Neuropsychiatric symptoms in genetic frontotemporal dementia: developing a new module for Clinical Rating Scales

Abstract

Background: Current clinical rating scales in frontotemporal dementia (FTD) often do not incorporate neuropsychiatric features and may therefore inadequately measure disease stage.

Methods: 832 participants from the Genetic FTD Initiative (GENFI) were recruited: 522 mutation carriers and 310 mutation-negative controls. The standardised GENFI clinical questionnaire assessed the frequency and severity of 14 neuropsychiatric symptoms: visual, auditory, and tactile hallucinations, delusions, depression, anxiety, irritability/lability, agitation/aggression, euphoria/elation, aberrant motor behaviour, hypersexuality, hyperreligiosity, impaired sleep, and altered sense of humour. A principal component analysis (PCA) was performed to identify key groupings of neuropsychiatric and behavioural items in order to create a new neuropsychiatric module that could be used as an addition to the Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center Behaviour and Language Domains (NACC FTLD) rating scale.

Results: Overall, 46.4% of mutation carriers had neuropsychiatric symptoms (51.6% C9orf72, 40.8% GRN, 46.6% MAPT) compared with 24.5% of controls. Anxiety and depression were the most common in all genetic groups but fluctuated longitudinally and loaded separately in the PCA. Hallucinations and delusions loaded together, with the remaining neuropsychiatric symptoms loading with the core behavioural features of FTD. These results suggest using a single 'psychosis' neuropsychiatric module consisting of hallucinations and delusions. Adding this to the CDR plus NACC FTLD, called the CDR plus NACC FTLD-N, leads to a number of participants being scored more severely, including those who were previously considered asymptomatic now being scored as prodromal.

Conclusions: Neuropsychiatric symptoms occur in mutation carriers at all disease stages across all three genetic groups. However, only psychosis features provided additional staging benefit to the CDR plus NACC FTLD. Inclusion of these features brings us closer to optimising the rating scale for use in trials.

Keywords: FRONTOTEMPORAL DEMENTIA; GENETICS; NEUROPSYCHIATRY.

Figure 1

Frequency (top panel) and severity (bottom panel) of symptoms in the GENFI neuropsychiatric symptom scale in all mutation carriers when asymptomatic (CDR plus NACC FTLD global score of 0), prodromal (score of 0.5) and symptomatic (score of 1+). Frequency and severity of symptoms in the individual genetic groups (C9orf72, GRN and MAPT) are shown similarly to the right of the combined mutation carrier group. CDR, Clinical Dementia Rating; GENFI, Genetic FTD Initiative; NACC FTLD, National Alzheimer’s Coordinating Center Behaviour and Language Domains.

Figure 2

Visual representation of the principal component analysis (PCA) results. The PCA of the neuropsychiatric symptom scale revealed four components, named for the items which loaded most strongly: ‘psychosis’, ‘mood’ and ‘behavioural’, with a fourth component of hyperreligiosity. The dotted boxes represent the finding that in a further PCA which included the core behavioural symptoms of FTD these items loaded alongside the ‘behavioural’ features of the neuropsychiatric symptom scale. FTD, frontotemporal dementia.

Figure 3

Longitudinal change in depression and anxiety in asymptomatic (CDR plus NACC FTLD global score of 0), prodromal (0.5) and symptomatic (≥1) mutation carriers: (A) mean severity of depression (solid line) and anxiety (dotted line) within all carriers; (B, C) Sankey diagrams showing individual change in depression (B) and anxiety (C) scores. CDR, Clinical Dementia Rating; NACC FTLD, National Alzheimer’s Coordinating Center Behaviour and Language Domains.

Figure 4

Comparison of the standard CDR plus NACC FTLD with a new CDR plus NACC FTLD plus Neuropsychiatric Score (CDR plus NACC FTLD-N). The top figure shows the change in global score in individual participants (five participants moved from 0 to 0.5 and 1 participant from 1 to 2). The bottom figure shows the percentage of symptomatic participants with a particular CDR score (left shows standard CDR plus NACC FTLD, right shows the change with the new CDR plus NACC FTLD-N). bvFTD, behavioural variant frontotemporal dementia; CDR, Clinical Dementia Rating; NACC FTLD, National Alzheimer’s Coordinating Center Behaviour and Language Domains; PPA, Primary Progressive Aphasia.

Figure 5

Comparison of the standard CDR plus NACC FTLD with the CDR plus NACC FTLD-N-B+. The top figure shows the change in global score in individual participants (50 participants moved from 0 to 0.5, 1 participant from 0 to 1, 4 participants from 0.5 to 1, 2 participants from 1 to 0.5 and 4 participants from 1 to 2). The bottom figure shows the percentage of symptomatic participants with a particular CDR score (left shows standard CDR plus NACC FTLD, right shows the change with the new CDR plus NACC FTLD-N-B+). CDR, Clinical Dementia Rating; FTD, behavioural variant frontotemporal dementia; NACC FTLD, National Alzheimer’s Coordinating Center Behaviour and Language Domains.