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

Neurobiology of Disease, Journal Year: 2021, Volume and Issue: 161, P. 105557 - 105557

Published: Nov. 8, 2021

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

Language: Английский

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

Neurobiology of Disease, Journal Year: 2022, Volume and Issue: 164, P. 105626 - 105626

Published: Jan. 11, 2022

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

Language: Английский

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A postmortem study suggests a revision of the dual-hit hypothesis of Parkinson’s disease

npj Parkinson s Disease, Journal Year: 2022, Volume and Issue: 8(1)

Published: Nov. 30, 2022

The dual-hit hypothesis of Parkinson's disease (PD) originally postulated that a neurotropic pathogen leads to formation α-synuclein pathology in the olfactory bulb (OB) and dorsal motor nucleus vagus (DMV) then invades brain from these two entry points. Little work has been conducted validate an important underlying premise for hypothesis, namely initial Lewy does arise simultaneously OB enteric nervous system (ENS) plexuses DMV at earliest stage. We focused re-analysis postmortem datasets, which included large numbers mild body (LBD) cases. found cases with restricted peripheral autonomic and/or lower brainstem (early body-first LBD cases) very rarely had any pathology, suggesting commonly arises ENS without concomitant involvement OB. In contrast, amygdala-predominant brain-first nearly always showed pathology. This is compatible first being triggered or amygdala followed by secondary spreading connected structures, but early brainstem. These observations support pathologic process starts either ENS, gut simultaneously. More studies on neuropathological datasets are warranted reproduce findings. agreement between revised single-hit recently proposed vs. model discussed.

Language: Английский

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The heterogeneity of Parkinson’s disease

Journal of Neural Transmission, Journal Year: 2023, Volume and Issue: 130(6), P. 827 - 838

Published: May 11, 2023

The heterogeneity of Parkinson's disease (PD), i.e. the various clinical phenotypes, pathological findings, genetic predispositions and probably also implicated pathophysiological pathways pose a major challenge for future research projects therapeutic trail design. We outline several concepts, mechanisms, including presumed roles α-synuclein misfolding aggregation, Lewy bodies, oxidative stress, iron melanin, deficient autophagy processes, insulin incretin signaling, T-cell autoimmunity, gut-brain axis evidence that microbial (viral) agents may induce molecular hallmarks neurodegeneration. hypothesis is discussed, whether PD might indeed be triggered by exogenous (infectious) in susceptible individuals upon entry via olfactory bulb (brain first) or gut (body-first), which would support idea mechanisms change over time. unresolved have contributed to failure past trials, attempted slow course PD. thus conclude patients need personalized approaches tailored specific phenomenological etiologic subtypes disease.

Language: Английский

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The brain-first vs. body-first model of Parkinson’s disease with comparison to alternative models

Journal of Neural Transmission, Journal Year: 2023, Volume and Issue: 130(6), P. 737 - 753

Published: April 16, 2023

Language: Английский

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Parkinson’s disease and gut microbiota: from clinical to mechanistic and therapeutic studies

Translational Neurodegeneration, Journal Year: 2023, Volume and Issue: 12(1)

Published: Dec. 15, 2023

Parkinson's disease (PD) is one of the most prevalent neurodegenerative diseases. The typical symptomatology PD includes motor symptoms; however, a range nonmotor symptoms, such as intestinal issues, usually occur before symptoms. Various microorganisms inhabiting gastrointestinal tract can profoundly influence physiopathology central nervous system through neurological, endocrine, and immune pathways involved in microbiota-gut-brain axis. In addition, extensive evidence suggests that gut microbiota strongly associated with PD. This review summarizes latest findings on microbial changes their clinical relevance, describes underlying mechanisms which bacteria may mediate PD, discusses correlations between microbes anti-PD drugs. this outlines status research therapies for future directions PD-gut research.

Language: Английский

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Brain-first vs. body-first Parkinson's disease: An update on recent evidence

Parkinsonism & Related Disorders, Journal Year: 2024, Volume and Issue: 122, P. 106101 - 106101

Published: March 15, 2024

We recently proposed a new disease model of Parkinson's – the -Synuclein Origin site and Connectome model. The posits that initial pathology starts either in olfactory bulb or amygdala leading to brain-first subtype, enteric nervous system body-first subtype. These subtypes should be distinguishable early course on range imaging, clinical, neuropathological markers. Here, we review recent original human studies, which tested predictions model.Molecular imaging studies were generally agreement with model, whereas structural such as MRI volumetry, showed conflicting findings. Most large-scale clinical supportive, reporting clustering relevant markers including REM-sleep behavior disorder, constipation, autonomic dysfunction, neuropsychiatric symptoms, cognitive impairment. Finally, -synuclein deposition antemortem postmortem tissues revealed distribution pathology, supports

Language: Английский

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Parkinson’s Disease and Dementia with Lewy Bodies: One and the Same

Journal of Parkinson s Disease, Journal Year: 2024, Volume and Issue: 14(3), P. 383 - 397

Published: April 16, 2024

The question whether Parkinson’s disease dementia (PDD) and with Lewy bodies (DLB) are expressions of the same underlying has been vigorously debated for decades. recently proposed biological definitions body disease, which do not assign any particular importance to dopamine system over other degenerating neurotransmitter systems, once more brought discussion about different types forefront. Here, we briefly compare PDD DLB in terms their symptoms, imaging findings, neuropathology, ultimately finding them be indistinguishable. We then present a conceptual framework demonstrate how one can view clinical syndromes as manifestations shared disease. Early isolated RBD, pure autonomic failure perhaps even psychiatric represent diverse initial stages They characterized by heterogeneous comparatively limited neuronal dysfunction damage. In contrast, dementia, an encompassing term both DLB, represents uniform advanced stage Patients this category display extensive severe pathology, frequently accompanied co-existing pathologies, well multi-system degeneration. Thus, propose that should viewed single entity. Phenotypic variance is caused presence individual risk factors, mechanisms, co-pathologies. Distinct subtypes therefore defined subtype-specific mechanisms or biomarkers.

Language: Английский

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Inflammatory bowel disease induces pathological α‐synuclein aggregation in the human gut and brain

Neuropathology and Applied Neurobiology, Journal Year: 2024, Volume and Issue: 50(1)

Published: Feb. 1, 2024

Abstract Aims According to Braak's hypothesis, it is plausible that Parkinson's disease (PD) originates in the enteric nervous system (ENS) and spreads brain through vagus nerve. In this work, we studied whether inflammatory bowel diseases (IBDs) humans can progress with emergence of pathogenic α‐synuclein (α‐syn) gastrointestinal tract midbrain dopaminergic neurons. Methods We have analysed gut ventral from subjects previously diagnosed IBD form a DSS‐based rat model inflammation terms α‐syn pathology. Results Our data support existence both brain, thus reinforcing potential role ENS as contributing factor PD aetiology. Additionally, effect demonstrate (i) appearance P‐α‐syn inclusions Auerbach's Meissner's plexuses (gut), (ii) an increase expression mesencephalon (brain) (iii) degeneration nigral neurons, which all are considered classical hallmarks PD. Conclusion These results strongly plausibility hypothesis emphasise significance peripheral gut‐brain axis initiating aggregation transport substantia nigra, resulting neurodegeneration.

Language: Английский

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

Brain, Journal Year: 2021, Volume and Issue: 144(9), P. 2732 - 2744

Published: June 28, 2021

Abstract Previous studies have reported substantial involvement of the noradrenergic system in Parkinson’s disease. Neuromelanin-sensitive MRI sequences and PET tracers become available to visualize cell bodies locus coeruleus density terminal transporters. Combining these methods, we investigated relationship neurodegeneration distinct compartments We examined 93 subjects (40 healthy controls 53 disease patients) with neuromelanin-sensitive turbo spin-echo calculated coeruleus-to-pons signal contrasts. Voxels highest intensities were extracted from published coordinates transformed individual MRI. To also investigate a potential spatial pattern degeneration, rostral, middle, caudal third coeruleus. Additionally, study-specific probabilistic map was created used extract mean contrast entire each rostro-caudal subdivision. Locus volumes measured using manual segmentations. A subset 73 had 11C-MeNER determine noradrenaline transporter density, distribution volume ratios transporter-rich regions computed. Patients showed reduced independently selected method (voxel approaches: P < 0.0001, 0.001; map: 0.05), specifically on clinically-defined most affected side (P 0.0001). Reduced confined middle approach, rostral: = 0.48, middle: caudal: 0.05; map, 0.90, 0.01, 0.05). The lower patients diseasein all (group effect No significant correlation observed between density. In contrast, 0.001). Our multimodal imaging approach revealed pronounced loss relative cellular degeneration disease; latter followed middle-caudal portion being more than rostral part. data shed first light interaction axonal body their differential susceptibility disease, which may eventually direct research towards novel treatment approaches.

Language: Английский

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