Benserazide as a potential novel fetal hemoglobin inducer: an observational study in non-carriers of hemoglobin disorders.

Induction of fetal hemoglobin production with hydroxyurea is an effective strategy in sickle cell disease and beta thalassemias, but up to 20% of patients do not respond to or cannot tolerate it. Benserazide is used in the treatment of Parkinson's disease and was noticed to induce gamma globin in preclinical models. We hypothesized that chronic treatment with benserazide-containing medication may be associated with increase in HbF production and in circulating F-cells. Blood samples were collected from 50 subjects including 35 patients on benserazide for Parkinson's disease, 10 healthy controls, and 5 patients with sickle cell anemia as positive controls for high fetal hemoglobin. We found a strong correlation between HbF and circulating F-cells in the entire population, but we found no significant increase in HbF and F-cell percentage in patients taking benserazide up to 700 mg daily. No hematologic abnormalities attributable to benserazide use after up to 22 years were detected. Our data support long-term safety and tolerability of benserazide at doses ten times higher than used in preclinical models to induce fetal hemoglobin. Further clinical trials enrolling patients with sickle cell disease and thalassemia are warranted to provide insight into its efficacy to treat those populations.

Is Ataxia an Underestimated Symptom of Huntington's Disease?

Background: Huntington's disease (HD) is a progressive disorder characterized by motor, cognitive and psychiatric features. Cerebellar ataxia is classically considered as uncommon in HD clinical spectrum. Objective: To determine the prevalence of cerebellar ataxia in patients with HD, both in the early and in the late stages of HD. Methods: Seventy-two individuals considered eligible were assessed by two trained doctors, applying the Scale for Assessment and Rating of Ataxia (SARA) and Brief Ataxia Rating Scale (BARS) for ataxia, the Unified Huntington's Disease Rating Scale (UHDRS) and also, Barthel Index (BI), in order to evaluate functional capacity. Results: Fifty-one patients (70.8%) presented with clinical ataxia at the time of examination (mean time of disease was 9.1 years). Six (8.33%) patients presented with cerebellar ataxia as first symptom. When stratified according to time of disease, a decline in the presence of chorea (p = 0.032) and an increase in cognitive deficit (p = 0.023) were observed in the patients as the disease progressed. The presence of ataxia was associated with longer duration of illness and severity of illness (UHDRS) (p < 0.0001), and shorter Barthel (less functionality) (p = 0.001). Conclusions: Cerebellar involvement may play an important role in natural history of brain degeneration in HD. The presence of cerebellar ataxia in HD is relevant and it may occur even in early stages, and should be included as part of the motor features of the disease.

Differential Pattern of Cerebellar Atrophy in Tremor-Predominant and Akinetic/Rigidity-Predominant Parkinson's Disease.

Parkinson's disease (PD) is an akinetic-rigid disorder characterized by basal ganglia dysfunction and a possible cerebello-thalamo-cortical circuit involvement. This study aims to investigate the pattern of cerebellar involvement in PD and to assess whether it correlates with clinical parameters. MRI scans were acquired from 50 healthy controls (HC) and 63 patients; 44 were classified as tremor-predominant-PD (PDT) and 19 as akinetic/rigidity-predominant-PD (PDAR). We designed an analysis of covariance including the three groups and contrasted as follows: (1) all 63 PD vs HC, (2) PDT vs HC, (3) PDAR vs HC, and (4) PDT vs PDAR. For a precise evaluation of the cerebellum, we used the SUIT tool for voxel-based morphometry. Applying p = 0.001 and extent threshold = 20 voxels, the overall PD group vs HC showed decreased gray matter (GM) in the left lobules VI and crus I. The PDT group showed decreased cerebellar GM when compared with HC at left lobules VI, VIIb, and VIIIa; at right lobules Crus I, VIIb, and VIIIb; and vermal lobules VI and VIIIa. When compared with PDAR, PDT also showed a decrease in the left lobules VIIIa (p < 0.001). There were small clusters of both positive and negative correlation between disease duration and PDT group. The PDAR group showed no cerebellar changes. Our findings support the growing evidence of cerebellar involvement in the pathogenesis of the resting tremor.

Pattern of Reduced Functional Connectivity and Structural Abnormalities in Parkinson's Disease: An Exploratory Study.

BACKGROUND: MRI brain changes in Parkinson's disease (PD) are controversial. OBJECTIVES: We aimed to describe structural and functional changes in PD. METHODS: Sixty-six patients with PD (57.94 ± 10.25 years) diagnosed according to the UK Brain Bank criteria were included. We performed a whole brain analysis using voxel-based morphometry (VBM-SPM 8 software), cortical thickness (CT) using CIVET, and resting-state fMRI using the Neuroimaging Analysis Kit software to compare patients and controls. For VBM and CT we classified subjects into three groups according to disease severity: mild PD [Hoehn and Yahr scale (HY) 1-1.5], moderate PD (HY 2-2.5), and severe PD (HY 3-5). RESULTS: We observed gray matter atrophy in the insula and inferior frontal gyrus in the moderate PD and in the insula, frontal gyrus, putamen, cingulated, and paracingulate gyri in the severe groups. In the CT analysis, in mild PD, cortical thinning was restricted to the superior temporal gyrus, gyrus rectus, and olfactory cortex; in the moderate group, the postcentral gyrus, supplementary motor area, and inferior frontal gyrus were also affected; in the severe PD, areas such as the precentral and postentral gyrus, temporal pole, fusiform, and occipital gyrus had reduced cortical thinning. We observed altered connectivity at the default mode, visual, sensorimotor, and cerebellar networks. CONCLUSION: Subjects with mild symptoms already have cortical involvement; however, further cerebral involvement seems to follow Braak's proposed mechanism. Similar regions are affected both structurally and functionally. We believe the combination of different MRI techniques may be useful in evaluating progressive brain involvement and they may eventually be used as surrogate markers of disease progression.