Frontotemporal dementia
Frontotemporal dementia, also called frontotemporal degeneration disease or frontotemporal neurocognitive disorder, encompasses several types of dementia involving the progressive degeneration of the brain's frontal and temporal lobes. Men and women appear to be equally affected. FTD generally presents as a behavioral or language disorder with gradual onset. Signs and symptoms tend to appear in mid adulthood, typically between the ages of 45 and 65, although it can affect people younger or older than this. there is no cure or approved symptomatic treatment for FTD, although some off-label drugs and behavioral methods are prescribed.
Features of FTD were first described by Arnold Pick between 1892 and 1906. The name Pick's disease was coined in 1922, but is reserved for the behavioral variant of FTD, in which characteristic Pick bodies and Pick cells are present. These were first described by Alois Alzheimer in 1911. Common signs and symptoms include significant changes in social and personal behavior, disinhibition, apathy, blunting and dysregulation of emotions, and deficits in both expressive and receptive language.
Each FTD subtype is relatively rare. FTDs are mostly early onset syndromes linked to frontotemporal lobar degeneration, which is characterized by progressive neuronal loss predominantly involving the frontal or temporal lobes, and a typical loss of more than 70% of spindle neurons, while other neuron types remain intact. The three main subtypes or variant syndromes are a behavioral variant previously known as Pick's disease, and two variants of primary progressive aphasia : semantic and nonfluent. Two rare distinct subtypes of FTD are neuronal intermediate filament inclusion disease and basophilic inclusion body disease. Other related disorders include corticobasal syndrome, and FTD with amyotrophic lateral sclerosis.
Signs and symptoms
Frontotemporal dementia is an early onset disorder that mostly occurs between the ages of 45 and 65, but can begin earlier, and in 20–25% of cases onset is later. Men and women appear to be equally affected. It is the most common early presenting dementia. FTD is the second most prevalent type of early onset dementia after Alzheimer's disease.The International Classification of Diseases recognizes the disease as causative to disorders affecting mental and behavioural aspects in humans. Dissociation from family, compulsive buying disorder, vulgar speech characteristics, screaming, and inability to control emotions, behavior, personality, or temperament are characteristic social display patterns. The gradual onset and progression of subtle changes in behavior or language deficits commonly leads to a long delay between the onset of symptoms and time of presentation to a neurologist.
Subtypes and related disorders
The main subtypes of frontotemporal dementia are behavioral variant FTD, two variants of primary progressive aphasia – semantic dementia and progressive nonfluent aphasia – as well as FTD associated with amyotrophic lateral sclerosis. Two distinct rare subtypes are neuronal intermediate filament inclusion disease, and basophilic inclusion body disease. Related disorders are corticobasal syndrome, and progressive supranuclear palsy.Behavioral variant frontotemporal dementia
Behavioral variant frontotemporal dementia was previously known as Pick's disease, and is the most common of the FTD types. BvFTD is diagnosed four times as often as the PPA variants. Behavior can change in BvFTD in either of two ways—it can change to being impulsive and disinhibited, acting in socially unacceptable ways; or it can change to being listless and apathetic. About 12–13% of people with bvFTD develop motor neuron disease.The Pick bodies which are present in behavioral variant FTD are spherical inclusion bodies found in the cytoplasm of affected cells. They consist of tau fibrils as a major component together with a number of other protein products including ubiquitin and tubulin.
Semantic dementia
is characterized by the loss of semantic understanding, resulting in impaired word comprehension. However, speech remains fluent and grammatical.Progressive nonfluent aphasia
is characterized by progressive difficulties in speech production.Neuronal intermediate filament inclusion disease
Neuronal intermediate filament inclusion disease is a rare distinct variant. The inclusion bodies that are present in NIFID are cytoplasmic and made up of type IV intermediate filaments. NIFID has an early age of onset between 23 and 56. Symptoms can include behavioral and personality changes, memory and cognitive impairments, language difficulties, motor weakness, and extrapyramidal symptoms. NIFID is one of the frontotemporal lobar degeneration -FUS proteopathies. Imaging commonly shows atrophy in the frontotemporal region, and in part of the striatum in the basal ganglia. Post-mortem studies show a marked reduction in the caudate nucleus of the striatum; frontotemporal gyri are narrowed, with widened intervening sulci, and the lateral ventricles are enlarged.Basophilic inclusion body disease
Another rare FTD variant, also a FTLD-FUS proteopathy, is basophilic inclusion body disease.Other characteristics
In later stages of FTD, the clinical phenotypes may overlap. People with FTD tend to struggle with binge eating and compulsive behaviors. Binge eating habits are often associated with changes in food preferences, eating inedible objects and snatching food from others. Recent findings from structural MRI research have indicated that eating changes in FTD are associated with atrophy in the right ventral insula, striatum, and orbitofrontal cortex.People with FTD show marked deficiencies in executive functioning and working memory. Most become unable to perform skills that require complex planning or sequencing. In addition to the characteristic cognitive dysfunction, a number of primitive reflexes known as frontal release signs are often able to be elicited. Usually the first of these frontal release signs to appear is the palmomental reflex which appears relatively early in the disease course whereas the palmar grasp reflex and rooting reflex appear late in the disease course.Importantly, the presence of primitive reflexes in FTD is not highly sensitive or specific for the disease process, but their presence is helpful when considered within a broader neurological assessment, particularly with other suggestive features like behavioral and personality changes, disinhibition, executive dysfunction, and memory impairment.
In rare cases, FTD can occur in people with amyotrophic lateral sclerosis, a motor neuron disease., the prognosis for people with ALS was worse when combined with FTD, shortening survival by about a year. Up to 50% of patients with ALS go on to develop cognitive and behavioral symptoms, with around 10-15% meeting criteria for FTD, most commonly the behavioral variant. Some FTD patients conversely also go on to develop features of motor neuron disease similar to those of ALS. The two disease entities are thought to have interrelated clinical and genetic factors and are considered part of a disease spectrum rather than two completely separate processes.
Cerebrospinal fluid leaks are a known cause of reversible frontotemporal dementia. This is due to a spontaneous intracranial hypertension which may present with neuropsychiatric symptoms that mimic FTD, particularly the behavioral type. Treatment of the leak results in partial or complete resolution of symptoms in the majority of cases, in contrast with neurodegenerative FTD, which is a primary and mostly irreversible process.
Genetics
A higher proportion of frontotemporal dementias seem to have a familial component than other neurodegenerative diseases such as Alzheimer's disease. More and more mutations and genetic variants are being identified all the time, needing constant updating of genetic influences.- Tau-positive frontotemporal dementia and parkinsonism linked to chromosome 17 is caused by mutations in the MAPT gene on chromosome 17 that encodes the tau protein. It has been determined that there is a direct relationship between the type of tau mutation and the neuropathology of gene mutations. The mutations at the splice junction of exon 10 of tau lead to the selective deposition of the repetitive tau in neurons and glia. The pathological phenotype associated with mutations elsewhere in tau is less predictable, with both typical neurofibrillary tangles and Pick bodies having been described. The presence of tau deposits within glia is also variable in families with mutations outside of exon 10. This disease is now informally designated FTDP-17T. FTD shows a linkage to the region of the tau locus on chromosome 17, but it is believed that there are two loci leading to FTD within megabases of each other on chromosome 17. The only other known autosomal dominant genetic cause of FTLD-tau is a hypomorphic mutation in VCP which is associated with a unique neuropathology called vacuolar tauopathy.
- FTD caused by FTLD-TDP43 has numerous genetic causes. Some cases are due to mutations in the GRN gene, also located on chromosome 17. Others are caused by hypomorphic VCP mutations, although these patients present with a complex picture of multisystem proteinopathy that can include amyotrophic lateral sclerosis, inclusion body myopathy, Paget's disease of bone, and FTD. The most recent addition to the list was a hexanucleotide repeat expansion in intron 1 of C9ORF72. Only one or two cases have been reported describing TARDBP mutations in a clinically pure FTD.
- Several other genes have been linked to this condition. These include CYLD, OPTN, SQSTM1 and TBK1. These genes have been implicated in the autophagy pathway.
- No genetic causes of FUS pathology in FTD have yet been reported.
- Major alleles of TMEM106B SNPs have been found to be associated with risk of FTLD.