ABSTRACT
OBJECTIVE: The goal of this study was to characterize a Swedish family with members affected by spinocerebellar ataxia 27 (SCA27), a rare autosomal dominant disease caused by mutations in fibroblast growth factor 14 (FGF14). Despite normal structural neuroimaging, psychiatric manifestations and intellectual disability are part of the SCA27 phenotype raising the need for functional neuroimaging. Here, we used clinical assessments, structural and functional neuroimaging to characterize these new SCA27 patients. Since one patient presents with a psychotic disorder, an exploratory study of markers of schizophrenia associated with GABAergic neurotransmission was performed in fgf14-/- mice, a preclinical model that replicates motor and learning deficits of SCA27. METHODS: A comprehensive characterization that included clinical assessments, cognitive tests, structural neuroimaging studies, brain metabolism with 18 F-fluorodeoxyglucose PET ([18F] FDG PET) and genetic analyses was performed. Brains of fgf14-/- mice were studied with immunohistochemistry. RESULTS: Nine patients had ataxia, and all affected patients harboured an interstitial deletion of chromosome 13q33.1 encompassing the entire FGF14 and integrin subunit beta like 1 (ITGBL1) genes. New features for SCA27 were identified: congenital onset, psychosis, attention deficit hyperactivity disorder and widespread hypometabolism that affected the medial prefrontal cortex (mPFC) in all patients. Hypometabolism in the PFC was far more pronounced in a SCA27 patient with psychosis. Reduced expression of VGAT was found in the mPFC of fgf14-/- mice. CONCLUSIONS: This is the second largest SCA27 family identified to date. We provide new clinical and preclinical evidence for a significant psychiatric component in SCA27, strengthening the hypothesis of FGF14 as an important modulator of psychiatric disease.
Subject(s)
Brain/diagnostic imaging , Pedigree , Prefrontal Cortex/metabolism , Spinocerebellar Degenerations/genetics , Adolescent , Adult , Animals , Attention Deficit Disorder with Hyperactivity/complications , Chromosome Deletion , Chromosomes, Human, Pair 13 , Cognition Disorders/genetics , Fibroblast Growth Factors/genetics , Fluorodeoxyglucose F18 , Genotype , Humans , Immunohistochemistry , Integrin beta1/genetics , Magnetic Resonance Imaging , Mice, Knockout , Neuroimaging , Neuropsychological Tests , Phenotype , Positron-Emission Tomography , Psychotic Disorders/complications , Radiopharmaceuticals , Spinocerebellar Degenerations/diagnostic imaging , Sweden , Vesicular Inhibitory Amino Acid Transport Proteins/metabolism , Young AdultABSTRACT
The development of tau-specific positron emission tomography (PET) tracers allows imaging in vivo the regional load of tau pathology in Alzheimer's disease (AD) and other tauopathies. Eighteen patients with baseline investigations enroled in a 17-month follow-up study, including 16 with AD (10 had mild cognitive impairment and a positive amyloid PET scan, that is, prodromal AD, and six had AD dementia) and two with corticobasal syndrome. All patients underwent PET scans with [18F]THK5317 (tau deposition) and [18F]FDG (glucose metabolism) at baseline and follow-up, neuropsychological assessment at baseline and follow-up and a scan with [11C]PIB (amyloid-ß deposition) at baseline only. At a group level, patients with AD (prodromal or dementia) showed unchanged [18F]THK5317 retention over time, in contrast to significant decreases in [18F]FDG uptake in temporoparietal areas. The pattern of changes in [18F]THK5317 retention was heterogeneous across all patients, with qualitative differences both between the two AD groups (prodromal and dementia) and among individual patients. High [18F]THK5317 retention was significantly associated over time with low episodic memory encoding scores, while low [18F]FDG uptake was significantly associated over time with both low global cognition and episodic memory encoding scores. Both patients with corticobasal syndrome had a negative [11C]PIB scan, high [18F]THK5317 retention with a different regional distribution from that in AD, and a homogeneous pattern of increased [18F]THK5317 retention in the basal ganglia over time. These findings highlight the heterogeneous propagation of tau pathology among patients with symptomatic AD, in contrast to the homogeneous changes seen in glucose metabolism, which better tracked clinical progression.
Subject(s)
Alzheimer Disease/diagnostic imaging , Dementia/physiopathology , tau Proteins/metabolism , Aged , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Aniline Compounds/pharmacology , Brain/metabolism , Cognition , Cognitive Dysfunction/metabolism , Dementia/diagnostic imaging , Disease Progression , Female , Fluorodeoxyglucose F18/metabolism , Follow-Up Studies , Glucose/metabolism , Humans , Longitudinal Studies , Male , Middle Aged , Neuropsychological Tests , Positron-Emission Tomography/methods , Quinolines/pharmacology , RadiopharmaceuticalsABSTRACT
[(11)C]-PIB positron emission tomography ([(11)C]-PIB PET) is a sensitive marker of amyloid in Alzheimer's disease (AD), but its specificity has not been fully evaluated. Vascular amyloid-beta deposition is common in Parkinson's disease (PD) and alpha-synuclein, the major component of the Lewy bodies in PD, forms amyloid fibrils. We investigated five apparently cognitively normal PD patients with [(11)C]-PIB PET. The results were compared to 16 patients with AD and six healthy controls from a previous study. [(11)C]-PIB retention was not significantly increased in our patients who all had early stage PD. Further studies of more advanced PD patients are warranted.
Subject(s)
Benzothiazoles/metabolism , Parkinson Disease/diagnostic imaging , Positron-Emission Tomography/methods , Aged , Aniline Compounds , Brain Mapping , Female , Humans , Image Processing, Computer-Assisted , Male , Middle Aged , ThiazolesABSTRACT
Purpose: The aim of the study was to examine the utility of PET with 11C-Methionine in diagnosis and evaluation of the treatment efficacy in childhood brain tumors.Methods: 16 PET-studies were performed in 11 children, 4-17years old, 3 boys and 8 girls, with brain tumors or tumor suspicion. Reasons for PET-study were an unclear diagnosis of tumor (7 cases), treatment efficacy definition (5 cases) and identification of tumor recurrence (3 cases). Studies were performed after i.v. injection of 11C-Methionine (6-9 MBq/kg). MRI or CT of brain was done before the PET-study in all patients. Diagnosis was confirmed by clinical follow-up or biopsy.Results: In 2 of 7 patients with suspicion of brain tumor no areas with pathological uptake of 11C-Methionine were found. In a patient with unclear tumor a benign process (ependimoma) was revealed that allowed avoiding a biopsy. A benign tumor detection in 2 patients with malignancy suspicion considerably affected treatment tactics. In 2 patients supposed benign growth was confirmed. In 2 of 3 patients with question of recurrence after surgery or radiotherapy and inconclusive MRI and CT picture malignant growth was found and in 1 patient was rejected. Repeated PET-studies in 2 patients with prolactinoma during therapy allowed prompt (within a few days) control of tumor response.Conclusion: The assessment of tumor metabolic activity in paediatric oncological practice using PET with 11C-Methionine is a reliable method in the correct indication of brain tumor origin and in prompt evaluation of treatment efficacy and control of recurrence.
