Chapter 8
Frontotemporal Lobar Degeneration

History
Frontotemporal lobar degeneration (FTLD), with Pick’s disease as the prototype, is a progressive non-Alzheimer’s diseaseoften with the presenile onset and is characterized by degeneration and loss of neurons mainly in the frontal and temporal lobes,
causing marked behavioral abnormalities, psychiatric symptoms, and language impairment, while various degrees of motor
disorders may emerge during the course of disease. The concept, name, and classification of FTLD have changed over the years,
and terms such as frontal lobe degeneration of non-Alzheimer type and frontal lobe dementia were once used in the past.

Clinical classification
The term FTLD is used in cases with a definitive pathological and genetic diagnosis, while frontotemporal dementia(FTD) is used in cases with a clinical diagnosis. The term FTLD is adopted as the disease name in designated intractablediseases in Japan. In this guideline, FTLD is used and also includes clinically diagnosed cases.
FTLD is a classified clinically into three types: behavioral variant frontotemporal dementia (bvFTD) with mainly
prefrontal atrophy; semantic dementia (SD) with localized atrophy mainly in the temporal pole and middle/inferior temporalgyrus; and progressive non-fluent aphasia (PNFA), which is left-dominant and shows localized atrophy around the fissure of
Sylvius. Refer to CQ2-6 for the classification by type of aphasia.
Also, parkinsonism and motor neuron symptoms may be observed in patients with FTLD during the course of disease. The
disease type showing motor neuron symptoms is called frontotemporal dementia with motor neuron disease (FTD-MND).

Pathological classification
Pathologically, specific proteins aggregate and deposit as inclusion bodies in neurons and glial cells. Tau protein, TAR
DNA-binding protein of 43 kD (TDP-43), and fused in sarcoma (FUS) protein have been identified as the main componentsof the inclusion bodies 1).
Tau protein is one of the microtubule-binding proteins and is broadly classified by the number of repeats in the microtubularbinding region at the C-terminal side into three-repeat tau protein and four-repeat tau protein. Tauopathy is a general termfor diseases in which abnormal accumulation of phosphorylated tau protein is considered to be an essential pathogenic
mechanism. The subgroup of FTLD that exhibits tauopathy is called FTLD-tau. FTLD-tau comprises cases showing
accumulation of mainly three-repeat tau protein (Pick disease) and those showing accumulation of mainly four-repeat tau
protein. Corticobasal degeneration, progressive supranuclear palsy, and argyrophilic grain dementia are broadly interpreted
as four-repeat tauopathy with FTLD.
TDP-43 protein and FUS protein exist mainly in the nucleus, and both possess diverse functions such as transcription,
splicing, RNA transport, and stabilization. In FTLD, both TDP-43 protein and FUS protein disappear from the nucleus
and are observed as extracellular aggregates, and these disease types are called FTLD-TDP and FTLD-FUS, respectively.
See CQ1-8 for a detailed description of pathology.

Relationship between clinical classification and pathological classification
It has been reported that more than half of bvFTD cases are FTLD-TDP type, while approximately 70% of PNFA cases
are FTLD-tau type (PSP, CBD, Pick disease), and approximately 80% of SD are FTLD-TDP type 2).

Diagnosis
For diagnostic criteria, see CQ8-1.

Family history
Family history is evident in 30 to 50% of the cases in European and American countries but is almost absent in Japan. In
familial cases, mutations have been identified in several genes, including the tau gene, the TARDBP gene, the FUS gene, andthe progranulin gene. Abnormal expansion of a hexanucleotide repeat in intron 1 of the C9orf72 gene is the most frequentcause in European and American countries, but very rarely in Japan.

Treatment
FTLD is a progressive degenerative disease, and curative treatment that can modify the natural course has not been developed.
When patients show motor neuron symptoms, pay special attention to the onset of respiratory failure and dysphagia.
Parkinsonism and repeated falls may be observed, but levodopa preparations have limited use or are often ineffective.

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Clinical Practice Guideline for Dementia 2017▪ References
1) Lashley T, Rohrer JD, Mead S, et al. Review: An update on clinical, genetic and pathological aspects of frontotemporal lobar degenerations.
Neuropathol Appl Neurobiol. 2015; 41(7): 858-881.
2) D’Alton S, Lewis J. Therapeutic and diagnostic challenges for frontotemporal dementia. Front Aging Neurosci. 2014; 6: 204.

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CQ 8-1

What are the diagnostic key points and diagnostic criteria for frontotemporallobar degeneration (FTLD)?
AnswerAmong various types of frontotemporal lobar degeneration (FTLD), the criteria developed by the International
Behavioral Variant Frontotemporal Dementia Criteria Consortium (FTDC) in 2011 are recommended for the diagnosis
of behavioral variant frontotemporal dementia (bvFTD). For semantic dementia (SD), the use of the clinical diagnostic
characteristics for semantic dementia proposed in 1998 is recommended, with additional reference to the clinical diagnostic
features for semantic variant progressive aphasia proposed in 2011.
B

Comments and evidence
FTLD is classified clinically into behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), andprogressive non-fluent aphasia (PNFA). Among them, bvFTD and SD are included as designated intractable diseases inJapan.

1. Diagnostic criteria for bvFTD
The FTDC diagnostic criteria reported by Rascovsky et al. 1) are used. The sensitivity of the FTDC criteria is 93% forpossible bvFTD and 80% for probable bvFTD, and the positive predictive value of cases diagnosed as possible bvFTD is
90% 2). Harris et al. 3) studied mainly early-onset cases and reported high reliability, with 95% sensitivity and 82% specificity
for possible bvFTD, and 85% sensitivity and 95% specificity for probable bvFTD.
The major false-positive cases are Alzheimer’s disease dementia, while dementia with Lewy bodies also constitutes acertain percentage 2).
For the FTDC criteria, although the κ values (indicating interrater agreement rate) are high, with 0.81 for possible bvFTD
and 0.82 for probable bvFTD, there are some differences in agreement rate among individual items 4).
For characteristic image findings, see CQ8-2. Family history is evident in 30-50% of the patients in European andAmerican countries but in almost none of the Japanese patients.
In the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5), the term “neurocognitive disorder(NCD)” is introduced to replace the term “dementia. FTLD is called major or mild frontotemporal NCD, and broadlyclassified into behavioral variant and language variant. For diagnostic criteria of behavior variant, the criteria adopted arealmost the same as the above-mentioned FTDC criteria.

2. Diagnostic criteria of SD and characteristics of aphasia
According to the diagnostic criteria of Gorno-Tempini et al. 5) the diagnostic procedure is first to diagnose progressive
aphasia and then classify into semantic, non-fluent/grammatical, and logopenic (for classification based on aphasia, see
CQ2-6). SD manifests semantic aphasia (loss of word meaning). However, in SD with predominantly right temporal lobe
atrophy, some patients show conspicuous semantic deficits other than semantic aphasia (for example, semantic memory
impairment related to well-known buildings and faces) or behavioral disorders in the early stage. Consequently, there is lessconsensus compared to the bvFTD diagnostic criteria. The diagnostic criteria for designated intractable diseases adopt the
Gorno-Tempini diagnostic criteria for semantic variants characterized by aphasia, together with the diagnostic criteria ofNeary et al. 6) based on the evidence of characteristic semantic memory impairment regardless of the presence or absence ofprogressive aphasia.
In SD, impairment of object naming and word comprehension is consistent, and patients have difficulties with the same
objects and words under different test settings and in daily life. Surface dyslexia is observed in reading kanjis that havedifferent pronunciations, especially in idioms, where the words are read differently from the original kanjis.
Some patients develop impairment in recognizing the face of a known person, or cognitive impairments across multiple
modalities such as visual and auditory comprehension of an object. These patients cannot recognize the faces of well-known
persons, friends, or relatives whom they meet only occasionally. When they see these faces, they would say, “I can’t remember
anything” or “I don’t know”. The fact that recognition is not helped by providing sound or touch cues would indicate that174

Clinical Practice Guideline for Dementia 2017

the condition is different from the usual agnosia.
For clinical diagnosis of SD, after identifying the characteristic aphasia, differentiate from other diseases such as Alzheimer’s
disease dementia carefully from image and other clinical findings.

3. Characteristics of aphasia observed in PNFA
Diagnostic criteria of nonfluent/agrammatic aphasia characteristic of PNFA have been reported by Gorno-Tempini et al. 5).
As mentioned above, when using these criteria, first diagnose whether progressive aphasia is present. Nonfluent/agrammatic
aphasia is characterized by (1) agrammatism in speech, and (2) apraxia of speech characterized by inconsistent speech sounderrors and distortions (pronunciation not found in the Japanese language); at least one of the above should be present. While
single-word comprehension is spared, comprehension of grammatically complex sentences is impaired. Other features are
effortful speech, difficulty in initiating speech, halting speech, and inconsistent speech errors.

▪ References
1) Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of fronto-temporal dementia. Brain.
2011; 134(Pt 9): 2456-2477.
2) Balasa M, Gelpi E, Martin I, et al. Diagnostic accuracy of behavioral variant frontotemporal dementia consortium criteria (FTDC) in aclinicopathological cohort. Neuropathol Appl Neurobiol. 2015; 41(7): 882-892.
3) Harris JM, Gall C, Thompson JC, et al. Sensitivity and specificity of FTDC criteria for behavioral variant frontotemporal dementia. Neurology.
2013; 80(20): 1881-1887.
4) Lamarre AK, Rascovsky K, Bostrom A, et al. Interrater reliability of the new criteria for behavioral variant frontotemporal dementia. Neurology.
2013; 80(21): 1973-1977.
5) Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology. 2011; 76(11): 10061014.
6) Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology. 1998; 51: 15461554.

▪ Search formula
PubMed search: July 10, 2015 (Friday)#1 “Frontotemporal Lobar Degeneration/diagnosis” [Mesh] OR ((“frontotemporal lobar degeneration” [TI] OR “frontotemporal dementia” [TI]
OR FTD [TI] OR FTLD [TI] OR bvFTD [TI]) AND Dementia/diagnosis [Mesh]) OR ((“frontotemporal lobar degeneration” OR “frontotemporaldementia” OR FTD OR FTLD bvFTD) AND (diagnosis OR diagnoses OR diagnostic))
Ichushi search: July 10, 2015 (Friday)#1 (Frontotemporal lobar degeneration/TH OR Frontotemporal lobar degeneration/TI OR Dementia-frontotemporal type/TH OR Frontotemporal
type dementia/TI OR “Frontotemporal Lobar Degeneration”/TI OR “Frontotemporal Dementia”/TI OR FTD/TI OR FTLD/TI OR bvFTD)
AND ((SH = Diagnostic use, diagnosis, diagnostic imaging, X ray diagnosis, radionuclide diagnosis, ultrasound diagnosis)OR Diagnosis/TH OR
Diagnosis/TI)

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CQ 8-2

What are the characteristics of image findings of frontotemporal lobar
degeneration (FTLD)?
AnswerAmong FTLD disorders, behavioral variant frontotemporal dementia (bvFTD) shows MRI/CT findings of localized
atrophy in the frontal and temporal lobes, predominantly in the frontal lobe. On SPECT/PET, decreased metabolism/
decreased blood flow is observed in the frontal lobe and anterior temporal lobe, while the parietal and occipital lobes arespared.
Semantic dementia (SD) shows MRI/CT findings of atrophy in the temporal lobe predominantly involving the anterior
region and inferior temporal gyrus. Usually, atrophy is asymmetrical. As the disease progresses, frontal lobe atrophy also
appears. On SPECT/PET, decreased metabolism/decreased blood flow in the temporal lobe predominantly involving theanterior region and in the inferior temporal gyrus is observed.
Progressive non-fluent aphasia (PNFA) shows MRI/CT findings of atrophy in the left frontal lobe predominantly fromthe posterior region to the insula. On SPECT/PET, decreased metabolism/decreased blood flow in the left frontal lobe
predominantly from the posterior region to the insula is observed.
Imaging examination is useful for the diagnosis of FTLD, but a diagnosis cannot be made with images alone. B

Comments and evidence

1. General head MRI/CT and SPECT/PET findings 1)
For bvFTD, atrophy on MRI/CT and decreased metabolism and blood flow on SPECT/PET are observed in the frontal
lobes and anterior temporal lobes. For SD, atrophy on MRI/CT and decreased metabolism/blood flow on SPECT/PET are
observed in temporal lobes predominantly in the anterior region and in the inferior temporal gyrus. For PNFA, atrophy on
MR/CT and decreased metabolism/blood flow are observed in the left frontal lobe predominantly from the posterior region
to the insula.

2. Brain volumetric imaging
Brain volumetric imaging is useful for the differentiation of Alzheimer’s disease dementia, dementia with Lewy bodies,and FTLD 2).
In bvFTD, atrophy is observed in the frontal lobes involving the medial, dorsolateral, and orbitofrontal regions, as well as
the anterior temporal lobes. Atrophy in the frontal lobe, especially the medial surface, progresses from the earliest stage 1).
The results of a meta-analysis show that bvFTD is characterized by atrophy in the prefrontal cortex, in particular, atrophy of
the regions corresponding to superior and middle frontal gyrus, anterior cingulate gyrus, insula, caudate nucleus, andputamen 3).
SD is characterized by left-right asymmetric inferior temporal gyrus-dominant anterior temporal atrophy or decreased
blood flow/metabolism. The orbitofrontal cortex, insula, and caudate nucleus are also affected. In a longitudinal observational
study, temporal lobe atrophy progresses from the earliest stage, and atrophy in the frontal lobe, insula, caudate nucleus, andthalamus progress in the same manner.
PNFA is characterized by atrophy or decreased blood flow/metabolism in the posterior frontal lobe, including Broca’s area
and the superior premotor cortex, as well as in the insula. Lesions in the superior temporal gyrus and striatum are also
observed.

3. Diffusion tensor imaging 4)
In bvFTD, bilateral and widespread lesions in the white matter tracts are observed. The lesions are severe in the superior
longitudinal fasciculus, anterior cingulate fasciculus, anterior corpus callosum, uncinate fasciculus, and inferior longitudinalfasciculus, and are especially severe, usually in the anterior aspect of superior longitudinal fasciculus and inferior longitudinalfasciculus. In SD, left-dominant degeneration in the uncinate fasciculus and inferior longitudinal fasciculus is observed, andanterior-dominant degeneration in the anterior corpus callosum and arcuate fasciculus is also found. In PNFA, degeneration
is observed in the left superior longitudinal fasciculus, especially in the arcuate bundle projecting to the inferior frontal lobe.

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4. Resting-state functional MRI 4)
In bvFTD, decreased connectivity of the salience network, including the anterior cingulate gyrus and the anterior insula
has been reported.

5. Genetic mutation and brain volumetric imaging 5)
Compared to patients with mutations in tau and progranulin genes and patients with sporadic disease, patients with
mutations in C9orf72 gene show atrophy in the anterior temporal lobe, parietal lobe, occipital lobe, and cerebellum. Patientswith Tau gene mutations are characterized by atrophy in the anteromedial temporal lobe, and patients with progranulin genemutations are characterized by asymmetric atrophy in the temporoparietal lobe. In addition, the speed of atrophy of thebrain as a whole is faster in patients with progranulin gene mutations than in patients with C9orf72 or tau gene mutations.

6. Comparison of brain imaging findings with underlying pathological findings 6)
There is a limitation to estimate underlying pathology based on atrophy patterns observed on MRI. In recent years, highly
sensitive tau PET imaging capable of visualizing tau pathology has become available in some facilities, and further studies
are awaited 7, 8).

7. Phenocopy syndrome 1)
Some bvFTD cases show no apparent atrophy on MRI, and they are termed “bvFTD phenocopy syndrome”. Clinicalprogression in these patients is known to be very slow. FDG-PET also does not show any abnormalities. Various underlying
diseases, such as developmental disorders, are speculated.

▪ References
1) Whitwell JL, Josephs KA. Recent advances in the imaging of frontotemporal dementia. Curr Neurol Neurosci Rep. 2012; 12(6): 715-723.
2) Vemuri P, Simon G, Kantarci K, et al. Antemortem differential diagnosis of dementia pathology using structural MRI: Differential-STAND.
Neuroimage. 2011; 55(2): 522-531.
3) Pan PL, Song W, Yang J, et al. Gray matter atrophy in behavioral variant frontotemporal dementia: a meta-analysis of voxel-based morphometry
studies. Dement Geriatr Cogn Disord. 2012; 33(2-3): 141-148.
4) Risacher SL, Saykin AJ. Neuroimaging biomarkers of neurodegenerative diseases and dementia. Semin Neurol. 2013; 33(4): 386-416.
5) Whitwell JL, Weigand SD, Boeve BF, et al. Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin andsporadics. Brain. 2012; 135(Pt 3): 794-806.
6) Whitwell JL, Josephs KA. Neuroimaging in frontotemporal lobar degeneration—predicting molecular pathology. Nat Rev Neurol. 2011; 8(3): 131142.
7) Maruyama M, Shimada H, Suhara T, Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal
controls. Neuron. 2013; 79(6): 1094-1108.
8) Okamura N, Furumoto S, Fodero-Tavoletti MT, et al. Non-invasive assessment of Alzheimer’s disease neurobrillary pathology using 18F-THK5105
PET. Brain. 2014; 137(Pt 6): 1762-1771.

▪ Search formula
PubMed search: July 8, 2015 (Wednesday)#1 (“Frontotemporal Lobar Degeneration/diagnosis” [Mesh] OR ((“frontotemporal lobar degeneration” [TI] OR “frontotemporal dementia” [TI]
OR FTD [TI] OR FTLD [TI] OR bvFTD [TI]) AND “Dementia/diagnosis” [Mesh]) OR ((“frontotemporal lobar degeneration” OR “frontotemporaldementia” OR FTD OR FTLD bvFTD) AND (diagnosis OR diagnoses OR diagnostic))) AND (“Diagnostic Imaging” [Mesh] OR “magnetic
resonance imaging” OR “single-photon emission computed tomography” OR “positron emission tomography” OR MRI OR SPECT OR PET)
Ichushi search: July 10, 2015 (Friday)#1 (Frontotemporal lobar degeneration /TH OR Frontotemporal lobar degeneration/TI OR Dementia-frontotemporal type/TH OR Frontotemporal
type dementia/TI OR “Frontotemporal Lobar Degeneration”/TI OR “Frontotemporal Dementia”/TI OR FTD/TI OR FTLD/TI OR bvFTD)
AND ((SH = Diagnostic use, diagnosis, diagnostic imaging, X ray diagnosis, radionuclide diagnosis, ultrasound diagnosis)OR Diagnosis/TH OR
Diagnosis/TI) AND (Diagnostic imaging/TH OR MRI/TI OR magnetic resonance imaging OR magnetic resonance tomography OR Magnetic
resonance imaging OR Nuclear magnetic resonance imaging OR PET/TI OR Positron emission tomography OR Positron emission tomography OR
SPECT/TI OR Single photon emission computed tomography OR Single photon emission computed tomography OR Single photon computed
tomography OR Single photon emission computed tomography)

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CQ 8-3

Are there effective drugs for frontotemporal lobar degeneration (FTLD)?
Recommendation
The use of selective serotonin reuptake inhibitor (SSRI) is recommended for the purpose of improving behavioral
disorders in FTLD (off-label).
2C

Comments and evidence
Because FTLD is a clinical syndrome and has diverse underlying pathologies, there are few studies on pharmacotherapy.
The available studies are small-scale trials, which do not necessarily provide sufficient evidence 1, 2). A review reported by
Nardell and Tampi 2) suggests that SSRIs, trazodone, and amphetamines may be effective in improving some behavioral
symptoms, but none of the medications had an impact on cognition. The authors also pointed out various issues of thestudies reviewed, such as the use of different diagnostic criteria, inconsistent evaluation indicators, and use of indicators suchas Mini-Mental State Examination (MMSE) which are not sensitive to FTLD symptoms. Trazodone has been shown to beeffective in a double-blind, randomized control trial (RCT) 3).
Regarding SSRI, since the report of Swartz et al. 4) in 1997, some reports have shown that these drugs are effective fordisinhibition, stereotyped behavior, and abnormal eating behavior, while other reports observed no effectiveness. In Japan,
an open-label trial has reported the effectiveness of SSRI for repetitive behavior, stereotyped behavior, and compulsive
complaint in FTLD 5). Lanctot et al. 6) used PET to investigate the mechanism of action of SSRI for FTLD, and reported
significant decreases in serotonin 5-HT1A receptor binding potential in all the brain regions examined in FTLD patientscompared with controls. Using electroencephalography and magnetoencephalography, Hughes et al. 7) reported recovery of
the activity of inferior frontal gyrus in FTLD patients treated with SSRI.
Views on the usefulness of cholinesterase inhibitors (ChEIs) remain divided 1, 2). There are reports of no effectiveness of
ChEIs and reports of worsening of disinhibition. Thus caution is required when administering ChEIs. A recent review
concludes that the efficacy of ChEIs for FTD cannot be confirmed and that ChEIs are associated with more gastrointestinal
adverse effects 8). Besides, two RCTs failed to demonstrate the usefulness of memantine, an NMDA receptor antagonist,compared with placebo.
Nasal oxytocin at a dose of 24 IU has been reported to improve the behavioral score of Neuropsychiatric Inventory (NPI)
and reduce episodes of anger and fear compared with placebo 9). Preparation of a large-scale and long-term clinical trial isongoing 10).

▪ References
1) Riedl L, Mackenzie IR, Forstl H, et al. Frontotemporal lobar degeneration: current perspectives. Neuropsychiatr Dis Treat. 2014;10:297-310.
2) Nardell M, Tampi RR. Pharmacological treatments for frontotemporal dementias: a systematic review of randomized controlled trials. Am J
Alzheimers Dis Other Demen. 2014;29(2): 123-132.
3) Lebert F, Stekke W, Hasenbroekx C, et al. Frontotemporal dementia: a randomised, controlled trial with trazodone. Dement Geriatr Cogn Disord.
2004;17(4): 355-359.
4) Swartz JR, Miller BL, Lesser IM, et al. Frontotemporal dementia: treatment response to serotonin selective reuptake inhibitors. J Clin Psychiatry.
1997;58: 212-216.
5) Ikeda M, Shigenobu K, Fukuhara R, et al. Efficacy of fluvoxamine as a treatment for behavioral symptoms in frontotemporal lobar degeneration
patients. Dement Geriatr Cogn Disord. 2004;17(3): 117-121.
6) Lanctot KL, Herrmann N, Ganjavi H, et al. Serotonin-1A receptors in frontotemporal dementia compared with controls. Psychiatry Res.
2007;156(3): 247-250.
7) Hughes LE, Rittman T, Regenthal R, et al. Improving response inhibition systems in frontotemporal dementia with citalopram. Brain. 2015;138(Pt7): 1961-1975.
8) Li Y, Hai S, Zhou Y, et al. Cholinesterase inhibitors for rarer dementias associated with neurological conditions. Cochrane Database Syst Rev.
2015;(3): CD009444.
9) Jesso S, Morlog D, Ross S, et al. The effects of oxytocin on social cognition and behaviour in frontotemporal dementia. Brain. 2011;134(Pt 9): 24932501.
10) Finger EC, MacKinley J, Blair M, et al. Oxytocin for frontotemporal dementia: a randomized dose-finding study of safety and tolerability.
Neurology. 2015;84(2): 174-181.

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▪ Search formula
PubMed search: July 10, 2015 (Friday)#1 “Frontotemporal Lobar Degeneration/drug therapy” [Mesh] OR ((“frontotemporal lobar degeneration” [TI] OR “frontotemporal dementia” [TI]
OR FTD [TI] OR FTLD [TI] OR bvFTD [TI]) AND Dementia/drug therapy [Mesh]) OR ((“frontotemporal lobar degeneration” OR“frontotemporal dementia” OR FTD OR FTLD bvFTD) AND (“drug therapy” OR chemotherapy OR pharmacotherapy OR “pharmacologicaltherapy”))
Ichushi search: July 9, 2015 (Thursday)#1 (Frontotemporal lobar degeneration/TH OR Frontotemporal lobar degeneration/TI OR Dementia-frontotemporal type/TH OR Frontotemporal
type dementia/TI OR “Frontotemporal Lobar Degeneration”/TI OR “Frontotemporal Dementia”/TI OR FTD/TI OR FTLD/TI OR bvFTD)
AND ((SH = Pharmacotherapy) OR Pharmacotherapy/MTH OR Therapeutic use/MTH OR Drug treatment/TI OR Pharmacotherapy/TI OR
Therapeutic drug/TI)

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CQ 8-4

Are there effective non-pharmacological therapies for frontotemporal lobar
degeneration (FTLD)?
Recommendation
Non-pharmacotherapy therapies such as care and behavioral therapy based on FTLD symptomatology are recommended.

2C

Comments and evidence
The characteristics described in the diagnostic criteria for behavioral variant frontotemporal dementia (bvFTD) areessential in developing treatment strategies for behavioral disorders of FTLD.
Although there is little evidence, non-pharmacological therapies are useful and are the mainstay of treatment. In particular,
by utilizing the patient’s preserved functions and taking into account the characteristic symptoms and the patient’s lifestyle,it may be possible to mitigate behavioral abnormalities and reduce the burden on caregivers 1).
Shinagawa et al. 2) reviewed case reports, expert opinions, and clinical trials (excluding retrospective studies) of nonpharmacological management 2). Ikeda et al. 3) studied six patients with FTLD, and reported that care that utilized thepatient’s preserved episodic memory, procedural memory, and visuospatial cognitive function was effective and resulted in
the improvement of quality of life (QOL). Mioshi et al. 4) and McKinnon et al. 5) showed that a learning program comprising
mainly of cognitive appraisal and coping strategies improved the burden on caregivers.
Ikeda et al. 6) conducted a detailed assessment of behavioral disorders and behavioral interventions given to patients underhospitalized observation, and reported the effectiveness of conducting individualized family guidance based on behavioral
disorder assessments of the patients and improvement of families’ attitude toward the patients.
Lough et al. 7) reported that the compulsive behaviors of a patient with FTLD were changed to socially acceptable behavior
in response to behavioral modification techniques. Tokikawa et al. 8) reported that the introduction of a daycare program fora patient with FTLD resolved the patient’s obsessive-compulsive behaviors by acquiring a stereotyped behavior pattern.
However, this report also pointed out the problems of newly acquired emotional compulsive behaviors such as coming to
daycare, even on holidays, and not able to wait for the pick-up person.
Tokimasa et al. 9) compared the cooking activities of 2 patients with FTLD and five patients with Alzheimer’s disease
dementia. In patients with Alzheimer’s disease dementia, because of episodic memory impairment and apraxia, constantsupervision is needed from the early stage, and acquisition of generalized compensation method is difficult. On the other
hand, in patients with FTLD, after cautiously forming an intimate relationship, helping the patients form the habit of doing
activities of daily living (ADL) utilizing stereotyped behavior is a crucial point for care.
In daycare and institutional care, reports have emphasized that to respond to severe mental symptoms; there is a need for
one-on-one response at least when care is initiated 6, 8, 10). The usefulness of group homes where meticulous care can beprovided has been reported 11).

▪ References
1) Merrilees J. A model for management of behavioral symptoms in frontotemporal lobar degeneration. Alzheimer Dis Assoc Disord. 2007; 21(4):S64-S69.
2) Shinagawa S, Nakajima S, Plitman E, et al. Non-pharmacological management for patients with frontotemporal dementia: a systematic review. J
Alzheimers Dis. 2015; 45(1): 283-293.
3) Ikeda M, Tanabe H, Horino T, et al. Care for Patients with pick’s disease: by using their preserved procedural memory. Psychiatr Neurol Jpn(Seishin Shinkeigaku Zasshi) 1995; 97(3): 179-192. (In Japanese)4) Mioshi E, McKinnon C, Savage S, et al. Improving burden and coping skills in frontotemporal dementia caregivers: A pilot study. Alzheimer Dis
Assoc Disord. 2013; 27(1): 84-86.
5) McKinnon C, O’Connor CM, Savage S, et al. Qualitative results of a structured group program for carers of people with frontotemporal dementia.
Int J Geriatr Psychiatry. 2013; 28(2): 217-218.
6) Ikeda M, Imamura T, Ikejiri Y, et al. The efficacy of short-term hospitalizations in family care for patients with Pick’s disease. Psychiatr Neurol Jpn(Seishin Shinkeigaku Zasshi) 1996; 98(10): 822-829. (In Japanese)
7) Lough S, Hodges JR. Measuring and modifying abnormal social cognition in frontal variant frontotemporal dementia. J Psychosom Res. 2002;
53(2): 639-646.

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Clinical Practice Guideline for Dementia 20178) Tokikawa S, Ideda M, Shigenobu K, et al. A day care program for a patient with fronto-temporal dementia (Pick type): mainly for her disinhibited
behavior. General Rehabilitation (Sogo Rihabiriteshon) 2000; 28(5): 477-481. (In Japanese)9) Tokimasa A, Ikeda M, Hirono N, et al. Maintaining activity in dementia; study on cooking performance. General Rehabilitation (Sogo
Rihabiriteshon) 1996; 24(9): 861-869. (In Japanese)10) Takahashi J, Yokota O, Fujisawa Y. Person-centered care for demented elderly in a psychiatric hospital- impact on behavioral and psychologicalsymptoms of dementia, quality of life, and caregiver burden-. Japanese Journal of Geriatric Psychiatry (Ronen Seishin Igaku Zasshi) 2007; 18(12):861-869. (In Japanese)11) Yokota O, Fujisawa Y, Takahashi J, et al. Effects of group-home care on behavioral symptoms, quality of life, and psychotropic drug use in patientswith frontotemporal dementia. J Am Med Dir Assoc. 2006; 7(5): 335-337.

▪ Search formula
PubMed search: July 10, 2015 (Friday)#1 ((“Frontotemporal Lobar Degeneration/therapy” [Mesh] OR(“Frontotemporal Lobar Degeneration” [Majr]AND “Therapeutics” [Mesh]) OR((“frontotemporal lobar degeneration” [TI] OR “frontotemporal dementia” [TI] OR FTD [TI] OR FTLD [TI] OR bvFTD [TI] OR pick disease*[TI] OR picks disease* [TI] OR “frontal lobe dementia” [TI] OR “frontotemporal lobe dementia” [TI] OR “frontal variant frontotemporaldementia” [TI]) AND Dementia/therapy [Mesh]) OR ((“frontotemporal lobar degeneration” OR “frontotemporal dementia” OR FTD OR FTLD
OR bvFTD OR pick disease* OR picks disease* OR “frontal lobe dementia” OR “frontotemporal lobe dementia” OR “frontal variant frontotemporaldementia”) AND (therapy OR therapeutic OR treatment OR intervention*))) NOT (“Frontotemporal Lobar Degeneration/drug therapy” [Mesh]
OR (“Frontotemporal Lobar Degeneration” [Majr] AND “Drug therapy” [Mesh]) OR ((“frontotemporal lobar degeneration” [TI] OR“frontotemporal dementia” [TI] OR FTD [TI] OR FTLD [TI] OR bvFTD [TI] OR pick disease* [TI] OR picks disease* [TI] OR “frontal lobe
dementia” [TI] OR “frontotemporal lobe dementia” [TI] OR “frontal variant frontotemporal dementia” [TI]) AND Dementia/drug therapy[Mesh]) OR ((“frontotemporal lobar degeneration” OR “frontotemporal dementia” OR FTD OR FTLD OR bvFTD OR pick disease* OR picks
disease* OR “frontal lobe dementia” OR “frontotemporal lobe dementia” OR “frontal variant frontotemporal dementia”) AND (“drug therapy” ORchemotherapy OR pharmacotherapy OR “pharmacological therapy”)))) OR (“nonpharmacological therapy” OR “non pharmacological therapy” OR“nonpharmacologic therapy” OR “non pharmacologic therapy” OR “nonpharmacological treatment” OR “non pharmacological treatment” OR“nonpharmacologic treatment” OR “non pharmacologic treatment” OR nonpharmacological intervention* OR non pharmacological intervention*
OR nonpharmacologic intervention* OR non pharmacologic intervention* OR “nonpharmacological management” OR “non pharmacologicalmanagement” OR “nonpharmacologic management” OR “non pharmacologic management”) AND (“Frontotemporal Lobar Degeneration” [Mesh]
OR “frontotemporal lobar degeneration” OR “frontotemporal dementia” OR FTD OR FTLD OR bvFTD OR pick disease* OR picks disease* OR“frontal lobe dementia” OR “frontotemporal lobe dementia” OR “frontal variant frontotemporal dementia”)OR “Frontotemporal Lobar
Degeneration/rehabilitation” [Mesh] OR(“Frontotemporal Lobar Degeneration/therapy” [Mesh] AND “Rehabilitation” [Mesh]) OR((“frontotemporal lobar degeneration” [TI] OR “frontotemporal dementia” [TI] OR FTD [TI] OR FTLD [TI] OR bvFTD [TI] OR pick disease*[TI] OR picks disease* [TI] OR “frontal lobe dementia” [TI] OR “frontotemporal lobe dementia” [TI] OR “frontal variant frontotemporaldementia” [TI]) AND (rehabilitation [TI] OR “occupational therapy” [TI] OR “activities of daily living” [TI] OR “activity of daily living” [TI]))
OR ((“frontotemporal lobar degeneration” OR “frontotemporal dementia” OR FTD OR FTLD OR bvFTD OR pick disease* OR picks disease*
OR “frontal lobe dementia” OR “frontotemporal lobe dementia” OR “frontal variant frontotemporal dementia”) AND (rehabilitation OR“occupational therapy” OR “activities of daily living” OR “activity of daily living”)) OR “Frontotemporal Lobar Degeneration/nursing” [Mesh] OR(“Frontotemporal Lobar Degeneration/ therapy” [Mesh] AND “Nursing” [Mesh]) OR ((“frontotemporal lobar degeneration” [TI] OR“frontotemporal dementia” [TI] OR FTD [TI] OR FTLD [TI] OR bvFTD [TI] OR pick disease* [TI] OR picks disease* [TI] OR “frontal lobe
dementia” [TI] OR “frontotemporal lobe dementia” [TI] OR “frontal variant frontotemporal dementia” [TI]))AND nursing [TI] OR((“frontotemporallobar degeneration” OR “frontotemporal dementia” OR FTD OR FTLD OR bvFTD OR pick disease* OR picks disease* OR “frontal lobe
dementia” OR “frontotemporal lobe dementia” OR “frontal variant frontotemporal dementia”)AND nursing)OR “Frontotemporal Lobar
Degeneration/diet therapy” [Mesh] OR (“Frontotemporal Lobar Degeneration/therapy” [Mesh] AND “Nutrition therapy” [Mesh]) OR((“frontotemporal lobar degeneration” [TI] OR “frontotemporal dementia” [TI] OR FTD [TI] OR FTLD [TI] OR bvFTD [TI] OR pick disease*[TI] OR picks disease* [TI] OR “frontal lobe dementia” [TI] OR “frontotemporal lobe dementia” [TI] OR “frontal variant frontotemporaldementia” [TI]) AND (nutrition therapy* [TI] OR diet therapy* [TI])) OR ((“frontotemporal lobar degeneration” OR “frontotemporal dementia”
OR FTD OR FTLD OR bvFTD OR pick disease* OR picks disease* OR “frontal lobe dementia” OR “frontotemporal lobe dementia” OR “frontal
variant frontotemporal dementia”) AND (nutrition therapy* OR diet therapy*))OR “Frontotemporal Lobar Degeneration/ surgery” [Mesh]
OR(“Frontotemporal Lobar Degeneration/therapy” [Mesh]AND “Surgical Procedures, Operative” [Mesh]) OR ((“frontotemporal lobar
degeneration” [TI] OR “frontotemporal dementia” [TI] OR FTD [TI] OR FTLD [TI] OR bvFTD [TI] OR pick disease* [TI] OR picks disease*[TI] OR “frontal lobe dementia” [TI] OR “frontotemporal lobe dementia” [TI] OR “frontal variant frontotemporal dementia” [TI]) AND (surgery[TI] OR surgical [TI] OR operation [TI] OR operative [TI])) OR ((“frontotemporal lobar degeneration” OR “frontotemporal dementia” OR FTD
OR FTLD OR bvFTD OR pick disease* OR picks disease* OR “frontal lobe dementia” OR “frontotemporal lobe dementia” OR “frontal variant
frontotemporal dementia”) AND (surgery OR surgical OR operation OR operative)) OR “Frontotemporal Lobar Degeneration/radiotherapy”[Mesh] OR (“Frontotemporal Lobar Degeneration/therapy” [Mesh] AND “Radiotherapy” [Mesh]) OR ((“frontotemporal lobar degeneration” [TI]
OR “frontotemporal dementia” [TI] OR FTD [TI] OR FTLD [TI] OR bvFTD [TI] OR pick disease* [TI] OR picks disease* [TI] OR “frontal
lobe dementia” [TI] OR “frontotemporal lobe dementia” [TI] OR “frontal variant frontotemporal dementia” [TI]) AND (radiotherapy* [TI] OR
chemoradiotherapy* [TI] OR radiosurgery* [TI])) OR ((“frontotemporal lobar degeneration” OR “frontotemporal dementia” OR FTD OR FTLD
OR bvFTD OR pick disease* OR picks disease* OR “frontal lobe dementia” OR “frontotemporal lobe dementia” OR “frontal variant frontotemporaldementia”) AND (radiotherapy* OR chemoradiotherapy* OR radiosurgery*)) OR (“Frontotemporal Lobar Degeneration/therapy” [Mesh]AND“Psychotherapy” [Mesh]) OR ((“frontotemporal lobar degeneration” [TI] OR “frontotemporal dementia” [TI] OR FTD [TI] OR FTLD [TI] OR
bvFTD [TI] OR pick disease* [TI] OR picks disease* [TI] OR “frontal lobe dementia” [TI] OR “frontotemporal lobe dementia” [TI] OR “frontal

Chapter 8181variant frontotemporal dementia” [TI]) AND psychotherapy* [TI]) OR ((“frontotemporal lobar degeneration” OR “frontotemporal dementia” OR
FTD OR FTLD OR bvFTD OR pick disease* OR picks disease* OR “frontal lobe dementia” OR “frontotemporal lobe dementia” OR “frontal
variant frontotemporal dementia”)AND psychotherapy*) OR (“Frontotemporal Lobar Degeneration/therapy” [Mesh]AND “Patient Care” [Mesh])
OR ((“frontotemporal lobar degeneration” [TI] OR “frontotemporal dementia” [TI] OR FTD [TI] OR FTLD [TI] OR bvFTD [TI] OR pickdisease* [TI] OR picks disease* [TI] OR “frontal lobe dementia” [TI] OR “frontotemporal lobe dementia” [TI] OR “frontal variant frontotemporaldementia” [TI]) AND (care [TI] OR cares [TI])) OR ((“frontotemporal lobar degeneration” OR “frontotemporal dementia” OR FTD OR FTLD
OR bvFTD OR pick disease* OR picks disease* OR “frontal lobe dementia” OR “frontotemporal lobe dementia” OR “frontal variant frontotemporaldementia”) AND (care OR cares))
Ichushi search: July 9, 2015 (Thursday)#1 (((Frontotemporal lobar degeneration/TH OR Frontotemporal lobar degeneration/TI OR Dementia-frontotemporal type/TH OR Frontotemporal
type dementia/TI OR “Frontotemporal Lobar Degeneration”/TI OR “Frontotemporal Dementia”/TI OR FTD/TI OR FTLD/TI OR bvFTD OR
Pick disease/TI OR Pick disease OR Anterior type dementia/TI OR Anterior type dementia/TI OR Frontotemporal dementia/TI) AND ((SH =Therapeutic use, Treatment, Surgical therapy, Transplantation, Dietary therapy, Radiotherapy, Nursing, Rehabilitation, Prevention)OR Treatment/
MTH OR Treatment/TI OR Therapy/TI)) NOT ((Frontotemporal lobar degeneration/TH OR Frontotemporal lobar degeneration/TI OR
Dementia-frontotemporal type/TH OR Frontotemporal type dementia/TI OR “Frontotemporal Lobar Degeneration”/TI OR “Frontotemporal
Dementia”/TI OR FTD/TI OR FTLD/TI OR bvFTD OR Pick disease/TI OR Pick disease OR Anterior type dementia/TI OR Anterior typedementia/TI OR Frontotemporal dementia/TI) AND ((SH = Pharmacotherapy) OR Pharmacotherapy/TH OR Therapeutic use/MTH OR Drugtreatment/TI OR Pharmacotherapy/TI OR Therapeutic drug/TI))) OR ((Frontotemporal lobar degeneration/TH OR Frontotemporal lobar
degeneration/TI OR Dementia-frontotemporal type/TH OR Frontotemporal type dementia/TI OR “Frontotemporal Lobar Degeneration”/TI OR“Frontotemporal Dementia”/TI OR FTD/TI OR FTLD/TI OR bvFTD OR Pick disease/TI OR Pick disease OR Anterior type dementia/TI OR
Anterior type dementia/TI OR Frontotemporal dementia/TI) AND ((SH = Surgical therapy, Transplantation, Radiation therapy, Dietary therapy,
Psychological therapy, Nursing, Rehabilitation) OR Non-pharmacotherapy/TI OR Non-pharmacological treatment/TI OR Rehabilitation/MTH
OR Rehabilitation/TI OR Nursing/MTH OR Nursing/TI OR Surgical operation/MTH OR Surgery/TI OR Surgery/TI OR Transplantation/TI
OR Nutritional management/MTH OR Nutritional therapy/TI OR Dietary therapy/TI OR Diet therapy/TI OR Therapeutic food/TI OR
Psychological therapy/TH OR Psychological therapy/TI OR Psychotherapy/TI OR Psychotherapy/TI OR Radiation treatment/MTH OR
Radiation treatment/TI OR Radiation therapy/TI))

182

Clinical Practice Guideline for Dementia 2017

CQ 8-5

What kind of instructions should be given to families and caregiversof frontotemporal lobar degeneration (FTLD) patients?
AnswerFamily and caregiver education based on FTLD symptomatology is recommended.

C

Comments and evidence
In FTLD, psychiatric symptoms and behavioral disorders such as disinhibition, asocial behaviors, stereotypic behaviors,
abnormal eating behaviors, and increased emotional susceptibility become evident from an earlier stage compared to Alzheimer’s
disease dementia 1-3). Due to these various behavioral disorders, caregivers of FTLD patients have a more significant care burden
than caregivers of Alzheimer’s disease dementia patients 4-7). Based on the assessments of patients’ behavioral abnormalities andlanguage impairment, it is vital to help patients’ families understand the disease conditions of individual patients and to provide
them guidance on interventions. Also, FTLD has been designated an intractable disease in Japan since July 1, 2015, and it isimperative to explain and provide guidance on how to apply for a subsidy of medical expenses.
Kumamoto et al. 7) studied two FTLD patients and found that behavioral abnormalities exhibited by these patients,
particularly behaviors of stuffing food into the mouth, poor table manners, resistance to care, and restlessness, were associatedwith substantial care burden 7). Therefore, for family caregivers, individual guidance and support are required according to
the patient’s conditions. Understanding of the disease condition by the family changes the way caregivers interact with thepatients, and the burden on caregivers is often significantly reduced 8).
Nunnemann et al. 9) pointed out that there are very few publications on the burden, problems, and needs of caregivers of
FTLD patients. Specific problems include delayed diagnosis, young-onset age, behavioral disturbances, lack of informationand suitable care facilities, caregivers’ depression, social isolation, and personal needs. Research is needed to identify the realneeds of caregivers of FTLD patients.

▪ References

1) Bozeat S, Gregory CA, Ralph MA, et al. Which neuropsychiatric and behavioural features distinguish frontal and temporal variants of frontotemporaldementia from Alzheimer’s disease? J Neurol Neurosurg Psychiatry. 2000; 69(2): 178-186.
2) Bathgate D, Snowden JS, Varma A, et al. Behaviour in frontotemporal dementia, Alzheimer’s disease and vascular dementia. Acta Neurol Scand.
2001; 103(6): 367-378.
3) Ikeda M, Brown J, Holland AJ, et al. Changes in appetite, food preference, and eating habits in frontotemporal dementia and Alzheimer’s disease.
J Neurol Neurosurg Psychiatry. 2002; 73(4): 371-376.
4) Shigenobu K. Care burden for frontotemporal lobar degeneration: comparison with care burden for Alzheimer’s disease dementia. Japanese Journalof Geriatric Psychiatry (Ronen Seishinigaku Zasshi) 2004; 15(Suppl 1): 88-94. (In Japanese)5) de Vugt ME, Riedijk SR, Aalten P, et al. Impact of behavioural problems on spousal caregivers: a comparison between Alzheimer’s disease andfrontotemporal dementia. Dement Geriatr Cogn Disord. 2006; 22(1): 35-41.
6) Boutoleau-Bretonniere C, Vercelletto M, Volteau C, et al. Zarit burden inventory and activities of daily living in the behavioral variant offrontotemporal dementia. Dement Geriatr Cogn Disord. 2008; 25(3): 272-277.
7) Kumamoto K, Arai Y, Hashimoto N, et al. Problems family caregivers encounter in home care of patients with frontotemporal lobar degeneration.
Psychogeriatrics. 2004; 4(2): 33-39.
8) Kaneda K, Hashimoto M, Ikeda M. Degenerate dementia- frontotemporal lobar dementia. Med Rehabil. 2008; 91: 47-54.
9) Nunnemann S, Kurz A, Leucht S, et al. Caregivers of patients with frontotemporal lobar degeneration: a review of burden, problems, needs, andinterventions. Int Psychogeriatr. 2012; 24(9): 1368-1386.

▪ Search formula

PubMed search: July 10, 2015 (Friday)#1 (“Frontotemporal Lobar Degeneration” [Majr] OR “frontotemporal lobar degeneration” [TI] OR “frontotemporal dementia” [TI] OR FTD [TI]
OR FTLD [TI] OR bvFTD [TI] OR Pick disease* [TI] OR Picks disease* [TI] OR “frontal lobe dementia” [TI] OR “frontotemporal lobe dementia”[TI] OR “frontal variant frontotemporal dementia” [TI]) AND (care OR education OR burden OR support*) AND (caregiver* OR family)
Ichushi search: July 10, 2015 (Friday)#1 (Frontotemporal lobar degeneration/TH OR Frontotemporal lobar degeneration/TI OR Dementia-frontotemporal type/TH OR Frontotemporal
type dementia/TI OR “Frontotemporal Lobar Degeneration”/TI OR “Frontotemporal Dementia”/TI OR FTD/TI OR FTLD/TI OR bvFTD OR Pickdisease/TI OR Pick disease OR Anterior type dementia/TI OR Anterior type dementia/TI OR Frontotemporal dementia/TI) AND (Family/TH OR
Family OR Caregiver/TH OR Care) AND (Care burden/TH OR Burden OR Stress/TH OR Stress OR Guidance OR Education OR Support)

Chapter 8183