The recent identification of the transactive response DNA binding protein with a molecular weight of 43 kDa (TDP-43) as the major pathological protein, in both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U), provides the new insight into understanding disease processes. The pathogenesis of both diseases is unclear, although they are related by having some overlap of symptoms and now by the shared histopathology of TDP-43 deposition. The number of degenerative diseases associated with TDP-43 has increased, leading to the new designation "TDP-43 proteinopathy". TDP-43 is a highly conserved protein ubiquitously expressed in many tissues including the central nervous system where it is present in neuronal and glial nuclei and to a lesser extent in the cytoplasm. Currently, TDP-43 has been implicated in regulating gene transcription and alternative splicing, in addition to maintaining mRNA stability. However, we still need to investigate the effects of posttranslational modifications of TDP-43, including phosphorylation, ubiquitination, and cleavage, on its regulation of various cellular processes. We review recently published studies of TDP-43 and its relationship to human disease with a special focus on ALS and FTLD-U. We conclude that the TDP-43 proteinopathies represent a novel class of neurodegenerative disorders and both ALS and FTLD-U are closely related conditions linked to similar mechanism of neurodegeneration.
Alternative Splicing ; Amyotrophic Lateral Sclerosis ; Central Nervous System ; Cytoplasm ; DNA ; DNA-Binding Proteins ; Frontotemporal Dementia ; Frontotemporal Lobar Degeneration ; Humans ; Molecular Weight ; Neurodegenerative Diseases ; Neurons ; Phosphorylation ; Protein Processing, Post-Translational ; RNA Stability ; TDP-43 Proteinopathies ; Ubiquitin ; Ubiquitination

A 62-year-old man presented with a one-year history of word finding difficulty, impaired single word comprehension and personality changes including aggression, apathy and eating change. Brain MRIs showed severe atrophy in the left anterior temporal lobe. The clinical syndromic diagnosis was semantic variant primary progressive aphasia. He died at age 70 of pneumonia. At autopsy, transactive response DNA-binding protein (TDP) immunoreactive long dystrophic neurites were predominantly found in the cerebral cortices, which were compatible with frontotemporal lobar degeneration-TDP type C pathology.
Aggression ; Apathy ; Aphasia, Primary Progressive ; Atrophy ; Autopsy ; Brain ; Cerebral Cortex ; Comprehension ; Diagnosis ; Eating ; Frontotemporal Dementia ; Frontotemporal Lobar Degeneration ; Humans ; Magnetic Resonance Imaging ; Middle Aged ; Neurites ; Pathology ; Pneumonia ; Semantics ; TDP-43 Proteinopathies ; Temporal Lobe

Frontotemporal lobar degeneration (FTLD) is a progressive dementia with prominent neuropsychiatric features, aphasia or both. FTLD predominantly affects the frontal and anterior part of temporal cortex. FTLD is classified into frontotemporal dementia (FTD), progressive nonfluent aphasia (PA), and semantic dementia (SD). FTLD is estimated to account for 20% of cases of degenerative dementia with presenile onset. This disease typically has onset in the mid- or early fifties. FTD is characterized by behavioral change and executive dysfunction, PA features a progressive nonfluent aphasia. SD is characterized by a progressive semantic aphasia and associative agnosia. Structural imaging shows atrophy of the frontal lobe and the anterior portion of the temporal lobe, bilaterally symmetric or asymmetric. Pathologically, FTLD can be classified into tau-positive pathology, tau-negative, ubiquitin positive pathology, dementia lacking distinctive histology. At present, there are no specific pharmacological therapies approved for use in any of the FTLD syndrome.
Agnosia ; Aphasia ; Atrophy ; Dementia ; Frontal Lobe ; Frontotemporal Dementia ; Frontotemporal Lobar Degeneration* ; Pathology ; Primary Progressive Nonfluent Aphasia ; Temporal Lobe ; Ubiquitin

It is not uncommon for idiopathic parkinson's disease (IPD) to occur concurrently with other degenerative dementing disorders such as Alzheimer's disease. However, there has been no report about the comorbidity of IPD and frontotemporal lobar degeneration. We report a 70-year-old man diagnosed with IPD accompanied by progressive non-fluent aphasia (PA). Brain MRI showed left frontal opercular atrophy, and an 18F-FDG PET scan revealed predominant left frontotemporal hypometabolism. It remains unknown whether or not the co-occurrence of IPD and PA was coincidental.
Aged ; Alzheimer Disease ; Aphasia ; Atrophy ; Brain ; Comorbidity ; Dementia ; Fluorodeoxyglucose F18 ; Frontotemporal Lobar Degeneration ; Humans ; Magnetic Resonance Imaging ; Parkinson Disease* ; Positron-Emission Tomography ; Primary Progressive Nonfluent Aphasia*

Frontotemporal dementia (FTD), formerly called Pick's disease, is a progressive dementia that is associated with focal atrophy of the frontal and/or temporal lobes. FTD has three major clinical subtypes ; 1) a frontal variant of frontotemporal dementia (fvFTD), 2) semantic dementia (SD), and 3) progressive nonfluent aphasia (PNFA). These different variants differ in their clinical symptoms, cognitive deficits, and affected brain regions. The insidious onset of personality changes and behavioral abnormalities is the most prominent feature of fvFTD. Poor insight, loss of personal and social awareness, and blunting of affect are common behavioral changes in fvFTD. The most common presenting complaint in SD involves language, and is often described as a loss of memory for words or a loss of word meaning. Patients with PNFA present with changes in fluency, pronunciation, or word finding difficulty. An accumulating body of evidence suggests that FTD overlaps with three other neurodegenerative diseases: motor neuron disease (MND), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP). Treatment for FTD consists of behavioral and pharmacological approaches. Medications such as selective serotonin reuptake inhibitors, antipsychotics have used in FTD. Cholinesterase inhibitors do not consistently improve cognitive and behavioral symptoms of FTD. Further research should be directed at developing new therapeutic methods to improve the patients' symptoms.
Antipsychotic Agents ; Atrophy ; Behavioral Symptoms ; Brain ; Cholinesterase Inhibitors ; Dementia ; Frontotemporal Dementia ; Frontotemporal Lobar Degeneration ; Humans ; Memory ; Motor Neuron Disease ; Neurobehavioral Manifestations ; Pick Disease of the Brain ; Primary Progressive Nonfluent Aphasia ; Serotonin Uptake Inhibitors ; Supranuclear Palsy, Progressive ; Temporal Lobe

Approximately 15% of patients with frontotemporal dementia (FTD) have co-occurring motor neuron disease (MND). FTD-MND cases have frontotemporal lobar degeneration (FTLD)-transactive response DNA-binding protein (TDP) pathology, which is divided into four subtypes (types A, B, C, and D) based on the morphological appearance, cellular location, and distribution of the abnormal TDP inclusions and dystrophic neurites. We report a patient with FTD-MND whose pathological diagnosis was FTLD-TDP type B. This is the first documented autopsy-confirmed case of FTD-MND in Korea.
Autopsy* ; Diagnosis ; Frontotemporal Dementia* ; Frontotemporal Lobar Degeneration ; Humans ; Korea ; Motor Neuron Disease* ; Motor Neurons* ; Neurites ; Pathology

Approximately 15% of patients with frontotemporal dementia (FTD) have co-occurring motor neuron disease (MND). FTD-MND cases have frontotemporal lobar degeneration (FTLD)-transactive response DNA-binding protein (TDP) pathology, which is divided into four subtypes (types A, B, C, and D) based on the morphological appearance, cellular location, and distribution of the abnormal TDP inclusions and dystrophic neurites. We report a patient with FTD-MND whose pathological diagnosis was FTLD-TDP type B. This is the first documented autopsy-confirmed case of FTD-MND in Korea.
Autopsy* ; Diagnosis ; Frontotemporal Dementia* ; Frontotemporal Lobar Degeneration ; Humans ; Korea ; Motor Neuron Disease* ; Motor Neurons* ; Neurites ; Pathology

Aged ; Agraphia ; etiology ; Amyotrophic Lateral Sclerosis ; complications ; pathology ; Female ; Frontotemporal Lobar Degeneration ; complications ; pathology ; Humans ; Magnetic Resonance Imaging

Semantic dementia is a rare, distinct form of frontotemporal lobar degeneration, characterized by a deficit in semantic memory with relative preservation of attention and executive functions. We report a case of semantic dementia that pre-sented with a 3-year history of progressive word-finding difficulty and prosopagnosia. Brain MRI showed prominent atrophic changes in the left temporal region and neuropsychological tests demonstrated semantic memory deficits.
Brain ; Executive Function ; Frontotemporal Dementia* ; Frontotemporal Lobar Degeneration ; Magnetic Resonance Imaging ; Memory ; Memory Disorders ; Neuropsychological Tests ; Prosopagnosia ; Semantics*

Criticisms about amyloid cascade hypothesis of Alzheimer's disease(AD) are based on the findings, first, that the degree of dementia does not correlate with the number of plaques, and second, that the neurofibrillary tangle formation seems to predate plaque formation. In addition, neurofibrillary tangle counts correlate well with the degree of cognitive impairment. These findings suggest the independent importance of tau abnormality in AD research which is involved in the neurofibrillary tangle formation. Recently, tau pathology without amyloid deposits and mutations in tau protein gene were reported to be the major pathogenic mechanism in Pick's disease, progressive supranuclear palsy, corticobasal degeneration and FTDP-17(frontotemporal dementia and parkinsonism linked with chromosome 17). These data suggest that understanding the causes and consequences of tau dysfunction might give new clinical and therapeutic solutions to many known tauopathies.
Amyloid ; Dementia ; Frontotemporal Dementia ; Frontotemporal Lobar Degeneration ; Molecular Biology* ; Neurofibrillary Tangles ; Parkinsonian Disorders ; Pathology ; Pick Disease of the Brain ; Plaque, Amyloid ; Prednisolone ; Supranuclear Palsy, Progressive ; tau Proteins* ; Tauopathies