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Lewy bodies (LBs) are alpha-synuclein-immunoreactive neuronal inclusions with a predilection for specific cortical and subcortical regions, including the amygdala. In this study, the presence of LBs was assessed in 347 cases of Alzheimer disease (AD). In 87 cases, LB pathology was diagnostic of brainstem (n=3), transitional (n=32), or diffuse (n=52) Lewy body disease (LBD). The remaining 260 cases of AD were screened for amygdala LBs (AD/ALB) and 62 (24%) cases were found. If AD/LBD cases are included, LBs were detected in 149 (43%) cases of AD. The presence alpha-synuclein pathology was assessed in multiple brain regions of the 62 cases of AD/ALB and 57 randomly selected cases of AD, and only sparse alpha-synuclein pathology was detected in both. The burden of alpha-synuclein pathology in brainstem nuclei, amygdala, and neocortex was significant lower in AD/ALB than in AD/LBD. In comparison to AD/LBD, AD/ALB did not differ in age at death, disease duration, male-to-female ratio, brain weight, Braak neurofibrillary tangle stage, average senile plaque density, or apolipoprotein E epsilon4 allele frequency. The results suggest that AD/ALB is pathologically different from AD/LBD, suggesting that it is a neuropathologically distinct and isolated alpha-synucleinopathy.

To determine whether TAR-DNA binding protein 43 (TDP-43) immunoreactivity was present in brains of argyrophilic grain disease (AGD), we immunohistochemically examined 15 cases of AGD (mean age at death: 84 years) using a panel of anti-TDP-43 antibodies, including both phosphorylation-independent and -dependent ones. Nine AGD cases (60%) showed TDP-43 immunoreactivities mainly in the limbic regions and lateral occipitotemporal cortex. TDP-43 positive structures included neuronal cytoplasmic inclusions, dystrophic neurites, glial cytoplasmic inclusions, grain-like dot-shaped structures, and neurofibrillary tangle (NFT)-like structures. The distribution of these TDP-43 positive structures was largely consistent with that of argyrophilic grains. Double-labeling confocal microscopy revealed, however, that many of phospho-TDP-43 positive structures were not colocalized with phospho-tau staining. Colocalization of phospho-TDP-43 and phospho-tau was observed only in part of neuronal cytoplasmic inclusions, grain-like structures and NFT-like structures. There were no differences in demographics, disease duration, brain weight, NFT Braak stage, or severity of amyloid burden between AGD cases with and without TDP-43-immunoreactivity. However, cases of AGD with TDP-43-immunoreactivity were assigned to higher AGD stages than those without TDP-43-immunoreactivity (P < 0.05). Furthermore, the TDP-43 pathology tended to be prominent in cases with severe grain pathology. The results of the present study indicate for the first time a high frequency of concomitant TDP-43 pathology in AGD, and suggest that abnormal accumulation of TDP-43 may be involved in the pathological process and disease progression of AGD.

Recently, Braak and coworkers proposed a pathologic staging scheme for Parkinson disease (PD). In this staging, scheme substantia nigra pathology occurs at midstage disease, while involvement of anterior olfactory nucleus, medulla, and pontine tegmentum occur earlier. In the last stages, Lewy bodies (LBs) involve cortical areas. The general principles of the proposed staging system have been confirmed in several studies of PD, but it does not appear to fit with all LB disorders. We studied the density and distribution of LBs with alpha-synuclein immunohistochemistry in normal elderly with incidental LBs (N = 12); progressive supranuclear palsy (PSP) with incidental LBs (N = 18); Lewy body disease (LBD) with minimal or no Alzheimer type pathology (N = 52); LBD with concomitant Alzheimer disease (AD) (N = 84); and cases of AD with amygdala predominant LBs (N = 64). The proportion of cases that fit the PD staging scheme was 67% for incidental LBs; 86% for PSP with LBs; 86% for pure LBD; and 84% for LBD with AD; but only 6% for AD with amygdala predominant LBs. The PD staging scheme is valid, except in the setting of advanced AD. In this situation, LBs may be unrelated to PD and more likely related to factors inherent to AD and the selective vulnerability of the amygdala to both Alzheimer and alpha-synuclein pathologies.

No abstract

Missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common causes of both familial and sporadic forms of Parkinson disease (PD) and are also associated with a diverse pathological alterations. The mechanisms whereby LRRK2 mutations cause these pathological phenotypes are unknown. We employed immunohistochemistry with 3 distinct anti-LRRK2 antibodies to characterize the expression of LRRK2 in the brains of 21 subjects with various neurodegenerative disorders and 7 controls. LRRK2 immunoreactivity was localized in a subset of brainstem-type Lewy bodies (LBs) but not in cortical-type LBs, tau-positive inclusions or TAR-DNA binding protein-43-positive inclusions. LRRK2 immunoreactivity frequently appeared as enlarged granules or vacuoles within neurons of affected brain regions, including the substantia nigra, amygdala and entorhinal cortex in patients with PD or dementia with Lewy bodies (DLB). The volumes of LRRK2-positive granular structures in neurons of the entorhinal cortex were significantly increased in DLB brains compared to aged-matched control brains (p<0.05). Double immunolabeling demonstrated that these LRRK2-positive granular structures frequently colocalized with the late-endosomal marker Rab7B and occasionally with the lysosomal marker, LAMP2. These results suggest that LRRK2 normally localizes to the endosomal-lysosomal compartment within morphologically altered neurons in neurodegenerative diseases, particularly in the brains of patients with LB diseases.

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There is emerging evidence implicating a role for the autophagy-lysosome pathway in the pathogenesis of Lewy body disease. We investigated potential neuropathologic and biochemical alterations of autophagy-lysosome pathway-related proteins in the brains of patients with dementia with Lewy bodies (DLB), Alzheimer disease (AD), and control subjects using antibodies against Ras-related protein Rab-7B (Rab7B), lysosomal-associated membrane protein 2 (LAMP2), and microtubule-associated protein 1A/1B light chain 3 (LC3). In DLB, but not in control brains, there were large Rab7B-immunoreactive endosomal granules. LC3 immunoreactivity was increased in vulnerable areas of DLB brains relative to that in control brains; computerized cell counting analysis revealed that LC3 levels were greater in the entorhinal cortex and amygdala of DLB brains than in controls. Rab7B levels were increased, and LAMP2 levels were decreased in the entorhinal cortex of DLB brains. In contrast, only a decrease in LAMP2 levels versus controls was found in AD brains. LC3 widely colocalized with several types of Lewy pathology; LAMP2 localized to the periphery or outside of brainstem-type Lewy bodies; Rab7B did not colocalize with Lewy pathology. Immunoblot analysis demonstrated specific accumulation of the autophagosomal LC3-II isoform in detergent-insoluble fractions from DLB brains. These results support apotential role for the autophagy-lysosome pathway in the pathogenesis of DLB.