Frontotemporaldementia is a dementia syndrome characterized by slow onset of personality changes, speech disorders, and behavioral abnormalities in middle-aged and elderly patients with frontotemporal lobe atrophy on neuroimaging and no Pick vesicles or Pick cells on pathological examination. Frontotemporal dementia is a group of dementia syndromes characterized by frontotemporal lobe atrophy, including Pick’s disease and Pick’s syndrome with similar clinical manifestations, which in turn includes frontal lobe dementia and primary progressive aphasia. It is characterized clinically by marked personality and behavioral changes and cognitive impairment.
Frontotemporal dementia
Frontotemporal dementia (I)
Frontotemporal dementia is a dementia syndrome characterized by frontotemporal lobe atrophy and is a common cause of neurodegenerative dementia, accounting for about 1/4 of all dementia patients. 1/4 of frontotemporal dementia patients have Pick’s vesicles and can be diagnosed as Pick’s disease. Frontotemporal dementia actually includes Pick’s disease and Pick’s syndrome with similar clinical presentation, followed by frontal lobe dementia and spontaneous progressive aphasia. The peak incidence is 60 years of age and is more frequent in women.
Pick (1892) first described a group of patients with frontotemporal lobe atrophy as a pathological feature, showing slowly progressive behavioral abnormalities, cognitive deficits and aphasia, which are rare in clinical practice. Onari and Spatz (1926) named it Pick’s disease, which is distinctly different from AD. Pick’s disease is difficult to distinguish from frontotemporal dementia in the absence of pathological evidence, and it is now mostly advocated to classify Pick’s disease as frontotemporal dementia. It has been suggested that frontotemporal dementia actually includes Pick’s disease with the presence of Pick’s vesicles and other Pick’s syndromes with similar clinical manifestations without Pick’s vesicles, the latter including frontal lobe dementia ( The latter includes frontaldementia and primaryprogressiveaphasia.
Frontotemporal dementia (FTD) is a progressive and ultimately fatal neurological disease. approximately 10% of ALS cases and 30% of FTD cases are familial, the genetic traits are usually autosomal dominant and have different epistasis, and overlap between ALS and FTD phenotypes can occur within the same family. Copper or zinc superoxide dismutase 1 (SOD1) mutations are found in about 20% of familial ALS and about 3% of sporadic ALS cases, but are not associated with dementia. Microtubule-associated protein tau (MAPT) mutations were detected in approximately 30% of familial FTD families. Dominant ALS with FTD was previously thought to be associated with 9q21, and ALS alone was associated with the 16q21, 18q21 and 20p13 loci. In this study, we report the results of an extensive genomic linkage study of a large family of ALS combined with FTD using Affymetrix 10K GeneChip microarray analysis. Single nucleotide polymorphism (SNP) linkage analysis data showed a consistently positive logarithm of dominance (LOD) score for autosomal 9p (highest LOD score of 2.4).
Symptoms and signs
1. Cryptogenic onset and slow progression. Early onset of personality and affective changes, such as irritability, violent
Frontotemporal dementia (II)
The disease gradually develops behavioral abnormalities, such as inappropriate behavior, unmotivated, indifferent to things and impulsive behavior, etc. Kluver-Bucy syndrome may appear, showing sluggishness, indifference, rapid change of visual recognition and thinking, excessive mouth activity, good muscle, gluttony, obesity, putting anything into the mouth to try, accompanied by amnesia, aphasia, etc. Inability to think, little speech, poor vocabulary, stereotyped and imitated language and even silence, abnormal sensation of the body and fragmented delusions, etc.
2, neurological signs in the early stage of the disease can be seen sucking reflex, strong grip reflex, late myoclonus, cone bundle signs and Parkinson’s syndrome.
Primary progressive aphasia Mesulam (1982) first reported 6 cases of chronic progressive aphasia without dementia, and Weintraub et al. (1990) named it PPA, which usually develops before 65 years of age and has a long course of more than 10 years. The main clinical feature is a slowly progressive language impairment without other cognitive deficits, which progresses to severe aphasia or muteness in 6-7 years and is a point of differentiation from AD or frontotemporal dementia. There may be visual loss of recognition or spatial impairment, but life remains self-sustaining and eventually dementia develops without neurological signs.MRI shows significant frontal, temporal and parietal atrophy of the dominant hemisphere. Pathology reveals frontotemporal lobe atrophy without Pick’s vesicles.
Disease etiology
The etiology and pathogenesis of frontotemporal dementia and Pick’s disease are unclear and may be due to idiopathic degeneration of neuronal cell bodies.
Frontotemporal dementia (III)
It may be due to idiopathic degeneration of the neuronal cell body, or axonal injury secondary to cytosolic changes. Familial frontotemporal dementia has been shown to be autosomal dominant in about half of the cases, and Wilhelmsen et al. (1994) localized the lesion gene to chromosome 17 (17q21). Neurons and glia contain microtubule-associated tau protein inclusion bodies, and approximately 20% of patients with frontotemporal dementia have mutations in this gene; therefore, frontotemporal dementia is classified as a tau protein disease. Etiology.
Wilhelmsen (1994) identified the gene on chromosome 17 in a large family of frontotemporal dementia with extrapyramidal symptoms and confirmed the association with mutations in the tau protein gene, which has been found to be present in approximately 20% of patients with frontotemporal dementia.
Pathophysiology
The histopathology of frontotemporal dementia and Pick disease is characterized by characteristic limited frontotemporal lobe atrophy with involvement of the amygdala, hippocampus, substantia nigra, and basal ganglia; Pick disease is characterized by Pick cells and Pick inclusions, and lacks the neurogenic fiber tangles and amyloid plaques characteristic of Alzheimer’s disease. Microscopically, there was a significant decrease in neuronal cells in all layers of the atrophic cerebral lobe cortex, which was evident in layers II and III; glial cells were diffusely proliferated with spongiform changes.
Diagnostic tests
(A) Auxiliary examinations.
1. Early EEG is normal, with a few wave amplitude decreases and alpha wave reduction; late alpha wave is minimal or absent, out
Frontotemporal dementia (IV)
Irregular medium-amplitude δ waves, spike waves in a few patients, reduced sleep fusiform waves, difficult appearance of κ integrated waves, and reduced slow waves.
2, CT or MRI shows limited frontal or anterior temporal lobe atrophy, widening of the cerebral sulcus, balloon-like enlargement of the frontal horn, thinning of the frontal and anterior temporal pole cortices, enlargement of the temporal horn, widening of the lateral fissure pool, mostly asymmetrical, which can appear at an early stage. spECT shows asymmetrical frontotemporal blood flow reduction, PET shows asymmetrical frontotemporal metabolism reduction, which is more sensitive than MRI and can be diagnosed at an early stage.
3, genetic examination found a variety of tau protein gene mutations can help confirm the diagnosis.
(B) Diagnosis and differential diagnosis.
1.Diagnosis
Diagnosis of frontotemporal dementia, including Pick’s disease, is based on early onset (50-60 years old), family history, more pronounced behavioral impairment than cognitive impairment, and CT and MRI showing frontal and anterior temporal lobe atrophy. The diagnosis is usually not confirmed before birth and depends on histopathological evidence, such as limited frontotemporal lobe atrophy, tau protein inclusion bodies found in neurons and glia, Pick vesicles and cells found in Pick disease, and lack of characteristic neurogenic fiber tangles and amyloid plaques in AD.
2.Differential diagnosis
The disease should be differentiated from Alzheimer’s disease. AD usually presents early cognitive dysfunction, such as amnesia, visuospatial orientation and computational impairment, with relatively preserved socialization and manners; Pick’s disease or frontotemporal dementia presents early personality changes, behavioral abnormalities and speech disorders, and typical cases present with Kluver-Bucy most and signs, with better preservation of spatial orientation and near memory. The spatial orientation and near memory preservation are better. Neuroimaging shows frontotemporal lobe atrophy in Pick’s disease and extensive brain atrophy in Alzheimer’s disease. The prognosis is poor, with a disease duration of 5-12 years, and most deaths are due to complications such as pulmonary and urinary tract infections and decubitus ulcers.
Treatment options
There is no treatment available. Acetylcholinesterase inhibitors are usually ineffective. Small doses of Valium, selective 5-hydroxytryptamine reuptake inhibitors, or insulin may be used judiciously for behavioral disorders such as aggression, irritability, and belligerence. Appropriate life care and behavioral guidance can be provided by a caregiver when available.
Epidemiology
The incidence and prevalence of dementia increases with age Foreign surveys have shown that the prevalence of dementia increases at the age of 85 years and above.
Frontotemporal dementia (V)
The prevalence of Alzheimer’s disease (Alzheimer’s diseaseAD) accounts for 50%; multifocal infarct dementia (also known as vascular dementia VaD) accounts for 12% to 20% of the remaining types of dementia accounts for 15% to 20%. In China, the prevalence of dementia is 0.75% to 4.69% in people over 60 years of age. Frontotemporal dementia and Pick’s disease have also been frequently reported, but no disaggregated incidence statistics have been found.
Pathogenesis
Frontotemporal dementia
The pathogenesis is unknown. It has been reported in the literature that tau protein consists of 6 subunits formed by different splicing of tau genes, and tau protein amino acid polypeptide can have an insertion peptide of 35 amino acids at the carboxyl end, which can bind to other polypeptides to form microtubules, and an increase in tau(4R) containing the insertion peptide or an exon 10 point mutation can lead to increased free tau protein causing cell death. The pathological features are similar to those of Pick’s disease. The gross pathology is mainly frontal and/or temporal lobe atrophy in about 1/3 of patients with bilateral symmetric atrophy, severe cerebral cortex involvement, mild to moderate enlargement of the temporal horn in the anterior horn of the lateral ventricles, and microscopically, the number of neuronal cells in all layers of the atrophic cerebral cortex is significantly reduced, the loss of neurons in layer II and III is evident with diffuse glial cell proliferation, and the residual neurons are degenerated to varying degrees without Pick’s vesicles. The absence of Pick vesicles and Pick cells is the main pathological differentiation point between this disease and Pick disease.
Clinical manifestations
Frontotemporal dementia
1. The clinical manifestations of this disease are the same as those of Pick’s disease, which starts insidiously at the age of 50-60 years and progresses slowly, with early personality changes, speech disorders and behavioral abnormalities, such as Klüver-Bucy syndrome. If there is a family history, CT and MRI show frontotemporal lobe atrophy genetic examination found a variety of tau protein gene coding region or intron 10 related mutations, pathological examination without Pick vesicles and Pick cells, the diagnosis can be confirmed. 2, primary progressive aphasia (primaryprogressiveaphasiaPPA) is a progressive decline in language function for 2 years or more, and other cognitive functions remain normal, distinctly different from AD and other frontotemporal dementias. The pathology is also characterized by frontal and temporal lobe atrophy without Pick’s vesicles.
Mesulam (1982) first reported six cases of chronic progressive aphasia without dementia, and Weintraub et al. (1990) named it primary progressive aphasia. The main clinical features are.
(1) It usually develops before the age of 65 years, with slowly progressive aphasia, which may be combined with visual loss spatial impairment or loss of use without other cognitive impairment, and the ability to perform daily activities may be preserved intact.
(2)The course of the disease can be up to 10 years or more, language impairment can exist for several years alone, 6-7 years to develop into severe aphasia or muteness, but can still maintain self-care, and eventually dementia some cases initially manifested as progressive aphasia disease progresses rapidly in a short time to develop Pick’s disease, motor neuron disease or corticobasal nucleus degeneration, etc.
(3) Neurological examination without positive signs, MRI shows significant atrophy of the frontal temporal and parietal lobes of the dominant hemisphere SPECT shows reduced blood flow in the left temporal and frontal lobes or bilateral frontal lobes.
Complications
In addition to the obvious dementia (cognitive impairment) with the progression of the disease, patients are commonly combined with aphasia depression severe psychiatric behavior abnormalities, etc. In addition, secondary pulmonary infections urinary tract infections should be noted.
Diagnosis
Frontotemporal dementia image analysis
At present, there is no uniform diagnostic criteria for frontotemporal dementia and Pick’s disease, and the following criteria can be used for reference: 1. Early onset of personality changes, emotional changes and inappropriate behavior in middle-aged and elderly people (usually 50-60 years old), and gradual emergence of behavioral abnormalities, such as Klüver-Bucy syndrome.
2.Speech disorders appear early such as reduced speech, poor vocabulary stereotyped language and imitative language followed by marked aphasia early computational preservation memory impairment is milder visuospatial orientation is relatively preserved.
3, late onset of intellectual decline amnesia urinary incontinence and mutism, etc.
4. CT and MRI showed asymmetric atrophy of the frontal and/or temporal lobes.
5.Pick vesicles and Pick cells are found on pathological examination.
With 1 to 4 items, excluding other dementia diseases, the clinical diagnosis of frontotemporal dementia can be confirmed if there is a family history of genetic examination and tau protein gene mutation is found; with 1 to 5 items, the diagnosis of Pick disease can be confirmed. The absence of Pick vesicles and Pick cells is the main pathological differentiation between frontotemporal dementia and Pick disease.
Diagnosis of frontotemporal dementia, including Pick’s disease, is based on early onset (50-60 years old), may have a family history, more pronounced behavioral impairment than cognitive impairment, and frontal and anterior temporal lobe atrophy on CT and MRI. The diagnosis is usually not confirmed before birth and depends on histopathological evidence such as limited frontotemporal lobe atrophy, tau protein inclusion bodies found in neurons and glia, Pick vesicles and cells found in Pick’s disease, and lack of neurogenic fiber tangles and amyloid plaques characteristic of AD.
A team of researchers at the Wellcome Trust Centre for Neuroimaging at the University of London has demonstrated the results of scans of the brains of patients with frontotemporal dementia. The computer can identify damage specific to the brains of people with Alzheimer’s disease, “using computer scans which test faster and with greater accuracy than the now common diagnostic methods, as well as being cheaper.” Professor Richard Frackowiak of the center explains, “The new method avoids human intervention making the diagnosis more objective. The new method was discovered when a computer scan of the brains of frontotemporal dementia patients and healthy people was used to compare them. The two conditions can be distinguished with a high degree of accuracy with a single clinical MRI scan.”
The computer can accurately find the difference between a normal person and a person with frontotemporal dementia with a single set of scans, and then use the correct diagnosis as the basis for scanning the rest of the cases. The accuracy rates are all better than the current best clinical practice diagnosis of 86 percent accuracy. Frontotemporal dementia is in many cases misdiagnosed as Alzheimer’s disease.
Professor Frackowiak emphasizes that the human brain undergoes considerable damage in the brain to produce a sign of disease, so making an accurate diagnosis early is important to improve the effectiveness of stopping brain degeneration. “The next step is to see if we can use a technique to determine the extent to which a patient has the disease.” Professor Frackowiak says, “This would allow a quick test with non-invasive tools that reflect the efficacy of new drug treatments.”
Differential diagnosis
The main differentiator should be Alzheimer’s disease, both of which have an insidious onset and slow progression with many clinical features in common. The most important differentiating factor is the chronology of progressive dementia symptoms during the course of the disease. CT and MRI can help to differentiate the two, AD can be seen as extensive brain atrophy frontotemporal dementia shows frontal and/or temporal lobe atrophy; clinical confirmation requires histopathological examination.
Tests
Laboratory tests: determination of ApoE polymorphism Tau protein quantification and beta amyloid fragment in cerebrospinal fluid and serum has diagnostic or differential diagnostic significance.
Other auxiliary examinations: 1, EEG examination is mostly normal in the early stage and a few can be seen with reduced wave amplitude α waves; in the late stage, low background activity α waves are rare or there are no irregular medium amplitude δ waves, a few patients have spike waves during sleep with few spindle waves κ synthesis waves and reduced slow waves 2, CT and MRI examination can be seen with characteristic limited frontal and (or) temporal lobe atrophy, narrow brain gyrus, wide brain sulcus and balloon-like enlargement of frontal horn SPECT shows asymmetric frontal and temporal lobe blood flow reduction PET shows asymmetric frontotemporal lobe metabolism reduction both of which are more sensitive than MRI for early diagnosis. Treatment There is no effective therapy similar to Pick’s disease, mainly symptomatic treatment with acetylcholinesterase inhibitors is usually ineffective. Small doses of benzodiazepines, selective 5-HT reuptake inhibitors, psychostimulants and propranolol can be used cautiously for those with behavioral disorders such as aggression, irritability and belligerence, and can be hospitalized if available, or given appropriate life and behavioral guidance and symptomatic management by trained caregivers. Prevention and prognosis: The duration of the disease rarely exceeds 10 years, and the prognosis is poor mostly due to pulmonary infections urinary tract infections and decubitus ulcers. Prevention: There is no effective prevention method yet symptomatic management is an important part of clinical medical care. Early diagnosis and early treatment may slow the irreversible process of dementia.