Search

Objective To describe atypical longitudinal disease progression in Huntington’s disease (HD). Subjects and methods We selected two HD subjects from a cohort of 104 Italian patients participating in the REGISTRY-Enroll-HD study. Patient 1 is a 66 year-old man presenting depressive symptoms at age 46. First motor symptoms, noticed at age 51 (9 year later than expected from his CAG length), were mild eye movement defects and difficulties in tongue protrusion. He had very few choreic movements. Genetic test showed 20/45 CAG repeats. At age 56 UHDRS-TMS was 15 and TFC 11. In this subject both motor and cognitive impairment progressed very slowly during follow-up. After 10-year UHDRS-TMS was 28 and TFC 5. The change per year in the cognitive tests were: Symbol-Digit-Modalities-Test 0/y (baseline = 20); Verbal Fluency −0.3/year; Color-Naming −3.6/year; Word-Reading +0.7/year; and Stroop-Interferences −0.6/year. Patient 2 is a 59 year-old man, who presented motor symptoms at age 49 (11 years earlier than expected). At baseline TFC was 13 and UHDRS-TMS was 9. Genetic test showed 19/40 CAG repeats. After 10 years UHDRS-TMS was 18 and TFC 10. Cognitive tests are available only for the last 6 years of follow-up. The changes per year were: Symbol-Digit-Modalities-Test −2.3/year (baseline = 26); Verbal Fluency −1/year; Color-Naming −14.3/year; Word-Reading −2.8/year, and Stroop-Interferences −4.2/year. For both patients volumetric brain MRI and multi-tissue DNA analyses are performed. Conclusion The identification of HD individuals with atypically mild motor and/or cognitive progression may allow the study of possible genetic/epigenetic modifying factor/s significantly slowing the clinical disease progression.

Objectives Premanifest Huntington’s disease mutation carriers (preHD) are known to present functional and neuroradiological abnormalities before the motor onset. This study evaluated brain morphometry and posture in preHD. Participants and methods 29 preHD (13F/16 M, mean age 36.5 years, CAG range 37–48) and 25 sex-age matched controls were enrolled (14F/11 M, mean age 35.7 years). Inclusion criteria were: CAG expansion > 36; UHDRS-TMS Results PreHD and controls did not differ in total intracranial volume, caudate volumes, and cortical thickness. Only in close-to-onset preHD caudate volumes and occipital cortical thickness were reduced in comparison with controls (p = 0.002; p = 0.0098) and far-from-onset preHD (p = 0.002; p = 0.007). Caudate volumes and occipital cortical thickness directly correlated with years to onset (ρ = 0.58, 0.74; p = 0.003, p Posturography parameters were similar in pre-HD and controls for all conditions, except for wide-base-closed-eyes test, in which preHD presented a greater number of sway peaks (p = 0.006). In close-to-onset preHD the number of sway peaks was greater than controls (p = 0.001) and far-from-onset preHD (p = 0.016). Conclusions Our study confirms that caudate volumes and occipital cortical thickness are the earliest markers of brain degeneration in the preHD. Posturography may represent a simple and rapid test to investigate early stance abnormalities.

Objectives We aimed to identify markers of cognitive and structural brain abnormalities in premanifest Huntington’s disease subjects (preHD). Participants and methods We enrolled 29 preHD (13F/16 M, age 36.5 years, CAG range 37–48; UHDRS-TMS Results PreHD and controls did not differ in total intracranial volume, caudate volumes, and cortical thickness, and presented scores within normal range in all cognitive tests. However, preHD scored significantly worse than controls in SDMT (p = 0.048), in MMSE (p = 0.0013) and in Calculation test (p = 0.014). Analyses of sub-item of the Calculation test showed that preHD, and in particular the group of close-to-onset preHD (−16 years), made specifically more mistakes than controls in the subtraction task (p = 0.0089), while preHD and controls did not differ in multiplications. The SDMT score correlated with left occipital cortical thickness (p = 0.0029) and Calculation test total score with caudate nucleus volumes (p = 0.032). Conclusions We confirm that SDMT can identify very early abnormalities in preHD and the scores directly correlate with occipital cortical thickness. The results of the Calculation test suggest that preHD have selective executive deficits in calculation, as demonstrated in the subtraction process, while in the multiplication task, implying mainly memory retrieval, no differences were found.

Objective A functional MRI (fMRI) study to identify and localise the earliest neural changes, in a group of young premanifest Huntington’s disease (preHD) individuals, far from estimated clinical onset. Methods Sixteen preHD, and 18 age/sex matched healthy participants were enrolled. All preHD subjects previously underwent the predictive genetic testing for HD, and did not present neurological signs consistent with HD clinical onset (UHDRS TMS score = 0). Cognitive evaluation of both groups of subjects did not reveal abnormalities. The subjects were submitted to volumetric MRI and fMRI, during the execution of the exogenous covert orienting of attention task. Considering the fMRI task (Posner paradigm) correlation analyses were restricted to the frontal oculomotor cortex identified by the means of a prosaccadic task. In preHD group, multiple regression analysis was performed between fMRI results and the probability to develop the disease onset in the next 5 years (p5HD). Results fMRI task behavioural performance did not differ between the two groups, while, mean BOLD signal changes of oculomotor frontal cortex was significantly different in the two groups, and, in preHD, correlates with p5HD (r2 = 0.52). A modest correlation (r2 = 0.29) was observed between right putamen volume and p5HD. Conclusion fMRI activations in the right frontal cortex, correlates with p5HD in a group of preHD individuals very far from onset. This result needs to be confirmed in a larger cohort of preHD subjects enrolled in a longitudinal study, and could represent a possible fMRI biomarker for preHD.

Objective To report a 6-year experience of a programme for predictive test (PT) in Huntington disease (HD). Participants and Methods At-risk individuals for HD, aged >18 years, performed three consecutive visits, and an optional follow-up visit at 4–6 months. Symptom Check List 90 Revised (SCL90 R), and Beck Depression Inventory (BDI) tests were administered. The psychiatrist/psychologist did not meet the at-risk subjects during the PT, but cooperated with the multidisciplinary team integrating psychological support at the disclosure of genetic results. Results From 2006 and 2011, 159 individuals (78M/81F) at-risk for HD underwent the programme for PT. The mean age was 37.4±11.6 years (range 16–77) Married subjects were 51.3%. Positive symptoms at the SCL90R test were 26.0± 17.6 (range 1–78). Age, sex, marital status and results at psychological tests were similar in each year of the study. Only years of education were significantly lower for the subjects asking for PT in 2011 (10 years) in comparison with the subjects performing PT in 2006 (13.3) (p=0.0065). None of the subjects had clinically relevant depressive symptoms (BDI scores Conclusions During the 6 years of the programme we did not observe significant adverse events. Socio-demographic characteristics of the at-risk HD population undergoing PT remained similar from 2006 to 2011, except for education.