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Original Investigation
December 20, 2019

Association of Cognitive and Behavioral Features Between Adults With Tuberous Sclerosis and Frontotemporal Dementia

Author Affiliations
  • 1Memory and Aging Center, University of California, San Francisco
  • 2Providence Health & Services, Portland, Oregon
  • 3Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles
  • 4Associate Editor, JAMA Neurology
JAMA Neurol. 2020;77(3):358-366. doi:10.1001/jamaneurol.2019.4284
Key Points

Question  Do individuals with tuberous sclerosis–associated neuropsychiatric disorders meet criteria for the neurodegenerative disease frontotemporal dementia (FTD)?

Findings  In this case-control study, quantitative clinical measurements showed that adults with tuberous sclerosis–associated neuropsychiatric disorders exhibit behavioral and cognitive difficulties similar to those seen in FTD. Compared with FTD, significant overlap in cerebrospinal fluid biomarkers was seen in patients with tuberous sclerosis complex, and similarly, a subset of these subjects demonstrated punctate focal retention of the tau PET ligand fluorine 1B–labeled flortaucipir.

Meaning  Additional longitudinal studies should be performed on adults affected with tuberous sclerosis complex to assess risk for developing a neurodegenerative disease such as FTD.


Importance  Individuals with tuberous sclerosis complex can develop a progressive neuropsychiatric syndrome known as tuberous sclerosis–associated neuropsychiatric disorders. Tuberous sclerosis–associated neuropsychiatric disorders symptoms overlap with clinical criteria for frontotemporal dementia, yet the association between the 2 has not been explored.

Objective  To investigate the potential association between tuberous sclerosis–associated neuropsychiatric disorders and frontotemporal dementia.

Design, Setting, and Participants  Case-control study that enrolled patients with tuberous sclerosis complex with normal IQs in an observational clinical study at the University of California, San Francisco, from 2017 to 2019 where they underwent a comprehensive clinical evaluation including neuropsychologic testing, cerebral spinal fluid biomarker profiling, and structural neuroimaging. The study included adults who fulfilled the clinical criteria for tuberous sclerosis complex and had normal IQs, had frontotemporal dementia, or were healthy control individuals.

Main Outcomes and Measures  Tuberous sclerosis–associated neuropsychiatric disorders checklist severity score, neuropsychologic test scores, cerebral spinal fluid concentrations of phosphorylated tau181, total tau, amyloid-β 42, and neurofilament light chain. Amyloid and tau positron emission tomography scans were obtained in a subset of patients.

Results  Eighteen patients with tuberous sclerosis complex (mean [SD] age, 48 years [9.54]; 13 women [72%]), 16 with frontotemporal dementia (60 [6.93] years; 7 women [44%]) and 18 healthy control individuals (63 [3.85] years; 9 women [50%]) were included. The tuberous sclerosis–associated neuropsychiatric disorders checklist and neuropsychological test results were not significantly different when the tuberous sclerosis complex and frontotemporal dementia cohorts were compared. The tuberous sclerosis complex cohort exhibited elevated cerebral spinal fluid phosphorylated tau181 and neurofilament light chain with a mean of 32 pg/mL and 2300 pg/mL, respectively, when compared to healthy control individuals. All 3 patients with tuberous sclerosis complex who underwent fluorine 1B–labeled flortaucipir tau positron emission tomographic neuroimaging showed punctate foci of elevated [18F]flortaucipir binding in the frontal and temporal regions.

Conclusions and Relevance  Adults with tuberous sclerosis complex showed phenotypic overlap with frontotemporal dementia. The results support a possible clinical continuum between tuberous sclerosis–associated neuropsychiatric disorders and frontotemporal dementia and highlights a potential pathophysiological link between neurodevelopmental and neurodegenerative processes. Quantitative neuropsychological testing and the tuberous sclerosis–associated neuropsychiatric disorders checklist, potentially supplemented by cerebral spinal fluid and imaging biomarkers, could be used to screen and prognosticate for risk of a neurodegenerative process in adult patients with tuberous sclerosis complex.

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