Parkinson disease and incidental Lewy body disease

Iacono, Diego; Geraci-Erck, Maria; Rabin, Marcie L.; Adler, Charles H.; Serrano, Geidy E.; Beach, Thomas G.; Kurlan, Roger

doi:10.1212/wnl.0000000000002102

Cited by 108 publications

(73 citation statements)

References 50 publications

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“…At first glance, our findings seem consistent with the suppositions of Cersosimo, who recently posited an olfactory origin of the limbic α‐synucleinopathy in DLB . However, we hesitate to conclude that our OB/AON infusion model fully simulates DLB, PD or even iLBD, as these conditions are associated with loss of dopaminergic markers of the nigrostriatal pathway and true nigral cell death, and PD and DLB are associated with a more widespread extent of Lewy‐related pathology than in our murine model . For example, a ~40% loss of pigmented nigral neurons and a ~50% reduction in TH is already evident in the striatum of iLBD patients .…”

Section: Discussionsupporting

confidence: 86%

The center of olfactory bulb‐seeded α‐synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice

et al. 2019

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At early disease stages, Lewy body disorders are characterized by limbic vs. brainstem α‐synucleinopathy, but most preclinical studies have focused solely on the nigrostriatal pathway. Furthermore, male gender and advanced age are two major risk factors for this family of conditions, but their influence on the topographical extents of α‐synucleinopathy and the degree of cell loss are uncertain. To fill these gaps, we infused α‐synuclein fibrils in the olfactory bulb/anterior olfactory nucleus complex—one of the earliest and most frequently affected brain regions in Lewy body disorders—in 3‐month‐old female and male mice and in 11‐month‐old male mice. After 6 months, we observed that α‐synucleinopathy did not expand significantly beyond the limbic connectome in the 9‐month‐old male and female mice or in the 17‐month‐old male mice. However, the 9‐month‐old male mice had developed greater α‐synucleinopathy, smell impairment and cell loss than age‐matched females. By 10.5 months post‐infusion, fibril treatment hastened mortality in the 21.5‐month‐old males, but the inclusions remained centered in the limbic system in the survivors. Although fibril infusions reduced the number of cells expressing tyrosine hydroxylase in the substantia nigra of young males at 6 months post‐infusion, this was not attributable to true cell death. Furthermore, mesencephalic α‐synucleinopathy, if present, was centered in mesolimbic circuits (ventral tegmental area/accumbens) rather than within strict boundaries of the nigral pars compacta, which were defined here by tyrosine hydroxylase immunolabel. Nonprimate models cannot be expected to faithfully recapitulate human Lewy body disorders, but our murine model seems reasonably suited to (i) capture some aspects of Stage IIb of Lewy body disorders, which displays a heavier limbic than brainstem component compared to incipient Parkinson’s disease; and (ii) leverage sex differences and the acceleration of mortality following induction of olfactory α‐synucleinopathy.

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Section: Discussionsupporting

confidence: 86%

The center of olfactory bulb‐seeded α‐synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice

et al. 2019

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“…Finally, spinal LBs were associated with more severe nigral neuronal loss in the brainstem. (28, 36)…”

Section: Discussionmentioning

confidence: 99%

Spinal Lewy body pathology in older adults without an antemortem diagnosis of Parkinson's disease

et al. 2017

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To test the hypothesis that Lewy body pathology (LBs) is present in the spinal cord of older community-dwelling adults without a clinical diagnosis of Parkinson's disease (PD). We studied 162 prospective autopsies from older adults with PD (N = 6) and without PD (N = 156). We documented the presence of LBs in cerebrum and brainstem structures from each of the six regions used for Braak PD staging and four spinal cord levels (C5/6, T7, L4/5 and S4/5). Parkinsonism proximate to death was based on a previously validated measure present if two or more of the four signs of parkinsonism were present based on a modified version of the Unified Parkinson's Disease Rating Scale (UPDRS). Fifty-three of 156 individuals without PD (34%) had LBs in a least one site within the CNS. About half of cases with LBs in the cerebrum or brainstem, (25/53, 47%) also had spinal LBs. Almost 90% (22/25, 88%) of cases with spinal LBs had LBs in the cerebrum (Braak stages 4-6) and about 10% (3/25, 12%) had only brainstem LBs (Braak stages 1-3). Four of six cases with PD showed LBs in cerebrum, brainstem and spinal cord. Individuals with LBs in the spinal cord were more likely to have clinical parkinsonism proximate to death compared to individuals with LBs in brainstem and cerebrum alone (52% vs. 32%; Chi-Square x = 5.368, d.f. = 1, P = 0.0.021) and more severe nigral neuronal loss (48% vs. 11%; Chi-Square x = 9.049, d.f. = 1, P = 0.003). These findings were unchanged when we included cases with a history of PD. Older community-dwelling adults without a clinical diagnosis of PD have evidence of LBs throughout the CNS including the spinal cord which is associated with parkinsonism and more severe nigral neuronal loss.

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“…Individuals with ILBD may have been in the prodromal stage of a clinically manifest α‐synucleinopathy and, thus, had they lived longer, they may have gone on to develop PD, MSA, or DLB. Evidence to suggest that ILBD is prodromal PD includes the finding of an approximately 50% decrease in striatal dopaminergic markers as well as significantly decreased numbers of substantia nigra pigmented neurons . A reduction in epicardial tyrosine hydroxylase activity has also been found .…”

Section: Prodromal Pdmentioning

confidence: 99%

Neuropathological basis of nonmotor manifestations of Parkinson's disease

2016

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Non-motor manifestations of Parkinson’s disease (PD) can begin well before motor PD begins. It is now clear, from clinical and autopsy studies, that there is significant Lewy type alpha-synucleinopathy present outside the nigro-striatal pathway, and that this may underlie these non-motor manifestations. This review will discuss neuropathological findings that may underlie non-motor symptoms that either predate motor findings or occur as the disease progresses.

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Parkinson disease and incidental Lewy body disease

Cited by 108 publications

References 50 publications

The center of olfactory bulb‐seeded α‐synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice

The center of olfactory bulb‐seeded α‐synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice

Spinal Lewy body pathology in older adults without an antemortem diagnosis of Parkinson's disease

Neuropathological basis of nonmotor manifestations of Parkinson's disease

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