An order in Lewy body disorders: Retrograde degeneration in hyperbranching axons as a fundamental structural template accounting for focal/multifocal Lewy body disease

Abstract

Initial clinical recognition of "paralysis agitans" by James Parkinson was expanded by Jean-Martin Charcot, who recognized additional clinical findings of his own, such as slowness (distinct from paralysis), rigidity (distinct from spasticity) and characteristic countenance. Charcot assembled these findings under the umbrella of "Parkinson disease (PD)". This purely clinical concept was so prescient and penetrating that subsequent neuropathological and biochemical evidences were ordered along this axis to establish the nigra-central trinity of PD (dopamine depletion, nigral lesion with Lewy bodies: LBs). Although dramatic efficacy of levodopa boosted an enthusiasm for this nigra-centralism, extranigral lesions were identified, especially after identification of alpha-synuclein (αS) as a major constituent of LBs. Frequent αS lesions in the lower brainstem with their presumed upward spread were coupled with the self-propagating property of αS molecule, as a molecular template, to constitute the prion-Braak hypothesis. This hybrid concept might expectedly explain clinical, structural and biochemical features of PD/dementia with Lewy bodies (DLB) as if they were stereotypic. In spite of this ordered explanation, recent studies have demonstrated unexpectedly that αS lesions in the human brain, as well as their corresponding clinical manifestations, are much more disordered. Even with such a chaos of LB disorders, affected neuronal groups are uniformly characterized by hyperbranching axons, which may facilitate distal-dominant degeneration and retrograde progression of LB-related degeneration along axons as a fundamental structural order to template LB disorders. This "structural template" hypothesis may explain why: (i) some selective groups are prone to develop Lewy pathology; (ii) their clinical manifestations (especially non-motor components) are vague and generalized without somatotopic accentuation; (iii) distal axons and terminals are preferentially affected early, which is clinically detectable as reduced myocardial uptake of metaiodobenzylguanidine in PD/DLB. Because each Lewyprone system develops LBs independently, their isolated presentation as "focal LB disease" or their whatever combinations as "multifocal LB disease" are a more plausible framework to explain clinicopathological diversities of LB disorders. Clinical criteria are now being revised to integrate these clinicopathological disorders of PD/DLB. To gain closer access to the reality of the human brain, it is necessary to facilitate more interactions between clinicopathological and experimental fields so that both are mutually critical and complementary for improved diagnosis and treatment.

Dynactin is involved in Lewy body pathology

“…19,20 Uchihara et al reported that p-SNCA pathology may initiate at distal axons and spread toward neuronal cell bodies and that p-SNCA lesions occur independently in different areas. 21,22 In conjunction with our findings and these previous reports, we propose that retrograde transport may be closely associated with α-synucleinopathy in PD and DLB. However, Braak et al suggested that p-SNCA deposits initially occur at lower brainstem nuclei, such as the dorsal nucleus of the vagus nerve, followed by the locus coeruleus and then the substantia nigra.…”

“…Previous reports demonstrated that SNCA interacts with dynein‐dynactin complexes and is transported retrogradely along microtubules . Uchihara et al reported that p‐SNCA pathology may initiate at distal axons and spread toward neuronal cell bodies and that p‐SNCA lesions occur independently in different areas . In conjunction with our findings and these previous reports, we propose that retrograde transport may be closely associated with α‐synucleinopathy in PD and DLB.…”

Neuropathology of Lewy body disease: Clinicopathological crosstalk between typical and atypical cases

“…Furthermore, four patients with PD who had received transplants of embryonic mesencephalic neurons later showed LBs within the grafted neurons . These findings spurred the suggestion that the spread of Lewy pathology is mediated by prion‐like transmission of α‐synuclein between neurons via synaptic connections …”

“…The absence of falls in the early stage and the presence of cognitive fluctuation, hallucination, and a vertical gaze palsy with a more severe defect in upward gaze distinguish DLB with vertical gaze palsy from PSP . Uchihara reported a case clinically diagnosed as having CBS due to a marked laterality of upper limb clumsiness and cerebral blood flow, as determined by single‐photon emission computed tomography, but the pathological diagnosis of the case was DLB with a marked laterality of Lewy pathology in the motor cortex . Kasanuki et al .…”

Parkinson's disease: Is it a consequence of human brain evolution?

“…29 This model implies that symptoms should follow a stereotyped sequence, with the earliest symptoms being peripheral. In contrast, the "telencephalization hypothesis" predicts symptoms should manifest themselves in parallel, 30 with local or patient-specific factors governing the precise sequence of symptoms ( Fig. 2A,B).…”