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1.  Prodromal Huntington Disease as a Model for Functional Compensation of Early Neurodegeneration 
PLoS ONE  2014;9(12):e114569.
Functional compensation demonstrated as mechanism to offset neuronal loss in early Alzheimer disease may also occur in other adult-onset neurodegenerative diseases, particularly Huntington disease (HD) with its genetic determination and gradual changes in structural integrity. In HD, neurodegeneration typically initiates in the dorsal striatum, successively affecting ventral striatal areas. Investigating carriers of the HD mutation with evident dorsal, but only minimal or no ventral striatal atrophy, we expected to find evidence for compensation of ventral striatal functioning. We investigated 14 pre- or early symptomatic carriers of the mutation leading to HD and 18 matched healthy controls. Participants underwent structural T1 magnetic resonance imaging (MRI) and functional MRI during a reward task that probes ventral striatal functioning. Motor functioning and attention were assessed with reaction time (RT) tasks. Structural images confirmed a specific decrease of dorsal striatal but only marginal ventral striatal volume in HD relative to control subjects, paralleling prolonged RT in the motor response tasks. While behavioral performance in the reward task during fMRI scanning was unimpaired, reward-related fMRI signaling in the HD group was differentially enhanced in the bilateral ventral striatum and in bilateral orbitofrontal cortex/anterior insula, as another region sensitive to reward processing. We provide evidence for the concept of functional compensation in premanifest HD which may suggest a defense mechanism in neurodegeneration. Given the so far inevitable course of HD with its genetically determined endpoint, this disease may provide another model to study the different aspects of the concept of functional compensation.
PMCID: PMC4277279  PMID: 25541992
2.  The personal experience of parenting a child with Juvenile Huntington's Disease: perceptions across Europe 
European Journal of Human Genetics  2013;21(10):1042-1048.
The study reported here presents a detailed description of what it is like to parent a child with juvenile Huntington's disease in families across four European countries. Its primary aim was to develop and extend findings from a previous UK study. The study recruited parents from four European countries: Holland, Italy, Poland and Sweden,. A secondary aim was to see the extent to which the findings from the UK study were repeated across Europe and the degree of commonality or divergence across the different countries. Fourteen parents who were the primary caregiver took part in a semistructured interview. These were analyzed using an established qualitative methodology, interpretative phenomenological analysis. Five analytic themes were derived from the analysis: the early signs of something wrong; parental understanding of juvenile Huntington's disease; living with the disease; other people's knowledge and understanding; and need for support. These are discussed in light of the considerable convergence between the experiences of families in the United Kingdom and elsewhere in Europe.
PMCID: PMC3778352  PMID: 23443023
Juvenile Huntington's disease; parent; qualitative
3.  Development of an ELISA assay for the quantification of soluble huntingtin in human blood cells 
BMC Biochemistry  2013;14:34.
Huntington’s disease (HD) is a monogenic disorder caused by an aberrant expansion of CAG repeats in the huntingtin gene (HTT). Pathogenesis is associated with expression of the mutant (mHTT) protein in the CNS, with its levels most likely related to disease progression and symptom severity. Since non-invasive methods to quantify HTT in the CNS do not exist, measuring amount of soluble HTT in peripheral cells represents an important step in development of disease-modifying interventions in HD.
An ELISA assay using commercially available antibodies was developed to quantify HTT levels in complex matrices like mammalian cell cultures lysates and human samples. The immunoassay was optimized using a recombinant full-length HTT protein, and validated both on wild-type and mutant HTT species. The ability of the assay to detect significant variations of soluble HTT levels was evaluated using an HSP90 inhibitor that is known to enhance HTT degradation. Once optimized, the bioassay was applied to peripheral blood mononuclear cells (PBMCs) from HD patients, demonstrating good potential in tracking the disease course.
The method described here represents a validated, simple and rapid bio-molecular assay to evaluate soluble HTT levels in blood cells as useful tool in disease and pharmacodynamic marker identification for observational and clinical trials.
PMCID: PMC4221641  PMID: 24274906
4.  Biological and clinical manifestations of Huntington’s disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data 
Lancet neurology  2009;8(9):791-801.
Huntington’s disease (HD) is an autosomal dominant, fully penetrant, neurodegenerative disease that most commonly affects adults in mid-life. Our aim was to identify sensitive and reliable biomarkers in premanifest carriers of mutated HTT and in individuals with early HD that could provide essential methodology for the assessment of therapeutic interventions.
This multicentre study uses an extensive battery of novel assessments, including multi-site 3T MRI, clinical, cognitive, quantitative motor, oculomotor, and neuropsychiatric measures. Blinded analyses were done on the baseline cross-sectional data from 366 individuals: 123 controls, 120 premanifest (pre-HD) individuals, and 123 patients with early HD.
The first participant was enrolled in January, 2008, and all assessments were completed by August, 2008. Cross-sectional analyses identified significant changes in whole-brain volume, regional grey and white matter differences, impairment in a range of voluntary neurophysiological motor, and oculomotor tasks, and cognitive and neuropsychiatric dysfunction in premanifest HD gene carriers with normal motor scores through to early clinical stage 2 disease.
We show the feasibility of rapid data acquisition and the use of multi-site 3T MRI and neurophysiological motor measures in a large multicentre study. Our results provide evidence for quantifiable biological and clinical alterations in HTT expansion carriers compared with age-matched controls. Many parameters differ from age-matched controls in a graded fashion and show changes of increasing magnitude across our cohort, who range from about 16 years from predicted disease diagnosis to early HD. These findings might help to define novel quantifiable endpoints and methods for rapid and reliable data acquisition, which could aid the design of therapeutic trials.
CHDI/High Q Foundation.
PMCID: PMC3725974  PMID: 19646924
5.  Evaluation of multi-modal, multi-site neuroimaging measures in Huntington's disease: Baseline results from the PADDINGTON study☆ 
NeuroImage : Clinical  2012;2:204-211.
Macro- and micro-structural neuroimaging measures provide valuable information on the pathophysiology of Huntington's disease (HD) and are proposed as biomarkers. Despite theoretical advantages of microstructural measures in terms of sensitivity to pathology, there is little evidence directly comparing the two.
40 controls and 61 early HD subjects underwent 3 T MRI (T1- and diffusion-weighted), as part of the PADDINGTON study. Macrostructural volumetrics were obtained for the whole brain, caudate, putamen, corpus callosum (CC) and ventricles. Microstructural diffusion metrics of fractional anisotropy (FA), mean-, radial- and axial-diffusivity (MD, RD, AD) were computed for white matter (WM), CC, caudate and putamen. Group differences were examined adjusting for age, gender and site. A formal comparison of effect sizes determined which modality and metrics provided a statistically significant advantage over others.
Macrostructural measures showed decreased regional and global volume in HD (p < 0.001); except the ventricles which were enlarged (p < 0.01). In HD, FA was increased in the deep grey-matter structures (p < 0.001), and decreased in the WM (CC, p = 0.035; WM, p = 0.053); diffusivity metrics (MD, RD, AD) were increased for all brain regions (p < 0.001). The largest effect sizes were for putamen volume, caudate volume and putamen diffusivity (AD, RD and MD); each was significantly larger than those for all other metrics (p < 0.05).
The highest performing macro- and micro-structural metrics had similar sensitivity to HD pathology quantified via effect sizes. Region-of-interest may be more important than imaging modality, with deep grey-matter regions outperforming the CC and global measures, for both volume and diffusivity. FA appears to be relatively insensitive to disease effects.
► Macro and microstructural metrics are sensitive to HD pathology cross-sectionally. ► Largest effect sizes for putamen volume, caudate volume and putamen diffusivity ► No significant advantage of highest performing macro over microstructural metrics ► Grey matter regions outperformed CC and global measures within each modality. ► FA appears to be relatively insensitive to disease effects.
PMCID: PMC3777685  PMID: 24179770
Huntington's disease; MRI; Diffusion; Volumetric
6.  Disease Severity and Progression in Progressive Supranuclear Palsy and Multiple System Atrophy: Validation of the NNIPPS – PARKINSON PLUS SCALE 
PLoS ONE  2011;6(8):e22293.
The Natural History and Neuroprotection in Parkinson Plus Syndromes (NNIPPS) study was a large phase III randomized placebo-controlled trial of riluzole in Progressive Supranuclear Palsy (PSP, n = 362) and Multiple System Atrophy (MSA, n = 398). To assess disease severity and progression, we constructed and validated a new clinical rating scale as an ancillary study.
Methods and Findings
Patients were assessed at entry and 6-montly for up to 3 years. Evaluation of the scale's psychometric properties included reliability (n = 116), validity (n = 760), and responsiveness (n = 642). Among the 85 items of the initial scale, factor analysis revealed 83 items contributing to 15 clinically relevant dimensions, including Activity of daily Living/Mobility, Axial bradykinesia, Limb bradykinesia, Rigidity, Oculomotor, Cerebellar, Bulbar/Pseudo-bulbar, Mental, Orthostatic, Urinary, Limb dystonia, Axial dystonia, Pyramidal, Myoclonus and Tremor. All but the Pyramidal dimension demonstrated good internal consistency (Cronbach α≥0.70). Inter-rater reliability was high for the total score (Intra-class coefficient = 0.94) and 9 dimensions (Intra-class coefficient = 0.80–0.93), and moderate (Intra-class coefficient = 0.54–0.77) for 6. Correlations of the total score with other clinical measures of severity were good (rho≥0.70). The total score was significantly and linearly related to survival (p<0.0001). Responsiveness expressed as the Standardized Response Mean was high for the total score slope of change (SRM = 1.10), though higher in PSP (SRM = 1.25) than in MSA (SRM = 1.0), indicating a more rapid progression of PSP. The slope of change was constant with increasing disease severity demonstrating good linearity of the scale throughout disease stages. Although MSA and PSP differed quantitatively on the total score at entry and on rate of progression, the relative contribution of clinical dimensions to overall severity and progression was similar.
The NNIPPS-PPS has suitable validity, is reliable and sensitive, and therefore is appropriate for use in clinical studies with PSP or MSA.
Trial Registration NCT00211224
PMCID: PMC3150329  PMID: 21829612
7.  Caudate Nucleus and Insular Activation During a Pain Suppression Paradigm Comparing Thermal and Electrical Stimulation 
Pain modulation is an integral function of the nervous system. It is needed to adapt to chronic stimuli. To gain insights into pain suppression mechanisms, two studies concerning the suppression of the feeling of pain with different stimulation modalities (heat vs. electrical stimuli) but using the same stimulation paradigms were compared: 15 subjects each had been stimulated on both hands under the instruction to suppress the feeling of pain.
Anterior insula and DLPFC activation was seen in both single modality studies and seems to be a common feature of pain suppression, as it is absent in the interaction analyses presented here.
During the task to suppress the feeling of pain, there were no consistent activations stronger under thermostimulation. But during electrostimulation, there was significantly stronger activation than during thermal stimulation in the caudate nucleus bilaterally and in the contralateral posterior insula. This may be attributed to the higher sensory-discriminative content and more demand on subjective rating and suppression of the painful electrical stimulus, compared to thermostimulation. The caudate nucleus seems to play an important role not only in the motor system but also in the modulation of the pain experience.
PMCID: PMC3106353  PMID: 21643502
Functional MRI; pain; caudate; insula; electrical; thermal.
8.  Summary of cerebrospinal fluid routine parameters in neurodegenerative diseases 
Journal of Neurology  2010;258(6):1034-1041.
In neurodegenerative diseases, cerebrospinal fluid analysis (CSF) is predominantly performed to exclude inflammatory diseases and to perform a risk assessment in dementive disorders by measurement of tau proteins and amyloid beta peptides. However, large scale data on basic findings of CSF routine parameters are generally lacking. The objective of the study was to define a normal reference spectrum of routine CSF parameters in neurodegenerative diseases. Routine CSF parameters (white cell count, lactate and albumin concentrations, CSF/serum quotients of albumin (Qalb), IgG, IgA, IgM, and oligoclonal IgG bands (OCB)) were retrospectively analyzed in an academic research setting. A total of 765 patients (Alzheimer’s disease (AD), Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), vascular dementia (VD), frontotemporal lobar degeneration (FTLD), progressive supranuclear palsy (PSP), multisystem atrophy (MSA), motor neuron diseases (MND), spinocerebellar ataxia (SCA), Huntington’s disease (HD)) and non-demented control groups including a group of patients with muscular disorders (MD). The main outcome measures included statistical analyses of routine CSF parameters. Mildly elevated Qalb were found in a small percentage of nearly all subgroups and in a higher proportion of patients with PSP, MSA, VD, PDD, and MND. With the exception of 1 MND patient, no intrathecal Ig synthesis was observed. Isolated OCBs in CSF were sometimes found in patients with neurodegenerative diseases without elevated cell counts; lactate levels were always normal. A slightly elevated Qalb was observed in a subgroup of patients with neurodegenerative diseases and does not exclude the diagnosis. Extensive elevation of routine parameters is not characteristic and should encourage a re-evaluation of the clinical diagnosis.
Electronic supplementary material
The online version of this article (doi:10.1007/s00415-010-5876-x) contains supplementary material, which is available to authorized users.
PMCID: PMC3101362  PMID: 21188408
Cerebrospinal fluid; Neurochemical investigation; Standard routine parameters; Neurodegenerative disorders; CSF flow
9.  Five siRNAs targeting three SNPs in Huntingtin may provide therapy for three-quarters of Huntington’s disease patients 
Current biology : CB  2009;19(9):774-778.
Among dominant neurodegenerative disorders, Huntington’s disease (HD) is perhaps the best candidate for treatment with small interfering RNAs (siRNAs) [1–9]. Invariably fatal, HD is caused by expansion of a CAG repeat in the Huntingtin gene, creating an extended polyglutamine tract that makes the Huntingtin protein toxic [10]. Silencing mutant Huntingtin mRNA should provide therapeutic benefit, but no siRNA strategy can yet distinguish among the normal and disease Huntingtin alleles and other mRNAs containing CAG repeats [11]. siRNAs targeting the disease isoform of a heterozygous single-nucleotide polymorphism (SNP) in Huntingtin provide an alternative [12–16], because such siRNAs should preserve expression of normal Huntingtin, which likely contributes to neuronal function [17–19]. We sequenced 22 predicted SNP sites in 225 human samples corresponding to HD and control subjects. We find that 48% of our patient population is heterozygous at a single SNP site; one isoform of this SNP is associated with HD. Several other SNP sites are frequently heterozygous. Consequently, five allele-specific siRNAs, corresponding to just three SNP sites, could be used to treat three-quarters of the United States and European HD patient populations. We have designed and validated selective siRNAs for the three SNP sites, laying the foundation for allele-specific RNAi therapy for HD.
PMCID: PMC2746439  PMID: 19361997
10.  Genetic Variants of the α-Synuclein Gene SNCA Are Associated with Multiple System Atrophy 
PLoS ONE  2009;4(9):e7114.
Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia and autonomic dysfunction. Pathogenic mechanisms remain obscure but the neuropathological hallmark is the presence of α-synuclein-immunoreactive glial cytoplasmic inclusions. Genetic variants of the α-synuclein gene, SNCA, are thus strong candidates for genetic association with MSA. One follow-up to a genome-wide association of Parkinson's disease has identified association of a SNP in SNCA with MSA.
We evaluated 32 SNPs in the SNCA gene in a European population of 239 cases and 617 controls recruited as part of the Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS) study. We used 161 independently collected samples for replication. Two SNCA SNPs showed association with MSA: rs3822086 (P = 0.0044), and rs3775444 (P = 0.012), although only the first survived correction for multiple testing. In the MSA-C subgroup the association strengthened despite more than halving the number of cases: rs3822086 P = 0.0024, OR 2.153, (95% CI 1.3–3.6); rs3775444 P = 0.0017, OR 4.386 (95% CI 1.6–11.7). A 7-SNP haplotype incorporating three SNPs either side of rs3822086 strengthened the association with MSA-C further (best haplotype, P = 8.7×10−4). The association with rs3822086 was replicated in the independent samples (P = 0.035).
We report a genetic association between MSA and α-synuclein which has replicated in independent samples. The strongest association is with the cerebellar subtype of MSA.
Trial Registration NCT00211224. [NCT00211224]
PMCID: PMC2743996  PMID: 19771175

Results 1-10 (10)