Importance: While mutations in glucocerebrosidase (GBA1) are associated with an increased risk for Parkinson disease (PD), it is important to establish whether such mutations are also a common risk factor for other Lewy body disorders.Objective: To establish whether GBA1 mutations are a risk factor for dementia with Lewy bodies (DLB). Design:We compared genotype data on patients and controls from 11 centers. Data concerning demographics, age at onset, disease duration, and clinical and pathological features were collected when available. We conducted pooled analyses using logistic regression to investigate GBA1 mutation carrier status as predicting DLB or PD with dementia status, using common control subjects as a reference group. Random-effects meta-analyses were conducted to account for additional heterogeneity.Setting: Eleven centers from sites around the world performing genotyping.Participants: Seven hundred twenty-one cases met diagnostic criteria for DLB and 151 had PD with dementia.We compared these cases with 1962 controls from the same centers matched for age, sex, and ethnicity.Main Outcome Measures: Frequency of GBA1 mutations in cases and controls.Results: We found a significant association between GBA1 mutation carrier status and DLB, with an odds ratio of 8.28 (95% CI, 4.78-14.88). The odds ratio for PD with dementia was 6.48 (95% CI, 2.53-15.37). The mean age at diagnosis of DLB was earlier in GBA1 mutation carriers than in noncarriers (63.5 vs 68.9 years; P Ͻ.001), with higher disease severity scores.Conclusions and Relevance: Mutations in GBA1 are a significant risk factor for DLB. GBA1 mutations likely play an even larger role in the genetic etiology of DLB than in PD, providing insight into the role of glucocerebrosidase in Lewy body disease.

Accumulation of the DNA/RNA binding protein fused in sarcoma as cytoplasmic inclusions in neurons and glial cells is the pathological hallmark of all patients with amyotrophic lateral sclerosis with mutations in FUS as well as in several subtypes of frontotemporal lobar degeneration, which are not associated with FUS mutations. The mechanisms leading to inclusion formation and fused in sarcoma-associated neurodegeneration are only poorly understood. Because fused in sarcoma belongs to a family of proteins known as FET, which also includes Ewing's sarcoma and TATA-binding protein-associated factor 15, we investigated the potential involvement of these other FET protein family members in the pathogenesis of fused in sarcoma proteinopathies. Immunohistochemical analysis of FET proteins revealed a striking difference among the various conditions, with pathology in amyotrophic lateral sclerosis with FUS mutations being labelled exclusively for fused in sarcoma, whereas fused in sarcoma-positive inclusions in subtypes of frontotemporal lobar degeneration also consistently immunostained for TATA-binding protein-associated factor 15 and variably for Ewing's sarcoma. Immunoblot analysis of proteins extracted from post-mortem tissue of frontotemporal lobar degeneration with fused in sarcoma pathology demonstrated a relative shift of all FET proteins towards insoluble protein fractions, while genetic analysis of the TATA-binding protein-associated factor 15 and Ewing's sarcoma gene did not identify any pathogenic variants. Cell culture experiments replicated the findings of amyotrophic lateral sclerosis with FUS mutations by confirming the absence of TATA-binding protein-associated factor 15 and Ewing's sarcoma alterations upon expression of mutant fused in sarcoma. In contrast, all endogenous FET proteins were recruited into cytoplasmic stress granules upon general inhibition of Transportin-mediated nuclear import, mimicking the findings in frontotemporal lobar degeneration with fused in sarcoma pathology. These results allow a separation of fused in sarcoma proteinopathies caused by FUS mutations from those without a known genetic cause based on neuropathological features. More importantly, our data imply different pathological processes underlying inclusion formation and cell death between both conditions; the pathogenesis in amyotrophic lateral sclerosis with FUS mutations appears to be more restricted to dysfunction of fused in sarcoma, while a more global and complex dysregulation of all FET proteins is involved in the subtypes of frontotemporal lobar degeneration with fused in sarcoma pathology.

Abstract-Most strokes are covert and observed incidentally on brain scans, but their presence increases risk of overt stroke and dementia. Amyloid angiopathy, associated with Alzheimer Disease (AD) causes stroke, and when even small strokes coexist with AD, they lower the threshold for dementia. Diffuse ischemic white matter disease impairs executive functioning, information processing speed, and gait. A fter a stroke approximately one third of patients become demented, increasing their dependence and tripling mortality. 1 However, clinically overt stroke is the tip of a more ominous cerebrovascular disease (CVD) iceberg. Silent strokes are 10 to 20 times as prevalent as overt strokes. 2 In the Rotterdam Study (Ͼ1000 normal elderly over age 60 followed over 4 years), subcortical lacunes (Ն3 mm) occurred in 25%, conferring twice the dementia risk 3 and a 5 times risk of clinical stroke. 4 Incidental hyperintensities, called leukoaraiosos, 5 are focal or confluent on Proton Density (PD)/T2 or FLAIR MRI. Relatively hypointense on T1 images, they are observed in 96% of community volunteers over age 65. 6 However, periventricular hyperintensities (PVH) appear clinically silent except in 20% with extensive PVH, who showed impaired cognition, and gait. 6 Cerebrovascular and Alzheimer Disease RelationshipsEven small infarcts, when combined with Alzheimer disease (AD), can lower the dementia threshold. In the "nun" autopsy study, 57% of elderly sisters meeting pathological AD criteria were premorbidly demented, but in 39% with subcortical infarcts, cognitive function was lower, less AD pathology was needed for dementia, and 93% met dementia criteria. 7 Similar studies confirm this finding, some reporting additive infarct effects 8 and others claiming impact only in milder stage AD. 9 Population autopsy series reveal combined pathologies as the rule for dementia. 10 In a British study, the frequency of vascular pathologies (78%) exceeded AD (70%), 11 and ADϩCVD was the commonest dementia substrate in a U.S. community sample. 12 For dementia associated with infarcts alone, multiple microinfarcts, not macroscopic infarcts, appear to be culprit. 13 These close ADϩCVD interrelationships, including shared vascular risk factors, 14 suggest ischemia may drive pathophysiology in sporadic AD. 15 Amyloid ␤ (A␤) is toxic to vascular endothelium and neurons; 16 A␤40 deposits in arterioles and most capillaries in AD-vulnerable regions, causing occlusion, vasculitis, hemorrhage, and vessel obliteration. 14,17 Vascular myocytes in AD constrict rather than dilate arterioles in response to ischemia. 18 Some contend that sporadic AD is a primary vasculopathy, 14 but selective vulnerability of particular neuronal networks counts against this. Others propose that synaptic loss with aging is a contributing precondition for emergence of AD dementia. 19 Measuring Small Vessel Disease in Vivo:Challenges and OpportunitiesTo understand the burden of vascular disease in aging and dementia, optimal deployment of in vivo and postmortem neuroimaging i...

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Mutations in the gene encoding the fused in sarcoma (FUS) protein are responsible for ~3% of familial amyotrophic lateral sclerosis (ALS) and <1% of sporadic ALS (ALS-FUS). Descriptions of the associated neuropathology are few and largely restricted to individual case reports. To better define the neuropathology associated with FUS mutations, we have undertaken a detailed comparative analysis of six cases of ALS-FUS that include sporadic and familial cases, with both juvenile and adult onset, and with four different FUS mutations. We found significant pathological heterogeneity among our cases, with two distinct patterns that correlated with the disease severity and the specific mutation. Frequent basophilic inclusions and round FUS-immunoreactive (FUS-ir) neuronal cytoplasmic inclusions (NCI) were a consistent feature of our early-onset cases, including two with the p.P525L mutation. In contrast, our late-onset cases, that included two with the p.R521C mutation, had tangle-like NCI and numerous FUS-ir glial cytoplasmic inclusions. Double-labeling experiments demonstrated that many of the glial inclusions were in oligodendrocytes. Comparison with the neuropathology of cases of frontotemporal lobar degeneration with FUS-ir pathology showed significant differences and suggests that FUS mutations are associated with a distinct pathobiology.

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Corticobasal syndrome (CBS) is a rare cognitive and movement disorder characterized by asymmetric rigidity, apraxia, alien-limb phenomenon, cortical sensory loss, myoclonus, focal dystonia, and dementia. It occurs along the clinical spectrum of frontotemporal lobar degeneration (FTLD), which has recently been shown to segregate with truncating mutations in progranulin (PGRN), a multifunctional growth factor thought to promote neuronal survival. This study identifies a novel splice donor site mutation in the PGRN gene (IVS7+1G-->A) that segregates with CBS in a Canadian family of Chinese origin. We confirmed the absence of the mutant PGRN allele in the RT-PCR product which supports the model of haploinsufficiency for PGRN-linked disease. This report of mutation in the PGRN gene in CBS extends the evidence for genetic and phenotypic heterogeneity in FTLD spectrum disorders.

To estimate the allele frequency of C9orf72 (G 4 C 2 ) repeats in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer disease (AD), and Parkinson disease (PD).Design: The number of repeats was estimated by a 2-step genotyping strategy. For expansion carriers, we sequenced the repeat flanking regions and obtained APOE genotypes and MAPT H1/H2 haplotypes.Setting: Hospitals specializing in neurodegenerative disorders. Subjects:We analyzed 520 patients with FTLD, 389 patients with ALS, 424 patients with AD, 289 patients with PD, 602 controls, 18 families, and 29 patients with PD with the LRRK2 G2019S mutation.Main Outcome Measure: The expansion frequency.Results: Based on a prior cutoff (Ͼ30 repeats), the expansion was detected in 9.3% of patients with ALS, 5.2% of patients with FTLD, and 0.7% of patients with PD but not in controls or patients with AD. It was significantly Author Affil the end of th Author Affiliations are listed at the end of this article.