Convergent molecular defects underpin diverse neurodegenerative diseases

Portelius

Journal of Neurochemistry

et al. 2018

Neurodegenerative dementias constitute a broad group of diseases in which abnormally folded proteins accumulate in specific brain regions and result in tissue reactions that eventually cause neuronal dysfunction and degeneration. Depending on where in the brain this happens, symptoms appear which may be used to classify the disorders on clinical grounds. However, brain changes in neurodegenerative dementias start to accumulate many years prior to symptom onset and there is a poor correlation between the clinical picture and what pathology that is the most likely to cause it. Thus, novel drug candidates having disease-modifying effects that is targeting the underlying pathology and changes the course of the disease needs to be defined using objective biomarker-based measures since the clinical symptoms are often non-specific and overlap between different disorders. Furthermore, the treatment should ideally be initiated as soon as symptoms are evident or when biomarkers confirm an underlying pathology (pre-clinical phase of the disease) to reduce irreversible damage to, for example, neurons, synapses and axons. Clinical trials in the pre-clinical phase bring a greater importance to biomarkers since by definition the clinical effects are difficult or slow to discern in a population that is not yet clinically affected. Here, we discuss neuropathological changes that may underlie neurodegenerative dementias, including how they can be detected and quantified using currently available biofluid-based biomarkers and how more of them could be identified using targeted proteomics approaches.

Section: Summary Of Discussed Potential Csf‐based Biomarkers Across Nmentioning

confidence: 99%

Fluid‐based proteomics targeted on pathophysiological processes and pathologies in neurodegenerative diseases

Portelius

Journal of Neurochemistry

et al. 2018

“…Microglia-induced complement activation might also contribute to synaptic dysfunction and loss, especially in the context of amyloid deposition and neuritic plaque formation . On the other hand, synaptic firing can influence microglia activation via specific membrane receptors and ion channels (Tofaris and Buckley, 2018).…”

Section: Discussionmentioning

confidence: 99%

Neuroinflammation and functional connectivity in Alzheimer’s disease: interactive influences on cognitive performance

Passamonti

Tsvetanov

Jones

et al. 2019

Preprint

Neuroinflammation is a key part of the etio-pathogenesis of Alzheimer's disease. We test the relationship between neuroinflammation and the disruption of functional connectivity in large-scale networks, and their joint influence on cognitive impairment.We combined [ 11 C]PK11195 positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) in 28 humans (13 females/15 males) with clinical diagnosis of probable Alzheimer's disease or mild cognitive impairment with positive PET biomarker for amyloid, and 14 age-, sex-, and education-matched healthy humans (8 Significance StatementNeuroinflammation is an important aspect of Alzheimer's disease (AD), but it was not known whether the influence of neuroinflammation on brain network function in humans was important for cognitive deficit.Our study provides clear evidence that in vivo neuroinflammation in AD impairs largescale network connectivity; and that the link between inflammation and functional network connectivity is relevant to cognitive impairment.We suggest that future studies should address how neuroinflammation relates to network function as AD progresses; and whether the neuroinflammation in AD is reversible, as the basis of immunotherapeutic strategies to slow the progression of AD.

“…Neurodegenerative diseases have some neuropathology, clinical and/or genetic crossover. 13,14 For example, Parkinson's disease dementia (PDD) has both a-synuclein and Ab deposits in the brain that may co-cause the disease onset. 15,16 ALS and FTD share some common causal genes such as C9orf72.…”

Section: Introductionmentioning

confidence: 99%

Association of rare variants in neurodegenerative genes with familial Alzheimer’s disease

Zhang

Jiao

Xiao

et al. 2020

Ann Clin Transl Neurol

Objective: To investigate the impact of rare variants underlying neurodegenerative-related genes to familial Alzheimer's disease (AD). Methods: We performed targeted sequencing of 277 neurodegenerative-related genes on probands from 75 Chinese AD families non-carrying causative mutation of dementia genes. Rare coding variants segregated in families were tested for association in an independent cohort of 506 patients with sporadic AD and 498 cognitively normal controls. East Asians data from the Exome Aggregation Consortium (ExAC) were used as a reference control. Results: A novel rare variant, P410S of PLD3 was found in an early-onset AD family. LRRK2 I2012T, a causative mutation of Parkinson's disease, was identified in another early-onset AD family. Missense variants in ABCA7 (P143S and A1507T) and CR1 (T239M) were significantly associated with familial AD (P = 0.005437, 0.001383, 0.000549), a missense variant in TREM2(S183C) was significantly associated with AD (P = 0.000396) when compared with the East Asian controls in ExAC database. A non-frameshift variant in FUS (G223del) was frequent in AD cases and significantly associated with familial AD (P = 0.008). Interpretation: Multiple rare coding variants of causal and risk neurodegenerative genes were presented in clinically diagnosed AD families that may confer risk of AD. Our data supported that the clinical, pathological, and genetic architectures of AD, PD, and FTD/ALS may overlapping. We propose that targeted sequencing on neurodegenerative-related genes is necessary for genetically unclear AD families.