ABSTRACT
BACKGROUND: The P3 event-related potential (ERP) is presumably partly generated by the basal ganglia. Because degeneration of these brain structures starts many years before clinical disease onset in Huntington's disease (HD), studying the interplay between P3 characteristics and basal ganglia volumes in 'premanifest' carriers might lead to new insights into the disease process. METHODS: Fourteen premanifest\ HD mutation carriers and twelve non-mutation carriers underwent clinical, MRI and P3-ERP investigations. The P3 was measured during the Sustained Attention to Response Task. RESULTS: P3 amplitude and latency did not differ between groups. In carriers, longer P3 latency during Go-trials was strongly associated with smaller caudate, putamen and globus pallidus volumes (r values up to -0.827, P ≤ 0.001). CONCLUSION: The exceptionally strong relations of P3 latency with basal ganglia volumes in carriers suggest that the P3 may provide a marker for disease progression in HD.
Subject(s)
Basal Ganglia/physiopathology , Event-Related Potentials, P300/physiology , Huntington Disease/physiopathology , Atrophy , Basal Ganglia/pathology , Early Diagnosis , Electroencephalography/methods , Heterozygote , Humans , Huntingtin Protein , Huntington Disease/pathology , Nerve Tissue Proteins/genetics , Nuclear Proteins/genetics , Predictive Value of Tests , Prognosis , Reaction Time/geneticsABSTRACT
OBJECTIVE: Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the HD gene (HTT). We aimed to assess whether interaction between CAG repeat sizes in the mutant and normal allele could affect disease severity and progression. METHODS: Using linear regression and mixed-effects models, the influence of mutant and normal CAG repeat sizes interaction was assessed on 1) age at onset in 921 patients with HD, 2) clinical severity and progression in 512 of these patients with follow-up data available, and 3) basal ganglia volume on magnetic resonance images in 16 premanifest HD mutation carriers. RESULTS: Normal and mutant CAG repeat sizes interacted to influence 1) age at onset (p = 0.001), 2) severity or progression of motor, cognitive, and functional, but not behavioral, symptoms in patients with HD (all p < 0.05), and 3) in premanifest subjects, basal ganglia volumes (p < 0.05). In subjects with mutant CAG expansions in the low range, increasing size of the normal repeat correlated with more severe symptoms and pathology, whereas for those subjects with expansions in the high range, increasing size of the normal repeat correlated with less severe symptoms and pathology. CONCLUSIONS: Increasing CAG repeat size in normal HTT diminishes the association between mutant CAG repeat size and disease severity and progression in Huntington disease. The underlying mechanism may involve interaction of the polyglutamine domains of normal and mutant huntingtin (fragments) and needs further elucidation. These findings may have predictive value and are essential for the design and interpretation of future therapeutic trials.
Subject(s)
Huntington Disease/epidemiology , Huntington Disease/genetics , Serotonin Plasma Membrane Transport Proteins/genetics , Trinucleotide Repeat Expansion , Adolescent , Adult , Age of Onset , Aged , Basal Ganglia/pathology , Child , Disease Progression , Female , Follow-Up Studies , Humans , Huntington Disease/pathology , Magnetic Resonance Imaging , Male , Middle Aged , Mutation , Prospective Studies , Severity of Illness Index , Young AdultABSTRACT
OBJECTIVE: Neurological symptoms have been reported in patients treated with anti-TNF-alpha. In a pilot study we evaluated the effect of anti-TNF-alpha on cerebral parenchyma using advanced Magnetic Resonance (MR) techniques. METHODS: Seven patients with a systemic inflammatory disease (5 rheumatoid arthritis, 2 psoriatic arthritis) had Magnetization Transfer Imaging, Diffusion Weighted Imaging (DWI) and Magnetic Resonance Spectroscopy (MRS) of the brain before and after administration of anti-TNF-alpha. Four patients were neuropsychologically evaluated. RESULTS: After treatment with TNF-alpha blocking agents the Magnetization Transfer Ratio histogram Peak-heights (MTR-Pht) of the white and gray matter decreased (p < 0.01 and p < 0.05 respectively). The Apparent Diffusion Coefficient for the white and gray matter and the metabolite ratios in the centrum semiovale did not significantly change after therapy. Neuropsychological assessment showed no difference before and after anti-TNF-alpha. CONCLUSION: The decrease of the MTR-Pht after anti-TNF-alpha therapy suggests loss of parenchyma integrity; however, these changes could not be attributed to inflammation or demyelination based on our complementary DWI and MRS data. The decrease of the MTR-Pht did not result in decreased cognitive function.
