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We aimed to determine the origin and genetic characteristics of Huntington disease (HD) in the Middle East. We performed genetic and genealogical analyses to establish the ancestral origin of the HTT pathgenic variant from a large kindred from Oman (hereafter called the OM-HD-01 pedigree) by single-nucleotide polymorphism and dense haplotype analysis genotyping. We traced the oldest ancestry of the largest, eight-generation, OM-HD-01 pedigree (n = 302 subjects, with 54 showing manifest HD) back to sub-Saharan Africa and identified a unique HD haplotype carried by all pedigree members, which consisted of portions of the C6 and C9 haplotypes and was carried by all affected members. Such a unique HD haplotype was of African origin and appeared to be associated with large CAG repeat expansions on average and high frequency of juvenile-onset HD. Three other families from the same area were also identified and found carrying a Caucasian HD haplotype A, also shared by most families of Arab ancestry. Mutated HTT spread into Middle East with a unique haplotype of African origin, appeared to be associated with juvenile-onset, a HD condition frequently occurring in Black Africans, and may have a significant impact on further development of novel targeted genetic therapies.

We focused on Cognitive Reserve (CR) in patients with early Huntington Disease (HD) and investigated whether clinical outcomes might be influenced by lifetime intellectual enrichment over time. CR was evaluated by means of the Cognitive Reserve Index questionnaire (CRIq), an internationally validated scale which includes three sections: education, working activity, and leisure time. The clinical HD variables were quantified at three different time points (baseline-t0, 1 year follow up-t1 and 2 years follow up-t2) as per the Unified Huntington’s Disease Rating Scale (UHDRS), an internationally standardized and validated scale including motor, cognitive, functional and behavioral assays. Our sample consisted of 75 early manifest patients, withclinical stage scored according to the Total Functional Capacity (TFC) scale. Our correlational analysis highlighted a significant inverse association between CRIq leisure time (CRIq_LA) and longitudinal functional impairment (namely, the differential TFC score between t2 and t0 or ΔTFC) (p < 0.05), and the multidimensional progression of HD as measured by the composite UHDRS (cUHDRS, p < 0.01). CRIq_LA was significantly and positively associated with better cognitive performances at all time points (p < 0.05). Our results suggest that higher is the CRIq_LA, milder is the progression of HD in terms of functional, multidimensional and cognitive outcome.

The “Spazio Huntington—A Place for Children” program was launched in 2019. The aim was to contact at risk kids within Huntington disease (HD) families, to provide counseling to their parents and to start a prospective follow-up of kids suspicious to manifest pediatric HD (PHD). We met 25 at risk kids in two years, four of whom with PHD and highly expanded (HE) mutations beyond 80 CAG repeats. We rated motor, neuropsychological and behavioral changes in all PHD kids by the Unified HD Rating Scale (UHDRS)-total motor score (TMS) and additional measures of (1) cognitive level (Leiter International Performance Scale), (2) adaptive functioning (Adaptive Behavior Assessment Systems), (3) receptive language (Peabody Picture Vocabulary Test) and (4) behavioral abnormalities (Child Behavior Check List and Children’s Yale–Brown Obsessive Compulsive Scale). All PHD kids showed a severe progression of neurological and psychiatric manifestations including motor, cognitive and behavioral changes. The magnetic resonance imaging contributed to confirm the suspicious clinical observation by highlighting very initial striatum abnormalities in PHD. Spazio Huntington is a program to prospectively study PHD, the most atypical face of HD, and may represent the basis to recruit PHD patients in future clinical trials.

Background Juvenile-onset Huntington’s disease (joHD, neurological onset ≤20 years) is a rare HD variant associated with large CAG repeat-size alleles (>60), showing different clinical features from adulthood HD. Aims The aim of this study is twofold: i) To evaluate multimodal hybrid PET-MRI data fusion for characterizing joHD longitudinal brain changes; ii) to identify potential markers of disease progression, which might be useful in future trials to test disease-modifying drugs. Methods A 20-year-old female with stage-2 joHD, 62 CAG repeats and onset at 16 years, underwent 3T [18F]fluorodeoxyglucose (FDG) PET-MRI at two timepoints (Oct 2019, UHDRS-motor score=45 units and Feb 2021, UHDRS-motor score=53 units). The protocol included the simultaneous acquisition of FDG-PET, T1-weighted and resting-state functional MRI (rs-fMRI). Voxel-wise percentage changes at follow-up relative to baseline status were calculated on (i) grey matter (GM) density, (ii) FDG-PET uptake, (iii) rs-fMRI regional homogeneity (ReHo), and (iv) rs-fMRI amplitude of low frequency fluctuation (fALFF). Results Whole-brain GM density decreased by 31.9±21.1%. FDG uptake increased in the frontoparietal network (approx. 20%), while decreasing in the remaining regions, including the thalamus. ReHo and fALFF followed the pattern of PET changes, also highlighting increased functional connectivity in the frontal cortex opposed to decreased connectivity in posterior regions. Conclusion Hybrid PET/MRI is an emerging technique that allows individually-tailored evaluation of brain changes. Preliminary results are promising and showed rapid structural and metabolic changes in an adult patient with stage 2 joHD, resembling the trajectories reported in the literature in advanced adult HD patients, and involving specific regions thought to be key hubs affected by this disease.

Background With the development of new therapies entering clinical trials for HD, there is an increasing need to develop and validate biomarkers in accessible biofluids, such as blood, to follow disease progression and predict treatment outcomes. Some biomarkers do exist; however, reliable and readily available additional ones will be crucial in assessing the pathogenic process and pharmacologic responses to therapeutic interventions. Aims For the first time in HD, we detect and characterize circRNAs in peripheral blood of a cohort of gender and age-matched controls and HD patients at various stages of the disease. We studied their potential as biomarkers by evaluating their correlation with disease progression and the size of the CAG repeat. Methods 50 blood samples were collected from both HD patients and a healthy cohort of individuals. Total RNA was used for RNA sequencing, and the obtained data were aligned with STAR. DCC program was used to quantify circRNAs and CircTest (R package) to identify differentially expressed circRNA between different disease stages and controls. CAG repeat size correlation was also tested. To validate our findings, candidate circRNAs were quantified via RT-qPCR in our samples. Results Our study led to the discovery of 7, stringently defined circRNAs that possess 3 characteristics: differentially expressed in HD patients (all up-regulated, p-value 0.3 and p-value Conclusions We identified for the first time circRNAs whose expression increases in the blood of HD patients. Currently, we aim to validate these circular molecules in independent blood cohorts as well as in cerebrospinal fluid and plasma samples to fully elucidate whether these highly stable RNA molecules could be used as disease biomarkers.

Background The development of effective therapies for Huntington’s disease (HD) requires an active, informed, and lasting commitment from HD families to research. Specifically, those traditionally less involved in studies should be heard and engaged in this process: persons at risk for HD (HDRisk) and persons with premanifest HD (PreHD). Aim To determine which factors affect the willingness of persons with HDrisk and PreHD to participate in research and check for differences related to HD status. Methods The European Huntington Association (EHA) created an online survey to assess the perceptions and experiences about research participation among persons with HDRisk and PreHD. The two groups were compared on their answers to questions about research experience and knowledge, sources of information about research, the importance of reasons for getting involved and not getting involved in studies, and factors preventing and facilitating study participation. Results/Outcome The survey was filled by 263 persons with HDRisk and 262 persons with PreHD. While the overall motivation of both groups to engage in research was high, respondents with PreHD reported significantly more research experience and better research knowledge than respondents with HDRisk. Respondents with HDRisk identified more barriers to research participation and the need for more support to engage in studies compared to respondents with PreHD. Conclusions Motivation to take part in studies is high, despite limited research experience and literacy. This motivation is strongly influenced by HD status. Our findings highlight the relevance of planning tailored interventions to better support an informed participation of specific HD groups in research.

There has been great progress in Huntington’s disease (HD) research. Yet, effective treatments to halt disease before the onset of disabling symptoms are still unavailable. Scientific breakthroughs require an active and lasting commitment from families. However, they are traditionally less involved and heard in studies. Accordingly, the European Huntington Association (EHA) surveyed individuals at risk (HDRisk) and with premanifest HD (PreHD) to determine which factors affect their willingness to participate in research. Questions assessed research experience and knowledge, information sources, reasons for involvement and noninvolvement, and factors preventing and facilitating participation. The survey included 525 individuals, of which 68.8% never participated in studies and 38.6% reported limited research knowledge. Furthermore, 52% trusted patient organizations to get research information. Reasons for involvement were altruistic and more important than reasons for noninvolvement, which were related to negative emotions. Obstacles included time/financial constraints and invasive procedures, while professional support was seen as a facilitator. PreHD individuals reported less obstacles to research participation than HDRisk individuals. Overall, a high motivation to participate in research was noted, despite limited experience and literacy. This motivation is influenced by subjective and objective factors and, importantly, by HD status. Patient organizations have a key role in fostering motivation through education and support.

Background: Cognitive abnormalities in Huntington’s Disease (HD) can involve the specific impairment of the social perspective taking as well as difficulties in recognizing others’ mental state many years before the onset of motor symptoms. Aims: At the scope of assessing how the difficulties in mental state recognition might be an HD early sign before motor symptoms appear, our study was aimed to investigate how the recognition of others’ mental states in HD subjects is moderated by different stimulus related features (gender, difficulty (low, medium, high), and valence (positive, negative, neutral) of the mental states that are to be recognized). Methods: Subjects with premanifest (n = 20) and manifest (n = 40) HD performed the revised ‘Reading the Mind in the Eyes Test’ and were compared with age-matched healthy controls (HC, 40 subjects per cohort). Results: Our results highlight an early impairment in mental state recognition preceding manifest HD symptoms and a deterioration of these abilities with HD progression. Moreover, we found in HD premanifest subjects an impairment concerning the recognition of negative and neutral mental states, as well as of mental states with moderate recognition difficulty. Finally, we found that participant gender did not influence the performance in recognizing others’ mental states, while all participants recognized mental states displayed by females more accurately than those displayed by males. Conclusions: We conclude that difficulties in the recognition of complex mental states can be considered as an early sign of HD, before evident behavioral manifestations, and peculiar features of the stimulus influence it.

Introduction Behavioral and cognitive changes can be observed across all Huntington disease (HD) stages. Our multicenter and retrospective study investigated the association between cognitive and behavioral scale scores in manifest HD, at three different yearly timepoints. Methods We analyzed cognitive and behavioral domains by the Unified Huntington's Disease Rating Scale (UHDRS) and by the Problem Behaviors Assessment Short Form (PBA‐s), at three different yearly times of life (t0 or baseline, t1 after one year, t2 after two years), in 97 patients with manifest HD (mean age 48.62 ± 13.1), from three ENROLL‐HD Centers. In order to test the disease progression, we also examined patients’ motor and functional changes by the UHDRS, overtime. Results The severity of apathy and of perseveration/obsession was associated with the severity of the cognitive decline (p, Severity of apathy and perseveration/obsessions are significantly associated with the severity of the executive function impairment. This association may represent an additional key factor contributing to the severity of Huntington disease course. This cognitive‐behavior pattern determines a common underlying deficit attributable to a dysexecutive syndrome.

(1) Background: Sleep patterns are frequently disrupted in neurodegenerative disorders such as Huntington disease (HD); however, they are still poorly understood, especially their association with clinic features. Our study aimed to explore potential correlations between sleep features and motor, cognitive, behavioural and functional changes in manifest HD subjects. (2) Methods: We enrolled 42 patients who were assessed by the Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI) questionnaires; clinical features were evaluated by the validated ENROLL-HD platform assay, including the Unified Huntington’s Disease Rating Scale (UHDRS) and the Problem Behaviours Assessment Short Form (PBA-s). (3) Results: We found a significant association between the patients’ perception of sleep abnormalities and scores of impaired independence, cognitive and motor performances. Specifically, sleep efficiency (PSQI—C4 subscores) and the use of sleep medications (PSQI—C6 subscores) seem to be more frequently associated with the severity of the disease progression. (4) Conclusion: sleep abnormalities represent an important part of the HD clinical profile and can impair patients’ quality of life by affecting their level of independence, cognition performance and mental well-being.

The psychopathological profile of patients with medication overuse headache (MOH) appears to be particularly complex. To better define it, we evaluated their performance on a targeted psychological profile assessment. We designed a case-control study comparing MOH patients and matched healthy controls (HC). Headache frequency, drug consumption, HIT-6, and MIDAS scores were recorded. All participants filled in the following questionnaires: Beck Depression Inventory-II Edition (BDI-2), trait subtest of State-Trait Anxiety Inventory (STAI-Y), Difficulties in Emotion Regulation Scale (DERS), Barratt Impulsiveness Scale (BIS-11), Toronto Alexithymia Scale (TAS-20). The primary endpoint was to establish if MOH patients have an altered psychopathological profile. The secondary endpoint was to establish whether the worst profile correlates with the worsening of headache and disability measures. We enrolled 48 consecutive MOH patients and 48 HC. MOH patients showed greater difficulty in recognition/regulation of emotions (DERS, TAS-20), depression (BDI-2), anxiety (STAI-Y), and impulsiveness (BIS-11). We found a positive correlation among DERS, BDI-2, STAI-Y, and BIS scores and MIDAS and HIT-6 scores and among DERS and headache frequency and drug consumption. MOH patients showed a high rate of emotion regulation difficulties, depression, and anxiety, which may negatively affect their headaches. The ability to regulate/recognize emotions may play a central role in sustaining medication overuse.

Introduction: The study aims at investigating psychometric properties of the Edinburgh cognitive and behavioural ALS screen (ECAS) in Parkinson’s (PD) and Huntington’s (HD) diseases. The sensitivity and specificity of the ECAS in highlighting HD and PD cognitive-behavioural features and in differentiating between these two populations and from healthy controls (HC) were evaluated. Moreover, correlations between the ECAS and traditional cognitive measures, together with core clinical features, were analysed. Methods: Seventy-three PD patients, 38 HD patients, and 49 education-matched healthy participants were enrolled. Participants were administered the ECAS, together with other cognitive screening tools and psychological questionnaires. Patients’ behavioural assessment was also carried out with carers. Results: The ECAS distinguished between HD patients and HC and between the two clinical syndromes with high sensitivity and specificity. Even if the diagnostic accuracy of the ECAS in distinguishing between PD and HC was low, the PD cognitive phenotype was very well described by the ECAS performances. Convergent validity of the ECAS against other traditional cognitive screening was observed, as well as correlations with psychological aspects and typical clinical features, especially for the HD group. Conclusions: The ECAS represents a rapid and feasible tool, useful also in other neurodegenerative disorders affecting verbal-motor abilities than the amyotrophic lateral sclerosis such as PD and HD. Clinical applications in these neurodegenerative conditions require further investigations and, probably, some adaptations of the original test.

Huntington’s disease (HD) is a genetic neurodegenerative disorder that affects not only the motor but also the cognitive domain. In particular, cognitive symptoms such as impaired executive skills and deficits in recognizing other individuals’ mental state may emerge many years before the motor symptoms. This study was aimed at testing two cognitive hypotheses suggested by previous research with a new Stroop task created for the purpose: 1) the impairment of emotion recognition in HD is moderated by the emotions’ valence, and 2) inhibitory control is impaired in HD. Forty manifest and 20 pre-manifest HD patients and their age- and gender-matched controls completed both the traditional “Stroop Color and Word Test” (SCWT) and the newly created “Stroop Emotion Recognition under Word Interference Task” (SERWIT), which consist in 120 photographs of sad, calm, or happy faces with either congruent or incongruent word interference. On the SERWIT, impaired emotion recognition in manifest HD was moderated by emotion type, with deficits being larger in recognizing sadness and calmness than in recognizing happiness, but it was not moderated by stimulus congruency. On the SCWT, six different interference scores yielded as many different patterns of group effects. Overall our results corroborate the hypothesis that impaired emotion recognition in HD is moderated by the emotions’ valence, but do not provide evidence for the hypothesis that inhibitory control is impaired in HD. Further research is needed to learn more about the psychological mechanisms underlying the moderating effect of emotional valence on impaired emotion recognition in HD, and to corroborate the hypothesis that the inhibitory processes involved in Stroop tasks are not impaired in HD. Looking beyond this study, the SERWIT promises to make important contributions to disentangling the cognitive and the psychomotor aspects of neurological disorders. The research was approved by the Ethics Committee of the “Istituto Leonarda Vaccari”, Rome on January 24, 2018.

SummaryAims To analyze brain functional connectivity in the somatomotor and default-mode networks (DMNs) of patients with Huntington disease (HD), its relationship with gray matter (GM) volume loss, and functional changes after pridopidine treatment. Methods Ten patients and ten untreated controls underwent T1-weighted imaging and resting-state functional magnetic resonance imaging (fMRI); four patients were also assessed after 3 months of pridopidine treatment (90 mg/d). The seed-based functional connectivity patterns from the posterior cingulate cortex and the supplementary motor area (SMA), considered cortical hubs of the DMN and somatomotor networks, respectively, were computed. FMRIB Software Library voxel-based morphometry measured GM volume. Results Patients had GM volume decrease in all cortical and subcortical areas of the somatomotor network with preservation of the SMA, and increased somatomotor and DMN connectivity. In DMN structures, functional connectivity impairment preceded volume loss. Pridopidine reduced the intensity of these aberrant connections. Conclusion The abnormal connectivity of the somatomotor and DMN observed in HD patients may represent an early dysfunction marker, as it preceded volume loss in DMN. Pridopidine reduced connectivity of these networks in all four treated patients, suggesting that connectivity is sensitive to treatment response.

Huntington disease (HD) is a neurodegenerative, dominantly inherited disorder, which may result in a debilitating movements disorder and cognitive decline with progressive loss of independence. HD frequency in the Middle East has never been defined after the HTT gene discovery and cases of HD have been reported only sporadically.1 In July 2013, Italian League for Research on Huntington Disease Foundation was contacted by a family from Oman, who reported to be affected by HD since many generations. Indeed, that family may represent the largest HD cluster ever described in the Middle East, owing to a high number of intermarriages and subsequent increase in mutation heritability risk. Given the gaps in our knowledge about HD in the Middle East, we took the opportunity to study and determine the incidence and prevalence of HD in this region. We performed an observational, service based, study from August 2013 to March 2019 in the Muscat region, Sultanate of Oman. Prevalence was estimated on the number of affected and at-risk individuals, who were referred to the National Genetic Centre (NGC) of the Royal Hospital in Muscat, the main Ministry of Health Country health organisation. We are, therefore, confident to have an accurate representation of most HD cases and families who reside in this region. A priori risk, that is, the risk of disease associated with an individual at birth, was separated into groups: 50% risk (a first-degree relative is affected with or mutation-positive for HD), and >50% risk (an individual with both at-risk parents or one affected and one at-risk parent). All subjects were clinically evaluated by the Unified HD Rating Scale (UHDRS)2 and examined by the same neurologist (FS) with expertise in HD. Clinical characteristics, including age at onset, age at death and symptoms presentation, were recorded based on first relevant neurological and …

Background LIRH Foundation started to collect data from HD subjects and families since 2001. The collection includes data from LIRH archives, REGISTRY (since 2004) and ENROLL-HD (since 2014) data. Aims To develop a large HD database starting from ENROLL-HD data. Methods The database was constructed through shiny, plyr and DT R packages (R 3.4.4 version) for automatically merging different clinical items. Results Since July 2014, we recruited 626 people into ENROLL-HD, until May 2018. Follow-ups are available for 432 subjects (one-year), 268 (two-years) and 152 (three years). Our cohort includes 404 gene positive (346 patients and 58 pre-manifest) individuals, 153 genetically ‘unknown’ (50% at risk), 36 gene negative and 43 family member subjects. Mean age at onset is 47,6±14,7 (range 7–86), thus including adolescent ( 60 years; N=35 subjects) cohorts. Onset symptoms includes motors signs in 47,9%, mixed in 34,9%, psychiatric in 15.6% and cognitive in 1.5% cases. Suicide ideation occurred in 17,4%, calculated according to the C-SSRS scale activation. Mean, fully penetrant expanded repeat number is 44,4±5,06 (range 40–84); two 2 subjects have intermediate alleles (29,5±0,7; range 29–30), and 23 reduced penetrance (38,2±0,8; range 36–39). Disease stage, according to the TFC scale score (9,7±3,9; range 1–13), ranges between 1 to 5. Conclusions A proper database and stratification of HD subjects according to genetic condition, symptom presentation, mutation length and development of further symptoms is crucial for both improving the disease knowledge and to driving people to research plans.

Background Huntington’s Disease (HD) cognitive dysfunction may start before unequivocal motor signs become apparent. Main early cognitive abnormal domains may include deficits in psychomotor speed, negative emotion recognition and executive functioning. Previous studies have demonstrated an impaired performance in several frontal tasks in HD patients. Aim The present study aimed to investigate the executive control of cognition in pre-manifest (pre) HD subjects, by means of a task-switching protocol. Methods We enrolled 30 preHD subjects (DCL Results preHD subjects showed slower reaction times than HC in both switch (pre-HD2: 1201.133±19.99; pre-HD 1: 1099.7±15.76; HC: 755.61±12.63; p Conclusions The executive control is impaired before HD becomes manifest. Such abnormalities worsen in preHD subjects with first subtle motor features that are still insufficient and unspecific to document the onset. Considering that such abilities have obvious implication with behavior and independence, the beneficial effect of early rehabilitation programs focused on executive function should be tested.

Background Huntington’s Disease (HD) cognitive dysfunction may start before unequivocal motor signs become apparent. Main early cognitive abnormal domains may include deficits in psychomotor speed, negative emotion recognition, executive functioning and decision making. Game of Dice Task (GDT) activates various prefrontal cortex areas (PFC), i.e. dorsolateral PFC (DLPFC), that is a region showing a reduced activation in pre-manifest HD (pre-HD) stage. Aim Our study aimed at investigating the decision making processing in pre-HD subjects, by means of GDT. Methods We enrolled 28 preHD subjects (i.e. Total Motor Score ranging between 1 and 9 and DCL Results The preHD group showed longer decision and feedback times with respect to HC in both disadvantageous (respectively p=0,009 and p Conclusions PreHD subjects look more cautious in providing the answers to GDT than the HC cohort. Furthermore, they need a time to process a feedback from the previous trial longer than HC subjects. This explains their slowdown in providing the answer. Accordingly, the preHD group showed an increased carefulness, preferring ‘safe’ options. This could depict a typical profile of preHD behavior in risky decision-making.

Background People often make complicated decisions to help or to punish perfect strangers. Harming someone or breaking some moral imperative is usually linked to feeling guilt, and several researches suggested the existence of two different kinds of guilt: altruistic/empathic and deontological. Aim Our study aimed to investigate the decision-making processes in moral and nonmoral judgments and assess how specific situations in which the subject is close to the victim or flanked by an authority can influence his decisions. Methods We used three different moral conditions: Empathic Moral (the decision has made while physically close to the potential victims), Deontological Moral (the decision has made while flanked by an “authority”), and Standard Moral (without any influence); a fourth condition is represented by Nonmoral dilemmas (the subject must make a choice between two different things and this does not cause any harm or victims). Previously, a pilot study was carried out for validating the experimental stories to be used in the main study. Results We observed a higher number of utilitarian/positive responses when individuals had to respond to Empathic Moral condition, with respect to Deontological Moral and Nonmoral dilemmas. Moreover, looking at the time needed to read the dilemma, under empathic guilt condition, people tended to be slower in reading the dilemmas than in other conditions and this both in case of positive and negative responses. No significant differences in time needed to effectively respond emerged. Conclusions These findings suggested that be physically close to potential victims or be flanked by an “authority” differentially influence the decision-making processes in moral judgment, inducing slower decisions and more utilitarian answers, particularly in the scenario of physical proximity.

Objective: Huntington disease (HD) generally manifests in adulthood. Large mutations with CAG repeat expansion in HTT gene may rarely cause juvenile Huntington disease (JHD) in early childhood or adolescence with atypical clinical features, i.e., atypical parkinsonism, if compared to adult patients. Our objective is to characterize the rare occurrence of clinical manifestations in children carrying mutations in the low-mild size, generally causing adult HD with typical choreic movements. Methods: We are following up a subgroup of young subjects with HD mutation who manifested with disabling psychiatric condition since early childhood or adolescence. We are collecting data by the observational studies Registry and ENROLL-HD since 2004. Among 60 JHD patients we are currently following-up, we selected people who carry a mutation in the mild range of CAG expansions (i.e., expected to manifest in adulthood), psychiatric manifestations and no neurological signs or movement disorders suggestive of HD. All patients were genetically (i.e., CAG size analysis) and clinically (i.e., total motor score within the Unified HD Rating Scale) characterized. Results: We found four subjects who showed the characteristics for this analysis. All four subjects presented a CAG expansion size

Background The spatial pattern of atrophy of a disease is related to its functional connectivity structure, mapped by resting-state functional magnetic resonance imaging (fMRI). Increased somatomotor and default mode resting-state networks play key roles in Huntington’s disease pathophysiology. Objectives To analyse brain functional connectivity in the somatomotor and default mode networks in patients with different Huntington’s disease stages and HTT gene mutation sizes, its relationship with grey matter volume loss, and functional changes after pridopidine treatment. Methods Ten patients and 10 controls without treatment underwent T1-weighted imaging and resting-state fMRI; four patients were also assessed after 3 months of pridopidine treatment (90 mg/day). The seed-based functional connectivity patterns from the posterior cingulate cortex and the supplementary motor area (SMA), considered cortical hubs of the somatomotor and default mode networks, respectively, were computed. Grey matter volume was measured by FSL voxel-based morphometry. Results There was decreased grey matter volume in all cortical and subcortical areas involved in the somatomotor network in patients, with preservation of the SMA. Increased somatomotor and default mode network connectivity was seen in patients compared with controls. The volume of the SMA may be dependent on its connectivity. Pridopidine reduced the intensity of these aberrant connexions. Conclusions Abnormal functional connectivity of the somatomotor and default mode networks was observed in patients with Huntington’s disease, independent of brain atrophy, which may represent a marker of early dysfunction. Pridopidine modulates these netwoks by reducing connectivity. Results suggest that network connectivity may be used to measure response to experimental therapies.

Background and rationale The San Marino Republic is located in the heart of Northern Italy and it is a politically independent small Country: according to census 2013, San Marino’s population counts 31.448 inhabitants. As an independent Country, its Government has implemented its own health care system which allows the General Hospital – the only Hospital in the Country - to access to all the inhabitants’ health data, even those managed by single territorial health structures. Methods Because San Marino Republic health organisation is completely independent from Italy, any single person affected by Huntington’s and other rare diseases is assisted by the General Hospital’s neurologists. This is the reason why we can easily count how many people are affected with Huntington’s disease (HD) and start to carefully retrieve all ancestries and genealogical data to link pedigrees for epidemiological purposes. Results We have so far identified 7, apparently unrelated families, with a total of 10 affected subjects, 19 with 50% risk, 18 with 25% risk and at two more relatives suspected to manifest first symptoms. Such data confirm an impressive frequency of HD in this restricted area with a preliminary estimation of 10/31.448 people (i.e. prevalence of 31.7/100.000 people), representing the highest prevalence esteem in Europe. Conclusion Thanks to such preliminary epidemiological analysis, San Marino’s Government promoted professionals’ training in the attempt to provide a correct patients’ standard of care, including patients’ monitoring, therapeutic initiatives and molecular genetics procedures for predictive testing and confirmation of clinical diagnosis.

Background The Italian population is genetically heterogeneous with a variable HD frequency ranging around 11/100,000 individuals (Squitieri et al., 2016) and unusual haplotypes distribution. Enroll-HD represents an opportunity to monitor HD and to collect data and samples for research studies. Aims To assist HD people following a model validated by research protocols. Methods Data were collected according to the ethically approved Enroll-HD protocol at LIRH sites in Northern, Middle and Southern Italy. Results Patients’ recruitment in Enroll-HD started in July 2014. At present, we have enrolled 329 subjects until May 2016, whose one-year follow-up was available for 177 of them. Our cohort included 278 gene positive (241 patients and 37 pre-manifest) individuals (84.5% of the whole samples), 37 genetically “unknown” subjects (mainly 50% at risk), five gene negative and 9 family member subjects (i.e. partners). Mean age at onset was 42.8 ± 12.2 years (range 10–83), thus including juvenile ( 60 years) cohorts. Onset symptoms included motors signs in 48.8%, mixed in 32.9%, psychiatric in 15.9% and cognitive in 1.9% cases. Suicide ideation occurred in 26.7%, calculated according to the C-SSRS scale activation. Mean repeat expansion number was 43.8 ± 4.9 CAG, spanning between low and high mutation size penetrance. Disease stage, according to the TFC scale score, ranged between 1 to 5. Conclusions LIRH initiative aims to connect patients’ community with hospitals and research centres focused on HD. HD staging is critical to properly assist and address people to clinical trials. Our data may represent a fruitful basis for new potential genotype-phenotype correlations and epidemiological analyses in our population. References Squitieri et al. Clin Genet 2016 Mar;89(3):367–70

Background Juvenile Huntington’s disease (JHD), affects onset before age 20. Largest CAG expansions present in infancy (age Objectives JHD characterisation to implement young patients recruitment for further therapeutic studies. Methods We revised JHD patients’ files retrospectively, since 2005, the year we started REGISTRY. Cross-sectional data was available for 30 JHD patients, whose we had full medical records (i.e., 10 infantiles), out of 55 JHD (i.e., 13 infantiles). Longitudinal data was available for 10 subjects, who are currently recruited in Enroll-HD study, six of them previously followed-up since REGISTRY. Results Age-at-onset was defined according to motor or severe cognitive/psychiatric manifestations or both. Infantile and adolescent onset groups showed a CAG mutation size of 83 ± 14 and 58 ± 7 repeats, respectively. Motor presentation was preceded by cognitive/psychiatric symptoms. Infantile cases were featured by remarkable dystonia and drug-resistant epilepsy in more then half cases. Adolescent subjects frequently developed parkinsonism, and their follow-up was challenged by suicide ideation in 4/17. Discussion Cognitive and behavioural symptoms precede motor manifestations in most JHD cases of even many years, often resulting in an undefined disabling condition. It is therefore possible that the JHD frequency is largely underestimated. Definition of onset criteria is critical to recruit JHD cases in future therapeutic trials.

Background LIRH Foundation is a not for profit organisation whose mission is to conduct and support research on Huntington’s disease (HD), providing patients with free of charge assistance, promoting awareness raising initiatives, training professionals and spreading research results. LIRH Foundation has outpatient services for HD in Northern, Middle and Southern Italy. Specific aim To encourage patients not to stay hidden but to seek for proper assistance by, at the same time, contributing to research progress. Methods A systematic, clear, easily accessible and scientifically validated communication and information activity conducted by press release, website, webmarketing campaigns, conferences, video, interviews, social networks, brochure, newsletter, networking. Results Incoming calls to our Toll-Free Number 800.388.330: 3.783 incoming calls in 2015 (20% increase vs 2014). 1.400 incoming calls in the first quarter of 2016. Website: 11.577 users (average) in the first quarter of 2016 vs 3.456 in the same period of 2015; 27.295 page views (average) in the first quarter of 2016 vs 13.135 same period 2015. Assisted HD subjects: Jul 2015-Jun 2016: 590 visits, including 72 first visits vs Jul 2014 – Jun 2016: 250 visits, including 25 first visits Conclusions Quality and consistency of disclosed information are recognised by patients, who feel encouraged to approach our organisation and to participate in experimental trials (i.e Enroll-HD, Legato-HD and Open PRIDE-HD).