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Frontotemporal dementia (FTD) is a condition resulting from the progressive deterioration of the frontal lobe of the brain. Over time, the degeneration may advance to the temporal lobe. Second only to Alzheimer’s disease (AD) in prevalence, FTD accounts for 20% of pre-senile dementia cases [1] Symptoms can begin to appear on average around 45 to 65 years of age, regardless of gender.[1] The most common symptoms include significant changes in social and personal behavior, as well as a general blunting of emotions. Currently, there is no cure to FTD, but there are treatment options available that help alleviate the symptoms.

Signs and symptoms

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FTD is traditionally difficult to diagnose due to the heterogeneity of the associated symptoms. Symptoms are classified into three groups based on the functions of the frontal and temporal lobes:

  • Behavioural variant FTD (bvFTD). Behavioural symptoms include lethargy and aspontaneityon one hand and disinhibition on the other. Apathetic patients may become socially withdrawn and stay in bed all day or no longer take care of themselves. Disinhibited patients can make inappropriate (sometimes sexual) comments or perform inappropriate acts. Patients with FTD can sometimes get into trouble with the law because of inappropriate behaviour such as stealing or speeding. Recent findings indicate that psychotic symptoms are rare in FTD, possibly due to limited temporal-limbic involvement. Among FTD patients, approximately 2% have delusions, sometimes with paranoid ideation. Hallucinations are rare. These psychotic symptoms are significantly less prevalent than what is seen in AD patients, in which approximately 20% have delusions and paranoia.[2] See ref. "Psychotic symptoms."
  • Progressive nonfluent aphasia (PNFA). Patients present with a breakdown in speech fluency due to articulation difficulty, phonological and/or syntactic errors but preservation of word comprehension.
  • Semantic dementia (SD). Some patients remain fluent with normal phonology and syntax but increasing difficulty with naming and word comprehension. It has been found that some may experience depression or lose their inhibitions and exhibit antisocial behavior.[3]

FTD patients tend to struggle with binge eating and compulsive behaviors.[4] These binge eating habits are often associated with abnormal eating behavior including overeating, stuffing onself with food, changes in food preferences (cravings for more sweets, carbohydrates), eating inedible objects and snatching food from others. Recent findings have indicated that the neural structures responsible for eating changes in FTD include atrophy in the right ventral insula, striatum and orbitofrontal cortex on structural MRI voxel-based morphometry (right hemisphere.[4]

Executive functionincludes the cognitive skill of planning and organizing. Most FTD patients become unable to perform skills that require complex planning or sequencing.[5] 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.

The following abilities in the FTD patients are preserved [1]:

The following abilities in FTD patients are affected [1]:

In rare cases, FTD can occur in patients with motor neuron disease (typically amyotrophic lateral sclerosis). The prognosis for people with MND is worse when combined with FTD, shortening survival by about a year.[6]

Pathology

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A number of case series have now been published looking at the pathological basis of FTD. As with other syndromes associated with frontotemporal lobar degeneration (FTLD), a number of different pathologies are associated with FTD:

  • Tau pathology. In a healthy individual, tau proteins stabilize microtubules, which are major component of the cytoskeleton. Examples include Pick's disease, now also referred to as FTLD-tau, and other tau-positive pathology including FTDP-17, corticobasal degeneration, progressive supranuclear palsy. Approximately 50% of FTD cases will present with tau pathology at post-mortem.
  • TDP-43 pathology. Previously described as dementia with ubiquitin positive, tau- and alpha-synuclein negative inclusions with and without motor neuron degeneration. FTLD-TDP43 accounts for approximately 40% of FTD(± MND).
  • FUS pathology. Cases with underlying FUS pathology tend to present with behavioural variant FTD (bvFTD) but the correlation is by no means reliable enough to predict the post mortem pathology. FTLD-FUS represents only 5–10% of clinically diagnosed FTD.
  • Dementia lacking distinctive histology (DLDH) is a rare entity and represents the remaining small percentage of FTD that cannot be positively diagnosed as any of the above at post-mortem.
  • In rare cases, patients with clinical FTD were found to have changes consistent with Alzheimer's disease on autopsy[7]
  • Evidence suggests that FTD selectively impairs spindle neurons,[8] a type of neuron which has only been found in the brains of humans, great apes, and whales.

Diagnosis

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According to DSM-IV, the diagnosis of FTD is primarily based on changes in behaviors, language and other neuropsychological symptoms. Brain imaging and neuropsychological tests are used to help to confirm an FTD diagnosis.[9]

Structural MRI scans often reveal frontal lobe and/or anterior temporal lobe atrophy but in early cases the scan may seem normal. Atrophy can be either bilateral or asymmetric .[1]. Registration of images at different time points of time (e.g., one year apart) can show evidence of atrophy that otherwise (at individual time points) may be reported as normal. Many research groups have begun using techniques such as magnetic resonance spectroscopy, functional imaging and cortical thickness measurements in an attempt to offer an earlier diagnosis to the FTD patient. Fluorine-18-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) scans classically show frontal and/or anterior temporal hypometabolism, which helps differentiate the disease from Alzheimer's disease. The PET scan in Alzheimer's disease classically shows biparietal hypometabolism. Meta-analyses based on imaging methods have shown that frontotemporal dementia mainly affects a frontomedian network discussed in the context of social cognition or 'theory of mind'.[10] This is entirely in keeping with the notion that on the basis of cognitive neuropsychological evidence, the ventromedial prefrontal cortex is a major locus of dysfunction early on in the course of the behavioural variant of frontotemporal degeneration.[11] The language subtypes of frontotemporal lobar degeneration (semantic dementia and progressive nonfluent aphasia) can be regionally dissociated by imaging approaches in vivo.[12] 

The confusion between Alzheimer’s and FTD is justifiable due to the similarities between their initial symptoms.  Patients do not have difficulty with movement and other motor tasks.[13]  As FTD symptoms appear, it is difficult to differentiate between a diagnosis of Alzheimer’s disease and FTD.  There are distinct differences in the behavioral and emotional symptoms of the two dementias, notably, the blunting of emotions seen in FTD patients..[1]  In the early stages of FTD, anxiety and depression are common, which may result in an ambiguous diagnosis.  However, over time, these ambiguities fade away as this dementia progresses and defining symptoms of apathy, unique to FTD, start to appear.

Through recent findings it has been suggested that vivo brain imaging of tau aggregation in frontal temporal dementia using [F-18] FDDNP positron emission tomography is more visual and has enhanced the ability to have a deeper understanding in frontal temporal dementia. Previous, fluorescent microscopy studies of Alzheimer’s disease (AD) brain specimens have shown that [F-18] FDDNP displays an excellent visualization of interneuronal neurofibrillary tangles (NFTs). [F-18]FDDNP is useful in imaging frontal temporal dementia. Visual images of [F-18] FDDNP-PET images emphasized a frontal signal in FTD compared to prominent temporal signals in AD. [F-18]FDDNP-PET has allowed the enhanced visualization of tauopathies in patients. This has aided in differentiating FTD from parietal and temporal signals in AD. Further, the ability of [F-18] FDDNP to entitle tauopathies in vivo gives a tool for monitoring the effect of therapies to eliminate NFT accumulation.[14]

Recent studies over several years have developed new criteria for the diagnosis of behavioral variant frontotemporal dementia (bvFTD). Six distinct clinical features have been identified as symptoms of bvFTD. [15]

  1. Disinhibition
  2. Apathy/Inertia
  3. Loss of sympathy/empathy
  4. Perseverative/compulsive behavior
  5. Hyperorality
  6. Dysexecutive neuropsychological profile

Of the six features, three must be present in a patient to diagnose one with possible bvFTD. Similar to standard FTD, the primary diagnosis stems from clinical trials that identify the associated symptoms, instead of imaging studies. [15] The above criteria are used to distinguish bvFTD from disorders such as Alzheimer’s and other causes of dementia. In addition, the new criteria allow for a diagnostic hierarchy distinguished possible, probable, and definite bvFTD based on the number of symptoms present.


Genetics

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A higher proportion of FTD cases seem to have a familial component than more common neurodegenerative diseases such as Alzheimer's disease. More and more mutations and genetic variants are being identified all the time, so the list of genetic influences requires consistent updating.

  • tau-positive frontotemporal dementia with parkinsonism (FTDP-17) is caused by mutations in the MAPT gene on chromosome 17 that encodes the Tau protein[16] 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 repetative tau in neurons and glia. The pathological phenotype associated with mutations elsewhere in tau is less predictable with both typical neurofibrillary tangles (consisting of both 3 repeat and 4 repeat tau) and Pick bodies (consisting of 3 repeat tau) having being described. (See Genetics section of Tau Protein page) 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.[17]
  • 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 VCP mutations, although these patients present with a complex mixture of Inclusion body myopathy, Paget's disease of bone, and FTD. The most recent addition to the list is a hexanucleotide repeat expansion in the promotor region of C9ORF72. Only one or two cases have been reported describing TARDBP (the TDP-43 gene) mutations in a clinically pure FTD (FTD without MND).
  • No genetic causes of FUS pathology in FTD have yet been reported.

Management

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Currently, there is no cure for FTD. Treatments are available to manage the behavioral symptoms. Disinhibition and compulsive behaviors can be controlled by selective serotonin reuptake inhibitors (SSRIs).[18] ]. Although Alzheimer’s and FTD share certain symptoms, they cannot be treated with the same pharmacological agents because the cholinergic systems are not affected in FTD.[1]

Because FTD often occurs in younger people (i.e. in their 40's or 50's), it can severely affect families. Patients often still have children living in the home. Financially, it can be devastating as the disease strikes at the time of life that is often the top wage-earning years. [citation needed]

Prognosis

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Symptoms of frontotemporal dementia progress at a rapid, steady rate. Patients suffering from the disease can survive between 2-10 years. Eventually patients will need 24-hour care for daily function. [19]

See also

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References

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  1. ^ a b c d e f g [ Snowden, Julie S., David Neary, and David M. A. Mann. "Frontotemporal dementia." British Journal of Psychiatry 180 (2002): 140-143.].
  2. ^ Mendez MF, Shapira JS, Woods RJ, Licht EA, Saul RE (2008). "Psychotic symptoms in frontotemporal dementia: prevalence and review". Dement Geriatr Cogn Disord. 25 (3): 206–11. doi:10.1159/000113418. PMID 18204254.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ Hodges, R. John. 1999. "Neuropsychology: The Differentiation of Semantic Dementia and Frontal Lobe Dementia. pg. 31-49
  4. ^ a b Piguet, oliver (17 May 2011). "Eating Disturbance in Behavioural-Variant Frontotemporal Dementia". Journal of Molecular Neuroscience. 5. 22 (8): 456–472. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |month= ignored (help)CS1 maint: date and year (link)
  5. ^ Kramer JH, Jurik J, Sha SJ; et al. (2003). "Distinctive neuropsychological patterns in frontotemporal dementia, semantic dementia, and Alzheimer disease". Cogn Behav Neurol. 16 (4): 211–8. doi:10.1097/00146965-200312000-00002. PMID 14665820. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  6. ^ Olney RK, Murphy J, Forshew D; et al. (2005). "The effects of executive and behavioral dysfunction on the course of ALS". Neurology. 65 (11): 1774–7. doi:10.1212/01.wnl.0000188759.87240.8b. PMID 16344521. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ Liscic RM, Storandt M, Cairns NJ, Morris JC (2007). "Clinical and psychometric distinction of frontotemporal and Alzheimer dementias". Arch. Neurol. 64 (4): 535–40. doi:10.1001/archneur.64.4.535. PMID 17420315. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ Seeley WW, Carlin DA, Allman JM, Macedo MN, Bush C, Miller BL, Dearmond SJ (2006). "Early frontotemporal dementia targets neurons unique to apes and humans". Ann. Neurol. 60 (6): 660–7. doi:10.1002/ana.21055. PMID 17187353. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ Demencia frontotemporal y enfermedad de motoneurona
  10. ^ Schroeter ML, Raczka KK, Neumann J, von Cramon DY (2008). "Neural networks in frontotemporal dementia – A meta-analysis". Neurobiology of Aging. 29 (3): 418–426. doi:10.1016/j.neurobiolaging.2006.10.023. PMID 17140704.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ Rahman S, Sahakian BJ, Hodges JR, Rogers RD, Robbins TW (1999). "Specific cognitive deficits in mild frontal variant frontotemporal dementia". Brain. 122 (Pt 8): 1469–93. PMID 10430832. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ Schroeter ML, Raczka KK, Neumann J, von Cramon DY (2007). "Towards a nosology for frontotemporal lobar degenerations – A meta-analysis involving 267 subjects". NeuroImage. 36 (3): 497–510. doi:10.1016/j.neuroimage.2007.03.024. PMID 17478101.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ [ Steinbart, Ellen J., et al. "Impact of DNA Testing for Early-Onset Familial Alzheimer Disease and Frontotemporal Dementia." Archives of Neurology 58 (2001): 1828-1831.]
  14. ^ Small, Gary (July 2004). "In Vivo Brain Imaging of Tau Aggregation in Frontal Temporal Dementia Using [F-18]FDDNP Positron Emission Tomography". Neurobiology of Aging. 2. 25 (26): 288–289. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)CS1 maint: date and year (link)
  15. ^ a b [ Rascovsky, Katya et al. "Sensitivity of revised diagnostic criteria for the behavioral variant of frontotemporal dementia." Brain: a Journal Of Neurology 134 (2011): 2456-2477.]
  16. ^ Luc Buée; André Delacourte (1999). "Comparative biochemistry of tau in progressive supranuclear palsy, corticobasal degeneration, FTDP-17 and Pick's disease" (PDF). Brain Pathology. 9 (4): 681–693. doi:10.1111/j.1750-3639.1999.tb00550.x. PMID 10517507.
  17. ^ Hardy, John (April 2006). Dementia "Frontal temporal dementia: dissecting the aetiology and pathogenesis". Brain: A journal of Neurology. 26. 4 (4): 830–831. Retrieved 1 December 2012. {{cite journal}}: Check |url= value (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)CS1 maint: date and year (link)
  18. ^ [ Swartz, J.R., Miller, B.L., Lesser, I.M., et al (1997) Frontotemporal dementia: treatment response to serotonin selective reuptake inhibitors. Journal of Clinical Psychiatry 58, 212-216.]
  19. ^ [ Kertesz, Andrew. "Frontotemporal Dementia/Picks Disease." Archives of Neurology 61 (2004): 969-971.]

Liu, W (1 March 2004). "Behavioral disorders in the frontal and temporal variants of frontotemporal dementia". Journal of Neurology. 5. 62: 742–748. doi:10.1212/01.WNL.0000113729.77161.C9. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: date and year (link)

Hodges, J.R (2 April 2003). "A study of stereotypic behaviours in Alzheimer's disease and frontal and temporal variant frontotemporal dementia". Neurol Neurosurg Psychiatry. 74 (10): 1398–1402. doi:10.1136/jnnp.74.10.1398. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |month= ignored (help)CS1 maint: date and year (link)

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Category:Dementia Category:Cognitive disorders Category:Psychiatric diagnosis

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