Spectrum Of Proteinopathies Research Articles

Lipid alterations in human frontal cortex in ALS-FTLD-TDP43 proteinopathy spectrum are partly related to peroxisome impairment.

AimPeroxisomes play a key role in lipid metabolism, and peroxisome defects have been associated with neurodegenerative diseases such as X‐adrenoleukodystrophy and Alzheimer's disease. This study aims to elucidate the contribution of peroxisomes in lipid alterations of area 8 of the frontal cortex in the spectrum of TDP43‐proteinopathies. Cases of frontotemporal lobar degeneration‐TDP43 (FTLD‐TDP), manifested as sporadic (sFTLD‐TDP) or linked to mutations in various genes including expansions of the non‐coding region of C9ORF72 (c9FTLD), and of sporadic amyotrophic lateral sclerosis (sALS) as the most common TDP43 proteinopathies, were analysed.MethodsWe used transcriptomics and lipidomics methods to define the steady‐state levels of gene expression and lipid profiles.ResultsOur results show alterations in gene expression of some components of peroxisomes and related lipid pathways in frontal cortex area 8 in sALS, sFTLD‐TDP and c9FTLD. Additionally, we identify a lipidomic pattern associated with the ALS‐FTLD‐TDP43 proteinopathy spectrum, notably characterised by down‐regulation of ether lipids and acylcarnitine among other lipid species, as well as alterations in the lipidome of each phenotype of TDP43 proteinopathy, which reveals commonalities and disease‐dependent differences in lipid composition.ConclusionGlobally, lipid alterations in the human frontal cortex of the ALS‐FTLD‐TDP43 proteinopathy spectrum, which involve cell membrane composition and signalling, vulnerability against cellular stress and possible glucose metabolism, are partly related to peroxisome impairment.

OVERLAPPING PROTEINOPATHIES IN THE ELDERLY AND THEIR SIGNIFICANCE

Neurodegenerative diseases of the elderly are characterised by neuronal loss and cerebral deposition of proteins with altered physicochemical properties. The major proteins are amyloid-β (Aβ), tau, α-synuclein, and TDP-43. Although neuropathological studies on elderly individuals have emphasized the importance of mixed pathologies, there have been few observations on the full spectrum of proteinopathies in the ageing human brain. During a community-based study (Vienna Trans-Danube Aging; VITA) study) we performed comprehensive mapping of neurodegeneration-related proteins and vascular pathology in the brains of 233 individuals (age at death 77-87). We applied immunostaining for neurodegeneration-related proteins in several anatomical regions. Logistic regression models were used to assess the univariate and multivariable effect of pathological variables. Our findings were compared to published cohorts. The major finding of our and other studies is that deposition of multiple proteins in the brain is frequent in the elderly, and their constellations have an impact on the clinical manifestation. In contrast to some studies, we found that α -synuclein pathology may also have an impact on cognitive decline, as reported also by others. We expand the group of tauopathies, and show that these influence the clinical presentation. Although detectable in cognitively normal elderly individuals, the importance of TDP-43 in relation to cognitive decline in the elderly has been emphasized by our and further studies. The issues whether severe AD-related neuropathological alterations may be associated with preserved cognitive functions or whether “reversible” clinical diagnosis of Alzheimer's disease (AD) associates with neuropathological alterations were also considered. Demonstration of the high number of possible combinations of proteinopathies may serve as a rationale for evaluating a panel of neurodegeneration-related proteins in body fluids as part of a personalised diagnostic signature. Furthermore, t his emphasizes the need for a personalised approach in the treatment of dementia. Acknowledgement: Project EU FP7-HEALTH-2011-DEVELAGE Nr.: 278486.

Non-Alzheimer neurodegenerative pathologies and their combinations are more frequent than commonly believed in the elderly brain: a community-based autopsy series

Neurodegenerative diseases are characterised by neuronal loss and cerebral deposition of proteins with altered physicochemical properties. The major proteins are amyloid-β (Aβ), tau, α-synuclein, and TDP-43. Although neuropathological studies on elderly individuals have emphasised the importance of mixed pathologies, there have been few observations on the full spectrum of proteinopathies in the ageing brain. During a community-based study we performed comprehensive mapping of neurodegeneration-related proteins and vascular pathology in the brains of 233 individuals (age at death 77-87; 73 examined clinically in detail). While all brains (from individuals with and without dementia) showed some degree of neurofibrillary degeneration, Aβ deposits were observed only in 160 (68.7 %). Further pathologies included α-synucleinopathies (24.9 %), non-Alzheimer tauopathies (23.2 %; including novel forms), TDP-43 proteinopathy (13.3 %), vascular lesions (48.9 %), and others (15.1 %; inflammation, metabolic encephalopathy, and tumours). TDP-43 proteinopathy correlated with hippocampal sclerosis (p < 0.001) and Alzheimer-related pathology (CERAD score and Braak and Braak stages, p = 0.001). The presence of one specific variable (cerebral amyloid angiopathy, Aβ parenchymal deposits, TDP-43 proteinopathy, α-synucleinopathy, vascular lesions, non-Alzheimer type tauopathy) did not increase the probability of the co-occurrence of others (p = 0.24). The number of observed pathologies correlated with AD-neuropathologic change (p < 0.0001). In addition to AD-neuropathologic change, tauopathies associated well with dementia, while TDP-43 pathology and α-synucleinopathy showed strong effects but lost significance when evaluated together with AD-neuropathologic change. Non-AD neurodegenerative pathologies and their combinations have been underestimated, but are frequent in reality as demonstrated here. This should be considered in diagnostic evaluation of biomarkers, and for better clinical stratification of patients.

Ubiquitinated, p62 immunopositive cerebellar cortical neuronal inclusions are evident across the spectrum of TDP-43 proteinopathies but are only rarely additionally immunopositive for phosphorylation-dependent TDP-43

Frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP), frontotemporal lobar degeneration with motor neuron disease/amyotrophic lateral sclerosis (FTLD-MND/ALS) and MND/ALS are thought to represent a clinicopathological spectrum of TDP-43 proteinopathies. The cerebellum has been little studied in these conditions, probably because of the lack of cerebellar signs in most cases. We examined p62 immunohistochemistry on cerebellar sections from 43 TDP-43 proteinopathies (including cases of FTLD-TDP, FTLD-MND/ALS and MND/ALS) together with 72 cases of other neurodegenerative diseases, seven controls and three other disease conditions. In 11 of the TDP-43 proteinopathies (26%) there were numerous p62-positive cerebellar inclusions, predominantly within the granular layer, but also the molecular and Purkinje cell layer. Furthermore, only one of the remaining 82 cases (a familial tauopathy) showed similar p62 positivity. Immunohistochemistry for ubiquitin was positive in the granular layer inclusions. The immunohistochemistry for phosphorylation-independent TDP-43, hyperphosphorylated tau, α-synuclein, fusion sarcoma protein (FUS), and neurofilament was negative. In only one case (a case of FTLD-TDP) were the inclusions positive for phosphorylation-dependent TDP43 (p-TDP-43). Those TDP-43 proteinopathy cases that showed the cerebellar inclusions also tended to display other common features, such as a notable excess of p62 pathology when compared to TDP-43 pathology, especially within the pyramidal neurones of the hippocampus but also in some cases within the neocortex. The results suggest that p62-positive inclusions within the cerebellum are seen in a proportion of cases across the range of the TDP-43 proteinopathy spectrum and they appear to be relatively specific for this group of diseases. The question as to whether these cerebellar-positive cases represent a distinct subgroup remains to be answered. Furthermore, the relationship of the p62 positivity in the cerebellum to the underlying pathological processes awaits to be established.

Sporadic amyotrophic lateral sclerosis of long duration is associated with relatively mild TDP-43 pathology

Recently, sporadic amyotrophic lateral sclerosis (SALS), a fatal neurological disease, has been shown to be a multisystem proteinopathy of TDP-43 in which both neurons and glial cells in the central nervous system are widely affected. In general, the natural history of SALS is short (<5 years). However, it is also known that a few patients may survive for 10 years or more, even without artificial respiratory support (ARS). In the present study using TDP-43 immunohistochemistry, we examined various regions of the nervous system in six patients with SALS of long duration (10-20 years) without ARS, in whom lower motor-predominant disease with Bunina bodies and ubiquitinated inclusions (UIs) in the affected lower motor neurons was confirmed. One case also showed UIs in the hippocampal dentate granule cells (UDG). In all cases, except one with UDG, the occurrence of TDP-43-immunoreactive (ir) neuronal cytoplasmic inclusions (NCIs) was confined to a few regions in the spinal cord and brainstem, including the anterior horns. In one case with UDG, TDP-43-ir NCIs were also detected in the substantia nigra, and some regions of the cerebrum, including the hippocampal dentate gyrus (granule cells). The number of neurons displaying NCIs in each region was very small (1-3 per region, except the dentate gyrus). On the other hand, the occurrence of TDP-43-ir glial cytoplasmic inclusions (GCIs) was more widespread in the central nervous system, including the cerebral white matter. Again, however, the number of glial cells displaying GCIs in each region was very small (1-3 per region). In conclusion, compared to the usual form of SALS, TDP-43 pathology shown in SALS of long duration was apparently mild in degree and limited in distribution, corresponding to the relatively benign clinical courses observed. It is now apparent that SALS of long duration is actually part of a TDP-43 proteinopathy spectrum.