Neuroimaging and neuropsychological findings in MAPT N279K mutation phenoconverters: Neuropsychiatry and behavioral neurology/Behavioral neurology. (7th December 2020)

• Record Type: Journal Article
• Authors: Forsberg, Leah K.; Fields, Julie A.; Brushaber, Danielle; Chen, Qin; Kantarci, Kejal; Senjem, Matthew L.; Jack, Clifford R.; Gavrilova, Ralitza H.; Graff‐Radford, Jonathan; Graff‐Radford, Neill R.; Jones, David T.; Knopman, David S.; Kremers, Walter K.; Petersen, Ronald C.; Savica, Rodolfo; Syrjanen, Jeremy; Rademakers, Rosa; Wszolek, Zbigniew; Boeve, Bradley F.
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 6
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.046759
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Characterization of the changes that occur throughout the transition from asymptomatic to symptomatic for those with familial frontotemporal dementia is essential for planning future disease‐modifying trials. Method: We identified four related microtubule associated protein tau ( MAPT ) N279K mutation carriers who have phenoconverted from the asymptomatic to the symptomatic state. Key features were as follows: Case 1 (female) initial exam age 36, onset age 44, current age 49; Case 2 (male) initial exam age 39, onset age 43, current age 48; Case 3 (female) initial exam age 41, onset age 47, current age 53; Case 4 (male) initial exam age 36, onset age 37, current age 46. MRI and neuropsychological data were analyzed. Result: Structural MRI was analyzed using Tensor Based Morphometry Symmetric Diffeomorphic Image Normalization (TBM‐SyN) methodology to quantify lobar volumes, which was then analyzed using a Mixed Effects Model to determine the annual change in lobar volumes. The phenoconverters had a greater estimated annual rate of cortical atrophy in temporal (p <0.001), frontal (p <0.01) and parietal (p <0.05) lobes compared to non‐carriers, with the rate of annual change in symptomatic individuals double that of asymptomatic individuals. Annual change in the parietal and occipital lobes was also analyzed and found to be similar to healthy controls of a similar age. Raw scores on neuropsychological measures were converted to z‐scores for analysis. Category fluency, letter fluency, and Trails A and B were all impaired (z‐score <‐1.5) following phenoconversion, but performance on these and other measures was variable across these four in the late asymptomatic state. Conclusion: For each of the four phenoconverters, structural MRI changes preceded symptom onset, whereas neuropsychological performance was more variable and occurred in closer proximity to the time of phenoconversion. Decrements in verbal fluency and cognitive flexibility were observed earlier than other cognitive domains. These findings suggest that changes in frontal and temporal volume on MRI precede symptom onset, with regional brain volumes most consistently tracking the evolution from the asymptomatic to symptomatic state in N279K MAPT mutation carriers. Supported by: AG063911, AG045390, NS092089, AG016976, AG016574, AG062677.