Magnetization transfer imaging in ‘premanifest’ Huntington’s disease

To investigate whether magnetization transfer imaging (MTI) is a useful detector of diffuse brain abnormalities in ‘premanifest’ carriers of the Huntington’s disease (HD) gene mutation. Furthermore we examined the relations between MTI, clinical measures and CAG repeat length. Sixteen premanifest carriers of the HD gene without motor manifestation and 14 non-carriers underwent a clinical evaluation and a MRI scan. MTI analysis of whole brain, grey matter and white matter was performed producing magnetization transfer ratio (MTR) histograms. A lower peak height of the grey matter MTR histogram in carriers was significantly associated with more UHDRS motor abnormalities. Furthermore, a lower peak height of the whole brain, grey and white matter was strongly associated with a longer CAG repeat length. MTI measures themselves did not differ significantly between carriers and non-carriers. In premanifest HD mutation carriers, a lower MTR peak height, reflecting worse histological brain composition, was related to subtle motor abnormalities and higher CAG repeat length. Although we could not detect altered MTI characteristics in carriers of the HD gene mutation without clinical manifestations, we did provide evidence that the MTR peak height might reflect genetic and subclinical disease burden and may be of value in monitoring further disease progression and provide insight in clinical heterogeneity

MRI T2 Hypointensities in basal ganglia of premanifest Huntington's disease

Increased iron levels have been demonstrated in the basal ganglia of manifest Huntington’s disease (HD). An excess in iron accumulation correlates with MRI T2-weighted hypointensity. Determination of the amount of hypointensities in the basal ganglia in the premanifest phase of HD may give more insight in the role of iron in the pathogenesis of HD. Therefore, the present study assessed whether the degree of hypointensities on T2-w MRI in the basal ganglia of premanifest gene carriers differs from non-carriers. Seventeen HD gene carriers without clinical motor signs and 15 non-carriers underwent clinical evaluation and MRI scanning. The amount of T2-w hypointensities was determined using a computer-assisted quantitative method that classified each pixel in the basal ganglia as hypointense or not, resulting in a total of hypointense pixels for each individual. Carriers showed an increased amount of hypointensities in the basal ganglia compared to non-carriers. More hypointensities were furthermore associated with a higher UHDRS total motor score, a longer CAG repeat length and a greater probability of developing symptoms within 5 years. We concluded that the increased amount of hypointensities in the basal ganglia of premanifest carriers of the HD gene may reflect excessive iron deposition and a role for iron in the neuropathology of HD. Furthermore, this phenomenon is associated with clinical and biological disease characteristics. An increased amount of hypointensities on T2-w MRI in the basal ganglia may be considered a biomarker for HD

Striatal metabolism and psychomotor speed as predictors of motor onset in Huntington's disease

The clinical diagnosis of Huntington's disease (HD) is based on the motor symptoms, although these can be preceded by cognitive and behavioral changes. Biomarker studies have shown that structural imaging modalities are useful biomarkers of HD onset, while functional imaging measures have been studied less often for this purpose. Our aim was to investigate the combined value of 18-fluorodesoxyglucose (FDG)-PET and cognitive measures as biomarkers of HD onset. Twenty-two premanifest mutation carriers of HD (PMCs) and 11 healthy controls were assessed twice with FDG-PET scan, neurological and neuropsychological assessments over a 2-year interval. Seventeen PMCs had an additional third neurological evaluation, 10 years after baseline. Disease load was defined as the probability of motor onset within 5 years. Metabolism in putamen, caudate and pallidum of PMCs was significantly lower than that of controls, at both assessments. Almost half of the PMCs had converted to manifest HD 10 years later and all converters had low average or abnormal putaminal metabolism at 2 year follow-up. In contrast, all PMCs with normal putaminal metabolism at 2 year follow-up remained premanifest during the following 8 years. Furthermore, glucose metabolism of putamen explained a substantial part of the variance in disease load. A composite score of psychomotor tests contributed significantly to the prediction model as well, while cognitive performance was comparable for PMCs and controls. We conclude that in future clinical trials a combination of psychomotor tests and putaminal glucose metabolism may be used to identify PMCs close to motor onset of HD

Effect of NOTCH3 EGFr Group, Sex, and Cardiovascular Risk Factors on CADASIL Clinical and Neuroimaging Outcomes

BACKGROUND A retrospective study has shown that EGFr (epidermal growth factor-like repeat) group in the NOTCH3 gene is an important cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) disease modifier of age at first stroke and white matter hyperintensity (WMH) volume. No study has yet assessed the effect of other known CADASIL modifiers, that is, cardiovascular risk factors and sex, in the context of NOTCH3 EGFr group. In this study, we determined the relative disease-modifying effects of NOTCH3 EGFr group, sex and cardiovascular risk factor on disease severity in the first genotype-driven, large prospective CADASIL cohort study, using a comprehensive battery of CADASIL clinical outcomes and neuroimaging markers. METHODS Patients with CADASIL participated in a single-center, prospective cohort study (DiViNAS [Disease Variability in NOTCH3 Associated Small Vessel Disease]) between 2017 and 2020. The study protocol included a clinical assessment, neuropsychological test battery and brain magnetic resonance imaging on a single research day. Multivariable linear, logistic and Cox regression models were used to cross-sectionally assess the effect of CADASIL modifiers on clinical severity (stroke, disability, processing speed) and neuroimaging markers (WMH volume, peak width of skeletonized mean diffusivity, lacune volume, brain volume, cerebral microbleed count). RESULTS Two hundred patients with CADASIL participated, of which 103 harbored a NOTCH3 EGFr 1-6 variant and 97 an EGFr 7-34 variant. NOTCH3 EGFr 1-6 group was the most important modifier of age at first stroke (hazard ratio, 2.45 [95% CI, 1.39-4.31]; P=0.002), lacune volume (odds ratio, 4.31 [95% CI, 2.31-8.04]; P=4.0×10-6), WMH volume (B=0.81 [95% CI, 0.60-1.02]; P=1.1×10-12), and peak width of skeletonized mean diffusivity (B=0.65 [95% CI, 0.44-0.87]; P=1.6×10-8). EGFr 1-6 patients had a significantly higher WMH volume in the anterior temporal lobes and superior frontal gyri and a higher burden of enlarged perivascular spaces. After NOTCH3 EGFr group, male sex and hypertension were the next most important modifiers of clinical outcomes and neuroimaging markers. CONCLUSIONS NOTCH3 EGFr group is the most important CADASIL disease modifier not only for age at first stroke and WMH volume but also strikingly so for a whole battery of clinically relevant disease measures such as lacune volume and peak width of skeletonized mean diffusivity. NOTCH3 EGFr group is followed in importance by sex, hypertension, diabetes, and smoking

Cognitive and motor functioning in gene carriers for Huntington's disease: A baseline study

The aim of this study was to investigate the first changes in cognitive and motor functioning in Huntington's disease. Forty-six gene carriers, not clinically diagnosed for HD, were compared with 88 non-gene carriers. Gene carriers performed significantly worse on the Benton Visual Retention Test. This result was due to a minority of participants who had already developed cognitive impairment. Marginal differences appeared on the motor times of single reaction time measures after correction for motor signs. The findings are discussed in the context of inconsistencies in previous studies and underscore the need for longitudinal researc

Clinical and genetic characteristics of late-onset Huntington's disease

Background: The frequency of late-onset Huntington's disease (>59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive. Objective: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database. Methods: Participants with late- and common-onset (30–50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of ≤35 or a UHDRS motor score of ≤5 were excluded. Results: Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late-onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P <.001). Overall motor and cognitive performance (P <.001) were worse, however only disease motor progression was slower (coefficient, −0.58; SE 0.16; P <.001) compared to the common-onset group. Repeat size was significantly lower in the late-onset (n = 40.8; SD 1.6) compared to common-onset (n = 44.4; SD 2.8) (P <.001). Fewer late-onset patients (n = 451) had a positive family history compared to common-onset (n = 2940) (P <.001). Conclusions: Late-onset patients present more frequently with gait and balance problems as first symptom, and disease progression is not milder compared to common-onset HD patients apart from motor progression. The family history is likely to be negative, which might make diagnosing HD more difficult in this population. However, the balance and gait problems might be helpful in diagnosing HD in elderly patients