Frontotemporal dementia with tauopathy: A review and preliminary immunohistochemical study of tau kinases and phosphatases

Recent work has shown that frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) is caused by tau gene mutations. Several different exonic and intronic mutations in the tau gene heve been found in many families with FTDP-17. Patients with tau gene mutations show a wide variety of clinicopathological conditions, such as frontotemporal dementia, corticobasal degeneration, multiple system tauopathy with presenile dementia, pallido-ponto-nigral degeneration, disinhibition-dementia-parkinsonism-amyotrophy complex, and progressive sub-cortical gliosis. A Japanese family of frontotemporal dementia with a missense mutation S305N in exon 10 of the tau gene is reported. Post-mortem examination of the brain revealed ring-shaped neurofibrillary tangles (NFT) partially surrounding the nucleus, which were most prominent in the frontal, temporal, insular, and postcentral cortices, as well as in the dentate gyrus. Cortical NFT were restricted primarily to layer II. The missense mutation S305N did not reduce the ability of tau to promote microtubule assembly. Instead, it increased splicing of exon 10. Weak immunoreactivities of kinases for tau phosphorylation were found in late-stage NFT in the dentate gyrus, whereas strong immunoreactivities were seen in early stage NFT in the temporal cortex. PP2B was present in temporal NFT. Although anti-PP2A antibody labeled neurons, NFT were not stained, which suggests that the activity of this phosphatase might be decreased in NFT.     

Frontotemporal dementia, motor neuron disease and tauopathy: clinical and neuropathological study in a family

We report a familial disorder occurring in three patients that presented as frontotemporal dementia (FTD). A neuropathological study was performed in a 58-year-old patient, who developed FTD 2 years prior to the onset of motor neuron disease (MND), and died at age 62. Lesions indicative of associated MND were observed: neuronal loss in the anterior horns of the spinal cord, Bunina bodies, axonal spheroids, degeneration of the pyramidal tracts, and of FTD: decreased neuronal density and laminar microvacuolation of layers II and III in the frontal and temporal cortex. Ubiquitin-only-immunoreactive changes were found in the spinal cord and medulla, but were absent from the temporal and frontal cortex. There were also widespread deposits of various neuronal and glial inclusions containing abnormally phosphorylated tau protein, the Western blotting pattern of which was characterized by two major bands of 64 and 69 kDa. There were no abnormalities of the entire coding sequences of microtubule-associated protein tau (MAPT) and copper-zinc superoxide dismutase (SOD₁) genes. Our results suggest that FTD associated with MND can be caused by a larger spectrum of neuropathological lesions than commonly accepted.     

Frontotemporal dementia

Frontotemporal dementia (FTD) is an uncommon but important form of degenerative disease. It may make up 50% of dementia cases presenting before age 60. The symptoms are related to the anatomic areas affected. Neary divided the clinical syndromes into "frontotemporal dementia," "progressive nonfluent aphasia," and "semantic dementia." However, the pathology may extend beyond the frontal and temporal lobes and additional symptoms may be found. Although most cases are sporadic, some cases are genetic. The best-known genetic mutation causing FTD is frontotemporal dementia with parkinsonism, linked to the microtubule-associated protein tau on chromosome 17. There are other known genes and chromosome loci related to FTD. The most common pathology found is frontotemporal degeneration with ubiquitin inclusions. In contrast, FTD with Pick bodies is rare. Although there are strategies to help patients and their families, there is no known treatment for the disease.     

Frontotemporal dementia

Frontotemporal dementia (FTD) is a focal clinical syndrome characterised by profound changes in personality and social conduct and associated with circumscribed degeneration of the prefrontal and anterior temporal cortex. Onset is typically in the middle years of life and survival is about 8 years. The presence of microtubule-associated-protein-tau-based pathological features in some patients and the discovery, in some familial cases, of mutations in the tau gene links FTD to other forms of tauopathy, such as progressive supranuclear palsy and corticobasal degeneration. However, more than half of all patients with FTD, including some with a strong family history, show no apparent abnormality in the tau gene or protein, indicating pathological and aetiological heterogeneity. FTD provides a challenge both for clinical management and for theoretical understanding of its neurobiological substrate.     

Frontotemporal dementia

PURPOSE OF REVIEW: The syndromes of frontotemporal lobar degeneration are increasingly recognized as an important cause of early-onset dementia. Diagnostic consensus criteria have now been established for almost a decade, and form the framework for its clinical classification. While these criteria remain useful, a growing body of evidence suggests that revisions may be necessary to improve their validity and applicability. RECENT FINDINGS: In each individual syndrome, the core features are not uniformly present, and criteria that are currently used to exclude a condition, such as impaired episodic memory, are often present. Imaging, however, may warrant increased diagnostic prominence, particularly for diagnosis in semantic dementia and prognosis in behavioural syndromes. There is clinical and pathological overlap between the syndromes, but the clinical distinction between progressive nonfluent aphasia and semantic dementia is strengthening. Several series have refined our understanding of the correspondence between clinical syndromes and histopathological subtype: strong for tau-negative, ubiquitin-positive forms and more variable for tau-positive forms, yet prospective studies are still rare. The influence of genetic factors varies substantially across the syndromes. SUMMARY: Further research should aim to integrate detailed clinical, radiological, pathological and genetic information.     

Frontotemporal dementia

Frontotemporal dementia (FTD) is a unique neurodegenerative disease that can be differentiated from Alzheimer's disease and other diseases that result in cognitive complaints. The primary anatomic focus of degeneration determines the clinical presentation, which can vary from aphasia to behavioral symptoms. Expanding knowledge about the genetics and biochemistry of FTD may lead to specific treatments.     

Frontotemporal dementia

Neurological Sciences - Frontotemporal dementia is a clinicopathological syndrome caused by progressive degeneration of the frontal lobes, anterior temporal lobes or both. A wide spectrum of...     

Frontotemporal dementia

Frontotemporal dementia (FTD) and related conditions are often considered daunting because of the numerous inter-related clinical syndromes and their apparently heterogeneous pathologic substrates. Although the labyrinthine complexity of the disease seemingly continues to grow, recent discoveries have made the maze of FTD somewhat more navigable, spurring new interest in the field. This review begins by surveying the fascinating clinical presentations of these conditions and the few currently available treatments, then turns to recent progress in understanding the pathophysiology of FTD. Among the important advances surveyed are clinicopathologic correlations that enable prediction of the pathologic substrate of certain clinical subtypes, and genetic studies that have been particularly fruitful in identifying new causes of FTD.     

Frontal lobe dementia with novel tauopathy: sporadic multiple system tauopathy with dementia

We present a novel tauopathy in a patient with a 10-yr history of progressive frontal lobe dementia and a negative family history. Autopsy revealed mild atrophy of frontal and parietal lobes and severe atrophy of the temporal lobes. There were occasional filamentous tau-positive inclusions, but more interesting were numerous distinctive globular neuronal and glial tau-positive inclusions in both gray and white matter of the neocortex. Affected subcortical regions included substantia nigra, globus pallidus, subthalamic nucleus, and cerebellar dentate nucleus, in a distribution similar to progressive supranuclear palsy (PSP), but without significant accompanying neuronal loss or gliosis. Predominantly straight filaments were detected by electron microscopy (EM), while other inclusions were similar to fingerprint bodies. No twisted ribbons were detected. Immuno-EM studies revealed that only the filamentous inclusions were composed of tau. Immunoblotting of sarkosyl-insoluble tau revealed 2 major bands of 64 and 68 kDa. Blotting analysis after dephosphorylation revealed predominantly 4-repeat tau. Sequence analysis of tau revealed that there were no mutations in either exons 9-13 or the adjacent intronic sequences. The unique cortical tau pathology in this case of sporadic multiple system tauopathy with dementia adds a new pathologic profile to the spectrum of tauopathies.     

Frontotemporal dementia and mitochondrial DNA transitions

Frontotemporal dementia (FTD) is the second most common type of primary degenerative dementia. Some patients present an overlap between Alzheimer's disease (AD) and FTD both in neuropathological and clinical aspects. This may suggest a similar overlap in physiopathology, namely an involvement of mitochondrial DNA (mtDNA) in FTD, as it has been associated to AD. To determine if mtDNA is involved in FTD, we performed a Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) analysis, specific to mtDNA NADH Dehydrogenase subunit 1 (ND1) nucleotides 3337-3340, searching for mutations previously described in Parkinson's and AD patients. We could identify one FTD patient with two mtDNA transitions: one already known (3316 G-to-A) and another unreported (3337 G-to-A). Additionally, mitochondrial respiratory chain complex I activity was reduced in leukocytes of this patient (36% of the control mean activity). To our knowledge, this is the first report of mtDNA variants in FTD patients.     

Frontotemporal dementia with tau pathology

Tau is a microtubule-associated protein involved in microtubule assembly and stabilization. Filamentous deposits made of tau constitute a major defining characteristic of several neurodegenerative diseases known as tauopathies including Alzheimer's disease. The involvement of tau in neurodegeneration has been clarified by the identification of genetic mutations in the tau gene in cases with familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Although the mechanism through which tau mutations lead to neuronal death is still unresolved, it is clear that tau mutations lead to formation of tau filaments that have a different morphology, contain different types of tau isoforms and produce distinct tau deposits. The range of tau pathology identified in FTDP-17 recapitulates the tau pathology present in sporadic tauopathies and indicates that tau dysfunction plays a major role also in these diseases.     

Frontotemporal dementia: a review

CLINICAL CHARACTERISTICS: Frontotemporal dementia (FTD) is a neurological disorder characterised by the progressive degeneration of the frontal and anterior temporal cortex. FTD, as well as nonfluent progressive aphasia and semantic dementia, belongs to the more generic entity of frontotemporal lobe degeneration. Considering the involvement of the frontal lobe, the initial clinical presentation of FTD may be psychiatric, such as changes in personality or behavioural disorders. Psychiatrists, therefore, have to establish the differential diagnosis with late-onset schizophrenia or affective disorders. An accurate history of the onset of symptoms, thanks to the patient and especially to his/her family, is essential to recognize this dementia. In addition to behavioural changes, memory impairment, and speech disturbances are often present from the beginning. Consensus criteria have been proposed in 1998 that help to bring this diagnosis to mind in clinical practice. The progressive occurrence of personality changes or inappropriate social conducts in the fifth or sixth decade must prompt cognitive evaluation. NEUROCOGNITIVE AND BRAIN IMAGING DATA: A brief cognitive evaluation, such as the frontal assessment battery (FAB) may help to identify a dysexecutive syndrome and to prompt a thorough neuropsychological evaluation. The pattern of neuropsychological impairment reflects the involvement of the frontal lobe and appears different from that of other degenerative diseases, such as Alzheimer's dementia, which involves hippocampal damage. Additional investigations should however be made to detect a potentially curable dementia. Cerebral imaging is essential to the differential diagnosis and also shows evidence for the positive diagnosis of FTD. Structural MRI may initially not show the bilateral atrophy of the frontal lobe, but functional imaging may be helpful in the early stages of the illness by showing evidence of abnormalities in the anterior cerebral hemisphere. PATHOPHYSIOLOGICAL FINDINGS: In recent years, significant advances in the understanding of the pathological characteristics of FTD were made with genetic contribution, especially the discovery of the tau protein involvement. In fact, neuropathological examination with immunohistochemical analysis defines Pick's disease with Pick bodies that belong to tauopathies. Ubiquitinated intraneuronal inclusions may also be found, and some types of FTD have no distinctive pathological feature. However, although a definite diagnosis would only be established after postmortem pathological examination, the clinical, neuropsychological and imaging data enable the early identification of patients with FTD and, subsequently, the appropriate management. THERAPEUTICS: Although the prevalence of FTD reaches 1 Alzheimer's disease (AD) to 1.6 FTD in the general population between 45- and 64-year old, only few studies have focused on the treatment of FTD. Some evidence supports the positive effect of serotonergic agents, especially with regard to behavioural symptoms. Selective serotonin reuptake inhibitors or trazodone should therefore be prescribed in preference to acetylcholinesterase medications as in AD. However, no drug yet has the ability to stop or slow down the degenerative process. The management of daily life also bears specificities related to the younger age of these patients and to their behavioural disorders. Caregivers should receive some education about the characteristics of this dementia and should be helped in social management. As concerns aggressive behaviour, neuroleptics should generally be avoided because of poor tolerance. Finally, the outcome is characterized by a rapid loss of autonomy and sometimes by a premature institutionalisation.     

Frontotemporal dementia: Pick type

The status of Pick's disease within the concept of frontotemporal dementia (FTD) is unclear. Some researchers have defined Pick's disease as FTD with Pick bodies. Alternatively, the confusion may be clarified by using the term Pick body dementia (PBD) rather than by using the term Pick's disease in a narrow sense. Pick body dementia is characterized by a prominent frontotemporal lobar atrophy, gliosis, severe neuronal loss, ballooned neurons, and the presence of neuronal inclusions called Pick bodies. In recent years, studies of Pick body dementia have advanced from the standpoint of the tau pathology. Tau-positive glial inclusions as well as neuronal inclusions have been observed in PBD and its related disorders. Various forms of FTD have been proposed based on the presence of neuronal or glial inclusions. We propose a new variant of FTD termed ‘glial tangle-predominant type’. More research is required to understand the tau abnormalities in the various forms of FTD.