Biology subjects

Rozemuller, A. J. M.

Publications and source records attributed to Rozemuller, A. J. M..

3 recordsLinked to original sources

bioRxiv2018

Neuropathology and cognitive performance in centenarians

AbstractWith aging, the incidence of neuropathological hallmarks of neurodegenerative diseases increases in the brains of cognitively healthy individuals. It is currently unclear to what extent these hallmarks associate with symptoms of disease at extreme ages. Forty centenarians from the 100-plus Study cohort agreed to post-mortem brain donation. Centenarians self-reported to be cognitive healthy at baseline, which was confirmed by a proxy. Objective ante-mortem measurements of cognitive performance were associated with the prevalence, distribution and quantity of age- and AD-related neuropathological hallmarks. Despite self-reported cognitive health, objective neuropsychological testing suggested varying levels of ante-mortem cognitive functioning. Post-mortem, we found that most neuropathological hallmarks related to age and neurodegenerative diseases such as A{beta} and Tau pathology, as well as atherosclerosis, were abundantly present in most or all centenarians, whereas Lewy body and pTDP-43 pathology were scarce. We observed that increased pathology loads correlated across pathology subtypes, and an overall trend of higher pathology loads to associate with a lower cognitive test performance. This trend was carried especially by the presence of neurofibrillary tangles (NFTs) and granulovacuolar degeneration (GVD) and to a lesser extent by A{beta}-associated pathologies. Cerebral Amyloid Angiopathy (CAA) specifically associated with lower executive functioning in the centenarians. In conclusion, we find that while the centenarians in this cohort escaped or delayed cognitive impairment until extreme ages, their brains reveal varying levels of disease-associated neuropathological hallmarks, some of which associate with cognitive performance.

neuroscience↗

bioRxiv2017

Insular cortex sub-region-dependent distribution pattern of α-synuclein immunoreactivity in Parkinson’s disease and dementia with Lewy bodies

The insular cortex is a heterogeneous and widely connected brain region. It plays a role in autonomic, cognitive, emotional and somatosensory functions. Its complex and unique cytoarchitecture includes a periallocortical agranular, pro-isocortical dysgranular, and isocortical granular sub-regions. In Parkinsons disease (PD), the insula shows -synuclein inclusions in advanced stages of the disease and its atrophy correlates with cognitive deficits. However, little is known regarding its regional neuropathological characteristics and vulnerability in Lewy body diseases. The aim of this study is to assess the distribution pattern of -synuclein pathology in the insular sub-regions and the selective vulnerability of its different cell types in PD and dementia with Lewy bodies (DLB). Human post-mortem insular tissues from 10 donors with incidental Lewy body disease (iLBD), PD, DLB, and age-matched controls were immunostained for -synuclein and glial fibrillary acid protein (GFAP). Results showed that a decreasing gradient of -synuclein pathology was present from agranular to granular sub-regions in iLBD, PD and PD with dementia (PDD) donors. The agranular insula was heavily inflicted, revealing various -synuclein immunoreactive morphological structures, predominantly Lewy neurites (LNs), and astroglial synucleinopathy. While dysgranular and granular sub-regions showed a decreasing gradient of inclusions and more Lewy bodies (LBs) in deeper layers. In DLB, this gradient was less pronounced and severe pathology was observed in the granular insula compared to PDD and regardless of disease stage. Protoplasmic astrocytes showed -synuclein inclusions and severe degenerative changes increasing with disease severity. While few von Economo neurons (VENs) in the fronto-insular region revealed inclusions, particularly in PDD patients. Our study reports novel findings on the differential involvement of the insular sub-regions in PD and particular involvement of the agranular sub-region, VENs and astrocytes. Thus, the differential cellular architecture of the insular sub-regions portrays the topographic variation and vulnerability to -synuclein pathology in Lewy body diseases.

neuroscience↗

bioRxiv2017

Lewy pathology in Parkinson’s disease consists of a crowded organellar membranous medley

Parkinsons disease, the most common age-related movement disorder, is a progressive neurodegenerative disease with unclear etiology. Key neuropathological hallmarks are Lewy bodies and Lewy neurites, which are neuronal inclusions that are immunopositive for the protein -synuclein. In-depth ultrastructural analysis of this Lewy pathology is crucial to understanding pathogenesis and progression of the disease. Using correlative light and electron microscopy/tomography on brain tissue from five Parkinsons disease brain donors, we identified -synuclein immunopositive Lewy pathology and could show that the majority of these features including Lewy bodies and Lewy neurites primarily consists of a crowded membranous medley of vesicular structures and dysmorphic organelles. Only a small fraction of observed Lewy bodies contained predominant proteinaceous filaments, as previously described. The crowding of organellar components was confirmed by STED- based super-resolution microscopy, and high lipid content within the -synuclein immunopositive inclusions was corroborated by confocal imaging, CARS/FTIR imaging and lipidomics. Applying this correlative high-resolution imaging and biophysical approach, we discovered in the postmortem brain of Parkinsons patients a subcellular protein-lipid compartmentalization not previously described in Lewy pathology.

neuroscience↗