Frontotemporal Lobe Degeneration (FTLD)

Degeneration of the frontotemporal lobe of the brain is associated with three types of dementia.  The most common is frontotemporal dementia comprising 8-15% of all dementia, ranking third behind Alzheimer's and Lewy body dementias.  The other two FTLD syndromes are called semantic dementia and progressive non-fluent aphasia.  Advances in MRI technology have led to an outpouring of recent studies on FTLD dementias.

At present, there is not much research on differing treatments for the differing dementias.  These diagnoses and the ability to separated them out from other dementias are relatively new.  

The median age of onset of Frontotemporal Dementia (FTD) is 58.  Many are being linked to specific genetic abnormalities with strong family histories. Frontal variant frontotemporal dementia (fvFTD) presents with disinhibition, impulsiveness, apathy, altered appetite, and stereotypic behaviors.  Patients are unable to recognize positive or negative emotions in others. Temporal variant frontotemporal dementia (tvFTD) patients are better able to recognize happiness in others.  Memory complaints occur in about 25% and somatic complaints are common. FTD is somewhat earlier in onset than the average for Alzheimer's disease.  Both develop gradually.  Early symptoms of FTD are apathy, disinhibition, irritability and aggressiveness, untidiness, difficulties in decision making, obsessions, and lack of concern for the others.  This can occur one to three years before the dementia, during which time the patients are still able to keep up their occupational activities, of course with increasing difficulty.  Brain CT or MRI scan may already show fronto-temporal atrophy.  One cause of FTD is a mutation on chromosome 17 resulting in an abnormal tau protein.  Tau form structure tubules in the cell used for transportation, division, and shape.

Two less common types of frontotemporal lobe degeneration are semantic dementia and progressive nonfluent aphasia.

Presenting Complaints: Forty-six patients with frontotemporal lobe degeneration were studied. Twenty-one patients had frontotemporal dementia (FTD), 17 semantic dementia (SD) and 8 progressive nonfluent aphasia (PA). The majority of the FTD patients presented without complaints or with somatic complaints and nearly a quarter of them expressed memory complaints. The presenting complaints of most of their caregivers differed from the patients' complaints and often consisted of cognitive complaints. In SD and PA, language problems but also forgetfulness were presented. Misrecognition of the initial symptoms in some cases seemed to have contributed to diagnostic delay. Initial complaints in frontotemporal lobar degeneration. Pijnenburg YA, Gillissen F, et al. VU University Medical Center, Amsterdam. Dement Geriatr Cogn Disord. 2004;17(4):302-6

Stereotypical Movements: Compared to 18 AD patients, 18 FTD patients had more stereotypical movements, including frequent rubbing and some self-injurious acts. All the FTD patients with stereotypical movements had compulsive-like behaviors, suggesting a similar pathophysiologic cause, and most had a decrease in their stereotypical movements with the administration of a serotonin selective reuptake inhibitor. Stereotypical movements and frontotemporal dementia. Mendez MF, et al. UCLA. Mov Disord. 2005 Mar 22

CERAD Subtests and MMSE for Differentiating: CERAD-NAB (Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery) data were compared between 51 patients with frontotemporal dementia, 13 with semantic dementia, and 69 with Alzheimer's disease. Compared with patients with Alzheimer's disease, patients with frontotemporal dementia were more impaired on Animal Fluency but not on any other CERAD-NAB subtest. Patients with semantic dementia performed worse in Animal Fluency and Boston Naming Test compared with frontotemporal dementia and Alzheimer's disease. Between frontotemporal dementia and Alzheimer's disease, the combination of Animal Fluency and Boston Naming Test correctly classified 90.5% of patients. In segregating semantic dementia and Alzheimer's disease, the combination of Boston Naming Test and Mini Mental State Examination resulted in a correct classification of 96.3%. Frontotemporal dementia, semantic dementia, and Alzheimer's disease: the contribution of standard neuropsychological tests to differential diagnosis. Diehl J, Monsch AU, et al. Technische Universitat Munchen, Germany. J Geriatr Psychiatry Neurol. 2005 Mar;18(1):39-44.

Recognition of Emotions in the Two Variants: Recent studies have suggested that the frontal and temporal variants of frontotemporal dementia (fvFTD and tvFTD) are both associated with impairments in emotional processing. Using the Florida Affect Battery to examine recognition of facial expressions of emotion in fvFTD and tvFTD patients who have no evidence of visual perceptual difficulties for faces, both groups were impaired at recognizing emotions compared with age-matched controls. In tvFTD, this deficit was limited to emotions with a negative valence (sadness, anger, fear), while fvFTD patients showed impairment for positive valence (happiness) as well. These results suggest that damage to frontal lobe regions in FTD may lead to more profound impairment in recognition of emotion than when damage is more limited to the temporal lobe. Recognition of emotion in the frontal and temporal variants of frontotemporal dementia. Rosen HJ, Pace-Savitsky K, et al. University of California, San Francisco. Dement Geriatr Cogn Disord. 2004;17(4):277-81

Differentiating FTD from AD and Semantic Dementia: In a study of 21 patients with frontotemporal dementia, 14 patients with semantic dementia, and 30 patients with Alzheimer disease comparable in terms of Mini Mental Status Examination score, age, and education, frontotemporal dementia and semantic dementia diagnoses were made clinically using the consensus criteria of Neary et al. Both the Alzheimer disease and semantic dementia groups were significantly impaired relative to the frontotemporal dementia group on verbal memory, whereas only the Alzheimer disease group was impaired on visual memory. Frontotemporal dementia patients performed significantly worse on backward digit span and made significantly more executive errors than Alzheimer disease and semantic dementia patients. Semantic dementia patients were more impaired than Alzheimer disease and frontotemporal dementia patients on confrontation naming. Discriminant function analyses identified the 5 most discriminating variables that correctly classified 89.2% of cases. Distinctive neuropsychological patterns in frontotemporal dementia, semantic dementia, and Alzheimer disease. Kramer JH, Jurik J, Sha SJ, Rankin KP, Rosen HJ, Johnson JK, Miller BL. UCSF. Cogn Behav Neurol. 2003 Dec;16(4):211-8

FTD Patients Institutionalized Much Less: Often Die Suddenly: In a study of 552 demented nursing home patients, FTD patients were younger (mean age at onset 59 years), had more often a family history of psychiatric disorders (20%), had a longer delay between first symptoms and first visit (5.9 years) and a higher Mini-Mental State Examination (MMSE) score at first visit (24.5) than patients with AD (19.9). The mean annual MMSE score decline was 0.9 point in FTD vs. 2.0 points in AD (p < 0.0004). Fewer patients with FTD than with AD entered an institution (RR: 0.20). After adjustment for sex, age at first visit, level of education and MMSE score at first visit, survival rates in FTD and AD did not differ significantly. Patients with FTD often had a sudden death, the cause of which could not be found. The earlier the first visit after onset, the longer the survival rate, whatever the diagnosis (RR: 0.76, p < 0.0001 per year of earlier first visit). Natural history of frontotemporal dementia: comparison with Alzheimer's disease. Pasquier F, Richard F, Lebert F. Lille, France. Dement Geriatr Cogn Disord. 2004;17(4):253-7

FTD Patients Deteriorate and Die Faster: Patients (70) with FTD had shorter survival from initial evaluation to death than 70 patients with AD (FTD = 4.2 years, AD = 6.0 years; p < 0.05), and they declined faster over one year on the MMSE (-6.7 points for FTD vs -2.3 points for AD). A greater proportion of patients with FTD were impaired in basic activities of daily living (ADLs) at initial evaluation, and lost the capacity for independent or minimally-assisted ADLs over the subsequent year. Rascovsky, UC, San Diego. Neurology. 2005 Aug 9;65(3):397-403.

Pick's disease, Frontotemporal dementia, Primary progressive aphasia, Corticobasal degeneration, and Progressive supranuclear palsy should be regarded as a clinically and biologically cohesive spectrum. The historically correct eponymic term Pick's complex, for both the clinical and pathological varieties is preferred. The discovery of tau mutations in frontotemporal dementia and parkinsonism linked to specific mutations in chromosome 17 and their resemblance to the sporadic cases validates the concept of Pick's complex. There are recently discovered overlaps between the three-repeat and four-repeat tauopathies, and the tau-negative varieties with or without motor neuron disease-type inclusions may be deficient in normal tau, therefore may be tauopathies also. Pick's complex and FTDP-17. Kertesz A., University of Western Ontario. Mov Disord. 2003 Sep;18 Suppl 6:S57-62

Frontotemporal Lobe Dementia Can Be Accurately Diagnosed Before Death: At the Mayo Alzheimer Center, there were 34 pathological FTLD cases among 433 subjects who underwent autopsy; 29 of the 34 were diagnosed as FTLD before death based on the sum of clinical, neuropsychological, and imaging features (sensitivity, 85%). The specificity was 99%. Of the 34, 79% had clinical histories diagnostic of an FTLD syndrome, 62% had neuropsychological profiles consistent with FTLD, 50% had magnetic resonance scans consistent with FTLD, and 7 of 8 who had functional imaging studies had ones consistent with FTLD. Antemortem diagnosis of frontotemporal lobar degeneration. Knopman DS, Boeve BF, et al. Mayo Clinic, Rochester, MN. Ann Neurol 2005;57:480-488.

Causes

Apolipoprotein(a) Small Variant a Risk Factor for FTD: A study of 52 Italian FTD patients found 56% of patients vs. 30% of controls had low molecular weight forms of apoliprotein(a). Association between small apolipoprotein(a) isoforms and frontotemporal dementia in humans. Emanuele E, Peros E, et al. Neurosci Lett. 2003 Dec 26;353(3):201-4

Genetic Causes: Abnormal Tau Gene on 17: Frontotemporal dementia (FTD) and Alzheimer's disease (AD) both have neurofibrillary tangles consisting of aggregations of hyperphosphorylated tau protein. Recently, a number of different pathogenic mutations in the tau gene have been identified in families with FTD and parkinsonism linked to chromosome 17 (FTDP-17). In a Swedish family with presenile degenerative dementia with bitemporal atrophy, the R406W mutation in exon 13 was identified in all affected cases. This mutation has previously been reported in two different FTDP-17 families of Dutch and Midwestern American origin. Common features to these two kindreds and the Swedish family are the late age at onset and long duration of the disease. The Swedish pedigree as well as the American one showed early memory impairment and pronounced temporal lobar atrophy similar to AD, while the Dutch cases showed more FTD features. The Tau R406W Mutation Causes Progressive Presenile Dementia with Bitemporal Atrophy. Ostojic J, Elfgren C, et al. Uppsala University, Sweden. Dement Geriatr Cogn Disord. 2004;17(4):298-301. Ed: Some tau gene abnormalities result in an increase in insoluble tau protein, while some other cases of FTD have been found due to tau gene abnormalities but not with an accumulation of insoluble tau. 

Genetics: More on Tau Mutations: Tau is the major component of the intracellular filamentous deposits that define a number of neurodegenerative diseases, including the largely sporadic Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, and argyrophilic grain disease, as well as the inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). About half of the known mutations have their primary effect at the protein level, and they reduce the ability of tau protein to interact with microtubules and increase its propensity to assemble into abnormal filaments. The other mutations have their primary effect at the RNA level, thus perturbing the normal ratio of three-repeat to four-repeat tau isoforms. Where studied, this resulted in the relative overproduction of tau protein with four microtubule-binding repeats in brain. Several Tau mutations give rise to diseases that resemble progressive supranuclear palsy, corticobasal degeneration, or Pick's disease. Moreover, the H1 haplotype of Tau has been identified as a significant risk factor for progressive supranuclear palsy and corticobasal degeneration.

Genetics: Microtubule-Associated Protein, Tau (MATP) Gene Central: Tauopathies are characterized by hallmark lesions consisting of fibrillar aggregates of the microtubule-associated protein, tau (MAPT). Mutations of the tau gene (MAPT) are the cause of frontotemporal dementia with parkinsonism linked to chromosome 17, giving tau a central role in the pathogenic process. The chromosomal region containing MAPT has been shown to evolve into two major haplotypes, H1 and H2. The more common haplotype H1 is over-represented in patients with progressive supranuclear palsy (PSP) and corticobasal degeneration. The structure of the tau haplotype in controls and in progressive supranuclear palsy. Pittman AM, Myers AJ, Duckworth J, Bryden L, Hanson M, Abou-Sleiman P, Wood NW, Hardy J, Lees A, De Silva R. Hum Mol Genet. 2004 Jun 15;13(12):1267-74

Genetic Causes: Two More Tau Gene Abnormality on 17: A second phenotype of frontotemporal dementia and parkinsonism was linked to chromosome 17 with S305N similar to Pick's disease pathology in two brothers. The brain of the older brother showed macroscopic atrophy compatible with Pick's disease, and subsequent tau gene analysis revealed heterozygous S305N mutation in exon 10 of the tau gene. Round-shaped neuronal inclusions similar to Pick's bodies were positive for phosphorylated serine 262 as well as other anti-tau antisera, which is different from immunoexpression of Pick's bodies. Ultrastructurally, these neuronal inclusions consisted of straight, randomly orientated fibrils measuring approximately 10-20 nm in width and 60-600 nm in length. This ultrastructural profile is similar to that of the first case of S305N. S305N reported here can cause another phenotype closely resembling Pick's disease. Pick's Disease Pathology of a Missense Mutation of S305N of Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17: Another Phenotype of S305N. Kobayashi K, Hayashi M, Kidani T, Ujike H, Iijima M, Ishihara T, Nakano H, Sugimori K, Shimazaki M, Kuroda S, Koshino Y. Kanazawa University, Kanazawa, Japan. Dement Geriatr Cogn Disord. 2004;17(4):293-7; Novel G335V mutation in the tau gene exon 12 associated with early onset familial frontotemporal dementia. Neumann M, Diekmann S, et al. Ludwig Maximilians University, Munich. Neurogenetics. 2005 Mar 12

Genetic Causes: Still More Tau Mutations on 17: 26 in all: Of 26 patients with FTD, 9 had clear tau mutations: 7 P301L and 2 G272V. Total tau and phosphorylated tau 181 levels in the cerebrospinal fluid of patients with frontotemporal dementia due to P301L and G272V tau mutations. Rosso SM, van Herpen E, Pijnenburg YA, Schoonenboom NS, Scheltens P, Heutink P, van Swieten JC. Erasmus Medical Center, Rotterdam.; 26 different tau gene mutations causing FTD with Parkinson's disease have now been found. Neurol Neurochir Pol. 2003 Jan-Feb;37(1):173-84

Genetic Causes: Chromosome 9 Defects Linked to FTD with Motor Neuron Disease; a Third FTD Disorder Linked to Chromosome 3: Recent work on frontotemporal dementia (FTD) has revealed the existence of at least 3 genetically distinct groups of inherited FTD: FTDP-17, FTD and motor neuron disease linked to chromosome 9, and FTD linked to chromosome 3 (FTD-3). Tau, on chromosome 17, is the only gene where mutations have been identified and its involvement in FTD has been firmly established. The genes on chromosome 9 and chromosome 3 associated with familial forms of FTD remain to be identified. Abnormal aggregates of tau protein characterize the brain lesions of FTDP-17 patients and ubiquitin inclusions have been found in FTD with motor neuron disease linked to chromosome 9. In this study the frontal cortices of 3 FTD-3 patients from a unique Danish family were examined for characteristic neuropathological features. In these brains tau inclusions were present in neurons and some glial cells in the absence of beta-amyloid deposits. The presence of filamentous tau protein in the frontal cortex of these patients suggests a possible link between tau and the genetic defect present on chromosome 3 and associated with FTD-3. Tau protein in frontotemporal dementia linked to chromosome 3 (FTD-3). Yancopoulou D, Crowther RA, Chakrabarti L, Gydesen S, Brown JM, Spillantini MG. University of Cambridge, UK. J Neuropathol Exp Neurol. 2003 Aug;62(8):878-82

Folate and B-12 Low in AD and FTD: In a study of AD (n=152) and FTD (n=28) patients, significantly negative correlations between levels of serum vitamin B12 and red cell folate and the degree of cognitive deterioration were found. In FTD patients, levels of vitamin B12 were also negatively correlated with both hallucinations (p=0.022) and diurnal rhythm disturbances (p=0.036). Correlations between cognitive, behavioural and psychological findings and levels of vitamin B12 and folate in patients with dementia. Engelborghs S, Vloeberghs E, Maertens K, Marien P, Somers N, Symons A, Clement F, Ketels V, Saerens J, Goeman J, Pickut BA, Vandevivere J, De Deyn PP. Antwerp, Belgium. Int J Geriatr Psychiatry. 2004 Apr;19(4):365-70

Head Trauma and Thyroid Disorders Risk Factors: A case control study in the Netherlands of 80 sporadic FTD patients and 128 controls found an OR of 3.3 for head trauma and 2.5 for thyroid disorders although the thyroid data did not reach statistical significance. Medical and environmental risk factors for sporadic frontotemporal dementia: a retrospective case-control study. Rosso SM, Landweer EJ, et al. J Neurol Neurosurg Psychiatry. 2003 Nov;74(11):1574-6

Treatment

Paroxetine No Help for Frontotemporal Dementia: In a small 10-patient DB PC crossover study 6 weeks on paroxetine and 6 on placebo for each patient found no evidence of benefit and evidence of impaired learning in three areas. U Cambridge.

Trazodone Might Help Frontotemporal Dementia: Behavioral troubles due to frontotemporal dementia (FTD) are difficult to treat. The serotonergic system is associated with frontal lobes, the degeneration of which contributes to FTD. Trazodone increases the extracellular 5-HT levels in the frontal cortex. In a DB PC cross-over study, there was a significant decrease in the Neuropsychiatry Inventory (NPI) total score with trazodone (p = 0.028) in the 26 patients. A decrease of more than 50% in the NPI score was observed in 10 patients with trazodone. This improvement was mainly based on the improvement of 4 items of the scale (irritability, agitation, depressive symptoms and eating disorders). The Mini-Mental State Examination was not modified and trazodone was well tolerated. Frontotemporal dementia: a randomised, controlled trial with trazodone. Lebert F, Stekke W, Hasenbroekx C, Pasquier F. Lille University Hospital, France. Dement Geriatr Cogn Disord. 2004;17(4):355-9

Fewer Serotonin Receptors and Reduced Glucose Metabolism: In patients with the frontal variant of frontotemporal lobar degeneration (fv-FTLD), apathy with motor slowness (apathetic form) to disinhibition with agitation (disinhibited form) occur. Researchers found a reduction of frontal glucose metabolism in fv-FTLD patients. Apathetic syndrome was associated with a prevalent dorsolateral and frontal medial hypometabolism, whereas the disinhibited syndrome demonstrated a selective hypometabolism in interconnected limbic structures (the cingulate cortex, hippocampus/amygdala, and accumbens nucleus). There was a significant reduction of 5-hydroxytryptamine-2A receptors in orbitofrontal, frontal medial, and cingulate cortices. SSRIs might help. Glucose metabolism and serotonin receptors in the frontotemporal lobe degeneration. Franceschi M, Anchisi D, et al. Varese, Italy. Ann Neurol. 2005 Feb;57(2):216-25.