Cognition and neuropsychiatry in behavioral variant frontotemporal dementia by disease stage

Abstract

Objective: To characterize the cognitive and neuropsychiatric symptoms of patients with behavioral variant frontotemporal dementia (bvFTD) over the natural course of the disease.

Methods: We examined the initial and subsequent neuropsychological test performance and neuropsychiatric symptoms in a large cohort of patients with bvFTD (n = 204) across progressive stages of disease as measured by the Clinical Dementia Rating (CDR). We also compared cognitive and neuropsychiatric impairments of patients with bvFTD to those of an age-matched cohort with Alzheimer disease (AD) dementia (n = 674).

Results: At the earliest stage (CDR = 0.5), patients with bvFTD had profound neuropsychiatric disturbances, insensitivity to errors, slower response times, and poor naming, with intact attention span, memory, and facial affect naming. Tests continuing to show progressive, statistically significant stepwise declines after the CDR = 1 stage included free recall, visuoconstruction, set-shifting, error insensitivity, semantic fluency, design fluency, emotion naming, calculations, confrontation naming, syntax comprehension, and verbal agility. At CDR = 0.5, patients with bvFTD significantly outperformed patients with AD in episodic memory and were faster in set-shifting, while scoring quantitatively worse in lexical fluency, emotion naming, and error sensitivity. The overall rate of disease progression in bvFTD was more rapid than in AD.

Conclusion: There are distinct patterns of cognitive deficits differentiating the earlier and later disease stages in bvFTD, with the pattern of cognitive decline revealing in greater detail the natural history of the disease. These cognitive symptoms are readily apparent clinical markers of dysfunction in the principal brain networks known to undergo molecular and anatomical changes in bvFTD, thus are important indicators of the evolving pathology in individual patients.

Figure 1. MMSE, episodic memory, visuospatial, and language performance by patients with bvFTD

Performance of patients with bvFTD is plotted against the stages of disease severity at 3 CDR stages (very mild, CDR = 0.5; mild, CDR = 1; moderate, CDR = 2). The plots depict the least square means corrected for age and sex, and the standard errors, derived from the mixed-model analysis, based on z-score estimates calculated using an age-matched control population. (A) MMSE. (B) Verbal free recall, depicted as the d′ of the number of words recalled from a 9-item CVLT word list after a 10-minute delay. (C) Verbal recognition, depicted by the d′ of the score achieved at recognizing the 9-item CVLT word list after 10 minutes. (D) Visual free recall, construction of Benson figure from memory after 10 minutes. (E) Location discrimination, as assessed by the number location task of the Visual Object and Space Perception Battery. (F) Visuoconstruction, as assessed by copy of the Benson figure. (G) Face recognition assessed by the face-matching subtest of the Comprehensive Affect Testing System involving 12 trials in which the participant determines whether 2 faces are the same or different. (H) Sentence repetition, assessed by having participants repeat 3 phonemically complex sentences following the examiner. Each subplot also illustrated the same measures for an AD patient group who were matched to the same age range of the bvFTD patient group. The d′ estimates of auditory free recall and auditory recognition for the control groups were calculated based on their performance on the CVLT long form (i.e., 16-item word list). Error bars indicate the standard errors derived from the mixed-model analysis. The asterisks indicate the significance from Tukey post hoc comparison between CDR stages within each patient group; *p < 0.05, **p < 0.01, ***p < 0.0001. AD = Alzheimer disease; bvFTD = behavioral variant frontotemporal dementia; CDR = Clinical Dementia Rating; CVLT = California Verbal Learning Test; MMSE = Mini-Mental State Examination.

Figure 2. Performance on attention and working memory, executive, and facial affect naming tasks by patients with bvFTD

Performance by patients with bvFTD is plotted against the stages of disease severity (very mild, CDR = 0.5; mild, CDR = 1; moderate, CDR = 2). The plots depict the least square means corrected for age and sex, and the standard errors, derived from the mixed-model analysis, based on z-score estimates calculated using an age-matched control population. (A) Auditory attention, assessed by the number of digits correctly repeated in the same order from a list read by the examiner. (B) Verbal working memory, number of digits correctly repeated backwards from a list read by the examiner. (C) Error insensitivity, number of errors made during the modified Trail Making Test during 60 seconds. (D) Cognitive control, number of words correctly read in the Stroop color inhibition test within 60 seconds divided by the number of correct words in the Stroop color naming test. (E) Semantic fluency, the number of animals listed within 60 seconds. (F) Lexical fluency, the number of words starting from the letter D listed within 60 seconds. (G) Set-shifting, assessed by the number of correct lines drawn per second in the modified Trail Making Test, which requires the patient to serially alternate between numbers and days of the week. (H) Emotion naming as assessed by the affect matching subtest of the Comprehensive Affect Testing System containing 16 trials in which the participant is shown a photograph of an emotional face and required to select the correct label from a list (i.e., happy, sad, angry, frightened, surprised, disgusted, or neutral). The y-axis of the subplot (C) depicting the error insensitivity was inverted to make it more intuitive. Each subplot also illustrates the same measures for an AD patient group who were matched to the same age range of the bvFTD patient group. Error bars indicate the standard errors derived from the mixed-model analysis. The asterisks indicate the significance from Tukey post hoc comparison between CDR stages within each patient group; *p < 0.05, **p < 0.01, ***p < 0.0001. AD = Alzheimer disease; bvFTD = behavioral variant frontotemporal dementia; CDR = Clinical Dementia Rating.

Figure 3. Neuropsychiatric symptoms and progression of dementia

Neuropsychiatric symptom battery listed in Neuropsychiatric Inventory used to assess the frequency of behavioral symptoms and their severity at the caregiver interview. The frequency-by-severity score denotes the product of the severity of any behavioral symptom graded out of 3, and the number of episodes. (A) Total of frequency-by-severity scores across all the behavioral symptoms, plotted against the disease severity denoted by 4 different CDR stages ranging from 0.5 to 3. (B) Total of caregiver distress calculated for each of the behavioral symptoms out of 5. (C) Frequency-by-severity scores at each CDR stage, for the top 9 neuropsychiatric symptoms (sorted according to score-ranks) of bvFTD and AD patient groups. CDR stages (very mild, CDR = 0.5; mild, CDR = 1; moderate, CDR = 2; severe, CDR = 3). Error bars indicate the standard errors derived from the mixed-model analysis. (D) Patients with bvFTD showed a faster progression of dementia compared to patients with AD as measured by CDR-SOB. The x-axis plots the difference of time between the first and the last evaluation and the y-axis shows the difference in CDR-SOB between the 2 evaluations. The analysis includes a subset of bvFTD and AD populations who have more than one evaluation. The open squares indicate patients with bvFTD whom we have identified as outliers and were not included in the regression equation. Number of patients in each group for subplots A–C: bvFTD (CDR 0.5, n = 47; CDR 1, n = 84; CDR 2, n = 66; CDR 3, n = 32); AD (CDR 0.5, n = 188; CDR 1, n = 229; CDR 2, n = 71; CDR 3, n = 20). Number of patients in each group for subplot D: AD, n = 162; bvFTD, n = 67. AD = Alzheimer disease; bvFTD = behavioral variant frontotemporal dementia; CDR = Clinical Dementia Rating; CDR-SOB = Clinical Dementia Rating–Sum of Boxes.