Frontotemporal lobar degeneration (FTLD) is a heterogeneous group of disorders characterized by disturbances of behavior and personality and different types of language impairment with or without ...concomitant features of motor neuron disease or parkinsonism. FTLD is characterized by atrophy of the frontal and anterior temporal brain lobes. Detailed neuropathological studies have elicited proteinopathies defined by inclusions of hyperphosphorylated microtubule-associated protein tau, TAR DNA-binding protein TDP-43, fused-in-sarcoma or yet unidentified proteins in affected brain regions. Rather than the type of proteinopathy, the site of neurodegeneration correlates relatively well with the clinical presentation of FTLD. Molecular genetic studies identified five disease genes, of which the gene encoding the tau protein (
MAPT
), the growth factor precursor gene granulin (
GRN
), and
C9orf72
with unknown function are most frequently mutated. Rare mutations were also identified in the genes encoding valosin-containing protein (
VCP
) and charged multivesicular body protein 2B (
CHMP2B
). These genes are good markers to distinguish underlying neuropathological phenotypes. Due to the complex landscape of FTLD diseases, combined characterization of clinical, imaging, biological and genetic biomarkers is essential to establish a detailed diagnosis. Although major progress has been made in FTLD research in recent years, further studies are needed to completely map out and correlate the clinical, pathological and genetic entities, and to understand the underlying disease mechanisms. In this review, we summarize the current state of the rapidly progressing field of genetic, neuropathological and clinical research of this intriguing condition.
With increasing feasibility of predicting conversion of mild cognitive impairment to dementia based on biomarker profiling, the urgent need for efficacious disease‐modifying compounds has become even ...more critical. Despite intensive research, underlying pathophysiological mechanisms remain insufficiently documented for purposeful target discovery. Translational research based on valid animal models may aid in alleviating some of the unmet needs in the current Alzheimer's disease pharmaceutical market, which includes disease‐modification, increased efficacy and safety, reduction of the number of treatment unresponsive patients and patient compliance. The development and phenotyping of animal models is indeed essential in Alzheimer's disease‐related research as valid models enable the appraisal of early pathological processes – which are often not accessible in patients, and subsequent target discovery and evaluation. This review paper summarizes and critically evaluates currently available animal models, and discusses their value to the Alzheimer drug discovery pipeline. Models dealt with include spontaneous models in various species, including senescence‐accelerated mice, chemical and lesion‐induced rodent models, and genetically modified models developed in Drosophila melanogaster, Caenorhabditis elegans, Danio rerio and rodents. Although highly valid animal models exist, none of the currently available models recapitulates all aspects of human Alzheimer's disease, and one should always be aware of the potential dangers of uncritical extrapolating from model organisms to a human condition that takes decades to develop and mainly involves higher cognitive functions.
LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue‐4
The objective of this systematic review was (1) to give an overview of the available short screening instruments for the early detection of Alzheimer's disease (AD) and (2) to review the psychometric ...properties of these instruments.
First, a systematic search of titles and abstracts of PubMed and Web of Science was conducted between February and July 2015 and updated in April 2016 and May 2018. Only papers written in English or Dutch were considered. All full-text papers about cognitive screening instruments for the early detection of AD were included, resulting in the identification of 38 pencil and paper tests and 12 computer tests. In a second step, the psychometric quality of these instruments was evaluated. Therefore, the same databases were searched again to identify papers that described the psychometric properties of the instruments meanwhile applying diagnostic criteria for the diagnostic groups included.
Out of 1454 papers, 96 clearly discussed the psychometric properties of the instruments. Eighty-nine papers discussed pencil and paper tests of which 80 were validated in a memory clinic setting. Based on the number of studies (31 articles) and the sensitivity (84%) and specificity (74%) values, the Montreal Cognitive Assessment (MoCA) seems to be a promising (pencil and paper) screening test for memory clinic testing as well as for population screening. Regarding computer tests, validation studies were only available for 7 out of 12 tests.
A large number of screening tests for AD are available. However, most tests are only validated in a memory clinic setting and description of the psychometric properties of the instruments is limited. Especially, computer tests require further research. The MoCA is a promising instrument, but the specificity to detect early AD is rather low.
Parkinson’s disease (PD) is a progressive neurodegenerative brain disease presenting with a variety of motor and non-motor symptoms, loss of midbrain dopaminergic neurons in the substantia nigra pars ...compacta and the occurrence of α-synuclein-positive Lewy bodies in surviving neurons. Here, we performed whole exome sequencing in 52 early-onset PD patients and identified 3 carriers of compound heterozygous mutations in the ATP10B P4-type ATPase gene. Genetic screening of a Belgian PD and dementia with Lewy bodies (DLB) cohort identified 4 additional compound heterozygous mutation carriers (6/617 PD patients, 0.97%; 1/226 DLB patients, 0.44%). We established that
ATP10B
encodes a late endo-lysosomal lipid flippase that translocates the lipids glucosylceramide (GluCer) and phosphatidylcholine (PC) towards the cytosolic membrane leaflet. The PD associated ATP10B mutants are catalytically inactive and fail to provide cellular protection against the environmental PD risk factors rotenone and manganese. In isolated cortical neurons, loss of ATP10B leads to general lysosomal dysfunction and cell death. Impaired lysosomal functionality and integrity is well known to be implicated in PD pathology and linked to multiple causal PD genes and genetic risk factors. Our results indicate that recessive loss of function mutations in
ATP10B
increase risk for PD by disturbed lysosomal export of GluCer and PC. Both ATP10B and glucocerebrosidase 1, encoded by the PD risk gene
GBA1
, reduce lysosomal GluCer levels, emerging lysosomal GluCer accumulation as a potential PD driver.
Aim: Coronary artery disease (CAD) and cognitive impairment are common in the elderly, with evidence for shared risk factors and pathophysiological processes. The coronary artery calcium (CAC) score ...is a marker of subclinical CAD, which may allow early detection of individuals prone to cognitive decline. Prior studies on associations of CAC and clinical CAD with cognitive impairment had discrepant results. This systematic review aims to evaluate the association of (sub)clinical CAD with cognitive function, cognitive decline, and diagnosis of mild cognitive impairment (MCI) or dementia. Methods: A systematic search was conducted in MEDLINE, Embase, and Web of Science until February 2019, supplemented with citations tracking. Two reviewers independently screened studies and extracted information including odds ratios (ORs) and hazard ratios (HRs). Results: Forty-six studies, 10 on CAC and 36 on clinical CAD, comprising 1,248,908 participants were included in the systematic review. Studies about associations of (sub)clinical CAD with cognitive function and cognitive decline had heterogeneous methodology and inconsistent findings. Two population-based studies investigated the association between CAC and risk of dementia over 6–12.2 years using different CAC scoring methods. Both found a tendency toward higher risk of dementia as CAC severity increased. Meta-analysis in 15 studies (663,250 individuals) showed an association between CAD and MCI/dementia (pooled OR 1.32, 95%CI 1.17–1.48) with substantial heterogeneity (I2=87.0%, p<0.001). Pooled HR of CAD for incident MCI/dementia over 3.2–25.5 years in six longitudinal studies (70,060 individuals) was 1.51 (95%CI 1.24–1.85), with low heterogeneity (I2=14.1%, p=0.32). Sensitivity analysis did not detect any study that was of particular influence on the pooled OR or HR. Conclusions: Limited evidence suggests the CAC score is associated with risk of dementia. In clinical CAD, risk of MCI and dementia is increased by 50%, as supported by stronger evidence.
Abstract
Quorum sensing peptides (QSPs) are bacterial peptides produced by Gram-positive bacteria to communicate with their peers in a cell-density dependent manner. These peptides do not only act as ...interbacterial communication signals, but can also have effects on the host. Compelling evidence demonstrates the presence of a gut-brain axis and more specifically, the role of the gut microbiota in microglial functioning. The aim of this study is to investigate microglial activating properties of a selected QSP (PapRIV) which is produced by
Bacillus cereus
species. PapRIV showed in vitro activating properties of BV-2 microglia cells and was able to cross the in vitro Caco-2 cell model and reach the brain. In vivo peptide presence was also demonstrated in mouse plasma. The peptide caused induction of IL-6, TNFα and ROS expression and increased the fraction of ameboid BV-2 microglia cells in an NF-κB dependent manner. Different metabolites were identified in serum, of which the main metabolite still remained active. PapRIV is thus able to cross the gastro-intestinal tract and the blood–brain barrier and shows in vitro activating properties in BV-2 microglia cells, hereby indicating a potential role of this quorum sensing peptide in gut-brain interaction.
The underlying pathophysiology of primary open‐angle glaucoma remains unclear, but the lamina cribrosa seems to be the primary site of injury, and raised intraocular pressure is a major risk factor. ...In recent years, a decreased intracranial pressure, leading to an abnormally high trans‐lamina cribrosa pressure difference, has gained interest as a new risk factor for glaucoma. New research now lends support to the hypothesis that a paravascular transport system is present in the eye analogous to the recently discovered ‘glymphatic system’ in the brain, which is a functional waste clearance pathway that promotes elimination of interstitial solutes, including β‐amyloid, from the brain along paravascular channels. Given that β‐amyloid has been reported to increase by chronic elevation of intraocular pressure in glaucomatous animal models and to cause retinal ganglion cell death, the discovery of a paravascular clearance system in the eye may provide powerful new insights into the pathophysiology of primary open‐angle glaucoma. In this review, we provide a new conceptual framework for understanding the pathogenesis of primary open‐angle glaucoma, present supporting preliminary data from our own post‐mortem study and hypothesize that the disease may result from restriction of normal glymphatic flow at the level of the lamina cribrosa owing to a low intracranial pressure and/or a high trans‐lamina cribrosa pressure gradient. If confirmed, this viewpoint could offer new perspectives for the development of novel diagnostic and therapeutic strategies for this devastating disorder.
Recent advances in the understanding of the pathophysiological mechanisms underlying Alzheimer's disease have pointed to novel strategies for drug development. Animal models have contributed ...considerably to these advances, and will have a key role in the evaluation of therapeutics that could have the potential not just to alleviate the dementia associated with Alzheimer's disease, but to modify the disease process. Here, we summarize and critically evaluate current rodent models of dementia, and discuss their role in drug discovery and development.
The underlying pathophysiology of chronic fatigue syndrome remains incompletely understood and there are no curative treatments for this disorder at present. However, increasing neuroimaging evidence ...indicates that functional and structural abnormalities exist in the brains of chronic fatigue syndrome patients, suggesting that the central nervous system is involved in this disorder and that at least some chronic fatigue syndrome patients may have an underlying neurological basis for their illness. In the present paper, we speculate that glymphatic dysfunction, causing toxic build up within the central nervous system, may be responsible for at least some cases of chronic fatigue syndrome. We further postulate that cerebrospinal fluid diversion such as lumboperitoneal shunting may be beneficial to this subgroup of patients by restoring glymphatic transport and waste removal from the brain. Although recent evidence indicates that at least some chronic fatigue syndrome patients may benefit from cerebrospinal fluid drainage, further studies are needed to confirm this finding and to determine whether this can be attributed to enhancement of glymphatic fluid flow and interstitial fluid clearance. If confirmed, this could offer promising avenues for the future treatment of chronic fatigue syndrome. Clearly, given the relative invasive nature of cerebrospinal fluid diversion, such procedures should be reserved for chronic fatigue syndrome patients who are severely debilitated, or for those with severe headaches. Anyhow, it seems worthwhile to make every effort to identify new therapies for patients who suffer from this devastating disease, especially given that there are currently no effective treatments for this condition.