The α-Synuclein Origin and Connectome Model (SOC Model) of Parkinson’s Disease: Explaining Motor Asymmetry, Non-Motor Phenotypes, and Cognitive Decline

Journal of Parkinson s Disease, Journal Year: 2021, Volume and Issue: 11(2), P. 455 - 474

Published: March 2, 2021

A new model of Parkinson’s disease (PD) pathogenesis is proposed, the α-Synuclein Origin site and Connectome (SOC) model, incorporating two aspects α-synuclein pathobiology that impact course for each patient: anatomical location initial inclusion, propagation dependent on ipsilateral connections dominate connectivity human brain. In some patients, pathology occurs within CNS, leading to a brain-first subtype PD. others, begins in peripheral autonomic nervous system, body-first subtype. cases, it proposed first appears unilaterally, often amygdala. If depends connection strength, unilateral focus will disseminate more hemisphere. Thus, spreads mainly structures including substantia nigra. The asymmetric distribution leads dopaminergic degeneration motor asymmetry. ascends via vagus both left right dorsal nuclei owing overlapping parasympathetic innervation gut. Consequently, inside CNS symmetric, which promotes symmetric brainstem, less At diagnosis, patients already have larger, burden pathology, turn faster progression accelerated cognitive decline. SOC supported by considerable body existing evidence may improved explanatory power.

Language: Английский

---

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

---

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

---

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

---

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

---

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

---

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

Journal of Parkinson s Disease, Journal Year: 2021, Volume and Issue: 11(4), P. 1677 - 1687

Published: July 30, 2021

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 more symmetric brainstem involvement hence degeneration. Isolated REM sleep behaviour disorder has been identified as a strong marker of the type.To analyse striatal asymmetry [18F]FDOPA PET [123I]FP-CIT DaT SPECT data from iRBD patients, de novo PD patients RBD (PD+RBD) without (PD-RBD). These groups were defined prodromal body-first, brain-first, respectively.We included scans 21 11 PD+RBD, 22 PD-RBD, 18 controls subjects. Also, unknown status PPPMI dataset was analysed. Lowest putamen specific binding ratio index (AI) defined.Nigrostriatal degeneration significantly versus or both FDOPA (p = 0.001) datasets.iRBD subjects PD+RBD present dopaminergic compared PD-RBD patients. The results support hypothesis is characterized by distribution most likely due propagation brain-first PD.

Language: Английский

---

Two-year clinical progression in focal and diffuse subtypes of Parkinson’s disease

npj Parkinson s Disease, Journal Year: 2023, Volume and Issue: 9(1)

Published: Feb. 17, 2023

Heterogeneity in Parkinson's disease (PD) presents a barrier to understanding mechanisms and developing new treatments. This challenge may be partially overcome by stratifying patients into clinically meaningful subtypes. A recent subtyping scheme classifies de novo PD three subtypes: mild-motor predominant, intermediate, or diffuse-malignant, based on motor impairment, cognitive function, rapid eye movement sleep behavior disorder (RBD) symptoms, autonomic symptoms. We aimed validate this approach large longitudinal cohort of early-to-moderate (n = 499) assessing the influence clinical characteristics at baseline two-year progression. Compared predominant (42%), diffuse-malignant (12%) showed involvement more domains, diffuse hypokinetic-rigid symptoms (decreased lateralization hand/foot focality), faster These findings extend classification subtypes suggest that different pathophysiological (focal versus cerebral propagation) underlie distinct subtype classifications.

Language: Английский

---

The Body, the Brain, the Environment, and Parkinson’s Disease

Journal of Parkinson s Disease, Journal Year: 2024, Volume and Issue: 14(3), P. 363 - 381

Published: April 9, 2024

The brain- and body-first models of Lewy body disorders predict that aggregated alpha-synuclein pathology usually begins in either the olfactory system or enteric nervous system. In both scenarios seems to arise structures are closely connected outside world. Environmental toxicants, including certain pesticides, industrial chemicals, air pollution therefore plausible trigger mechanisms for Parkinson’s disease dementia with bodies. Here, we propose toxicants inhaled through nose can lead pathological changes subsequently spread give rise a brain-first subtype disease. Similarly, ingested pass gut cause then extends via parasympathetic sympathetic pathways ultimately produce subtype. resulting be tracked by development symptoms, clinical assessments, vivo imaging, examination. integration environmental exposures into generates testable hypotheses, on prevalence conditions, their future incidence, imaging patterns, signatures. proposed link, though, has limitations leaves many questions unanswered, such as role skin, influence microbiome, effects ongoing exposures. Despite these limitations, interaction exogenous factors may explain mysteries open door toward ultimate goal –prevention.

Language: Английский

---

Prevalence of Non‐Motor Symptoms and Non‐Motor Fluctuations in Parkinson's Disease Using the MDS‐NMS

Movement Disorders Clinical Practice, Journal Year: 2020, Volume and Issue: 8(2), P. 231 - 239

Published: Nov. 23, 2020

Non-motor symptoms (NMS) are frequent in Parkinson's disease (PD).To estimate the prevalence of NMS and non-motor fluctuations (NMF) using Movement Disorders Society-Non-Motor Rating Scale (MDS-NMS) other scales assessing NMS, their relationship with sex PD severity.Cross-sectional study a sample 402 patients. The Hoehn Yahr staging system (HY), Clinical Impression Severity Index for (CISI-PD), MDS-NMS (including NMF- subscale), Non-Motor Symptoms scale (NMSS), MDS-Unified Disease (MDS-UPDRS) were applied. A was considered present when scored ≥1. Differences scores by HY, CISI-PD, MDS-UPDRS severity levels calculated Fisher's exact chi-squared tests.Using MDS-NMS, 99.7% patients mean number 16.13 (SD: 9.36). most prevalent muscle, joint or back pain (67.4% sample) least dopamine dysregulation syndrome (2.2%). Feeling sad depressed significantly more women. Using revealed than NMS. NMF 41% sample, fatigue being symptom (68.5% NMF), no differences sex. Patients greater had higher lower severity.Almost all experience many NMF. Prevalence rates on used increase severity.

Language: Английский

---