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

Abstract

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 PARTICIPANTSCase-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 MEASURESTuberous sclerosis-associated neuropsychiatric disorders checklist severity score, neuropsychologic test scores, cerebral spinal fluid concentrations of phosphorylated tau 181 , 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 tau 181 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 [ 18 F]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.

TSC1loss-of-function increases risk for tauopathy by inducing tau acetylation and preventing autophagy-mediated tau clearance

“…1C ). These results suggest that, similar to our earlier reports ( 11, 15 ), genetic variants that decrease levels of TSC1/hamartin are associated with tauopathy.…”

“…In earlier clinical-translational studies, we have shown a linkage between TSC1 gene and agerelated tauopathies (11,15). With this study, we establish the mechanistic basis for this linkage, adding TSC1 to a set of genes including glucocerebrosidase A (GBA), progranulin (PGRN) and cathepsin D (CTSD) in which pathogenic variants are associated with both childhood developmental and age-associated neurodegenerative diseases (7,8,53).…”

“…We have previously demonstrated a link between FTLD and pathogenic variants in TSC1 (11,15). To better understand the relationship between TSC1 and risk of tauopathies, we examined the frequency of rare TSC1 variants in a cohort of individuals diagnosed with early-onset Alzheimer's disease (EOAD) (16), which has a stronger contribution of tau pathology than its more common, late-onset counterpart.…”

“…TSC can manifest in a highly heterogeneous manner, ranging from cases characterized by early childhood onset of intractable seizures and severe developmental delay to those presenting in adulthood with only skin stigmata and mild psychiatric symptoms ( 13, 14 ). To determine if otherwise cognitively normal adults with TSC exhibited any evidence for pre-morbid cognitive decline, we gathered a cohort of adults with mild TSC and found an age-associated cognitive phenotype consistent with FTD ( 15 ). In our earlier studies, TSC1 mutations carriers exhibited evidence of tau accumulation in cell-based models, neuropathology ( 11 ) or by positivity on tau positron emission tomography (PET) imaging ( 15 ).…”

“…To determine if otherwise cognitively normal adults with TSC exhibited any evidence for pre-morbid cognitive decline, we gathered a cohort of adults with mild TSC and found an age-associated cognitive phenotype consistent with FTD ( 15 ). In our earlier studies, TSC1 mutations carriers exhibited evidence of tau accumulation in cell-based models, neuropathology ( 11 ) or by positivity on tau positron emission tomography (PET) imaging ( 15 ). Thus, clinical, genetic, experimental and neuroimaging data all support an association of TSC1 gene mutations with tauopathy.…”