Objective: We aimed to develop a novel tool capable of staging disease severity in frontotemporal dementia (FTD) based upon functional dependence and behavioral changes, and to assess change over time in the 3 main FTD variants (behavioral variant FTD [bvFTD]; progressive nonfluent aphasia [PNFA]; and semantic dementia [SemD]). Methods: The Frontotemporal Dementia Rating Scale (FRS) was developed in a validation cohort of 77 consecutive clinic attendees (bvFTD = 29; PNFA = 20; SemD = 28) and applied to an independent sample of 75 patients (bvFTD = 28; PNFA = 21; SemD = 26) to establish intergroup differences. Assessments from 42 patients followed up after 12 months were used to determine annual progression. Finally, a combined sample (n = 152) was used to determine length of symptoms in each severity category. Results: Six severity stages were identified and operationalized based upon a 30-item questionnaire (very mild to profound). The cross-sectional study revealed much greater levels of impairment in bvFTD than in the language variants, with limited correlation with general cognitive measures. Patients with SemD showed the closest association between length of symptoms and stage, taking, on average, 10 years to reach the severe stage. Patients with bvFTD appear to move most quickly between stages and patients with PNFA were intermediate. The FRS was capable of detecting functional deterioration in all 3 variants over 12 months. Conclusions: Disease progression differs across frontotemporal dementia (FTD) variants. Patients with behavioral variant FTD progress rapidly whereas those with semantic dementia progress more slowly. The Frontotemporal Dementia Rating Scale can aid in staging and determining disease progression. Length of symptoms and global cognitive assessments alone do not reflect disease severity and progression in FTD.

Rating scales that assess methodological quality of clinical trials provide a means to critically appraise the literature. Scales are currently available to rate randomised and non-randomised controlled trials, but there are none that assess single-subject designs. The Single-Case Experimental Design (SCED) Scale was developed for this purpose and evaluated for reliability. Six clinical researchers who were trained and experienced in rating methodological quality of clinical trials developed the scale and participated in reliability studies. The SCED Scale is an 11-item rating scale for single-subject designs, of which 10 items are used to assess methodological quality and use of statistical analysis. The scale was developed and refined over a 3-year period. Content validity was addressed by identifying items to reduce the main sources of bias in single-case methodology as stipulated by authorities in the field, which were empirically tested against 85 published reports. Inter-rater reliability was assessed using a random sample of 20/312 single-subject reports archived in the Psychological Database of Brain Impairment Treatment Efficacy (PsycBITE^TM). Inter-rater reliability for the total score was excellent, both for individual raters (overall ICC = 0.84; 95% confidence interval 0.73–0.92) and for consensus ratings between pairs of raters (overall ICC = 0.88; 95% confidence interval 0.78–0.95). Item reliability was fair to excellent for consensus ratings between pairs of raters (range k = 0.48 to 1.00). The results were replicated with two independent novice raters who were trained in the use of the scale (ICC = 0.88, 95% confidence interval 0.73–0.95). The SCED Scale thus provides a brief and valid evaluation of methodological quality of single-subject designs, with the total score demonstrating excellent inter-rater reliability using both individual and consensus ratings. Items from the scale can also be used as a checklist in the design, reporting and critical appraisal of single-subject designs, thereby assisting to improve standards of single-case methodology.

Primary progressive aphasia comprises a heterogeneous group of neurodegenerative conditions with diverse clinical profiles and underlying pathological substrates. A major development has been the publication of the recent International Consensus Criteria for the three major variants namely: semantic, non-fluent/agrammatic and logopenic. The logopenic variant is assumed to represent an atypical presentation of Alzheimer pathology although evidence for this is, at present, limited. The semantic and non-fluent/agrammatic variants are largely associated with frontotemporal lobar degeneration with TDP-43 and tau pathology, respectively. The applicability of the International Consensus Criteria to an unselected clinical sample is unknown and no agreed clinical evaluation scale on which to derive the diagnosis exists. We assessed 47 consecutive cases of primary progressive aphasic seen over a 3-year period in a specialist centre, using a newly developed progressive aphasia language scale. A subgroup of 30 cases underwent ¹¹C-labelled Pittsburgh Compound B positron emission tomography imaging, a putative biomarker of Alzheimer's disease that detects β-amyloid accumulation, and they were compared with an age-matched group (n = 10) with typical, predominately amnestic Alzheimer's disease. The application of an algorithm based on four key speech and language variables (motor speech disorders, agrammatism, single-word comprehension and sentence repetition) classified 45 of 47 (96%) of patients and showed high concordance with the gold standard expert clinical diagnosis based on the International Consensus Criteria. The level of neocortical β-amyloid burden varied considerably across aphasic variants. Of 13 logopenic patients, 12 (92%) had positive β-amyloid uptake. In contrast, one of nine (11%) semantic variant and two of eight (25%) non-fluent/agrammatic cases were positive. The distribution of β-amyloid across cortical regions of interest was identical in cases with the logopenic variant to that of patients with typical Alzheimer's disease although the total load was lower in the aphasic cases. Impairments of sentence repetition and sentence comprehension were positively correlated with neocortical burden of β-amyloid, whereas impaired single-word comprehension showed a negative correlation. The International Consensus Criteria can be applied to the majority of cases with primary progressive aphasic using a simple speech and language assessment scale based upon four key variables. β-amyloid imaging confirms the higher rate of Alzheimer pathology in the logopenic variant and, in turn, the low rates in the other two variants. The study offers insight into the biological basis of clinical manifestations of Alzheimer's disease, which appear topographically independent of β-amyloid load.

Background/Aims: Primary progressive aphasia (PPA) comprises three main subtypes, varying in clinical features, patterns of brain atrophy, and underlying pathology. Differentiation of these variants is important for treatment and planning; however, simple, effective cognitive tests to aid diagnosis are lacking. This study introduces a new language battery - the SYDBAT (Sydney Language Battery) - to assist clinicians. Methods: Fifty-seven PPA patients and 54 age- and education-matched healthy controls were compared on naming, repetition, word comprehension, and semantic association subtests. Results: Significant group differences were found for all tasks, reflecting different language profiles for each group. Using discriminative function analysis, 80% of PPA cases were correctly classified from three SYDBAT scores, from which a simple diagnostic algorithm was defined. Conclusion: The SYDBAT is a fast and simple tool which provides a valuable adjunct to clinicians diagnosing PPA.

Caregiver burden is greater in frontotemporal dementia (FTD) than in Alzheimer disease (AD). However, little is known of the impact of the 3 main clinical variants of FTD— behavioral-variant frontotemporal dementia (bvFTD), semantic dementia (SemDem), and progressive nonfluent aphasia (PNFA)—or the role of disease severity in caregiver burden. The Zarit Burden Inventory was used to measure caregiver burden of bvFTD (n=17), SemDem (n=20), PNFA (n=20), and AD (n=19) patients. Symptom duration, caregiver age, and relationship type were matched across groups. Moreover, a number of caregiver (mood, social network) and patient variables (functional disability, behavioral changes, relationship with caregiver, and dementia stage) were addressed to investigate their impact on caregiver burden. Caregivers of bvFTD patients reported the highest burden, whereas SemDem and PNFA caregivers reported burden similar to AD. A regression analysis revealed that caregiver burden in FTD, regardless of subtype, was explained by a model combining disease staging, relationship changes, and caregiver depression. Burden increased with disease severity in FTD. This study is the first to show that caregivers of SemDem, PNFA, and AD patients show similar burden, while confirming that bvFTD caregivers show higher burden than AD caregivers. More importantly, this study demonstrates that burden worsens with disease progression in FTD.

Our objective was to compare the cognitive and behavioural profile of patients with amyotrophic lateral sclerosis (ALS) and behavioural variant frontotemporal dementia (bvFTD), and to explore the continuum between these disorders according to neuropsychological and behavioural performance using novel methods of testing and analysis. Twenty patients with ALS, 20 bvFTD patients and 20 healthy controls completed a neuropsychiatric and neuropsychological assessment including cognitive screening, working memory, inhibitory control, decision making and emotion recognition. The resulting neuropsychological and behavioural data were analysed by Rasch analysis. ALS patients showed a similar profile to bvFTD patients on tests of working memory, inhibitory control and behavioural measures. Nine ALS patients (45%) had cognitive impairment and five (25%) met criteria for bvFTD. Even in a subset of MND patients with no impairment on the ACE-R, subtle impairment of inhibitory control together with moderate to severe apathy, were found. The Rasch analysis confirmed that all patients could be ranked on the same continuum, based on their neuropsychological performance and behaviour. Thus, the cognitive and behavioural profiles of ALS mirror those seen in bvFTD. Impaired inhibitory control and behavioural changes suggest subtle orbitofrontal dysfunction in ALS. The Rasch analysis revealed a clear overlap between bvFTD and ALS.