31 research outputs found
Dementia With Lewy Bodies A Clinicopathologic Series of False-positive Cases
Diagnosing dementia with Lewy bodies (DLB) is challenging as symptoms are heterogenous and not specific to the disease.
Here we present a clinicopathologic series of false-positive DLB
cases. Patients were enrolled retrospectively from the Netherlands
Brain Bank when they met the clinical criteria of probable DLB, but
with a pathologic diagnosis other than DLB or Parkinson’s disease
dementia. Twenty-two false-positive cases were selected. Alzheimer
disease with or without copathology was the most common (64%)
pathologic diagnosis. Other pathologic diagnoses, such as frontotemporal dementia, multiple-system atrophy, Creutzfeldt-Jakob disease, and autoimmune encephalitis, were also encountered. Atypical
clinical signs for DLB were present in almost half of the cases and
could be a trigger to consider other diagnoses than DLB. Additional
diagnostic examinations, feedback of pathologic diagnosis, and the
creation of a set of clinical features that are indicative of other conditions, could reduce the amount of false-positive DLB cases
Differential insular cortex subregional vulnerability to alpha-synuclein pathology in Parkinson's disease and dementia with Lewy bodies
Aim: The insular cortex consists of a heterogenous
cytoarchitecture and diverse connections and is
thought to integrate autonomic, cognitive, emotional
and interoceptive functions to guide behaviour. In
Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), it reveals a-synuclein pathology in advanced
stages. The aim of this study is to assess the insular
cortex cellular and subregional vulnerability to a-synuclein pathology in well-characterized PD and DLB subjects. Methods: We analysed postmortem insular tissue
from 24 donors with incidental Lewy body disease, PD,
PD with dementia (PDD), DLB and age-matched controls. The load and distribution of a-synuclein pathology and tyrosine hydroxylase (TH) cells were studied
throughout the insular subregions. The selective
involvement of von Economo neurons (VENs) in the
anterior insula and astroglia was assessed in all groups.
Results: A decreasing gradient of a-synuclein pathology
load from the anterior periallocortical agranular towards
the intermediate dysgranular and posterior isocortical
granular insular subregions was found. Few VENs
revealed a-synuclein inclusions while astroglial synucleinopathy was a predominant feature in PDD and DLB.
TH neurons were predominant in the agranular and dysgranular subregions but did not reveal a-synuclein inclusions or significant reduction in density in patient
groups. Conclusions: Our study highlights the vulnerability of the anterior agranular insula to a-synuclein
pathology in PD, PDD and DLB. Whereas VENs and
astrocytes were affected in advanced disease stages, insular TH neurons were spared. Owing to the anterior insula’s affective, cognitive and autonomic functions, its
greater vulnerability to pathology indicates a potential
contribution to nonmotor deficits in PD and DLB
Differential insular cortex sub-regional atrophy in neurodegenerative diseases: a systematic review and meta-analysis
The insular cortex is proposed to function as a central brain hub characterized by wide-spread connections and diverse functional
roles. As a result, its centrality in the brain confers high metabolic demands predisposing it to dysfunction in disease. However,
the functional profile and vulnerability to degeneration varies across the insular sub-regions. The aim of this systematic review
and meta-analysis is to summarize and quantitatively analyze the relationship between insular cortex sub-regional atrophy,
studied by voxel based morphometry, with cognitive and neuropsychiatric deficits in frontotemporal dementia (FTD),
Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia with Lewy bodies (DLB). We systematically searched
through Pubmed and Embase and identified 519 studies that fit our criteria. A total of 41 studies (n = 2261 subjects) fulfilled
the inclusion criteria for the meta-analysis. The peak insular coordinates were pooled and analyzed using Anatomic Likelihood
Estimation. Our results showed greater left anterior insular cortex atrophy in FTD whereas the right anterior dorsal insular cortex
showed larger clusters of atrophy in AD and PD/DLB. Yet contrast analyses did not reveal significant differences between disease
groups. Functional analysis showed t
Clinical and Pathological Phenotypes of LRP10 Variant Carriers with Dementia
BACKGROUND: Rare variants in the low-density lipoprotein receptor related protein 10 gene (LRP10) have recently been implicated in the etiology of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). OBJECTIVE: We searched for LRP10 variants in a new series of brain donors with dementia and Lewy pathology (LP) at autopsy, or dementia and parkinsonism without LP but with various other neurodegenerative pathologies. METHODS: Sanger sequencing of LRP10 was performed in 233 donors collected by the Netherlands Brain Bank. RESULTS: Rare, possibly pathogenic heterozygous LRP10 variants were present in three patients: p.Gly453Ser in a patient with mixed Alzheimer's disease (AD)/Lewy body disease (LBD), p.Arg151Cys in a DLB patient, and p.Gly326Asp in an AD patient without LP. All three patients had a positive family history for dementia or PD. CONCLUSION: Rare LRP10 variants are present in some patients with dementia and different brain pathologies including DLB, mixed AD/LBD, and AD. These findings suggest a role for LRP10 across a broad neurodegenerative spectrum
Neurofilament light chain is increased in the parahippocampal cortex and associates with pathological hallmarks in Parkinson's disease dementia
BackgroundIncreased neurofilament levels in biofluids are commonly used as a proxy for neurodegeneration in several neurodegenerative disorders. In this study, we aimed to investigate the distribution of neurofilaments in the cerebral cortex of Parkinson’s disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB) donors, and its association with pathology load and MRI measures of atrophy and diffusivity.MethodsUsing a within-subject post-mortem MRI-pathology approach, we included 9 PD, 12 PDD/DLB and 18 age-matched control donors. Cortical thickness and mean diffusivity (MD) metrics were extracted respectively from 3DT1 and DTI at 3T in-situ MRI. After autopsy, pathological hallmarks (pSer129-αSyn, p-tau and amyloid-β load) together with neurofilament light-chain (NfL) and phosphorylated-neurofilament medium- and heavy-chain (p-NfM/H) immunoreactivity were quantified in seven cortical regions, and studied in detail with confocal-laser scanning microscopy. The correlations between MRI and pathological measures were studied using linear mixed models.ResultsCompared to controls, p-NfM/H immunoreactivity was increased in all cortical regions in PD and PDD/DLB, whereas NfL immunoreactivity was increased in the parahippocampal and entorhinal cortex in PDD/DLB. NfL-positive neurons showed degenerative morphological features and axonal fragmentation. The increased p-NfM/H correlated with p-tau load, and NfL correlated with pSer129-αSyn but more strongly with p-tau load in PDD/DLB. Lastly, neurofilament immunoreactivity correlated with cortical thinning in PD and with increased cortical MD in PDD/DLB.ConclusionsTaken together, increased neurofilament immunoreactivity suggests underlying axonal injury and neurofilament accumulation in morphologically altered neurons with increased pathological burden. Importantly, we demonstrate that such neurofilament markers at least partly explain MRI measures that are associated with the neurodegenerative process.Neurological Motor Disorder
Characterization of Brain Lysosomal Activities in GBA-Related and Sporadic Parkinson’s Disease and Dementia with Lewy Bodies
Mutations in the GBA gene, encoding the lysosomal hydrolase glucocerebrosidase (GCase), are the most common known genetic risk factor for Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). The present study aims to gain more insight into changes in lysosomal activity in different brain regions of sporadic PD and DLB patients, screened for GBA variants. Enzymatic activities of GCase, β-hexosaminidase, and cathepsin D were measured in the frontal cortex, putamen, and substantia nigra (SN) of a cohort of patients with advanced PD and DLB as well as age-matched non-demented controls (n = 15/group) using fluorometric assays. Decreased activity of GCase (− 21%) and of cathepsin D (− 15%) was found in the SN and frontal cortex of patients with PD and DLB compared to controls, respectively. Population stratification was applied based on GBA genotype, showing substantially lower GCase activity (~ − 40%) in GBA variant carriers in all regions. GCase activity was further significantly decreased in the SN of PD and DLB patients without GBA variants in comparison to controls without GBA variants. Our results show decreased GCase activity in brains of PD and DLB patients with and without GBA variants, most pronounced in the SN. The results of our study confirm findings from previous studies, suggesting a role for GCase in GBA-associated as well as sporadic PD and DLB
A Large-Scale Full GBA1 Gene Screening in Parkinson's Disease in the Netherlands
Background: The most common
genetic risk factor for Parkinson’s disease known is a
damaging variant in the GBA1 gene. The entire GBA1
gene has rarely been studied in a large cohort from a
single population. The objective of this study was to
assess the entire GBA1 gene in Parkinson’s disease
from a single large population.
Methods: The GBA1 gene was assessed in 3402
Dutch Parkinson’s disease patients using nextgeneration sequencing. Frequencies were compared
with Dutch controls (n = 655). Family history of
Parkinson’s disease was compared in carriers and
noncarriers.
Results: Fifteen percent of patients had a GBA1 nonsynonymous variant (including missense, frameshift, and
recombinant alleles), compared with 6.4% of c