Elisa Unti

Differences in nigro‐striatal impairment in clinical variants of early Parkinson’s disease: evidence from a FP‐CIT SPECT study

Introduction:  In idiopathic Parkinson’s disease (PD), two different clinical phenotypes are usually distinguished: a tremor dominant variant (TD) and an akinetic‐rigid type (ART). TD patients are characterized by a slower disease progression and a minor cognitive impairment. Striatal density of DAT, as quantified by FP‐CIT SPECT, has been reported to correlate with rigidity and akinesia but not with tremor.

The hOGG1 Ser326Cys polymorphism and Huntington's disease

Increasing evidence supports a role for oxidative DNA damage and impaired DNA repair mechanisms in the pathogenesis of age related neurodegenerative diseases. Within this context there is a current interest in the understanding of the role played by polymorphisms of DNA repair genes in the inter-individual risk to develop neurodegenerative pathologies, as well as in the onset and the progression of disease symptoms. Particularly, somatic CAG repeat expansion of the gene encoding for huntingtin has been observed in tissues of patients affected by Huntingtons disease (HD), including blood and brain. Recent evidence suggests that somatic CAG repeat expansion in HD cells might contribute to disease age at onset and is mediated by the DNA repair OGG1 enzyme, during the removal of 8-oxoguanine (8-oxoG) from the DNA. There is also evidence that the expression of hMTH1, which removes 8-oxoG from the nucleotide pool, protects mice from HD-like symptoms, and progenitor striatal cells from the toxic effects of the mutant huntingtin. The hOGG1 Ser326Cys polymorphism results in reduced OGG1 activity and increased 8-oxoG formation. In the present study, performed on blood DNA from 91 HD subjects, we observed that bearers of the mutant Cys326 allele (Ser326Cys+Cys326Cys) tend to have an increased number of CAG repeats of the expanded HD allele (P=0.049); moreover bearers of at least one copy of the mutant Cys326 allele, mainly heterozygous subjects, showed a significant (P=0.041) earlier disease onset than Ser326Ser wild-type individuals, suggesting a possible role of the hOGG1 Ser326Cys polymorphism in HD phenotype.

“Parkinson-dementia” diseases: A comparison by double tracer SPECT studies

We performed 123I-FP-CIT/SPECT and ECD/SPECT in 30 patients with Parkinsons disease with dementia (PDD) and 30 patients with dementia with Lewy bodies (DLB) to evaluate whether presynaptic nigro-striatal function and/or cerebral perfusional pattern is different in these diseases. The striatal uptake of DAT tracer was statistically significantly lower in PDD and DLB with respect to control data (p < 0.0005), however no significant difference was found between PDD and DLB. Patients with PDD and DLB showed a significant reduction of rCBF (p < 0.001) in parieto-occipital and frontal areas, with respect to controls, but the comparison between the two groups did not result in any significant difference by SPM analysis. Finally no correlation was found between any regional perfusional changes and nigro-striatal dysfunction. We conclude that neither studies with 123I-FP-CIT nor ECD/SPECT were able to discriminate between DLB and PDD in vivo.

Apomorphine hydrochloride for the treatment of Parkinson’s disease

Apomorphine (APO) is a potent D1 and D2 dopamine agonist. Plasma maximal concentration is reached in 8–16 min with a plasma half-life of 34–70 min. Bioavailability is close to 100%. It has a rapid antiparkinsonian action after subcutaneous (sc.) administration with a size effect comparable with that of levodopa. Trials of sc., oral, sublingual, intravenous, rectal, intranasal and iontophoretic transdermal administration of APO have been attempted in Parkinson’s disease (PD), each of these routes have shown some potential for clinical effectiveness but the majority of studies indicate that APO intermittent sc. administration, on which this review is mainly focused, is an effective therapy for the management of motor symptoms in PD, particularly in advanced phases mainly characterized by motor fluctuations, such as wearing OFF and unpredictable “off”. Data on the effect of APO on non-motor symptoms in PD patients are limited but there is strong suggestion of a beneficial effect that warrants further investigation.

Event-Based Prospective Memory in Newly Diagnosed, Drug-Naive Parkinson's Disease Patients

The present study investigated memory for intention in individuals with Parkinsons disease (PD) who were newly diagnosed and not yet treated to avoid the effect of therapy as a potential confounding variable. A comprehensive neuropsychological battery and an event-based prospective memory task were administered to 41 subjects with de novo PD and 40 control subjects. Separate scores were computed for correct execution of intended action (prospective component) and recall of intention (retrospective component). PD patients performed marginally worse (p = .053) than controls on the prospective component of the task. On the other hand, the performance of the two groups was comparable for the retrospective component. Neuropsychological findings revealed lower performance of the PD group in episodic memory and in some measures of executive functions. These results suggested a subtle prospective memory dysfunction present at the initial stage of PD, which may be related to disruption of fronto-striatal circuitry.

Gait dynamics in Pisa syndrome and Camptocormia: The role of stride length and hip kinematics

This is an observational cross-sectional study evaluating gait dynamics in patients with Parkinsons Disease (PD) and severe postural deformities, PD without axial deviations and healthy subjects. Ten PS individuals with Pisa syndrome (PS) and nine subjects with Camptocormia (CC) performed 3-D Gait Analysis and were evaluated with walking and balance scales. Correlations with clinical and functional scales were investigated. Spatio-temporal and kinematic data were compared to ten PD subjects without postural deformities (PP) and ten healthy matched individuals (CG). Data obtained showed decreased walking velocity, stride and step length in PP, PS and CC groups compared to controls. The correlation analysis showed that stride and step length were associated with reduced functional abilities and disease severity in PS and CC groups. Kinematic data revealed marked reduction in range of movements (ROMs) at all lower-extremity joints in PS group. While, in CC group the main differences were pronounced in hip and knee joints. PS and CC groups presented a more pronounced reduction in hip articular excursion compared to PP subjects, revealing an increased hip flexion pattern during gait cycle. Moreover, the increased hip and knee flexion pattern adversely affected functional performance during walking tests. Results obtained provide evidence that step length, along with stride length, can be proposed as simple and clear indicators of disease severity and reduced functional abilities. The reduction of ROMs at hip joint represented an important mechanism contributing to decreased walking velocity, balance impairment and reduced gait performance in PD patients with postural deformities.

Antipsychotic drugs in Huntington’s disease

ABSTRACT Introduction: The aim of this review is to overview the pharmacological features of neuroleptics experienced in the treatment of Huntington’s disease (HD) symptoms. Despite a large number of case reports, randomized controlled trials (RCT) and drug comparison studies are lacking. Areas covered: After evaluating current guidelines and clinical unmet needs we searched PubMed for the term ‘Huntington’s disease’ cross referenced with the terms ‘Antipsychotic drugs’ ‘Neuroleptic drugs’ and single drug specific names. Expert commentary: In clinical practice antipsychotics represent the first choice in the management of chorea in the presence of psychiatric symptoms, when poor compliance is suspected or when there is an increased risk of adverse events due to tetrabenazine. Antipsychotics are considered valid strategies, with the second generation preferred to reduce extrapyramidal adverse events, however they may cause more metabolic side effects. In the future ‘dopamine stabilizers’, such as pridopidine, could replace antipsychotics modulating dopamine transmission.

Q09 Valproic Acid for the treatment of aggressiveness in Huntington's disease: 1-year follow-up

Background Huntingtons disease (HD) is characterised by involuntary movements, cognitive decline and psychiatric symptoms such as aggressiveness, and depression. In most cases involuntary movements and psychiatric symptoms are controlled by antipsychotic drugs, but sometimes side effects as parkinsonism or worsening of depression and apathy can reduce the therapeutic window of these drugs. Aims To evaluate the beneficial effect of Valproic Acid on psychiatric symptoms such as agitation and aggressiveness as well as depression in HD. Methods 10 symptomatic genetically confirmed HD patients (mean CAG repeat 40±2), mean disease duration (8±2 years) on antipsychotics, all with aggressiveness defined as disabling by the patients along with the care giver, were included in an open unblinded trial. Clinical evaluation including motor (UHDRS), psychiatric (NPI) and cognitive scales (MMSE) was performed at baseline and after 6 and 12 months of Valproic Acid (from 300 up to 1000 mg die). Results In our cases we reported a reduction of 10 points of NPI score in each patient persisting 1 year after the introduction of Valproate without any side effect reported. Conclusions The beneficial effect of Valproic Acid on aggressive patients is well documented since 19971 and, to our knowledge, there are only two case reports2 3 that support this effect in such psychiatric disturbance in HD. However no systematic study was done so far in this topic. Moreover, the successful use of Valproic acid in controlling aggressiveness allowed us not to increase the daily dose of neuroleptic, so preventing motor and psychiatric side effects. References 1. Haas S, Vincent K, Holt J, et al. Divalproex: a possible treatment alternative for demented, elderly aggressive patients. Ann Clin Psychiatry 1997;9:145–7. 2. Grove VE Jr, Quintanilla J, DeVaney GT. Improvement of Huntingtons disease with olanzapine and valproate. N Engl J Med 2000;343:973–4. 3. Rask G, Anderson C. Good effect of valproate against aggression in Huntington disease. Only two cases reported earlier. Lakartidningen 2010;107:3060–1.

Social Cognition and Oxytocin in Huntington’s Disease: New Insights

This study is aimed at relating social cognition in Huntington’s Disease (HD) to plasma levels of the social hormone oxytocin (OT). Indeed, HD patients commonly display reduced social skills and OT is involved in bonding behavior and improved recognition of facial emotions. Twelve mild-symptomatic HD patients (stage II Shoulson & Fahn) and 11 gender/age matched controls (healthy controls, HC), without concurrent psychiatric disorders, were investigated at baseline (T0) for OT plasma levels and social cognition through an extensive battery of neuropsychological tests. Social cognition was also re-examined after two years (T1) in 8 of the 12 patients. Results showed a trend for reduced T0-OT levels in HD vs. HC, mean ± stardard deviation: 6.5 ± 2.4 vs. 9.9 ± 7.2 pg/mL, without reaching statistical significance. At T0, patients showed significantly lower performances than controls at the “Faux-Pas” and “Strange Stories” tests (p < 0.05; p < 0.01); a reduced perception of visual emotions (p < 0.01) and verbal stimuli (p < 0.01) was also reported, involving anger, fear, and sadness (p < 0.05; p < 0.01). Additionally, in the HD population, OT concentrations positively correlated with T1-performances at Neutral\Faux-Pas test (p < 0.05), whereas the cognitive Montreal Cognitive Assessment (MoCA) and Mini Mental State Examination (MMSE) scores positively correlated with psychosocial perception at the “Strange Stories” and Karolinska Directed Emotional Faces (KDEF) tests (p < 0.05). This study, despite its limitations, supports correlations between OT and HD social cognition, suggesting a possible therapeutic use of this hormone. More subjects and additional body tissues/fluids, such as cerebrospinal fluid, should be investigated to confirm this hypothesis.

D5 Oxytocin plasma levels as predictor of social cognition in huntington’s disease

Background The role of Oxytocin (OT) as social hormone is supported by the improvement of recognition of the expression of the faces after administration of intranasal OT. Impaired social behaviour, partly related to altered perception of emotions, is commonly reported in Huntington’s disease (HD). Aims To evaluate OT plasma level as possible predictor of social cognition performances in a population of symptomatic HD patients. Methods 12 patients with symptomatic HD (stage II S&F) without cognitive impairment were evaluated at the baseline and after 2 years follow up (8 pt) for social cognition through an extensive battery of neuropsychological tests (Faux Pas test, Bush vignettes test, emotion recognition from both faces expression and verbal stimuli, Strange stories test). Plasma OT levels at the baseline were analysed in the whole cohort of subjects and the relationship between the levels of OT and social cognition at the baseline and at the follow up was analysed. OT plasma levels were also compared to that of a population of healthy controls matched for age. Results OT levels did not differ in the two populations, however with a trend for lower values in HD group (average 9.9 ± 7.2 controls, 6.5 ± 2.4 HD). At the baseline OT blood levels did show any significative correlation with social cognition and cognitive tests. The follow up analysis showed that higher OT levels correlated with better performances at the Neutral\Faux Pas score (p < 0.05) and with higher ability of recognising happiness from verbal stimuli (p < 0.05). Conclusions Even though not statistically significant patients showed lower OT circulating levels compared to controls; moreover the follow-up analysis pointed out a possible role of OT in predicting the progression of social cognition in HD. The present data, limited by the sample size and by the biological tissue studied, need to be confirmed in a larger population analysis even by correlating with cerebrospinal fluid measurement.