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

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-ß 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.

CSF nerve growth factor (ß-NGF) is increased but CSF insulin-like growth factor-(IGF-1) is normal in children with tuberous sclerosis and infantile spasms.

Tuberous sclerosis is associated with epilepsy that is often refractory. We examined cerebrospinal fluid (CSF) concentrations for neurotrophins, nerve growth factor (ß-NGF) and insulin-like growth factor (IGF-1) in children with infantile spasms between 1997 and 2010. We classified the patients as follows: tuberous sclerosis (n = 5), cryptogenic spasms (n = 6), postinfectious spasms (n = 5) and other symptomatic spasms (n = 22). We had 22 age- and sex-matched controls for CSF-NGF and 14 for CSF-IGF-1. The median of CSF-NGF was higher in those with tuberous sclerosis, 56 (minimum-maximum, 8.0-131) ng/L, in relative to age- and sex-matched controls, 6.7 (0.0-22) ng/L, and symptomatic infantile spasms, 0.0 (0.0-4.5) ng/L or cryptogenic cases of infantile spasms, 6.2 (3.9-8.8) ng/L, respectively. CSF-NGF were highest in children with postinfectious aetiology, 408 (89-778) ng/L. CSF-IGF-1 of tuberous sclerosis, 0.65 (0.35-0.98) µg/L, did not differ from the cryptogenic spasms, 0.68 (0.32-0.87) µg/L, or from age- and sex-matched controls 0.52 (0.22-0.77) µg/L. Patients with tuberous sclerosis and cryptogenic spasms had normal development prior the ACTH therapy. We suggest that increased CSF-NGF might indicate a persistent activation of inflammatory pathways in cortical tubers in tuberous sclerosis and this would reflect in CSF concentrations.

Kynurenic acid is decreased in cerebrospinal fluid of patients with infantile spasms.

Cerebrospinal fluid (CSF) from 8 patients with symptomatic infantile spasms was collected before specific treatment for infantile spasms. The concentration of CSF kynurenic acid (KYA) and 3-hydroxykynurenine (3-OHKY) in infantile spasms was analyzed by high-performance liquid chromatography and compared with CSF KYA from 10 age-matched controls. The levels of CSF KYA were significantly lower in infantile spasm patients compared to controls (P < .05). In contrast, the levels of CSF 3-OHKY were significantly higher in infantile spasm patients than in controls (P < .05). These findings suggest that the presence of seizures in infantile spasms is associated with altered metabolism of 3-OHKY. The possibility that seizures may be related to increased or decreased production of certain kynurenine metabolites is discussed.

Cerebrospinal fluid "specific" proteins in various degenerative neurological diseases.

Cerebrospinal fluid (CSF) from patients suffering from various degenerative neurological diseases was fractionated into "CSF-specific" and antigenically serum-like proteins, using affinity chromatography with antihuman serum antibodies. The samples were isoelectric focused. Protein patterns were compared to similarly treated CSF from young normal volunteers and age matched controls. Several changes are described and 2 pathological patterns of the CSF-specific fraction could be identified. One pattern was characteristic for Alzheimer's dementia (AD) and senile dementia of the Alzheimer type (SDAT), but also seen in a few other diseases. The other pattern was seen in several of the investigated groups, most prominent in Huntington's chorea.