Neurofilament light chain is increased in the parahippocampal cortex and associates with pathological hallmarks in Parkinson’s disease dementia

Background Increased 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.Methods Using 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-βload)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.Results Compared 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,neuro-filament immunoreactivity correlated with cortical thinning in PD and with increased cortical MD in PDD/DLB.Conclusions Taken 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.

Post-Mortem MRI and Histopathology in Neurologic Disease:A Translational Approach

In this review, combined post-mortem brain magnetic resonance imaging(MRI) and histology studies are highlighted, illustrating the relevance of translational approaches to de?ne novel MRI signatures of neuropathological lesions in neuroin?ammatory and neurodegenerative disorders. Initial studies combining post-mortem MRI and histology have validated various MRI sequences,assessing their sensitivity and speci?city as diagnostic biomarkers in neurologic disease. More recent studies have focused on de?ning new radiological(bio)markers and implementing them in the clinical(research) setting. By combining neurological and neuroanatomical expertise with radiological development and pathological validation,a cycle emerges that allows for the discovery of novel MRI biomarkers to be implemented in vivo. Examples of this cycle are presented for multiple sclerosis, Alzheimer's disease, Parkinson's disease, and traumatic brain injury.Some applications have been shown to be successful, while others require further validation. In conclusion, there is much to explore with post-mortem MRI and histology studies, which can eventually be of high relevance for clinical practice.

CSF total and oligomeric α-Synuclein along with TNF-α as risk biomarkers for Parkinson’s disease: a study in LRRK2 mutation carriers

Background Asymptomatic carriers of leucine-rich repeat kinase 2(LRRK2)gene mutations constitute an ideal population for discovering prodromal biomarkers of Parkinson’s disease(PD).In this study,we aim to identify CSF candidate risk biomarkers of PD in individuals with LRRK2 mutation carriers.Methods We measured the levels of CSF total-(t-),oligomeric(o-)and phosphorylated S129(pS129-)α-syn,total-tau(tTau),phosphorylated threonine 181 tau(pTau),amyloid-beta 40(Aβ-40),amyloid-beta-42(Aβ-42)and 40 inflammatory chemokines in symptomatic(n=23)and asymptomatic(n=51)LRRK2 mutation carriers,subjects with a clinical diagnosis of PD(n=60)and age-matched healthy controls(n=34).General linear models corrected for age and gender were performed to assess differences in CSF biomarkers between the groups.Markers that varied significantly between the groups were then analyzed using backward-elimination logistic regression analysis to identify an ideal biomarkers panel of prodromal PD.Results Discriminant function analysis revealed low levels of CSF t-α-syn,high levels of CSF o-α-syn and TNF-αbest discriminated asymptomatic LRRK2 mutation carriers from both symptomatic PD and healthy controls.Assessing the discriminative power using receiver operating curve analysis,an area under the curve>0.80 was generated.Conclusions The current study suggests that CSF t-,o-α-syn and TNF-αare candidate risk biomarkers for the detection of PD at the prodromal stage.Our findings also highlight the dynamic interrelationships between CSF proteins and the importance of using a biomarkers’panel approach for an accurate and timely diagnosis of PD.

Axonal degeneration in the anterior insular cortex is associated with Alzheimer’s co-pathology in Parkinson’s disease and dementia with Lewy bodies

Background:Axons,crucial for impulse transmission and cellular trafficking,are thought to be primary targets of neurodegeneration in Parkinson’s disease(PD)and dementia with Lewy bodies(DLB).Axonal degeneration occurs early,preceeding and exceeding neuronal loss,and contributes to the spread of pathology,yet is poorly described outside the nigrostriatal circuitry.The insula,a cortical brain hub,was recently discovered to be highly vulnerable to pathology and plays a role in cognitive deficits in PD and DLB.The aim of this study was to evaluate morphological features as well as burden of proteinopathy and axonal degeneration in the anterior insular sub-regions in PD,PD with dementia(PDD),and DLB.Methods:α-Synuclein,phosphorylated(p-)tau,and amyloid-βpathology load were evaluated in the anterior insular(agranular and dysgranular)subregions of post-mortem human brains(n=27).Axonal loss was evaluated using modified Bielschowsky silver staining and quantified using stereology.Cytoskeletal damage was comprehensively studied using immunofluorescent multi-labelling and 3D confocal laser-scanning microscopy.Results:Compared to PD and PDD,DLB showed significantly higherα-synuclein and p-tau pathology load,argyrophilic grains,and more severe axonal loss,particularly in the anterior agranular insula.Alternatively,the dysgranular insula showed a significantly higher load of amyloid-βpathology and its axonal density correlated with cognitive performance.p-Tau contributed most to axonal loss in the DLB group,was highest in the anterior agranular insula and significantly correlated with CDR global scores for dementia.Neurofilament and myelin showed degenerative changes including swellings,demyelination,and detachment of the axon-myelin unit.Conclusions:Our results highlight the selective vulnerability of the anterior insular sub-regions to various converging pathologies,leading to impaired axonal integrity in PD,PDD and DLB,disrupting their functional properties and potentially contributing to cognitive,emotional,and autonomic deficits.