Social cognition differentiates phenocopy syndrome of behavioural variant frontotemporal dementia from behavioural variant frontotemporal dementia.

BACKGROUND: Patients displaying clinical features of behavioural variant of frontotemporal dementia (bvFTD) but lacking both neuroimaging abnormalities and clinical progression are considered to represent the phenocopy syndrome of bvFTD (phFTD). Extensive clinical overlap between early phase bvFTD and phFTD hampers diagnostic distinction. We aimed to assess the diagnostic value of clinician-rated, self-reported and caregiver-reported symptoms for clinical distinction between phFTD and bvFTD. METHODS: There were 33 phFTD and 95 probable bvFTD patients included in the study (total N = 128). Clinician-rated, self-reported tests and caregiver-reported symptoms were compared between phFTD and bvFTD on social cognition, behaviour, mood and activities of daily living (ADL). Scores were compared between groups, followed by multiple logistic regression analysis, adjusted for age and sex. Receiver operating characteristic curves were plotted to assess diagnostic value. RESULTS: Using clinician-rated and self-reported tests, phFTD patients performed better on facial emotion recognition and reported more depressive symptoms. Caregiver-reported behavioural symptoms indicated higher behavioural and ADL impairment in phFTD compared to bvFTD. Facial emotion recognition provided highest diagnostic accuracy for distinction of phFTD from bvFTD (area under the curve (AUC) 0.813 95% CI 0.735-0.892, P < 0.001, sensitivity 81%, specificity 74%) followed by depressive symptoms (AUC 0.769 95% 0.674-0.864, P < 0.001 sensitivity 81%, specificity of 63%). CONCLUSION: Social cognition tests are most suitable for distinction of phFTD from bvFTD. Caregiver-reported questionnaires and phFTD diagnosis seemed inversely correlated, showing more symptoms in phFTD. Further research is needed on phFTD aetiology and in caregivers taking into account disease burden to assess what explains this discrepancy between clinician-rated and caregiver-based tools.

Diagnostic Instability Over Time in the Late-Onset Frontal Lobe Syndrome: When Can We Say it's FTD?

OBJECTIVES: Distinguishing sporadic behavioral variant of frontotemporal dementia (bvFTD) from late-onset primary psychiatric disorders (PPD) remains challenging with the lack of robust biomarkers. An early bvFTD misdiagnosis in PPD cases and vice-versa is common. Little is known about diagnostic (in)stability over longer period of time. We investigated diagnostic instability in a neuropsychiatric cohort up to 8 years after baseline visit and identified which clinical hallmarks contribute to diagnostic instability. DESIGN: Diagnoses of participants of the late-onset frontal lobe (LOF) study were collected from the baseline visit (T0) and the 2-year follow-up visit (T2). Clinical outcomes were retrieved 5-8 years after baseline visit (Tfinal). Endpoint diagnoses were categorized into bvFTD, PPD and other neurological disorders (OND). We calculated the total amount of participants that switched diagnosis between T0-T2 and T2-Tfinal. Clinical records of participants that switched diagnosis were assessed. RESULTS: Of the 137 patients that were included in the study, the final diagnoses at Tfinal were bvFTD 24.1% (n = 33), PPD 39.4% (n = 54), OND 33.6% (n = 46) and unknown 2.9% (n = 4). Between T0 and T2, a total of 29 (21.2%) patients switched diagnosis. Between T2 and Tfinal, 8 (5.8%) patients switched diagnosis. Prolonged follow-up identified few cases with diagnostic instability. Major contributors to diagnostic instability where a nonconverting diagnosis of possible bvFTD and a probable bvFTD diagnosis based on informant-based history and an abnormal FDG-PET scan whilst having a normal MRI. CONCLUSION: Considering these lessons, a FTD diagnosis remains stable enough to conclude that 2 years is sufficient to say if a patient with late-life behavioral disorder has FTD.

Early life involvement in C9orf72 repeat expansion carriers.

OBJECTIVES: The chromosome 9 open reading frame 72 gene (C9orf72) hexanucleotide repeat expansion (C9orf72RE) is the most common genetic cause of behavioural variant frontotemporal dementia (bvFTD). Since the onset of the C9orf72RE-associated disease is sometimes hard to define, we hypothesise that C9orf72RE may cause a lifelong neuropsychiatric vulnerability. The first aim of our study was to explore lifelong behavioural and personality characteristics in C9orf72RE. Second, we aimed to describe distinctive characteristics of C9orf72RE during disease course. METHODS: Out of 183 patients from the Amsterdam Dementia Cohort that underwent genetic testing between 2011 and 2018, 20 C9orf72RE bvFTD patients and 23 C9orf72RE negative bvFTD patients were included. Patients and their relatives were interviewed extensively to chart their biography. Data analysis was performed through a mixed-methods approach including qualitative and quantitative analyses. RESULTS: Education, type of professional career and number of intimate partners were not different between carriers and non-carriers. Carriers were more often described by their relatives as having 'fixed behavioural patterns in daily life' and with limited empathy already years before onset of bvFTD symptoms. In carriers, disease course was more often characterised by excessive buying and obsessive physical exercise than in non-carriers. CONCLUSION: This is the first study thoroughly exploring biographies of bvFTD patients with C9orf72RE, revealing that subtle personality traits may be present early in life. Our study suggests that C9orf72RE exerts a lifelong neuropsychiatric vulnerability. This may strengthen hypotheses of links between neurodevelopmental and neurodegenerative diseases. Moreover, the presence of a distinct C9orf72RE -associated syndrome within the FTD spectrum opens doors for investigation of vulnerable neuronal networks.

Recommendations to distinguish behavioural variant frontotemporal dementia from psychiatric disorders.

The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ∼50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5-6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features.

The bvFTD phenocopy syndrome: a case study supported by repeated MRI, [18F]FDG-PET and pathological assessment.

A clinical syndrome with neuropsychiatric features of bvFTD without neuroimaging abnormalities and a lack of decline is a phenocopy of bvFTD (phFTD). Growing evidence suggests that psychological, psychiatric and environmental factors underlie phFTD. We describe a patient diagnosed with bvFTD prior to the revision of the diagnostic guidelines of FTD. Repeated neuroimaging was normal and there was no FTD pathology at autopsy, rejecting the diagnosis. We hypothesize on etiological factors that on hindsight might have played a role. This case report contributes to the understanding of phFTD and adds to the sparse literature of the postmortem assessment of phFTD.

Effectiveness of Pharmacological Interventions for Symptoms of Behavioral Variant Frontotemporal Dementia: A Systematic Review.

BACKGROUND: Clinical guidance on the symptomatic treatment of behavioral variant frontotemporal dementia (bvFTD) is limited. OBJECTIVE: To provide a systematic review of pharmacological interventions for symptomatic treatment of bvFTD, based on the International bvFTD Criteria Consortium clinical diagnostic criteria: apathy, disinhibition, lack of empathy or sympathy, hyperorality, stereotypical behavior, and executive dysfunction. METHODS: We systematically searched the PubMed, Embase, and PsycINFO databases for reports on pharmacological interventions for individuals with bvFTD, published between 1970 and 2018, using key indicators and relevant terms. Studies were included if the efficacy of the intervention in alleviating bvFTD symptoms was provided as an outcome. Due to the high prevalence of depressive symptoms in individuals with bvFTD, we also evaluated the effect of the interventions on depression. RESULTS: We included 23 studies-11 randomized controlled trials, eight open-label studies, one proof-of-concept study, and three case series-reporting on a total of 573 individuals. Of the 23 studies, 16 used pharmacological interventions that improved bvFTD symptoms. Based on the Neuropsychiatric Inventory, trazodone had the greatest significant reductive effect on the symptoms of bvFTD. Overall, citalopram, rivastigmine, paroxetine, and trazodone all reduced multiple symptoms, including disinhibition, hyperorality, and depression. CONCLUSIONS: This review provides an overview of the pharmacological interventions that can be used to treat the main bvFTD symptoms as well as a guideline for managing bvFTD. More research is needed to investigate the efficacy of pharmacological interventions for bvFTD through use of a validated outcome and a focus on the specific behavioral problems associated with bvFTD.

Predicting progression in the late onset frontal lobe syndrome.

ABSTRACTA late onset frontal lobe syndrome (LOF) refers to a clinical syndrome with apathy, disinhibition, or stereotypical behavior arising in middle or late adulthood. Diagnostics are challenging, and both clinicians and patients need reliable predictors of progression to improve clinical guidance. In this longitudinal multicenter and genetically screened prospective study, 137 LOF patients with frontal behavior (FBI score≥11) and/or stereotypical behavior (SRI≥10) were included. Progression was defined as institutionalization, death, or progression of frontal or temporal atrophy at magnetic resonance imaging (MRI) after two years of follow up. Absence of progression at MRI in addition to stable or improved Mini Mental State Examination and Frontal Assessment Battery scores after two years was indicative for non-progression. The presence of stereotypy and a neuropsychological profile with executive deficits at baseline were found to be predictive for progression, while a history and family history with psychiatric disorders were predictors for non-progression. The combination of these clinical markers had a predictive value of 80.4% (p < 0.05). In patients presenting with late onset behavioral symptoms, an appraisal of the rate of deterioration can be made by detailed mapping of clinical symptoms. Distinction of progressive discourses from non-progressive or treatable conditions is to be gained.

Social Cognition Differentiates Behavioral Variant Frontotemporal Dementia From Other Neurodegenerative Diseases and Psychiatric Disorders.

OBJECTIVE: Although deficits in social cognition are established as core features in behavioral variant frontotemporal dementia (bvFTD), it remains unresolved if impaired social cognition distinguishes bvFTD from the broad differential diagnoses in clinical practice. Our aim was to study whether social cognition discriminates bvFTD from other neurodegenerative diseases and psychiatric disorders in patients presenting with late-onset frontal symptoms. Next, we studied the association of social cognition with frontal symptoms and cognitive functioning. METHODS: In this longitudinal multicenter study, besides clinical rating scales for frontal symptoms, social cognition was determined by Ekman 60 Faces test and Faux Pas in addition to neuropsychological tests for other cognitive domains in patients with probable and definite bvFTD (N = 22), other neurodegenerative diseases (N = 24), and psychiatric disorders (N = 33). Median symptom duration was 2.8 years, and patients were prospectively followed over 2 years. RESULTS: Total scores from Ekman 60 Faces test were significantly lower in bvFTD than in other neurodegenerative diseases and psychiatric disorders. Ekman 60 Faces test explained 91.2% of the variance of psychiatric disorders and other neurodegenerative diseases versus bvFTD (χ2 = 11.02, df = 1, p = 0.001) and was associated with all other cognitive domains. Faux Pas and the other cognitive domains did not differ between these diagnostic groups. CONCLUSION: In this clinical sample Ekman 60 Faces test distinguished bvFTD successfully from other neurodegenerative diseases and psychiatric disorders. Although associated with social cognition, other cognitive domains were not discriminative. This study provides arguments to add the Ekman 60 Faces test to the neuropsychological examination in the diagnostic procedure of bvFTD.

An intervention programme for caregivers of dementia patients with frontal behavioural changes: an explorative study with controlled effect on sense of competence.

AIM: Caregivers of dementia patients experience high levels of burden; this is especially true of caregivers of dementia patients with behavioural problems. As intervention studies for these caregivers are still lacking, we conducted an explorative pilot study into the efficacy of a support programme. METHODS: Participants were caregivers of dementia patients affected by apathy, disinhibition, and/or stereotypical behaviour. All patients had a Frontal Behavioural Inventory score of 11 or higher. Caregivers were randomized to the intervention group or control group (both n = 15). The intervention was a 6-month programme that consisted of psychoeducation, social support, and behavioural cognitive therapy. Quantitative and qualitative data were collected at baseline and after the intervention. RESULTS: An increased sense of competence was found in the intervention group. Burden, perceived stress, and depressive symptoms decreased, although the difference between the intervention and control groups was not significant. CONCLUSIONS: Caregivers' sense of competence improved as a result of the support programme, and caregivers revealed its comprehensive supportive effects. Further research into the efficacy of the programme on a larger scale is recommended.

Diagnostic Accuracy of the Frontotemporal Dementia Consensus Criteria in the Late-Onset Frontal Lobe Syndrome.

BACKGROUND/AIMS: We aimed to prospectively assess the diagnostic accuracy of the revised criteria for behavioural variant frontotemporal dementia (bvFTD) among subjects presenting with a frontal lobe syndrome in middle-late adulthood. METHODS: Patients were included based on a predominant behavioural clinical presentation, a Frontal Behavioural Inventory (FBI) score of ≥11 and/or a Stereotypy Rating Inventory (SRI) score of ≥10. At baseline, the fulfilment of the international consensus criteria for behavioural variant FTD (FTDC) was systematically recorded. The 2-year follow-up consensus diagnosis was used as the gold standard to calculate sensitivity and specificity of the FTDC criteria for possible and probable bvFTD. RESULTS: Two-year follow-up data were available for 116 patients (85%). Two-year follow-up consensus diagnoses consisted of probable/definite bvFTD (n = 27), other dementia (n = 30), psychiatric disorders (n = 46) and other neurological disorders (n = 13). Sensitivity for possible bvFTD was 85% (95% CI 70-95%) at a specificity of 27% (95% CI 19-37%). Sensitivity for probable bvFTD was 85% (95% CI 69-95%), whereas their specificity was 82% (95% CI 73-89%). CONCLUSIONS: We found a good diagnostic accuracy for FTDC probable bvFTD. However, the specificity for FTDC possible bvFTD was low. Our results reflect the symptomatic overlap between bvFTD, other neurological conditions and psychiatric disorders, and the relevance of adding neuroimaging to the diagnostic process.

Relationship Between Sporadic Behavioral Variant Frontotemporal Dementia and Primary Psychiatric Disorders: A Study in Families.

Background: Because the behavioral variant of frontotemporal dementia (bvFTD) shows major clinical overlap with primary psychiatric disorders (PPD) that affect similar neuroanatomical circuits, a common genetic vulnerability between FTD and PPD was hypothesized.Aims: We studied whether PPD are more prevalent in families of patients with sporadic frontotemporal dementia compared with healthy controls (HC), subjects with Alzheimer's disease (AD), and individuals with bipolar disorder (BD).Methods: In this case-control study performed between January 2013 and February 2019, we investigated the first-degree family history concerning depression, psychosis (including schizophrenia), BD, and autism spectrum disorder for 73 bvFTD patients, 153 patients with BD, 108 patients with AD, and 101 HC with a semistructured questionnaire (QFTD-NL 1.0) according to DSM-IV, DSM-5, or ICD-10 criteria.Results: Patients with bvFTD had a 2.58-fold higher odds of having a first-degree family member with depression compared to HC (P = .04). Furthermore, they showed 3.26-fold higher odds of having a first-degree relative with psychosis compared to HC (P = .09).Conclusions: Our results implicate a link between dementia, including sporadic bvFTD, and depression. Further study into the genetic overlap between bvFTD and PPD might provide clues to targeting common disease mechanisms.

Clinical Phenotypes of Behavioral Variant Frontotemporal Dementia by Age at Onset.

BACKGROUND: Behavioral variant frontotemporal dementia (bvFTD) is generally considered a young-onset dementia, although age at onset is highly variable. While several studies indicate clinical differences regarding age at onset, no biomarker validated cohort studies with updated clinical criteria have been performed. OBJECTIVE: We aimed to examine behavior, cognition, and mortality over the full age spectrum in a cohort of bvFTD patients with neuroimaging, genetic, or histopathological confirmation and exclusion of positive Alzheimer's disease biomarkers or severe cerebrovascular damage. METHODS: In total, 315 patients with a clinical diagnosis of probable or definite bvFTD were included from the Amsterdam Dementia Cohort and grouped into quartiles by age-at-diagnosis. Neuropsychiatric symptoms and cognitive functioning were assessed with the neuropsychiatric inventory, the geriatric depression scale and a neuropsychological test battery. Data on mortality was obtained from the Dutch municipal register. Associations between age-at-diagnosis and clinical features and mortality risk were examined. RESULTS: Age-at-diagnosis ranged from 26 to 85 years and established quartiles with mean ages of 52±6, 61±2, 66±2, and 74±3 years. In the total sample, 44.4%exceeded an age of 65 years at time of diagnosis. Earlier age-at-diagnosis was associated with more severe behavioral symptoms, while later age-at-diagnosis was associated with more severe memory impairment. Unexpectedly, mortality risk was not associated with age-at-diagnosis. CONCLUSION: In bvFTD, symptom profile is associated with age-at-diagnosis. This should be taken into account with regard to diagnostics, patient management, and trial design. Additionally, based on our sample, the prevalence of late-onset bvFTD is higher than generally thought.

The Value of Neuropsychological Assessment in the Differentiation Between Behavioral Variant Frontotemporal Dementia and Late-Onset Psychiatric Disorders.

OBJECTIVE: To investigate which neuropsychological tests can discriminate between behavioral variant frontotemporal dementia (bvFTD) and psychiatric disorders presenting with similar late-onset frontal behavioral changes, such as apathy, disinhibition, reduced empathy, or compulsive behavior. METHODS: Patients presenting with frontal behavioral changes in middle or late adulthood received extensive baseline examinations, including neuropsychological assessment and brain imaging. After 2 years, examinations were repeated and patients were diagnosed according to DSM-IV or international bvFTD consensus criteria. The study period was April 2011-June 2015. Two groups were selected: 32 patients with bvFTD and 53 patients with a psychiatric or psychological diagnosis. Associations between neuropsychological test scores and diagnostic group were investigated with logistic regression analyses, and diagnostic accuracy was investigated with a receiver operating characteristic curve. RESULTS: BvFTD patients scored lower on tests for confrontational naming, gestalt completion, and verbal abstraction compared to psychiatric patients (P < .01). The confrontational naming test (Boston Naming Test) showed the strongest association with diagnostic group: a lower score indicated a higher probability for a bvFTD diagnosis (P < .001). This test could discriminate between the groups with good diagnostic accuracy (area under the curve = 0.81). Tests for attention, memory, and executive functions showed no discriminative ability between the groups. CONCLUSIONS: Although one of the criteria of bvFTD is low performance on executive tests, these tests are not useful in differentiating bvFTD from psychiatric disorders. We recommend administering language tests, especially an extensive confrontational naming test, to aid differentiation between bvFTD and a psychiatric disorder in patients presenting with late-onset frontal behavioral changes.

End Stage Clinical Features and Cause of Death of Behavioral Variant Frontotemporal Dementia and Young-Onset Alzheimer's Disease.

BACKGROUND: Limited literature exists regarding the clinical features of end stage behavioral variant frontotemporal dementia (bvFTD). This data is indispensable to inform and prepare family members as well as professional caregivers for the expected disease course and to anticipate with drug-based and non-pharmacological treatment strategies. OBJECTIVE: The aim of the present study was to describe end stage bvFTD in a broad explorative manner and to subsequently evaluate similarities and dissimilarities with the end stage of the most prevalent form of young-onset dementia, Alzheimer's disease (yoAD). METHODS: We analyzed medical files on patients, using a mixed model of qualitative and quantitative approaches. Included were previously deceased patients with probable bvFTD and probable yoAD. End stage was defined as the last 6 months prior to death. Primary outcome measures comprised somatic, neurological, and psychiatric symptoms and the secondary outcome measure was cause of death. RESULTS: Out of 89 patients, a total of 30 patients were included (bvFTD; n = 12, yoAD; n = 18). Overall, the end stages of bvFTD and yoAD were characterized by a broad spectrum of clinical symptoms including severe autonomic dysfunction and an increased muscle tone. Patients with bvFTD displayed more mutism compared with yoAD while compulsiveness was only present in bvFTD. CONCLUSION: Our study describes the full clinical spectrum of end stage bvFTD and yoAD. In this study, symptoms extend far beyond the initial behavioral and cognitive features. By taking both somatic, psychiatric, and neurological features into account, family members and professional caregivers may anticipate (non) pharmacological treatment.

The Frontotemporal Dementia versus Primary Psychiatric Disorder (FTD versus PPD) Checklist: A Bedside Clinical Tool to Identify Behavioral Variant FTD in Patients with Late-Onset Behavioral Changes.

BACKGROUND: Differentiating early behavioral variant frontotemporal dementia (bvFTD) and primary psychiatric disorders (PPD) is complex and biomarkers have limited accuracy, leading to inaccurate diagnoses. OBJECTIVES: Develop a simple bedside clinical tool to differentiate bvFTD from PPD. METHODS: A checklist of clinical features differentiating bvFTD from PPD was developed based on literature and clinical experience. The checklist was filled prospectively for 29 consecutive patients (Montreal Neurological Hospital) with late-onset (≥ age 40) behavioral changes suggestive of bvFTD. The checklist was subsequently retrospectively completed on the baseline visit (N = 137) of the Late-Onset Frontal Lobe study (Amsterdam). In both cohorts, patients were followed 2 years to establish a final best clinical diagnosis, categorizing patients into Probable FTD (N = 46), Possible FTD (N = 8), Other Cognitive Disorder (N = 36), Other Neurological Disorder (N = 10), or PPD (N = 66). RESULTS: All items distinguished the two groups except "duration more than 5 years", which was removed to create a final 17-item version. Mean checklist scores were significantly different across all groups (Oneway ANOVA F(4,161) = 27.462, p < 0.001). The PPD group had lower scores than all other dementia categories, with the largest difference between Probable FTD (X¯= 12.04) and PPD (X¯= 7.48). A score ≥11 was found to be strongly indicative of bvFTD (specificity 93.9%, sensitivity 71.1%, PPV 89.2%). Scores ≤8 were strongly indicative of a PPD (specificity 91.3%, sensitivity 77.3%, PPV 92.7%). Patient with scores of 9-10 are considered indeterminate. CONCLUSIONS: Although further prospective validation is required, the "FTD vs PPD Checklist" could provide a simple tool to improve diagnostic accuracy, particularly in non-specialized settings.

[Behavioural changes as a symptom: diagnosing behavioural variant frontotemporal dementia]. / Gedragsverandering als symptoom.

Behavioural variant frontotemporal dementia (bvFTD) is a neurodegenerative disease, the symptoms of which are changes in character, behavioural changes and socio-cognitive changes occurring predominantly at an age between 40 and 70 years. Frontotemporal atrophy is apparent on diagnostic imaging in 70% of patients with bvFTD; a diagnostic dilemma arises if this is not clearly obvious. Validated questionnaires for stereotypical behaviour, depressive symptoms and apathy, and neuropsychological examination can be very helpful in differentiating between bvFTD and psychiatric and other neurological conditions. A brain MRI is always indicated in patients displaying behavioural changes; frontal or temporal atrophy on brain MRI provide sufficient support for the diagnosis 'probable bvFTD'. When in doubt, a supplementary 18F-FDG-PET scan can be performed, but hypometabolism on an 18F-FDG-PET scan can give a false-positive result. If bvFTD is suspected, a multidisciplinary approach, clinical follow-up for 2 years and referral to an FTD centre of excellence are recommended. Conflict of interest and financial support: none declared.

Disease trajectories in behavioural variant frontotemporal dementia, primary psychiatric and other neurodegenerative disorders presenting with behavioural change.

Behavioural variant frontotemporal dementia (bvFTD) is characterized by behavioural and social cognitive disturbances, while various psychiatric and neurodegenerative disorders may have similar clinical symptoms. Since neurodegenerative disorders are eventually progressive, whereas primary psychiatric disorders are not, this study aimed to investigate whether the change in clinical symptoms over time differed between groups and which biomarkers predicted rate of decline. Disease trajectories (median follow-up = 3 years) of frontal and stereotyped behaviour, general and frontal cognitive functioning, and social cognition were examined in bvFTD (n = 34), other neurodegenerative (n = 28) and primary psychiatric disorders (n = 43), all presenting with late-onset frontal lobe syndrome (45-75 years), using linear mixed models. To gain more insight in underlying pathological processes driving disease progression, we studied the association of baseline cerebrospinal fluid (CSF) (neurofilament light (NfL) and YKL-40 levels, phosphotau181 to total tau ratio) and neuroimaging markers with disease trajectories. Frontal behavioural symptoms (e.g., disinhibition, apathy) worsened over time in bvFTD, whereas they improved in psychiatric disorders and remained stable in other neurodegenerative disorders. General and frontal cognitive decline was observed in bvFTD and other neurodegenerative disorders, but not in psychiatric disorders. None of the groups showed change in stereotypy and social cognition. For all diagnostic groups, higher CSF NfL levels were associated with faster frontal cognitive decline. A modest association was observed between caudate volume and stereotyped behaviour. Tracking frontal behavioural symptoms and cognition has potential to distinguish bvFTD from other disorders. CSF NfL levels seem to be associated with decline in frontal cognitive functioning.

Psychosis in behavioral variant frontotemporal dementia.

BACKGROUND: Dementia is generally characterized by cognitive impairment that can be accompanied by psychotic symptoms; for example, visual hallucinations are a core feature of dementia with Lewy bodies, and delusions are often seen in Alzheimer's disease. However, for behavioral variant of frontotemporal dementia (bvFTD), studies on the broad spectrum of psychotic symptoms are still lacking. The aim of this study was to systematically and prospectively subtype the wide spectrum of psychotic symptoms in probable and definite bvFTD. METHODS: In this study, a commonly used and validated clinical scale that quantifies the broad spectrum of psychotic symptoms (Positive and Negative Symptom Scale) was used in patients with probable and definite bvFTD (n=22) and with a primary psychiatric disorder (n=35) in a late-onset frontal lobe cohort. Median symptom duration was 2.8 years, and the patients were prospectively followed for 2 years. RESULTS: In total, 22.7% of bvFTD patients suffered from delusions, hallucinatory behavior, and suspiciousness, although the majority of the patients exhibited negative psychotic symptoms such as social and emotional withdrawal and blunted affect (95.5%) and formal thought disorders (81.8%). "Difficulty in abstract thinking" and "stereotypical thinking" (formal thought disorders) differentiated bvFTD from psychiatric disorders. The combined predictors difficulty in abstract thinking, stereotypical thinking, "anxiety", "guilt feelings," and "tension" explained 75.4% of variance in the diagnosis of bvFTD versus psychiatric diagnoses (P<0.001). CONCLUSION: Delusions, hallucinatory behavior, and suspiciousness were present in one-fifth of bvFTD patients, whereas negative psychotic symptoms such as social and emotional withdrawal, blunted affect, and formal thought disorders were more frequently present. This suggests that negative psychotic symptoms and formal thought disorders have an important role in the psychiatric misdiagnosis in bvFTD; misdiagnosis in bvFTD might be reduced by systematically exploring the broad spectrum of psychiatric symptoms.

The Diagnostic Challenge of the Late-Onset Frontal Lobe Syndrome: Clinical Predictors for Primary Psychiatric Disorders Versus Behavioral Variant Frontotemporal Dementia.

OBJECTIVE: Primary psychiatric disorders (PsD) can present with symptomatology identical to that of behavioral variant frontotemporal dementia (bvFTD). To date, clinical guidelines do not provide a solution for this diagnostic challenge. The aim of our study was to prospectively determine which demographic, clinical, neuropsychological, neuroimaging, and cerebrospinal fluid biomarkers are important in distinguishing PsD from bvFTD. METHODS: Patients with late-onset behavioral disturbances (aged 45-75 years, 73% male) were included based on their scores on the Frontal Behavioral Inventory and the Stereotypy Rating Inventory and followed for 2 years from April 2011 to June 2015. Odds ratios (ORs) were calculated with backward stepwise logistic regression analyses to investigate the association between baseline clinical and demographic variables and the 2-year follow-up diagnosis of PsD (n = 46) (DSM-IV) versus probable/definite bvFTD (n = 27) (International Behavioral Variant FTD Criteria Consortium criteria). We separately measured the association between additional investigations and the 2-year follow-up diagnosis. Finally, we combined the selected variables to measure the predictive value of both clinical and additional investigations in a single model. RESULTS: Male gender (OR = 5.9; 95% CI, 1.3-26.0), less stereotypy (OR = 0.08; 95% CI, 0.02-0.34), and more depressive symptoms (OR = 1.13; 95% CI, 1.04-1.24) explained 49% of the variance predicting PsD versus bvFTD (χ²3 = 29.4, P < .001) and correctly classified 82.1% of the cases. Neuroimaging (OR = 0.02; 95% CI, 0.002-0.123) explained 55% of the variance (χ²1 = 37.5, P < .001) and, in combination with clinical variables, 66.1% of the variance (χ²3 = 44.06, P < .001). CONCLUSIONS: The present study demonstrated that PsD can be distinguished from probable/definite bvFTD with a thorough clinical evaluation by a psychiatrist and neurologist along with use of validated questionnaires for depression and stereotypy; these measures are even more effective in combination with neuroimaging.

Cerebrospinal fluid biomarker examination as a tool to discriminate behavioral variant frontotemporal dementia from primary psychiatric disorders.

INTRODUCTION: To prospectively determine the diagnostic value of cerebrospinal fluid (CSF) levels total-tau (tau) to amyloid-ß1-42 ratio (Aß1-42) ratio (tau/Aß1-42 ratio), phosphorylated-tau (p-tau) to tau ratio (p-tau/tau ratio), neurofilament light chain (NfL) and YKL40 in the late-onset frontal lobe syndrome, in particular for the differential diagnosis of behavioral variant frontotemporal dementia (bvFTD) versus primary psychiatric disorders (PSY). METHOD: We included patients with a multidisciplinary 2-year-follow-up diagnosis of probable/definite bvFTD (n = 22) or PSY (n = 25), who underwent a detailed neuropsychiatric clinical examination, neuropsychological test battery, and magnetic resonance imaging at baseline. In all cases, CSF was collected through lumbar puncture at baseline. We compared CSF biomarker levels between the two groups and measured the diagnostic accuracy for probable/definite bvFTD, using the follow-up diagnosis as the reference standard. RESULTS: The best discriminators between probable/definite bvFTD and PSY were the levels of CSF NfL (area under the curve [AUC] 0.93, P < .001, 95% confidence interval [CI] 0.85-1.00), p-tau/tau ratio (AUC 0.87, P < .001, 95% CI 0.77-0.97), and YKL40 (AUC 0.82, P = .001, 95% CI 0.68-0.97). The combination of these three biomarkers had a sensitivity of 91% (95% CI 66%-100%) at a specificity of 83% (95% CI 65%-95%) with an AUC of 0.94 (P < .001, 95% CI 0.87-1.00) for bvFTD. CSF tau/Aß1-42 ratio was less accurate in differentiating between bvFTD and PSY. DISCUSSION: We found a good diagnostic accuracy for higher levels of CSF NfL and YKL40 and reduced p-tau/tau ratio in distinguishing bvFTD from PSY. We advocate the use of these CSF biomarkers as potential additional tools to neuroimaging in the diagnosis of bvFTD versus PSY.