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Table 1 Synthesis of studies included in the present review

From: Phenocopy syndrome of behavioral variant frontotemporal dementia: a systematic review

Title Authors Year Population Design and methods Results
Progression in Frontotemporal Dementia: identifying a benign behavioral variant by magnetic resonance imaging Davies et al. 2006 N = 31 patients with bvFTD bvFTD was defined by Neary et al. (1998) and McKhan et al. criteria (2001). Longitudinal study (follow-up of 15 years). The study compared the prognosis of two groups: (1) bvFTD with normal or borderline MRI (2) bvFTD with marked frontotemporal atrophy Good prognosis was defined as independent for ADL after 3 years of follow-up, while poor prognosis was defined as death or institutionalization within the same period. The groups with normal or borderline MRI (N = 16 patients) had better prognosis (longer survival to institutionalization or death) than those (N = 15 patients) with marked frontotemporal atrophy.
Behavioural variant Frontotemporal Dementia: Not all it seems? Kipps et al. 2007 N = Two patients with bvFTD according to Neary et al. (1998) criteria Case report with clinical, neuropsychological and neuroimaging (MRI and FDG-PET). Case 1 had a clinical decline over 10 years from symptom onset, progressive atrophy, and frontotemporal hypometabolism. Case 2 did not develop atrophy or hypometabolism and remained clinically stable, a decade from symptom onset.
Novel cerebrospinal fluid biomarkers of axonal degeneration in frontotemporal dementia Mattsson et al. 2008 N = 24 FTD patients according to Neary et al. (1998) criteria, including: (1) 13 patients with rapidly progressive FTD (defined by marked brain atrophy after 3 years of follow-up) (2) 11 patients with slowly progressive FTD (defined by normal or inconclusive MRI, but abnormal SPECT/PET after at least 5 years of follow-up) This cross-sectional study compared two groups of FTD patients on CSF peptide analysis (mass spectrometry). Rapidly progressive FTD group presented a higher level of neurofilament light chain protein.
Executive function in progressive and nonprogressive behavioral variant frontotemporal dementia Hornberger et al. 2008 N = 90 participants, including: (1) 27 patients with progressive bvFTD (2) 23 patients with non-progressive bvFTD (3) 40 controls FTD patients fulfilled Neary et al. (1998) criteria. Non-progressive patients had (1) absence of marked frontotemporal atrophy and no decline on ACE-R over a 3-year period. This retrospective cohort study compared neuropsychological and behavioral tests across two bvFTD groups. The non-progressors performed in the normal range on executive tasks. Progressors were impaired on Digit Span Backward, Hayling Test, Letter Fluency, and Trails B. A subgroup of progressors had normal executive functioning.
Can progressive and non-progressive behavioural variant frontotemporal dementia be distinguished at presentation? Hornberger et al. 2009 N = 71 patients with bvFTD according to Neary et al. (1998) criteria, including: (1) Progressive (N = 45) (2) Non-progressive bvFTD patients (N = 26) Progression was defined as cognitive (measured on ACE-R) and functional decline over 3 years of follow-up. This retrospective cohort study (1991–2007) compared behavioral (CBI) and cognitive data between groups. Progressors had worse performance on the ACE-R, worse functional profile and higher frequency of distractibility, stereotypic speech. Depression was more frequent in non-progressors.
Combined magnetic resonance imaging and positron emission tomography brain imaging in behavioural variant frontotemporal degeneration: refining the clinical phenotype Kipps et al. 2009 24 bvFTD patients according to Brun et al. (1994) and Neary et al. (1998) criteria, including: (1) bvFTD with abnormal MRI (N = 15) (2) bvFTD with normal MRI (N = 9) Twelve healthy controls were also included. This cross-sectional study compared cognitive and behavioral measures (MMSE, ACE, CDR, CBI); and FDG-PET metabolism between bvFTD subgroups Most of bvFTD with abnormal MRI (14/15) showed frontotemporal hypometabolism on FDG-PET and clinical progression. Most bvFTD patients with normal MRI (7/9) had no hypometabolism and no clinical progression. Almost a third of bvFTD with abnormal MRI had ACE-R scores overlapping with the normal MRI subgroup.
Determinants of survival in behavioral variant frontotemporal dementia Garcin et al. 2009 N = 91 patients diagnosed with bvFTD, according to Neary et al. (1998) criteria, including: (1) Phenocopies (N = 24) defined as a lack of progression on the ACE and ADLs over a period of 3 years follow-up and normal MRI at presentation 2) “Pathological” bvFTD (N = 67) This retrospective review compared neurological and psychiatric assessments, cognitive and behavioral measures (CBI, MMSE, and ACE) and neuroimaging (MRI) data between subgroups. Phenocopy cases were younger and had longer survival than “pathologic” FTD.
Activities of daily living in behavioral variant frontotemporal dementia: differences in caregiver and performance-based assessments Mioshi et al. 2009 N = 18 bvFTD patients fulfilling Neary et al. (1998) criteria, including: (1) Phenocopy (N = 10), defined as bvFTD patients without evidence of atrophy on MRI at presentation and with no progression over at least 2 years of follow-up (2) Pathologic bvFTD (N = 8) This cross-sectional study compared subgroups on behavioral, neuropsychological measures and also on functional scales of activities of daily living (DAD and AMPS) and a qualitative assessment). PhFTD and pathologic bvFTD did not differ on the DAD, but differed at AMPS and qualitative rating assessment.
Rate of Change of Functional Abilities in Frontotemporal Dementia Mioshi et al. 2009 N = 26 participants, including: (1) bvFTD (N = 5 patients fulfilling Neary et al. criteria) (2) bvFTD phenocopies = 10 patients, with no atrophy in their initial MRI scans as well as on follow-up scans after 12 months phenocopies) fulfilling Neary et al. criteria (3) Semantic variant of PPA (N = 8) (4) PNFA (N = 3) This prospective cohort study compared behavioral and neuropsychological tests (initiation, planning, and execution scores) and functional scales of daily living between groups. Only phenocopies did not show a significant functional decline after 12 months. The decline in ADL and cognitive scores were significantly correlated.
How preserved is episodic memory in behavioral variant frontotemporal dementia? Hornberger et al. 2010 N = 62 participants, including: (1) bvFTD patients: progressors (N = 39) (2) bvFTD phenocopies (N = 23) (3) AD patients (N = 64) (4) Healthy controls (N = 64) bvFTD patients (progressors and phenocopies) fulfilled Neary et al. criteria. bvFTD cases were classified retrospectively into progressive and phenocopy based on the presence/absence of change over a 3-year period on ACE and ADLs. This retrospective cross-sectional compared groups on behavioral (CBI) and neuropsychological tests, including episodic memory test (RAVLT). Episodic memory deficits in “progressive” bvFTD were similar to AD. bvFTD phenocopies performed better than bvFTD progressors and AD patients.
Survival in a German Population with Frontotemporal Lobar Degeneration Nunnemann et al. 2011 N = 124 FTLD patients, including: (1) bvFTD (N = 81) (2) Semantic variant of PPA (N = 21) (3) PNFA (N = 22) The diagnosis of FTLD was established according to Neary et al. criteria (1998) Prospective follow-up study. Clinical data and interviews with caregivers Phenocopy cases were not identified in this sample.
Neural Correlates of Episodic Memory in Behavioral Variant Frontotemporal Dementia Pennington et al. 2011 N = 59 participants, including: (1) “classical” bvFTD (N = 14) (2) bvFTD phenocopies (N = 6) (3) AD (N = 14) (4) Healthy controls (N = 15) Both “classical” bvFTD and phenocopies fulfilled Rascovsky criteria (2011). Phenocopy was defined by relatively stable, non-progressive behavioral disturbance with a lack of progression over 2 years or more and preserved activities of daily living. Cross-sectional study. Cognitive assessment and MRI scanning with ratings of regional brain atrophy. BvFTD and AD patients were similarly impaired on memory scores. bvFTD phenocopies did not differ from controls on memory scores and atrophy ratings.
The neuropsychological correlates of pathological lying: evidence from behavioral variant frontotemporal dementia Poletti et al. 2011 N = 1 patient with clinical features of bvFTD according to Neary’s criteria (1998) Case report. Neurological, neuropsychiatric, neuropsychological, and neuroimaging exam. Pathological lying was observed in a patient 57-year-old, with suggestive bvFTD and lack of prefrontal hypometabolism.
Atypical, slowly progressive behavioural variant frontotemporal dementia associated with c9orf72 hexanucleotide expansion Khan et al. 2012 N = 384 patients (either with FTD or AD) were screened for C9orf72 mutation. 87 had bvFTD and 23 of them had C9orf72 mutation. Four patients (2 C9+, 2 C9-) were identified as slowly progressive course (bvFTD-SP) and were selected. These patients fulfilled Rascovsky criteria for bvFTD, had normal or limited atrophy on brain MRI and had no decline on CDR over at least 2 years after initial assessment. Case reports presenting neuropsychological and functional tests; structural MRI/with voxel based-morphometry (VBM) analysis. Both C9+ bvFTD-SP patients initially met the criteria for possible bvFTD and remained stable on neuropsychological and functional measures during the follow-up.
Differential Impairment of Source Memory in progressive Versus Non-progressive behavioral Variant Frontotemporal Dementia Irish et al. 2012 N = 35 participants, including: (1) progressive bvFTD (N = 7 patients) (2) non-progressive bvFTD (N = 12) (3) Healthy controls (N = 16). The diagnosis of bvFTD was established according to Neary et al. (1998) criteria. bvFTD patients were classified retrospectively into progressive versus non-progressive. Definition of non-progressors was based on the absence of decline on the ACE-R over the 3-year period following diagnosis. Cross-sectional study. Cognitive tests including a source monitoring task. Progressive bvFTD patients had more severe impairment of temporal source memory than non-progressive bvFTD patients.
Phenocopy or variant: a longitudinal study of very slowly progressive frontotemporal dementia Brodtman et al. 2013 N = 2 patients Case report of a patient and his father with very slowly progressive cognitive decline and personality change. Neuropsychological tests, MRI, and PET were performed on patient. Genetic testing in both cases. Histopathological examination was available for the patient’s father. PET and MRI scans were unchanged over 15 years in the patient. Neuropsychological assessments revealed no cognitive deterioration over this period. Histopathology of his father demonstrated early-stage frontotemporal lobar degeneration with ubiquitin.
Tracking the progression of social cognition in neurodegenerative disorders Kumfor et al. 2014 N = 61 participants including: (1) bvFTD (N = 20 patients) (2) AD (N = 17 patients) (3) Healthy controls (N = 24) bvFTD were classified on two subgroups according to brain atrophy at baseline: N = 8 bvFTD with limited brain atrophy [bvFTD-la] and N = 12 bvFTD with marked atrophy [bvFTD-ma]. The diagnosis of bvFTD was established according to Rascovsky et al. (2011) criteria. The clinical follow-up was inferior to 3 years. Prospective study, with behavioral and neuropsychological tests, including social cognition tests (Ekman 60 and TASIT). BvFTD with and without brain atrophy were impaired on the general cognition and emotion recognition tasks. On the sarcasm detection task, only the bvFTD-ma group was impaired. On the emotion recognition and sarcasm tasks, the bvFTD-ma group declined more rapidly than bvFTD-la and AD patients. The bvFTD-la group remained stable over time on the emotion recognition and sarcasm measures.
Two Distinct Amnesic Profiles in Behavioral variant Frontotemporal Dementia Bertoux et al. 2014 N = 134 participants including: (1) 56 AD (N = 56) (2) bvFTD (N = 44) (3) Phenocopies (N = 12) (4) Controls (N = 22) The diagnosis of bvFTD was established according to Rascovsky et al. (2011) criteria. Phenocopies fulfilled criteria for possible bvFTD and had no change on cognitive and functional measures over a 3-year period. Cross-sectional study, with neuropsychological assessment, focused on episodic memory (the Free and Cued Selective Reminding Test (FCSRT)). A subgroup of bvFTD had episodic memory impairment, similar to AD. Phenocopies and non-amnestic FTD performed similar to controls on the FCSRT.
The Added Value of 18-Fluorodeoxyglucose-Positron Emission Tomography in the Diagnosis of the Behavioral variant of Frontotemporal Dementia Kerklaan et al. 2014 N = 52 patients with suspected bvFTD according to Neary et al. (1998) criteria, and with no typical atrophy on brain MRI. Retrospective cohort study, with neuropsychological and behavioral assessment, structural neuroimaging, and 18-FDG-PET. Patients with functional decline over 2 years of follow-up (bvFTD/fd+) were compared with patients without functional decline (bvFTD/fd−). The sensitivity of FDG-PET for bvFTD/fd+ was 47% at a specificity of 92%. The 18F-FDG-PET was abnormal in only 1 of the 8 cases of the bvFTD/fd− group.
Familial benign frontotemporal deterioration with C9ORF72 hexanucleotide expansion Gomés-Tortoza et al. 2014 N = 3 patients of the same family with benign FTLD associated with C9orf72 gene hexanucleotide expansion Case report of three patients from the affected family Two siblings had cognitive complaints, preserved ADLs, mild-moderate atrophy on MRI and evolved to slow progression of deficits over more than 10 years. Their mother had mild cognitive impairment and slowly progressive dementia over a time frame of more than 30 years.
Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion Lee et al. 2014 N = 42 participants, including: (1) 28 patients with bvFTD (14 C9orf72 mutation carriers and 14 non carriers) (2) 14 healthy controls bvFTD patients met Neary et al. (1998) and Rascovsky et al. (2011) criteria. Cross-sectional study with neuropsychological exam and functional MRI (task-free). Compared to controls and mutation carriers, C9orf72 (−) bvFTD patients had increased DMN connectivity. C9orf72 (+) bvFTD patients with early stage or slowly progressive symptoms (N = 4) had salience network disruption and DMN enhancement.
Slowly progressive frontotemporal lobar degeneration caused by the C9ORF72 repeat expansion: a 20-year follow-up study Suhonen et al. 2015 N = 1 patient with slowly progressive FTLD, with mixed features of semantic variant of PPA and bvFTD. Case report, presenting neuropsychological data, MRI, and FDG-PET 52-year-old man with semantic deficits associated with C9orf72 mutation. MRI revealed mild frontal atrophy whereas FDG-PET showed significant hypometabolism in the temporal and frontal lobes. The disease did not progress to dementia for over 20 years from the onset.
Progression in Behavioral Variant Frontotemporal Dementia: A Longitudinal Study Devenney et al. 2015 N = 58 patients with bvFTD, according to Rascovsky et al. criteria (2011). At inclusion, 38 patients had probable bvFTD and 20 had possible bvFTD. The follow-up varied from 1 to 6 years. This prospective cohort study assessed the prognostic value of clinical, genetic, neuropsychological, and neuroimaging parameters. Nine out of 20 patients with possible bvFTD remained stable over time, while 11 progressed to probable bvFTD. Most of progressors (eight out 11) were C9orf72 carriers. A family history of dementia, episodic memory deficits, and clinical findings (e.g., parkinsonism, frontal release signs) were key features of clinical progression.
Structural and functional brain abnormalities place phenocopy frontotemporal dementia (FTD) in the FTD spectrum Steketee et al. 2016 N = 38 participants, including: (1) bvFTD patients (N = 11) (2) phFTD patients (N = 7) (3) Healthy controls (N = 20) The diagnosis of bvFTD was established according to Rascovsky et al. (2011) criteria. phFTD fulfilled criteria for possible bvFTD, had no imaging abnormalities suggestive of bvFTD, and no clinical decline for at least 1 year after initial diagnostic. None of the phenocopy patients had C9orf72 mutation. This cross-sectional study compared volumetric and perfusion MRI measures across groups. Gray matter volume did not differ between phFTD and controls, whereas bvFTD showed extensive frontotemporal atrophy. Compared to FTD, phFTD patients had increased perfusion in the left prefrontal cortex.
Psychiatric diagnoses underlying the phenocopy syndrome of behavioural variant frontotemporal dementia Gossink et al. 2016 N = 52 participants, including: (1) bvFTD patients (N = 19) (2) phFTD (N = 33) The diagnosis of bvFTD was established according to Rascovsky et al. (2011) criteria. Phenocopy cases were considered as possible bvFTD, with normal neuroimaging, without functional decline over at least 1 year of follow-up. Retrospective chart review; neurological and psychiatric evaluation. In the phenocopy group, 85.2% of patients had psychiatric or psychological conditions (e.g., cluster C personality traits) which were more frequent than in the bvFTD group (47.4%).
Slowly progressive behavioural presentation in two UK cases with the R406W MAPT mutation Wood et al. 2016 N = 2 patients with slowly progressive personality changes, over more than 10 years. Case reports, with clinical follow-up, neuropsychological test, and brain MRI Both patients presented a slowly progressive behavioral disorder with predominantly right temporal lobe atrophy, associated with the R406W MAPT mutation.
The bvFTD phenocopy syndrome: a clinicopathological report Devenney et al. 2016 N = 2 patients fulfilling criteria for possible bvFTD. The clinical follow-up for cases 1 and 2 was of 16 and 5 years, respectively. Report of clinical and pathological findings in two patients with slowly progressive behavioral disorders. Both cases showed behavioral changes consistent with bvFTD. They did not show brain atrophy or hypometabolism on neuroimaging. Both patients did not have FTLD at postmortem pathological exam.
Late life bipolar disorder evolving into frontotemporal dementia mimic Dols et al. 2016 N = 4 patients with bipolar disorder type 1. All patients fulfilled Rascovsky criteria (2011) for possible bvFTD. Report of cases with psychiatric, neurological, neuropsychological, and neuroimaging data. All cases had early- and late-onset bipolar disorder, who subsequently developed gradually progressive behavioral and social-emotional changes. During the clinical follow-up (3 to 7 years), there was no progression to “probable” bvFTD.
Functional connectivity and microstructural white matter changes in phenocopy frontotemporal dementia Meijboom et al. 2016 N = 36 participants, including: (1) bvFTD patients (N = 12) (2) phFTD patients (N = 7) (3) Healthy controls (N = 17) The diagnosis of bvFTD was established according to Rascovsky et al. criteria (2011). phFTD patients were defined by marked behavioral changes with no clinical decline during 1 year follow-up. This cross-sectional study compared functional (DMN) and structural (DTI) connectivity across groups. Compared to controls, phFTD had enhanced DMN connectivity and subtle microstructural changes in frontal tracts. Compared to phFTD, bvFTD had lower enhanced DMN connectivity and more extensive WM abnormalities on DTI analysis.
Slowly progressive behavioral frontotemporal dementia with C9orf72 mutation. Case report and review of the literature Llamas-Velasco et al. 2018 N = 1 patient with bvFTD according to Rascovsky criteria (2011) Case report. The patient had personality changes and functional decline over more of 30 years. She carried C9orf72 hexanucleotide expansion.
The behavioural variant frontotemporal dementia phenocopy syndrome is a distinct entity – evidence from a longitudinal study Devenney et al. 2018 N = 43 participants, including: (1) phFTD patients (N = 16) (2) Probable bvFTD patients (n = 27). The diagnosis of bvFTD was established according to Rascovsky et al. criteria (2011). phFTD patients had relative functional and cognitive preservation and no atrophy on brain MRI. The minimal follow-up was of 3 years. This is a prospective cohort study, presenting behavioral (CBI) and neuropsychological tests. Genetic screening for the C9orf72 was performed Long-term follow-up (13–21 years) were available in six phFTD cases. Most of phFTD patients remained stable over time, including those with long follow-up (13–21 years). Only one of 16 phFTD cases (6.25%) had the C9orf72 expansion.
  1. ACE-R Addenbrooke’s Cognitive Examination-Revised, ADL activities of daily living, AMPS Assessment of Motor and Process Skills, bvFTD behavioral variant frontotemporal dementia, CBI Cambridge Behavioral Inventory, CDR Clinical Dementia Rating, CSF cerebrospinal fluid, DAD Disability Assessment of Dementia, DMN default mode network, c9orf72 chromosome 9 open reading frame 72, DTI diffusion tensor imaging, FCSRT Free and Cued Selective Reminding Test, FDG-PET fluorodeoxyglucose-positron emission tomography, FTD frontotemporal dementia, FTLD frontotemporal lobar degeneration, MRI magnetic resonance imaging, PET positron emission tomography, phFTD phenocopy of FTD, PPA primary progressive aphasia, PMID PubMed Identifier Number, RAVLT Rey Auditory Verbal Learning Test, SPECT single-photon emission computed tomography, TASIT The Awareness of Social Inference Test