Pilar Santacruz

Clinical validity of the "mini-mental state" for Spanish speaking communities.

The Mini-Mental State (MMS) is a brief structured test of cognitive function. The purpose of this study was to adapt and normalise MMS for the Spanish population. The test was administered to 450 subjects (253 control volunteers, 86 mild memory/cognitive impairment without dementia subjects - CIWD and 111 Alzheimers Disease patients - AD). A cross-sectional statistical study in a population stratified by age and education was conducted. A more accurate diagnosis is provided by scores that have been adjusted for age and level of education. The recommended cut-off in our study was 24/25 (non-demented above 24). The adaptation and normalisation of MMS provides the Spanish population with a highly valuable screening tool.

Apolipoprotein E4 allele frequency in Spanish Alzheimer and control cases

We have found an APOE epsilon 4 allelic frequency of 0.289 (95% CI 0.195-0.383) in Spanish AD patients (n = 88; average age = 71.2 +/- 9.37) and of 0.061 (95% CI 0.023-0.099) in age-matched controls (n = 147; average age = 71.5 +/- 10.29). Remarkably no ApoE 4/4 subjects were observed in any of the age-matched control groups compared to a total of 22 AD patients with the ApoE 4/4 phenotype. The combined odds ratio for subjects with one or two epsilon 4 alleles in the present study is 6.25 (95% CI 3.13-12.60), which is one of the highest so far reported. Altogether our results suggest a trans-European difference in the ApoE epsilon 4 frequency but no differences in the strength of the association between APOE4 and AD.

l-Dopa/carbidopa intestinal gel and subthalamic nucleus stimulation: Effects on cognition and behavior

In Parkinsons disease (PD), effects on behavior and cognition of levodopa/carbidopa intestinal gel (LCIG) and subthalamic stimulation (STN‐DBS) and their practical consequences remain controversial. This study was designed to analyze the possible effects of these therapies on cognition and behavior after 1 year follow‐up.

An active cognitive lifestyle as a potential neuroprotective factor in Huntington's disease

ABSTRACT A cognitive stimulating lifestyle has been observed to confer cognitive benefits in multiple neurodegenerative diseases. However, the underlying neurobiological basis of this phenomenon remains unclear. Huntingtons disease can provide a suitable model to study the effects and neural mechanisms of cognitive engagement in neurodegeneration. In this study, we investigate the effect of lifestyle factors such as education, occupation and engagement in cognitive activities in Huntingtons disease gene carriers on cognitive performance and age of onset as well as the underlying neural changes sustaining these effects, measured by magnetic resonance imaging. Specifically, we analyzed both gray matter volume and the strength of connectivity of the executive control resting‐state network. High levels of cognitive engagement were significantly associated with more preserved executive functions, a delay in the appearance of symptoms, reduced volume loss of the left precuneus and the bilateral caudate and a modulation of connectivity strength of anterior cingulate cortex and left angular gyrus with the executive control network. These findings suggest that a cognitively stimulating lifestyle may promote brain maintenance by modulating the executive control resting‐state network and conferring protection against neurodegeneration, which results in a delayed onset of symptoms and improved performance in executive functions. HIGHLIGHTSIn Huntingtons disease, a cognitively active lifestyle is associated with benefits.These include better cognitive performance and delayed onset of symptoms.These effects could be mediated by less grey matter loss in caudate and precuneus.Reduced functional connectivity was related with a cognitively active lifestyle.Engaging in cognitive activities could potentially provide brain resistance.

F44 Disentangling apathy subtypes in huntington’s disease: a white matter biomarker of disease profile and progression

Along with motor and cognitive deterioration, neuropsychiatric symptoms form a common feature of Huntington’s disease. Of these, apathy has been shown to most highly correlate with disease progression, often emerging prior to clinical diagnosis. However, due to the multidimensional nature of apathy, its elusive etiology, and the lack of operative diagnostic criteria, treatment options are limited. The present study combine diffusion tensor imaging (DTI) with precise apathy scales to investigate the relationship between white matter microstructural change and apathy in premanifest (n=22) and early manifest Huntington’s disease (n=24) compared with controls (n=35).Global apathy was measured using both the short Problem Behavior Assessment and the Lille Apathy Rating Scale, short-form. Principle component analysis of the LARS-s produced three apathy subtypes: emotional, cognitive, and auto-activation deficit. We found that premanifest participant’s portrayed significantly higher auto-activation deficit apathy, with early manifest patients additionally showing significantly increased apathy in cognitive apathy as well as global apathy. Analysis by DTI showed a significant rightward disturbance in the uncinate fasciculus (UF), the frontostriatal tract (FST), and the dorsolateral prefrontal cortex to caudate nucleus tract (dlPFC-cn). Importantly, specific apathy subtypes were found to be associated with discrete tracts. Specifically, higher levels of subtype-specific apathy correlated with a lateralized decrease in structural connectivity in the dlPFC-cn and FST for the cognitive domain of apathy and in the UF for auto-activation deficit, predominantly on the right side. That apathy subtypes are associated with distinct white matter substrates supports the importance of an individualized approach to its diagnosis and treatment.

Reduced striato-cortical and inhibitory transcallosal connectivity in the motor circuit of Huntington's disease patients

Huntingtons disease (HD) is a neurodegenerative disorder which is primarily associated with striatal degeneration. However, the alterations in connectivity of this structure in HD have been underinvestigated. In this study, we analyzed the functional and structural connectivity of the left putamen, while participants performed a finger‐tapping task. Using fMRI and DW‐MRI, 30 HD gene expansion carriers (HDGEC) and 29 healthy participants were scanned. Psychophysiological interaction analysis and DTI‐based tractography were employed to examine functional and structural connectivity, respectively. Manifest HDGEC exhibited a reduced functional connectivity of the left putamen with the left and the right primary sensorimotor areas (SM1). Based on this result, the inhibitory functional connectivity between the left SM1 and the right SM1 was explored, appearing to be also decreased. In addition, the tract connecting these areas (motor corpus callosum), and the tract connecting the left putamen with the left SM1 appeared disrupted in HDGEC compared to controls. Significant correlations were found between measures of functional and structural connectivity of the motor corpus callosum, showing a coupling of both types of alterations in this tract. The observed reduction of functional and structural connectivity was associated with worse motor scores, which highlights the clinical relevance of these results. Hum Brain Mapp 39:54–71, 2018.

Spanish Validation of the Problem Behaviors Assessment–Short (PBA-s) for Huntington’s Disease

A prospective, observational multicenter study was carried out assessing neuropsychiatric symptoms in a sample of 117 subjects in order to validate the Spanish version of the Problem Behaviors Assessment-Short (PBA-s). The psychometric properties of this version were analyzed. Inter- and intra-rater reliability were good: the mean weighted Cohens kappa was 0.90 for severity scores and 0.93 for frequency scores. Four factors accounting for 56% of the total variance were identified after an exploratory factor analysis: apathy, irritability, depression, and perseveration. The PBA-s correlates strongly with the Neuropsychiatric Inventory, demonstrating its accuracy for assessing neuropsychiatric symptoms in patients with Huntingtons disease.

Sensory processing in Huntington’s disease

OBJECTIVE An intriguing electrophysiological feature of patients with Huntingtons disease (HD) is the delayed latency and decreased amplitude of somatosensory long-latency evoked potentials (LLeps). We investigated whether such dysfunction was associated with delayed conscious perception of the sensory stimulus. METHODS Sixteen HD patients and 16 control subjects faced a computer screen showing the Libets clock (Libet et al., 1983). In Rest trials, subjects had to memorize the position of the clock handle at perception of either electrical or thermal stimuli (AW). In React, additionally, they were asked to make a fist with their right hand, in a simple reaction time task (SRT). LLseps were recorded from Cz in both conditions. RESULTS LLeps negative peak latency (N2) and SRT were abnormally delayed in patients in all conditions. AW was only abnormally prolonged in the React condition but the time difference between AW and the negative peak of the LLeps was not different in the two groups. There was a significant negative correlation between SRT and AW or LLeps amplitude in patients but not in healthy subjects. CONCLUSION Our HD patients did not show abnormalities in conscious perception of sensory stimuli but their LLeps abnormalities were more marked when they had to react. This is compatible with failure to detect stimulus salience rather than with a cognitive defect. SIGNIFICANCE HD patients at early stages of the disease have preserved subjective perception of sensation but faulty sensorimotor integration.

D24 Intact emotional impulsivity in huntington’s disease despite altered structural connectivity in the uncinate fasciculus

Background Impulsivity in Huntington’s disease (HD) patients has been understudied despite its clear impact in daily life. Although it is known that there are different types of impulsivity, this trait has been mainly studied through impulsive actions in cued go/no-go tasks that contain an important motor component, while the more purely emotional/choice component of impulsivity in HD remains unknown. Objective To study the neurobiological basis that characterise individual differences in emotional impulsivity in HD. Methods Thirty-one controls and 32 HD patients (11 of which were pre-symptomatic) were scanned using diffusion tensor imaging (DTI) to study the relationship between the structural connectivity of the uncinate fasciculus (UF), the main tract involved in the motivational circuit, and the impulsivity trait (k), evaluated with a delay discounting task. Results No significant difference was observed in k between the two groups. In controls, k correlated with both right and left UF, whereas in HD patients, k correlated only with the left UF. On the other hand, only the right UF was found to be affected in HD patients compared with controls. Conclusion This study reveals that HD patients do not differ from controls in the impulse behaviour associated with delay discounting choices. Moreover, the connectivity pattern observed in HD patients and controls is consistent with previous studies that show that individual differences in microstructure integrity of the left UF are related to impulsivity levels in delay discounting tasks.

D23 The effect of cognitive reserve on age of onset and executive functions in huntington’s disease and its neurobiological bases

Background Although age of onset of Huntington’s disease (HD) is mainly determined by the size of the CAG repeat expansion, other factors may play a role. One potential factor is Cognitive Reserve (CR), as it has been shown in other neurodegenerative disorders and ageing. Objective The objective of this study is to investigate the effect of CR on age of onset in HD and to examine the neural bases underlying the individual differences in executive function that could be due to the effects of CR in HD. Methods Thirty-one HD patients completed a CR questionnaire and were scanned using functional magnetic resonance imaging. We analysed the Resting State Executive Control Network (RS-ECN), a novel approach to study the brain areas underlying executive function. The strength of connectivity with this network was calculated voxel-wise. The difference between the theoeretical and estimated age of onset (26 symptomatic-HD) was calculated for each patient. Results Our results revealed that high levels of CR significantly delayed the appearance of clinical symptoms. Functional connectivity and morphometry analysis showed a brain reorganisation modulated by CR, which changed the connectivity strength in the anterior cingulate cortex, in the left superior parietal cortex (SPC) and slowed the volume loss in the bilateral precuneus and the bilateral caudate. Furthermore, higher strength of connectivity in the left SPC was related to better performance in cognitive flexibility (TMT B-A) and working memory (Backward Digits Span) tasks. Conclusions These findings provide converging evidence that CR might act as a protective mechanism for the progression of the disease, delaying the onset of symptoms and improving the performance in executive functions by modulating the RS-ECN and slowing brain atrophy.