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Lancet (London, England) Oct 2015Frontotemporal dementia is an umbrella clinical term that encompasses a group of neurodegenerative diseases characterised by progressive deficits in behaviour, executive... (Review)
Review
Frontotemporal dementia is an umbrella clinical term that encompasses a group of neurodegenerative diseases characterised by progressive deficits in behaviour, executive function, or language. Frontotemporal dementia is a common type of dementia, particularly in patients younger than 65 years. The disease can mimic many psychiatric disorders because of the prominent behavioural features. Various underlying neuropathological entities lead to the frontotemporal dementia clinical phenotype, all of which are characterised by the selective degeneration of the frontal and temporal cortices. Genetics is an important risk factor for frontotemporal dementia. Advances in clinical, imaging, and molecular characterisation have increased the accuracy of frontotemporal dementia diagnosis, thus allowing for the accurate differentiation of these syndromes from psychiatric disorders. As the understanding of the molecular basis for frontotemporal dementia improves, rational therapies are beginning to emerge.
Topics: Adult; Aged; Alzheimer Disease; Aphasia; Diagnosis, Differential; Diagnostic Imaging; Frontotemporal Dementia; Frontotemporal Lobar Degeneration; Humans; Mental Disorders; Middle Aged; Motor Neuron Disease; Neurodegenerative Diseases
PubMed: 26595641
DOI: 10.1016/S0140-6736(15)00461-4 -
Neurologic Clinics May 2017Frontotemporal dementia (FTD) is a heterogeneous disorder with distinct clinical phenotypes associated with multiple neuropathologic entities. Presently, the term FTD... (Review)
Review
Frontotemporal dementia (FTD) is a heterogeneous disorder with distinct clinical phenotypes associated with multiple neuropathologic entities. Presently, the term FTD encompasses clinical disorders that include changes in behavior, language, executive control, and often motor symptoms. The core FTD spectrum disorders include behavioral variant FTD, nonfluent/agrammatic variant primary progressive aphasia, and semantic variant PPA. Related FTD disorders include frontotemporal dementia with motor neuron disease, progressive supranuclear palsy syndrome, and corticobasal syndrome. In this article, the authors discuss the clinical presentation, diagnostic criteria, neuropathology, genetics, and treatments of these disorders.
Topics: Brain; Frontotemporal Dementia; History, 20th Century; Humans; Supranuclear Palsy, Progressive
PubMed: 28410663
DOI: 10.1016/j.ncl.2017.01.008 -
European Journal of Neurology Oct 2020Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting primarily the motor system, but in which extra-motor manifestations are increasingly... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting primarily the motor system, but in which extra-motor manifestations are increasingly recognized. The loss of upper and lower motor neurons in the motor cortex, the brain stem nuclei and the anterior horn of the spinal cord gives rise to progressive muscle weakness and wasting. ALS often has a focal onset but subsequently spreads to different body regions, where failure of respiratory muscles typically limits survival to 2-5 years after disease onset. In up to 50% of cases, there are extra-motor manifestations such as changes in behaviour, executive dysfunction and language problems. In 10%-15% of patients, these problems are severe enough to meet the clinical criteria of frontotemporal dementia (FTD). In 10% of ALS patients, the family history suggests an autosomal dominant inheritance pattern. The remaining 90% have no affected family members and are classified as sporadic ALS. The causes of ALS appear to be heterogeneous and are only partially understood. To date, more than 20 genes have been associated with ALS. The most common genetic cause is a hexanucleotide repeat expansion in the C9orf72 gene, responsible for 30%-50% of familial ALS and 7% of sporadic ALS. These expansions are also a frequent cause of frontotemporal dementia, emphasizing the molecular overlap between ALS and FTD. To this day there is no cure or effective treatment for ALS and the cornerstone of treatment remains multidisciplinary care, including nutritional and respiratory support and symptom management. In this review, different aspects of ALS are discussed, including epidemiology, aetiology, pathogenesis, clinical features, differential diagnosis, investigations, treatment and future prospects.
Topics: Amyotrophic Lateral Sclerosis; C9orf72 Protein; DNA-Binding Proteins; Frontotemporal Dementia; Humans; Motor Neurons
PubMed: 32526057
DOI: 10.1111/ene.14393 -
Neurology India 2021Frontotemporal dementia (FTD) is an entity that includes a group of neurodegenerative disease with symptoms predominantly pertaining to deficits in behavior, executive... (Review)
Review
Frontotemporal dementia (FTD) is an entity that includes a group of neurodegenerative disease with symptoms predominantly pertaining to deficits in behavior, executive function (or) language. FTD is one of the most common type of dementia before 65 years of age and is one of the most underdiagnosed dementia as most often the symptoms overlap with psychiatric manifestations. Based on the clinical features, FTD is further subdivided into behavioral variant FTD (Bv-FTD) and primary progressive dementia (PPA). We searched PubMed, MEDLINE, and Google Scholar for articles about FTD disease published in English between January 1, 1975 till 2018. We used the search terms "frontotemporal dementia," "Fronto temporal dementia-motor neuron disease," "dementia," "cognition," "behavioral variant," and "primary progressive aphasia.
Topics: Aphasia, Primary Progressive; Executive Function; Frontotemporal Dementia; Humans; Language; Neurodegenerative Diseases
PubMed: 34747778
DOI: 10.4103/0028-3886.329593 -
Trends in Pharmacological Sciences Aug 2022Progranulin (PGRN, encoded by the GRN gene) plays a key role in the development, survival, function, and maintenance of neurons and microglia in the mammalian brain. It... (Review)
Review
Progranulin (PGRN, encoded by the GRN gene) plays a key role in the development, survival, function, and maintenance of neurons and microglia in the mammalian brain. It regulates lysosomal biogenesis, inflammation, repair, stress response, and aging. GRN loss-of-function mutations cause neuronal ceroid lipofuscinosis or frontotemporal dementia-GRN (FTD-GRN) in a gene dosage-dependent manner. Mutations that reduce PGRN levels increase the risk for developing Alzheimer's disease, Parkinson's disease, and limbic-predominant age-related transactivation response DNA-binding protein 43 encephalopathy, as well as exacerbate the progression of amyotrophic lateral sclerosis (ALS) and FTD caused by the hexanucleotide repeat expansion in the C9orf72 gene. Elevating and/or restoring PGRN levels is an attractive therapeutic strategy and is being investigated for neurodegenerative diseases through multiple mechanisms of action.
Topics: Frontotemporal Dementia; Humans; Microglia; Mutation; Neurodegenerative Diseases; Progranulins
PubMed: 35039149
DOI: 10.1016/j.tips.2021.11.015 -
Neurodegenerative Disease Management 2014Frontotemporal dementia (FTD) is a progressive neurologic syndrome with diverse clinical presentations and attendant underlying pathologies. Psychiatric prodrome,... (Review)
Review
Frontotemporal dementia (FTD) is a progressive neurologic syndrome with diverse clinical presentations and attendant underlying pathologies. Psychiatric prodrome, neuropsychiatric symptoms and language difficulties are common in FTD, but the diversity of presentation raises unique diagnostic challenges that can significantly impact patient care and counsel for caregivers regarding clinical status and prognosis. While neuropsychiatric symptom measures are helpful, more sensitive assessments delineating the specific behavioral and linguistic deficits accompanying FTD are needed. Comprehensive clinical assessment in combination with evaluation of language, socio-emotional functioning, cognition and neuroimaging aid in accurate and early diagnosis and treatment planning. In what follows, we review each of the FTD syndromes, highlight current research investigating the cognitive, behavioral and socio-emotional deficits observed with this disease, address common diagnostic challenges and summarize best practices associated with management of FTD.
Topics: Alzheimer Disease; Frontotemporal Dementia; Humans; Magnetic Resonance Imaging; Primary Progressive Nonfluent Aphasia
PubMed: 25531687
DOI: 10.2217/nmt.14.34 -
Acta Neuropathologica May 2019Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that overlap in their clinical presentation, pathology and genetics,... (Review)
Review
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that overlap in their clinical presentation, pathology and genetics, and likely represent a spectrum of one underlying disease. In ALS/FTD patients, neuroinflammation characterized by innate immune responses of tissue-resident glial cells is uniformly present on end-stage pathology, and human imaging studies and rodent models support that neuroinflammation begins early in disease pathogenesis. Additionally, changes in circulating immune cell populations and cytokines are found in ALS/FTD patients, and there is evidence for an autoinflammatory state. However, despite the prominent role of neuro- and systemic inflammation in ALS/FTD, and experimental evidence in rodents that altering microglial function can mitigate pathology, therapeutic approaches to decrease inflammation have thus far failed to alter disease course in humans. Here, we review the characteristics of inflammation in ALS/FTD in both the nervous and peripheral immune systems. We further discuss evidence for direct influence on immune cell function by mutations in ALS/FTD genes including C9orf72, TBK1 and OPTN, and how this could lead to the altered innate immune system "tone" observed in these patients.
Topics: Amyotrophic Lateral Sclerosis; Animals; Frontotemporal Dementia; Humans; Inflammation
PubMed: 30465257
DOI: 10.1007/s00401-018-1933-9 -
Continuum (Minneapolis, Minn.) Jun 2022This article reviews many of the complex facets of behavioral variant frontotemporal dementia (bvFTD) and frontotemporal lobar degeneration (FTLD). A particular focus is... (Review)
Review
PURPOSE OF REVIEW
This article reviews many of the complex facets of behavioral variant frontotemporal dementia (bvFTD) and frontotemporal lobar degeneration (FTLD). A particular focus is on improving diagnostic accuracy to reduce the arduous diagnostic odyssey that so many patients and families endure. Strategies to promote diagnostic accuracy and approach the management of problematic symptoms are also discussed.
RECENT FINDINGS
Although the International Consensus Criteria for bvFTD were published more than a decade ago and clinicopathologic studies have confirmed their utility, diagnostic confusion continues. This article presents updated data along with illustrative cases to emphasize the clinical pearls that are most useful for clinicians. Although accurate prediction of the underlying proteinopathy remains a challenge, the ability to differentiate bvFTD from atypical Alzheimer disease, psychiatric disorders, and other mimickers has improved. Knowledge about the genetic underpinnings in a significant minority of individuals with familial FTLD is enabling early and accurate diagnosis. Therapeutic optimism has also increased, particularly in familial FTLD, with a few clinical trials in progress and several more planned, some of which are designed to slow progression or delay the onset of symptoms, or both.
SUMMARY
The diagnosis and management of bvFTD is challenging for clinicians and particularly for patients and their families. Although much progress has been gained over recent years, several key research questions persist. Treatments that significantly improve symptoms or alter the course of FTLD remain elusive, but optimism is increasing as pathobiology is better understood and novel therapies are being developed.
Topics: Alzheimer Disease; Brain; Frontotemporal Dementia; Frontotemporal Lobar Degeneration; Humans
PubMed: 35678399
DOI: 10.1212/CON.0000000000001105 -
Nature Reviews. Neurology Sep 2018The discovery that repeat expansions in the C9orf72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has revolutionized... (Review)
Review
The discovery that repeat expansions in the C9orf72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has revolutionized our understanding of these diseases. Substantial headway has been made in characterizing C9orf72-mediated disease and unravelling its underlying aetiopathogenesis. Three main disease mechanisms have been proposed: loss of function of the C9orf72 protein and toxic gain of function from C9orf72 repeat RNA or from dipeptide repeat proteins produced by repeat-associated non-ATG translation. Several downstream processes across a range of cellular functions have also been implicated. In this article, we review the pathological and mechanistic features of C9orf72-associated FTD and ALS (collectively termed C9FTD/ALS), the model systems used to study these conditions, and the probable initiators of downstream disease mechanisms. We suggest that a combination of upstream mechanisms involving both loss and gain of function and downstream cellular pathways involving both cell-autonomous and non-cell-autonomous effects contributes to disease progression.
Topics: Amyotrophic Lateral Sclerosis; Animals; C9orf72 Protein; Disease Models, Animal; Frontotemporal Dementia; Humans
PubMed: 30120348
DOI: 10.1038/s41582-018-0047-2 -
Journal of Neurology, Neurosurgery, and... Feb 2021The frontotemporal dementia (FTD) spectrum of neurodegenerative disorders includes a heterogeneous group of conditions. However, following on from a series of important... (Review)
Review
The frontotemporal dementia (FTD) spectrum of neurodegenerative disorders includes a heterogeneous group of conditions. However, following on from a series of important molecular studies in the early 2000s, major advances have now been made in the understanding of the pathological and genetic underpinnings of the disease. In turn, alongside the development of novel methodologies for measuring proteins and other molecules in biological fluids, the last 10 years have seen a huge increase in biomarker studies within FTD. This recent past has focused on attempting to develop markers that will help differentiate FTD from other dementias (particularly Alzheimer's disease (AD)), as well as from non-neurodegenerative conditions such as primary psychiatric disorders. While cerebrospinal fluid, and more recently blood, markers of AD have been successfully developed, specific markers identifying primary tauopathies or TDP-43 proteinopathies are still lacking. More focus at the moment has been on non-specific markers of neurodegeneration, and in particular, multiple studies of neurofilament light chain have highlighted its importance as a diagnostic, prognostic and staging marker of FTD. As clinical trials get under way in specific genetic forms of FTD, measures of progranulin and dipeptide repeat proteins in biofluids have become important potential measures of therapeutic response. However, understanding of whether drugs restore cellular function will also be important, and studies of key pathophysiological processes, including neuroinflammation, lysosomal function and synaptic health, are also now becoming more common. There is much still to learn in the fluid biomarker field in FTD, but the creation of large multinational cohorts is facilitating better powered studies and will pave the way for larger omics studies, including proteomics, metabolomics and lipidomics, as well as investigations of multimodal biomarker combinations across fluids, brain imaging and other domains. Here we provide an overview of the past, present and future of fluid biomarkers within the FTD field.
Topics: Biomarkers; Diagnosis, Differential; Forecasting; Frontotemporal Dementia; Humans
PubMed: 33188134
DOI: 10.1136/jnnp-2020-323520