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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.

Author(s): Boeve, Bradley F; Boxer, Adam L; Rosen, Howard J; Forsberg, Leah K; Heuer, Hilary W; Brushaber, Danielle; Appleby, Brian; Biernacka, Joanna M; Bordelon, Yvette M; Botha, Hugo; Brannelly, Patrick; Dickerson, Brad C; Dickson, Dennis W; Kimiko, Domoto‐Reilly; Faber, Kelley; Fagan, Anne; Fields, Julie A; Fishman, Ann; Foroud, Tatiana M; Galasko, Doug R; Gavrilova, Ralitza H; Gendron, Tania F; Geschwind, Daniel H; Ghoshal, Nupur; Goldman, Jill; Graff‐Radford, Jonathan; Graff‐Radford, Neill R; Grant, Ian; Grossman, Murray; Hsiung, Ging‐Yuek Robin; Huang, Eric J; Huey, Edward; Irwin, David J; Jones, David T; Kantarci, Kejal; Karydas, Anna M; Kaufer, Daniel; Knopman, David S; Kramer, Joel H; Kremers, Walter K; Kornak, John; Kukull, Walter A; Lagone, Emma; Leger, Gabriel C; Litvan, Irene; Ljubenkov, Peter A; Lucente, Diane E; Mackenzie, Ian R; Manoochehri, Masood; Masdeu, Joseph C; McGinnis, Scott; Mendez, Mario F; Miller, Bruce L; Miyagawa, Toji; Nelson, Kevin M; Onyike, Chiadi U; Pantelyat, Alex; Pascual, Belen; Pearlman, Rodney; Petrucelli, Leonard; Rademakers, Rosa; Ramos, Eliana Marisa; Rankin, Katherine; Rascovsky, Katya; Rexach, Jessica E; Ritter, Aaron; Roberson, Erik D; Rojas, Julio C; Sabbagh, Marwan N; Salmon, David P; Savica, Rodolfo; Seeley, William W; Staffaroni, Adam M; Syrjanen, Jeremy; Tartaglia, Carmela; Tatton, Nadine; Taylor, Joanne; Toga, Arthur W; Weintraub, Sandra; Wheaton, Diana; Wong, Bonnie; Wszolek, Zbigniew

Author(s): Heuer, Hilary W; Wang, P; Rascovsky, K; Wolf, A; Appleby, B; Bove, J; Bordelon, Y; Brannelly, P; Brushaber, DE; Caso, C; Coppola, G; Dickerson, B; Dickinson, S; Domoto-Reilly, K; Faber, K; Ferrall, J; Fields, J; Fishman, A; Fong, J; Foroud, T; Forsberg, LK; Gearhart, D; Ghazanfari, B; Ghoshal, N; Goldman, J; Graff-Radford, J; Graff-Radford, N; Grant, I; Grossman, M; Haley, D; Hsiung, G-Y; Huey, E; Irwin, D; Jones, D; Kantarci, K; Karydas, A; Kaufer, D; Kerwin, D; Knopman, D; Kornak, J; Kramer, JH; Kraft, R; Kremers, WK; Kukull, W; Litvan, I; Ljubenkov, P; Mackenzie, IR; Maldonado, M; Manoochehri, M; McGinnis, S; McKinley, E; Mendez, MF; Miller, BL; Onyike, C; Pantelyat, A; Pearlman, R; Petrucelli, L; Potter, M; Rademakers, R; Ramos, EM; Rankin, KP; Roberson, ED; Rogalski, E; Sengdy, P; Shaw, L; Syrjanen, J; Tartaglia, MC; Tatton, N; Taylor, J; Toga, A; Trojanowski, J; Weintraub, S; Wong, B; Wszolek, Z; Boeve, BF; Rosen, HJ; Boxer, AL; ARTFL and LEFFTDS consortia | Abstract: IntroductionBehavioral 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.MethodsA total of 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 chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule-associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation.ResultsParticipants with f-bvFTD were younger and had earlier age at onset. s-bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI-Q) scores due to more frequent endorsement of depression and irritability.Discussionf-bvFTD and s-bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.

Author(s): Miyagawa, Toji; Brushaber, Danielle; Syrjanen, Jeremy; Kremers, Walter; Fields, Julie; Forsberg, Leah K; Heuer, Hilary W; Knopman, David; Kornak, John; Boxer, Adam; Rosen, Howard J; Boeve, Bradley F; Appleby, Brian; Bordelon, Yvette; Bove, Jessica; Brannelly, Patrick; Caso, Christina; Coppola, Giovanni; Dever, Reilly; Dheel, Christina; Dickerson, Bradford; Dickinson, Susan; Dominguez, Sophia; Domoto-Reilly, Kimiko; Faber, Kelley; Ferrell, Jessica; Fishman, Ann; Fong, Jamie; Foroud, Tatiana; Gavrilova, Ralitza; Gearhart, Debra; Ghazanfari, Behnaz; Ghoshal, Nupur; Goldman, Jill S; Graff-Radford, Jonathan; Graff-Radford, Neill; Grant, Ian; Grossman, Murray; Haley, Dana; Hsiung, Robin; Huey, Edward; Irwin, David; Jones, David; Jones, Lynne; Kantarci, Kejal; Karydas, Anna; Kaufer, Daniel; Kerwin, Diana; Kraft, Ruth; Kramer, Joel; Kukull, Walter; Litvan, Irene; Lucente, Diane; Lungu, Codrin; Mackenzie, Ian; Maldonado, Miranda; Manoochehri, Masood; McGinnis, Scott; McKinley, Emily; Mendez, Mario F; Miller, Bruce; Multani, Namita; Onyike, Chiadi; Padmanabhan, Jaya; Pantelyat, Alexander; Pearlman, Rodney; Petrucelli, Leonard; Potter, Madeline; Rademakers, Rosa; Ramos, Eliana M; Rankin, Kate; Rascovsky, Katya; Roberson, Erik D; Rogalski, Emily; Sengdy, Pheth; Shaw, Leslie; Tartaglia, Maria C; Tatton, Nadine; Taylor, Joanne; Toga, Arthur; Trojanowski, John Q; Wang, Ping; Weintraub, Sandra; Wong, Bonnie; Wszolek, Zbigniew | Abstract: IntroductionWe 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.MethodsThe 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.ResultsThe 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.DiscussionThe 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 The Advancing Research and Treatment in Frontotemporal Lobar Degeneration and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects longitudinal studies were designed to describe the natural history of familial-frontotemporal lobar degeneration due to autosomal dominant mutations. Methods We examined cognitive performance, behavioral ratings, and brain volumes from the first time point in 320 MAPT, GRN, and C9orf72 family members, including 102 non–mutation carriers, 103 asymptomatic carriers, 43 mildly/questionably symptomatic carriers, and 72 carriers with dementia. Results Asymptomatic carriers showed similar scores on all clinical measures compared with noncarriers but reduced frontal and temporal volumes. Those with mild/questionable impairment showed decreased verbal recall, fluency, and Trail Making Test performance and impaired mood and self-monitoring. Dementia was associated with impairment in all measures. All MAPT carriers with dementia showed temporal atrophy, but otherwise, there was no single cognitive test or brain region that was abnormal in all subjects. Discussion Imaging changes appear to precede clinical changes in familial-frontotemporal lobar degeneration, but specific early clinical and imaging changes vary across individuals.

Introduction Behavior/Comportment/Personality (BEHAV) and Language (LANG) domains were added to the Clinical Dementia Rating (CDR®) for improving evaluation of patients with frontotemporal lobar degeneration (FTLD) (CDR® plus NACC FTLD). Methods We analyzed the CDR® plus NACC FTLD among participants from the baseline visit of the Advancing Research and Treatment for Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects Consortium. Results The CDR® plus NACC FTLD was able to detect early symptoms in the mildly impaired participants who were rated as CDR® sum of boxes (CDR®-SB) = 0. The CDR®-SB was not sensitive, particularly in participants with mild nonfluent/agrammatic primary progressive aphasia. Participants with familial and sporadic behavioral variant FTD exhibited similar CDR® plus NACC FTLD profiles except that language impairment was more frequent in participants with mild sporadic behavioral variant FTD. Adding the BEHAV and/or LANG domains to the CDR®-SB significantly enhanced discriminatory power in differentiating among the FTLD spectrum disorders. Discussion The BEHAV and LANG domains enable the CDR® plus NACC FTLD to capture early symptomatology of FTLD.

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 Some models of therapy for neurodegenerative diseases envision starting treatment before symptoms develop. Demonstrating that such treatments are effective requires accurate knowledge of when symptoms would have started without treatment. Familial frontotemporal lobar degeneration offers a unique opportunity to develop predictors of symptom onset. Methods We created dementia risk scores in 268 familial frontotemporal lobar degeneration family members by entering covariate-adjusted standardized estimates of brain atrophy into a logistic regression to classify asymptomatic versus demented participants. The score's predictive value was tested in a separate group who were followed up longitudinally (stable vs. converted to dementia) using Cox proportional regressions with dementia risk score as the predictor. Results Cross-validated logistic regression achieved good separation of asymptomatic versus demented (accuracy = 90%, SE = 0.06). Atrophy scores predicted conversion from asymptomatic or mildly/questionably symptomatic to dementia (HR = 1.51, 95% CI: [1.16,1.98]). Discussion Individualized quantification of baseline brain atrophy is a promising predictor of progression in asymptomatic familial frontotemporal lobar degeneration mutation carriers.

Objective The aim of this study is to evaluate the correlation between resting state functional MRI (RS-fMRI) activity and motor and cognitive impairment in spinocerebellar ataxia type 6 (SCA6). Methods Twelve patients with genetically confirmed SCA6 and 14 age matched healthy controls were imaged with RS-fMRI. Whole brain gray matter was automatically parcellated into 1000 regions of interest (ROIs). For each ROI, the first eigenvariate of voxel time courses was extracted. For each patient, Pearson correlation coefficients between each pair of ROI time courses were calculated across the 1000 ROIs. The set of average control correlation coefficients were fed as an undirected weighted adjacency matrix into the Rubinov and Sporns (2010) modularity algorithm. The intranetwork global efficiency of the thresholded adjacency sub-matrix was calculated and correlated with ataxia scores and cognitive performance. Results SCA6 patients showed mild cognitive impairments in executive function and visual-motor processing compared to control subjects. These neuropsychological impairments were correlated with decreased RS functional connectivity (FC) in the attention network. Conclusions Mild cognitive executive functions and visual-motor coordination impairments seen in SCA6 patients correlate with decreased resting-state connectivity in the attention network, suggesting a possible metric for the study of cognitive dysfunction in cerebellar disease. Hum Brain Mapp 38:3001–3010, 2017. © 2017 Wiley Periodicals, Inc.

Introduction Conventional Z-scores are generated by subtracting the mean and dividing by the standard deviation. More recent methods linearly correct for age, sex, and education, so that these “adjusted” Z-scores better represent whether an individual's cognitive performance is abnormal. Extreme negative Z-scores for individuals relative to this normative distribution are considered indicative of cognitive deficiency. Methods In this article, we consider nonlinear shape constrained additive models accounting for age, sex, and education (correcting for nonlinearity). Additional shape constrained additive models account for varying standard deviation of the cognitive scores with age (correcting for heterogeneity of variance). Results Corrected Z-scores based on nonlinear shape constrained additive models provide improved adjustment for age, sex, and education, as indicated by higher adjusted-R2. Discussion Nonlinearly corrected Z-scores with respect to age, sex, and education with age-varying residual standard deviation allow for improved detection of non-normative extreme cognitive scores.

Purpose To determine cognitive impairment patterns in patients with spinocerebellar ataxia type 6 (SCA6) compared to patients with idiopathic late-onset cerebellar ataxia (ILOCA). Methods Neurocognitive testing was conducted on 21 SCA6, nine ILOCA, and 27 controls subjects. Intergroup differences were assessed using the Wilcoxon signed-ranked test or Student's t-test. Principal component analysis (PCA) was performed on nine cognitive variables, and Hotelling's T-squared test assessed group-specific differences. Pearson's correlations assessed changes in cognitive performance and disease progression. Intra-group differences among SCA6 were examined in a post-hoc analysis. Results SCA6 and ILOCA patients showed impairment in visuo-spatial executive function, phonemic verbal fluency, and semantic-verb word generation. ILOCA showed impairment in mental flexibility/response inhibition, verbal learning, semantic-noun verbal fluency, and forward numerical working memory. Within the first three principal components, SCA6 and ILOCA differed from controls and from each other. Verbal working and immediate visuo-spatial memory correlated with disease duration for SCA6. For ILOCA, Mini-Mental Status Exam and RCF copy correlated with disease duration. Conclusion Differing patterns of cognitive dysfunction were seen in SCA6 and ILOCA. PCA suggested that distinct SCA6 subgroups may exist, SCA61 with significant ILOCA overlap in several cognitive deficits, and SCA62 showing deficits in visuo-spatial performance only.

OBJECTIVE: The aim of this study is to evaluate the correlation between resting state functional MRI (RS‐fMRI) activity and motor and cognitive impairment in spinocerebellar ataxia type 6 (SCA6). METHODS: Twelve patients with genetically confirmed SCA6 and 14 age matched healthy controls were imaged with RS‐fMRI. Whole brain gray matter was automatically parcellated into 1000 regions of interest (ROIs). For each ROI, the first eigenvariate of voxel time courses was extracted. For each patient, Pearson correlation coefficients between each pair of ROI time courses were calculated across the 1000 ROIs. The set of average control correlation coefficients were fed as an undirected weighted adjacency matrix into the Rubinov and Sporns (2010) modularity algorithm. The intranetwork global efficiency of the thresholded adjacency sub‐matrix was calculated and correlated with ataxia scores and cognitive performance. RESULTS: SCA6 patients showed mild cognitive impairments in executive function and visual‐motor processing compared to control subjects. These neuropsychological impairments were correlated with decreased RS functional connectivity (FC) in the attention network. CONCLUSIONS: Mild cognitive executive functions and visual‐motor coordination impairments seen in SCA6 patients correlate with decreased resting‐state connectivity in the attention network, suggesting a possible metric for the study of cognitive dysfunction in cerebellar disease. Hum Brain Mapp 38:3001–3010, 2017. © 2017 Wiley Periodicals, Inc.

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. * Abbreviations : ICARS : International Cooperative Ataxia Rating Scale SCA : spinocerebellar ataxia SPLS : Sparse Partial Least Squares