Introduction-We created global rating scoring rules for the CDR® plus NACC FTLD to detect and track early frontotemporal lobar degeneration (FTLD) and to conduct clinical trials in FTLD.Methods-The CDR plus NACC FTLD rating was applied to 970 sporadic and familial participants from the baseline visit of Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS). Each of the eight domains of the CDR plus NACC FTLD was equally weighed in determining the global score. An interrater reliability study was completed for 40 participants.Results-The CDR plus NACC FTLD showed very good interrater reliability. It was especially useful in detecting clinical features of mild non-fluent/agrammatic variant primary progressive aphasia participants.Discussion-The global CDR plus NACC FTLD score could be an attractive outcome measure for clinical trials in symptomatic FTLD, and may be useful in natural history studies and clinical trials in FTLD spectrum disorders.

Introduction:Behavior/Comportment/Personality (BEHAV) and Language (LANG) domains were added to the Clinical Dementia Rating (CDR®) for improving evaluation of frontotemporal lobar degeneration (FTLD) patients (CDR® plus NACC FTLD). Methods:We analyzed the CDR® plus NACC FTLD among participants from the baseline visit of the ARTFL/LEFFTDS Consortium.

See King et al. (doi:10.1093/aww348) for a scientific commentary on this article.Detailed mapping of clinical dysfunctions to the cerebellar lobules in disease populations is necessary to establish the functional significance of lobules implicated in cognitive and motor functions in normal subjects. This study constitutes the first quantitative examination of the lobular correlates of a broad range of cognitive and motor phenomena in cerebellar disease. We analysed cross-sectional data from 72 cases with cerebellar disease and 36 controls without cerebellar disease. Cerebellar lobule volumes were derived from a graph-cut based segmentation algorithm. Sparse partial least squares, a variable selection approach, was used to identify lobules associated with motor function, language, executive function, memory, verbal learning, perceptual organization and visuomotor coordination. Motor dysfunctions were chiefly associated with the anterior lobe and posterior lobule HVI. Confrontation naming, noun fluency, recognition, and perceptual organization did not have cerebellar associations. Verb and phonemic fluency, working memory, cognitive flexibility, immediate and delayed recall, verbal learning, and visuomotor coordination were variably associated with HVI, Crus I, Crus II, HVII B and/or HIX. Immediate and delayed recall also showed associations with the anterior lobe. These findings provide preliminary anatomical evidence for a functional topography of the cerebellum first defined in task-based functional magnetic resonance imaging studies of normal subjects and support the hypotheses that (i) cerebellar efferents target frontal lobe neurons involved in forming action representations and new search strategies; (ii) there is greater involvement of the cerebellum when immediate recall tasks involve more complex verbal stimuli (e.g. longer words versus digits); and (iii) it is involved in spontaneous retrieval of long-term memory. More generally, they provide an anatomical background for studies that seek the mechanisms by which cognitive and motor dysfunctions arise from cerebellar degeneration. Beyond replicating these findings, future research should employ experimental tasks to probe the integrity of specific functions in cerebellar disease, and new imaging methods to quantitatively map atrophy across the cerebellum.

Introduction: Identifying clinical measures that track disease in the earliest stages of frontotemporal lobar degeneration (FTLD) is important for clinical trials. Familial FTLD provides a unique paradigm to study early FTLD. Executive dysfunction is a clinically relevant hallmark of FTLD and may be a marker of disease progression. Methods: Ninety-three mutation carriers with no symptoms or minimal/questionable symptoms ( MAPT , n = 31; GRN ,n = 28; C9orf72 ,n = 34; Clinical Dementia Rating scale plus NACC FTLD Module <1) and 78 noncarriers enrolled through Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects studies completed the Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH-EXAMINER) and the UDS neuropsychological battery. Linear mixed-effects models were used to identify group differences in cognition at baseline and longitudinally. We examined associations between cognition, clinical functioning, and magnetic resonance imaging volumes. Results: NIH-EXAMINER scores detected baseline and differences in slopes between carriers and noncarriers, even in carriers with a baseline Clinical Dementia Rating scale plus NACC FTLD Module = 0. NIH-EXAMINER declines were associated with worsening clinical symptoms and brain volume loss. Discussion: The NIH-EXAMINER is sensitive to cognitive changes in presymptomatic familial FTLD and is a promising surrogate endpoint.

INTRODUCTION:Behavioral variant Frontotemporal Dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments.METHODS: 135 sporadic (s-bvFTD; mean age 63.3 years; 34% female) and 99 familial (f-bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. F-bvFTD cases included 43 with known or presumed C9orf72 expansions, 28 with known or presumed MAPT mutations, 14 with known GRN mutations, and 14 with a strong family history of FTD but no identified mutation.RESULTS: F-bvFTD were younger and had earlier age of onset. S-bvFTD had higher total NPI-Q scores due to more frequent endorsement of depression and irritability.DISCUSSION: Familial and sporadic bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.