Early Neuropsychological Characteristics of Progranulin Mutation Carriers

Hallam, Bradley J.; Jacova, Claudia; Hsiung, Ging-Yuek Robin; Wittenberg, Dana; Sengdy, Pheth; Bouchard-Kerr, Phoenix; Slack, Penelope J.; Rademakers, Rosa; Baker, Matthew; Chow, Tiffany W.; Levine, Brian; Feldman, Howard

doi:10.1017/s1355617714000551

Cited by 23 publications

(23 citation statements)

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“…Furthermore, results from the GENFI study predicted that GRN + subjects would not show significant reduction in cortical volumes until approximately five years prior to illness onset, in which case, our GRN + subjects (on average eight years prior to predicted onset) might still be too early to demonstrate significant atrophy. However, it is interesting that both GENFI and a previous study of ours found that GRN + subjects demonstrate cognitive and neuropsychological deficits as well as changes in glucose metabolism as early as 10 years prior to illness onset ( Rohrer et al, 2015 ; Jacova et al, 2013 ; Hallam et al, 2014 ; Nasreddine et al, 2005 ); suggesting that the subtle decline in function precede obvious structural gray matter changes in the GRN + genetic subgroup. Finally, it is important to recognize that FTD represents a broad clinical spectrum with striking heterogeneity in the clinical features at the time of presentation, even among members of a family carrying a specific mutation.…”

Section: Discussionmentioning

confidence: 63%

“…All subjects underwent genetic analysis to establish whether they were carriers of their family's mutation; however, the subjects and the investigators performing the clinical assessments remained blinded to the genetic results. Some features of the cohort have been described previously ( Jacova et al, 2013 ; Hallam et al, 2014 ). Participants underwent a detailed neurological examination and were screened for cognitive deficits with various scales including the mini mental state examination (MMSE) ( Folstein et al, 1975 ; Folstein et al, 1983 ), Frontal Assessment Battery (FAB) ( Dubois et al, 2000 ), and the Frontal Behavioral Inventory (FBI) ( Kertesz et al, 2000 ).…”

Section: Methodsmentioning

confidence: 99%

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Gray matter changes in asymptomatic C9orf72 and GRN mutation carriers

Popuri

Dowds

Beg

et al. 2018

NeuroImage: Clinical

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Frontotemporal dementia (FTD) is a neurodegenerative disease with a strong genetic basis. Understanding the structural brain changes during pre-symptomatic stages may allow for earlier diagnosis of patients suffering from FTD; therefore, we investigated asymptomatic members of FTD families with mutations in C9orf72 and granulin (GRN) genes. Clinically asymptomatic subjects from families with C9orf72 mutation (15 mutation carriers, C9orf72+; and 23 non-carriers, C9orf72−) and GRN mutations (9 mutation carriers, GRN+; and 15 non-carriers, GRN−) underwent structural neuroimaging (MRI). Cortical thickness and subcortical gray matter volumes were calculated using FreeSurfer. Group differences were evaluated, correcting for age, sex and years to mean age of disease onset within the subject's family. Mean age of C9orf72+ and C9orf72− were 42.6 ± 11.3 and 49.7 ± 15.5 years, respectively; while GRN+ and GRN− groups were 50.1 ± 8.7 and 53.2 ± 11.2 years respectively. The C9orf72+ group exhibited cortical thinning in the temporal, parietal and frontal regions, as well as reduced volumes of bilateral thalamus and left caudate compared to the entire group of mutation non-carriers (NC: C9orf72− and GRN− combined). In contrast, the GRN+ group did not show any significant differences compared to NC. C9orf72 mutation carriers demonstrate a pattern of reduced gray matter on MRI prior to symptom onset compared to GRN mutation carriers. These findings suggest that the preclinical course of FTD differs depending on the genetic basis and that the choice of neuroimaging biomarkers for FTD may need to take into account the specific genes involved in causing the disease.

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Section: Discussionmentioning

confidence: 63%

Section: Methodsmentioning

confidence: 99%

Gray matter changes in asymptomatic C9orf72 and GRN mutation carriers

Popuri

Dowds

Beg

et al. 2018

NeuroImage: Clinical

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“…However, the measurable functional and structural brain abnormalities in mutation carriers revealed in this review are likely to result in at least subtle or mild symptoms on sensitive clinical tests. In fact, neuropsychological group differences compared to controls have been observed in GRN and MAPT mutation carriers[8, 40]. There have been reports of premorbid psychiatric diagnoses in GRN mutation carriers[40].…”

Section: Discussionmentioning

confidence: 99%

“…In this review, we utilized the existing neuroimaging evidence to map out emerging brain abnormalities in predementia FTD- GRN . We use the term “predementia” to refer to asymptomatic mutation carriers, as well as those displaying early symptoms that fall short of meeting FTD diagnostic criteria[7, 8]. …”

Section: Introductionmentioning

confidence: 99%

Predementia Brain Changes in Progranulin Mutation: A Systematic Review of Neuroimaging Evidence

Alexander

Pisner

Jacova

2019

Dement Geriatr Cogn Disord

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Background: Mutations in the progranulin (GRN) gene are a major cause of familial frontotemporal dementia. They result in a loss of progranulin levels and in GRN-related brain degenerative changes that unfold over years if not decades. The aim of our review was to summarize the evidence on emerging functional and structural brain abnormalities in carriers of GRN mutations. Summary: We performed a systematic search for studies that used at least one modality (structural MRI, fMRI, fluorodeoxyglucose positron emission tomography, diffusion tensor imaging) to compare mutation carriers to non-carrier controls. Our search produced 13 studies published between 2008 and 2017, the majority cross-sectional, with carrier sample sizes ranging from 5 to 65. Key Messages: The aggregate findings suggest that (1) measurable brain changes are detectable in at least some mutation carriers 20–25 years prior to disease onset; (2) functional/metabolic changes progress more consistently over time than structural changes; (3) the topographic pattern is anterior to posterior, not always asymmetric, and maps onto known functional networks.

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“…The Movement Disorder Society Task Force Guidelines were used to design the battery of clinical tests for Parkinson's disease patient cohort. The test battery was chosen to overlap as much as possible with several large-scale provincial initiatives (i.e., CIMA-Q 35 ONDRI 36 ) and several provincial disease-specific studies (FTD in British Columbia 37 and Parkinson's disease in Alberta 38 ). The battery requires between 2 and 3 h to administer.…”

Section: Neuropsychological Evaluationmentioning

confidence: 99%

The Comprehensive Assessment of Neurodegeneration and Dementia: Canadian Cohort Study

Chertkow

Borrie

Whitehead

et al. 2019

Can. J. Neurol. Sci.

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Background: The Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) cohort study of the Canadian Consortium on Neurodegeneration in Aging (CCNA) is a national initiative to catalyze research on dementia, set up to support the research agendas of CCNA teams. This cross-country longitudinal cohort of 2310 deeply phenotyped subjects with various forms of dementia and mild memory loss or concerns, along with cognitively intact elderly subjects, will test hypotheses generated by these teams. Methods: The COMPASS-ND protocol, initial grant proposal for funding, fifth semi-annual CCNA Progress Report submitted to the Canadian Institutes of Health Research December 2017, and other documents supplemented by modifications made and lessons learned after implementation were used by the authors to create the description of the study provided here. Results: The CCNA COMPASS-ND cohort includes participants from across Canada with various cognitive conditions associated with or at risk of neurodegenerative diseases. They will undergo a wide range of experimental, clinical, imaging, and genetic investigation to specifically address the causes, diagnosis, treatment, and prevention of these conditions in the aging population. Data derived from clinical and cognitive assessments, biospecimens, brain imaging, genetics, and brain donations will be used to test hypotheses generated by CCNA research teams and other Canadian researchers. The study is the most comprehensive and ambitious Canadian study of dementia. Initial data posting occurred in 2018, with the full cohort to be accrued by 2020. Conclusion: Availability of data from the COMPASS-ND study will provide a major stimulus for dementia research in Canada in the coming years. RÉSUMÉ : Évaluation complète d'une étude de cohorte canadienne portant sur la démence et la neuro-dégénérescence. Contexte : L'évaluation globale de la neuro-dégénérescence et de la démence (COMPASS-ND), étude de cohorte du Consortium canadien en neuro-dégénérescence associée au vieillissement (CCNV), représente une initiative nationale visant à promouvoir la recherche portant sur la démence et à soutenir les programmes de recherche des équipes du CCNV. Totalisant 2310 sujets recrutés partout au pays, cette cohorte longitudinale regroupe des individus fortement « phénotypés » qui présentent diverses formes de démence et de pertes de mémoire légères. En plus de sujets âgés dont les fonctions cognitives sont intactes, ces 2310 sujets ont permis de valider les hypothèses formulées par les équipes du CCNV. Méthodes : Nous avons utilisé de nombreux documents pour décrire cette étude : le protocole de la COMPASS-ND ; la demande initiale de subvention ; le cinquième rapport d'étape semi-annuel du CCNV soumis aux Instituts de recherche

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Early Neuropsychological Characteristics of Progranulin Mutation Carriers

Cited by 23 publications

References 50 publications

Gray matter changes in asymptomatic C9orf72 and GRN mutation carriers

Gray matter changes in asymptomatic C9orf72 and GRN mutation carriers

Predementia Brain Changes in Progranulin Mutation: A Systematic Review of Neuroimaging Evidence

The Comprehensive Assessment of Neurodegeneration and Dementia: Canadian Cohort Study

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