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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 -
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 -
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 -
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 -
Brain : a Journal of Neurology Nov 2022Focal anterior temporal lobe degeneration often preferentially affects the left or right hemisphere. While patients with left-predominant anterior temporal lobe atrophy...
Focal anterior temporal lobe degeneration often preferentially affects the left or right hemisphere. While patients with left-predominant anterior temporal lobe atrophy show severe anomia and verbal semantic deficits and meet criteria for semantic variant primary progressive aphasia and semantic dementia, patients with early right anterior temporal lobe atrophy are more difficult to diagnose as their symptoms are less well understood. Focal right anterior temporal lobe atrophy is associated with prominent emotional and behavioural changes, and patients often meet, or go on to meet, criteria for behavioural variant frontotemporal dementia. Uncertainty around early symptoms and absence of an overarching clinico-anatomical framework continue to hinder proper diagnosis and care of patients with right anterior temporal lobe disease. Here, we examine a large, well-characterized, longitudinal cohort of patients with right anterior temporal lobe-predominant degeneration and propose new criteria and nosology. We identified individuals from our database with a clinical diagnosis of behavioural variant frontotemporal dementia or semantic variant primary progressive aphasia and a structural MRI (n = 478). On the basis of neuroimaging criteria, we defined three patient groups: right anterior temporal lobe-predominant atrophy with relative sparing of the frontal lobes (n = 46), frontal-predominant atrophy with relative sparing of the right anterior temporal lobe (n = 79) and left-predominant anterior temporal lobe-predominant atrophy with relative sparing of the frontal lobes (n = 75). We compared the clinical, neuropsychological, genetic and pathological profiles of these groups. In the right anterior temporal lobe-predominant group, the earliest symptoms were loss of empathy (27%), person-specific semantic impairment (23%) and complex compulsions and rigid thought process (18%). On testing, this group exhibited greater impairments in Emotional Theory of Mind, recognition of famous people (from names and faces) and facial affect naming (despite preserved face perception) than the frontal- and left-predominant anterior temporal lobe-predominant groups. The clinical symptoms in the first 3 years of the disease alone were highly sensitive (81%) and specific (84%) differentiating right anterior temporal lobe-predominant from frontal-predominant groups. Frontotemporal lobar degeneration-transactive response DNA binding protein (84%) was the most common pathology of the right anterior temporal lobe-predominant group. Right anterior temporal lobe-predominant degeneration is characterized by early loss of empathy and person-specific knowledge, deficits that are caused by progressive decline in semantic memory for concepts of socioemotional relevance. Guided by our results, we outline new diagnostic criteria and propose the name, 'semantic behavioural variant frontotemporal dementia', which highlights the underlying cognitive mechanism and the predominant symptomatology. These diagnostic criteria will facilitate early identification and care of patients with early, focal right anterior temporal lobe degeneration as well as in vivo prediction of frontotemporal lobar degeneration-transactive response DNA binding protein pathology.
Topics: Humans; Frontotemporal Dementia; Semantics; Frontotemporal Lobar Degeneration; Atrophy; Magnetic Resonance Imaging; Aphasia, Primary Progressive; DNA-Binding Proteins; Neuropsychological Tests
PubMed: 35731122
DOI: 10.1093/brain/awac217 -
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 -
International Journal of Molecular... Jul 2023Frontotemporal dementia (FTD) is a neurodegenerative disease of growing interest, since it accounts for up to 10% of middle-age-onset dementias and entails a social,... (Review)
Review
Frontotemporal dementia (FTD) is a neurodegenerative disease of growing interest, since it accounts for up to 10% of middle-age-onset dementias and entails a social, economic, and emotional burden for the patients and caregivers. It is characterised by a (at least initially) selective degeneration of the frontal and/or temporal lobe, generally leading to behavioural alterations, speech disorders, and psychiatric symptoms. Despite the recent advances, given its extreme heterogeneity, an overview that can bring together all the data currently available is still lacking. Here, we aim to provide a state of the art on the pathogenesis of this disease, starting with established findings and integrating them with more recent ones. In particular, advances in the genetics field will be examined, assessing them in relation to both the clinical manifestations and histopathological findings, as well as considering the link with other diseases, such as amyotrophic lateral sclerosis (ALS). Furthermore, the current diagnostic criteria will be explored, including neuroimaging methods, nuclear medicine investigations, and biomarkers on biological fluids. Of note, the promising information provided by neurophysiological investigations, i.e., electroencephalography and non-invasive brain stimulation techniques, concerning the alterations in brain networks and neurotransmitter systems will be reviewed. Finally, current and experimental therapies will be considered.
Topics: Middle Aged; Humans; Frontotemporal Dementia; Neurodegenerative Diseases; Pick Disease of the Brain; Amyotrophic Lateral Sclerosis; Temporal Lobe
PubMed: 37511491
DOI: 10.3390/ijms241411732 -
The Lancet. Neurology Jul 2014Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic...
BACKGROUND
Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72--have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.
METHODS
We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10(-8)) single-nucleotide polymorphisms.
FINDINGS
We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10(-8)). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10(-8); odds ratio=1·204 [95% CI 1·11-1·30]), rs9268856 (p=5·51 × 10(-9); 0·809 [0·76-0·86]) and rs1980493 (p value=1·57 × 10(-8), 0·775 [0·69-0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10(-7); 0·814 [0·71-0·92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis.
INTERPRETATION
Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD.
FUNDING
The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center.
Topics: Adult; Aged; Aged, 80 and over; Female; Frontotemporal Dementia; Genome-Wide Association Study; Genotype; Humans; Male; Middle Aged
PubMed: 24943344
DOI: 10.1016/S1474-4422(14)70065-1