Frontotemporal dementia

Frontotemporal dementia (FTD) derives from focal neurodegeneration of the frontal or temporal lobes of the brain. It is estimated that approximately 30% of patients with FTD have a strong family history.[34][35] The behavioral forms show the highest heritability (around 48%); the heritability of other phenotypes is less clear.[35][36]

Most FTD heritability is associated with autosomal dominant mutations in the microtubule-associated protein tau (MAPT), progranulin (GRN), and chromosome 9 open reading frame 72 (C9orf72) genes, each of which accounts for between 5% and 10% of all FTDs.[35][37][38][39][40] One large cohort study noted that C9orf72 expansions were the most common cause of genetic FTD.[30] The C9orf72 gene is also associated with heritability of amyotrophic lateral sclerosis.[40][41][42] Mutations in a number of other genes have been associated with FTD, including TBK1, VCP, CHMP2B, TARDBP, FUS, SQSTM1, CHCHD10, OPTN, CCNF, and TIA1; taken together, these mutations are estimated to account for less than 5% of FTD cases.[35][43] Geographical variation has been reported for many of the gene mutations.[35][44]

There is increasing evidence that traumatic brain injury increases risk for future development of FTD.[45][46][47] Research also indicates that post-traumatic stress disorder (PTSD) may be a risk factor for dementia, with one study finding semantic FTD to be the most common dementia among people who have experienced PTSD.[48][49] There is no good evidence for the involvement of any other nongenetic etiologic factors in FTD.

Frontotemporal lobar degeneration (FTLD) is characterized by neuronal loss, gliosis, and microvascular changes of frontal lobes, anterior temporal lobes, anterior cingulate cortex, and insular cortex. FTLD is classified into several subtypes, according to the main protein component of neuronal and glial abnormal inclusions and their distribution. Major molecular subtypes of FTLD include FTLD-tau, FTLD-TDP, and FTLD-FET.[50][51][52] Although most patients with FTLD are found to have a single type of pathology at autopsy, cases with more than one pathology are not uncommon.[53]

FTLD-tau accounts for an estimated 36% to 50% of all cases of FTLD. It is characterized by abnormal intracellular accumulation of hyperphosphorylated tau, a characteristic feature of a number of neurodegenerative disorders (tauopathies) including FTD.[54] Subtypes of FTLD-tau are Pick disease, corticobasal degeneration and progressive supranuclear palsy, globular glial tauopathy, and autosomal dominant familial tau caused by mutations in the MAPT gene.

FTLD-TDP (sometimes known previously as FTLD-U) accounts for up to 50% of all cases of FTLD. It has eight different subtypes; four major subtypes (A, B, C, D) are recognized based on patterns of cytoplasmic intranuclear pathology and cortical association.[51][52] In addition there are familial variants characterized by mutations in the GRN, c9orf72, VCP, and TARDBP genes.[52] TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA-binding protein involved in several aspects of RNA processing, and accumulates in the great majority of cases of FTLD with tau-negative, ubiquitin-positive inclusions. The hallmark lesions of FTLD-TDP are neuronal cytoplasmic inclusions and dystrophic neurites that are immunoreactive for TDP-43, ubiquitin, and p62, but negative for other neurodegenerative disease-related proteins.

FTLD-FET accounts for around 4% of familial type amyotrophic lateral sclerosis (ALS). It is associated with mutations in the genes encoding FUS (fused in sarcoma), EWS (Ewing sarcoma), and TAF15 (TATA-binding protein-associated factor 15) (known collectively as the FET protein family).[52][55] Mutations in the FUS gene were noted in a small proportion of patients with ALS which overlaps with FTD.

A fourth type was identified as "atypical FTLD-U". A number of other rare variants have been described, each of which are associated with mutations in genes related to macrophage/microglial activity (CSF1R, TREM2, and DAP12).[55][56][57]

The molecular pathophysiology of FTD should not, however, be considered in isolation; the understanding of symptoms associated with FTD is also informed by a substantial body of research in social neuroscience.[58]

International consensus criteria for behavioral variant frontotemporal dementia (FTD)[7]

In 2011, an international consortium developed guidelines for the diagnosis of behavioral variant FTD (bvFTD). These criteria show encouragingly high sensitivity and specificity when applied to patients with early-onset dementia and provide a useful tool both for specialist researchers and for general clinicians.[7][8][9] The classification includes criteria for:

Neurodegenerative disease
Possible bvFTD
Probable bvFTD
Behavioral variant FTD with definite frontotemporal lobe degeneration (FTLD) pathology
Exclusionary criteria for bvFTD

Detailed criteria relating to behavioral variant FTD are outlined elsewhere in this topic. See Criteria.

Proposed research criteria for prodromal behavioral variant frontotemporal dementia[10]

A set of research criteria with core and supportive features has been proposed and validated for diagnosing ‘prodromal’ bvFTD or ‘mild behavioral and/or cognitive impairment in bvFTD’ (MBCI-FTD). Despite similarities to the international consensus criteria for bvFTD, there are some differences. For instance, irritability/agitation is noted to be a prominent feature at the expense of psychosis, which is only found in a small minority of participants.

International consensus criteria for classification of primary progressive aphasia and its variants[11]

The consensus diagnostic criteria for primary progressive aphasia (PPA) divide the condition into three main phenotypes: the nonfluent/agrammatic variant (nfvPPA), the semantic variant (svPPA), and the logopenic variant (lvPPA). Although the majority of patients with lvPPA have Alzheimer disease pathology, a small subgroup shows TDP-43 FTD pathology, which justifies its inclusion in the current group of diagnostic criteria for PPA.[12] Notably, some patients do not strictly fit into a single language variant.[13][14] The criteria describe the clinical features of each PPA type and any exclusions, and note that a definite diagnosis is made through pathologic exam or identification of a genetic mutation. Detailed criteria for primary progressive aphasia types are outlined elsewhere in this topic. See Criteria.

FTD with or without parkinsonism

A common approach to classification distinguishes between FTD with parkinsonism and FTD that does not manifest parkinsonism. The latter group includes patients who also manifest motor neuron features. Akinesia and parkinsonian gait or posture are found frequently but are mild in most instances, rigidity is seen in some patients, and resting tremor is a rare symptom.[15]

Criteria for FTD with overlap in motor disorders

Notably, the consensus criteria for bvFTD and PPA subtypes do not mention the overlap with motor disorders. Other criteria have been compiled to account for cognitive and behavioral manifestations occurring in amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD).[16] Similarly, separate criteria are available for corticobasal degeneration and progressive supranuclear palsy (PSP), which note the likelihood of behavioral symptoms and language deficits.[17][18]

Tauopathies and TAR DNA-binding protein (TDP) proteinopathies

A distinction can be made between tauopathies and TDP-43 proteinopathies, based on correlations between predominant clinical features and neuropathologic findings.[19]

Pathologic subtypes of FTLD are FTLD-tau, FTLD-TDP, and FTLD-FUS (fused in sarcoma).[20] A few cases of FTLD have ubiquitin-only or p62-only positive inclusions or no inclusions at all.[21]

Diagnostic and Statistical Manual of Mental Disorders, 5th ed., text revision (DSM-5-TR) classification of major and mild neurocognitive disorders[22][23]

DSM-5-TR defines major and mild neurocognitive disorders as being due to:

Alzheimer disease
Frontotemporal degeneration
Lewy body disease
Vascular disease
Traumatic brain injury
Substance/medication use
HIV infection
Prion disease
Parkinson disease
Huntington disease
Another medical condition
Multiple etiologies
Unknown etiology

Severity is defined for major neurocognitive disorders as mild, moderate, or severe; and the presence or absence of behavioral and psychologic symptoms is also specified.

Specific criteria relating to frontotemporal neurocognitive disorder are outlined elsewhere in this topic. See Criteria.

Pathophysiology

Classification