain the pathological findings in DLB.…”

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confidence: 99%

Prevalence and severity of symptoms suggestive of gastroparesis in prodromal dementia with Lewy bodies

Durcan

Donaghy

Barnett

et al. 2019

Int J Geriat Psychiatry

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Introduction Lewy body disease is postulated, by the Braak model, to originate in the enteric nervous system, before spreading to the central nervous system. Therefore, a high prevalence of gastroparesis symptoms would be expected in prodromal dementia with Lewy bodies (DLB) and be highest in those with a dopaminergic deficit on imaging. The aim of this study was to explore whether gastroparesis symptoms are an early diagnostic marker of prodromal DLB and explore the relationship between symptoms and dopaminergic imaging findings on FP‐CIT SPECT. Methods We recruited 75 patients over 60 with mild cognitive impairment (MCI), 48 with MCI with suspected Lewy body disease (MCI‐LB) and 27 with MCI with suspected Alzheimer's disease (MCI‐AD). All patients completed the Gastroparesis Cardinal Symptom Index (GSCI) questionnaire and also underwent FP‐CIT [123I‐N‐fluoropropyl‐2β‐carbomethoxy‐3β‐(4‐iodophenyl)] dopaminergic imaging. Results At least one symptom suggestive of gastroparesis was reported in 48% (n = 23) MCI‐LB vs 37% MCI‐AD (n = 10) (P = 0.36). Rates of definite symptoms of gastroparesis, as defined by a GCSI total score ≥ 1.90, were rare and rates in MCI‐LB were not different from MCI‐AD (6% vs 0%, p = 0.55). After adjusting for gender differences between groups, no difference in gastroparesis symptom prevalence (2.27 vs 0.81 P = 0.05) or severity score (0.62 vs 0.28, p = 0.28) was noted between normally and abnormally visually rated FP‐CIT SPECT scans. Conclusion The GCSI is not a useful tool for differentiating MCI‐LB from MCI‐AD. A low rate of definite gastroparesis was detected in prodromal DLB. No association was found between gastroparesis symptoms and FP‐CIT SPECT findings.

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In-vivo staging of pathology in REM sleep behaviour disorder: a multimodality imaging case-control study

Abstract: Lundbeck Foundation, Jascha Foundation, and the Swiss National Foundation.

Cited by 258 publications

References 49 publications

Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats

Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats

MIBG Myocardial Scintigraphy Identifies Premotor PD/DLB During a Negative DAT Scan Period: Second Report

Prevalence and severity of symptoms suggestive of gastroparesis in prodromal dementia with Lewy bodies

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