Increased oligomeric TDP-43 in the plasma of Korean frontotemporal dementia patients with semantic dementia.

INTRODUCTION: Semantic dementia (SD) is a progressive neurodegenerative disease associated with impaired vocabulary that progresses to memory impairment. Post-mortem immunohistochemical analysis is the current reliable method of differentiating TDP-43 deposits in cortical tissue; no means of antemortem diagnosis exists in biofluids, let alone in plasma. METHODS: Here the multimer detection system (MDS) was used to quantify the oligomeric TDP-43 (o-TDP-43) concentrations in plasma of Korean SD patients (n = 16, 6 male, 10 female, ages 59-87). The o-TDP-43 concentrations were compared with the total TDP-43 (t-TDP-43) concentrations quantified through conventional enzyme-linked immunosorbent assay (ELISA). RESULTS AND DISCUSSION: Only MDS showed a significant increase in o-TDP-43 concentrations in the plasma of patients with SD compared to other neurodegenerative disorders and normal controls (p < 0.05). Based on these results, o-TDP-43 concentrations through the application of MDS may be a useful plasma biomarker in SD-FTD (frontotemporal dementia) diagnosis.

A Microplate-Based Approach to Map Interactions between TDP-43 and α-Synuclein.

Trans-active response DNA-binding protein (TDP-43) is a multifunctional regulatory protein, whose abnormal deposition in neurons was linked to debilitating neurodegenerative diseases, such as amyotrophic lateral sclerosis, frontotemporal lobar degeneration, Limbic-predominant age-related TDP-43 encephalopathy, and Alzheimer's disease with a secondary pathology. Several reports showed that TDP-43 proteinopathy as a comorbidity can form aggregates with other pathological proteins. The co-deposition of alpha synuclein and TDP-43 inclusions was previously reported in glial cells and by observing TDP-43 proteinopathy in Lewy body disease. In this study, it was hypothesized that alpha synuclein and TDP-43 may co-aggregate, resulting in comorbid synucleinopathy and TDP-43 proteinopathy. A solid-phase microplate-based immunoassay was used to map out the epitopes of anti-TDP-43 antibodies and locate the interaction of TDP-43 with α-synuclein. A region of the low complexity domain of TDP-43 (aa 311-314) was shown to interact with full-length α-synuclein. Conversely, full-length TDP-43 was shown to bind to the non-amyloid beta component of α-synuclein. Using in silico sequence-based prediction, the affinity and dissociation constant of full-length TDP-43 and α-synuclein were calculated to be -10.83 kcal/mol and 1.13 × 10-8, respectively. Taken together, this microplate-based method is convenient, economical, and rapid in locating antibody epitopes as well as interaction sites of two proteins.

The influence of Aß-dependent and independent pathways on TDP-43 proteinopathy in Alzheimer's disease: a possible connection to LATE-NC.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that results from the accumulation of plaques by cleaved Aß42 peptides as well as neurofibrillary tangles of tau proteins. This accumulation triggers a complex cascade of cytotoxic, neuroinflammatory, and oxidative stresses that lead to neuronal death throughout the progression of the disease. Much of research in AD focused on the 2 pathologic proteins. Interestingly, another form of dementia with similar clinical manifestations of AD, but preferentially affected much older individuals, was termed as limbic-predominant age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy (LATE) and involved the cytotoxic intraneuronal deposition of phosphorylated TDP-43. TDP-43 proteinopathy was also found to be involved in AD pathology leading to the possibility that AD and LATE may share a common upstream etiology. This paper discusses the roles molecular pathways known in AD may have on influencing TDP-43 proteinopathy and the development of AD, LATE, or the 2 being comorbid with each other.

Autosomal Dominant Frontotemporal Lobar Degeneration in a Filipino Family with Progranulin Mutation.

BACKGROUND: Compared to Western populations, familial frontotemporal lobar degeneration (FTLD) is rare among Asians. Progranulin (GRN) gene mutation, which is a major cause of FTLD, is likewise rare. We present a family with FTLD from the Philippines with an autosomal dominant pattern of inheritance and GRN mutation and briefly review reports of GRN mutations in Asia. CASE PRESENTATION: The proband is 66 years old with progressive nonfluent aphasia (PNFA)-corticobasal syndrome . We assessed 3 generations of her pedigree and found 11 affected relatives with heterogenous phenotypes, usually behavioral variant frontotemporal dementia (FTD) and PNFA. Neuroimaging showed atrophy and hypometabolism consistent with FTD syndromes. White matter hyperintensities were seen in affected members even in the absence of vascular risk factors. A GRN mutation R110X was found in 6 members, 3 with symptoms and 3 were asymptomatic. Plasma GRN was low (<112 ng/mL) in all mutation carriers. No mutations were found in microtubule-associated protein tau, APP, PSEN1, and PSEN2 genes, and all were APOE3. CONCLUSION: This is the first Filipino family with autosomal dominant FTD documented with GRN mutation. Identifying families and cohorts would contribute to therapeutic developments in an area with FTD-GRN.

Diagnostic and Treatment Approaches Involving Transthyretin in Amyloidogenic Diseases.

Transthyretin (TTR) is a thyroid hormone-binding protein which transports thyroxine from the bloodstream to the brain. The structural stability of TTR in tetrameric form is crucial for maintaining its original functions in blood or cerebrospinal fluid (CSF). The altered structure of TTR due to genetic mutations or its deposits due to aggregation could cause several deadly diseases such as cardiomyopathy and neuropathy in autonomic, motor, and sensory systems. The early diagnoses for hereditary amyloid TTR with cardiomyopathy (ATTR-CM) and wild-type amyloid TTR (ATTRwt) amyloidosis, which result from amyloid TTR (ATTR) deposition, are difficult to distinguish due to the close similarities of symptoms. Thus, many researchers investigated the role of ATTR as a biomarker, especially its potential for differential diagnosis due to its varying pathogenic involvement in hereditary ATTR-CM and ATTRwt amyloidosis. As a result, the detection of ATTR became valuable in the diagnosis and determination of the best course of treatment for ATTR amyloidoses. Assessing the extent of ATTR deposition and genetic analysis could help in determining disease progression, and thus survival rate could be improved following the determination of the appropriate course of treatment for the patient. Here, the perspectives of ATTR in various diseases were presented.

Gut Microbiota and Their Neuroinflammatory Implications in Alzheimer's Disease.

The bidirectional communication between the central nervous system (CNS) and the gut microbiota plays a pivotal role in human health. Increasing numbers of studies suggest that the gut microbiota can influence the brain and behavior of patients. Various metabolites secreted by the gut microbiota can affect the cognitive ability of patients diagnosed with neurodegenerative diseases. Nearly one in every ten Korean senior citizens suffers from Alzheimer's disease (AD), the most common form of dementia. This review highlights the impact of metabolites from the gut microbiota on communication pathways between the brain and gut, as well as the neuroinflammatory roles they may have in AD patients. The objectives of this review are as follows: (1) to examine the role of the intestinal microbiota in homeostatic communication between the gut microbiota and the brain, termed the microbiota⁻gut⁻brain (MGB) axis; (2) to determine the underlying mechanisms of signal dysfunction; and (3) to assess the impact of signal dysfunction induced by the microbiota on AD. This review will aid in understanding the microbiota of elderly people and the neuroinflammatory roles they may have in AD.