Nuria Caballol

Cognitive dysfunction and dementia in Parkinson disease.

Impairment in different cognitive domains such as executive functions, language, memory, and visuospatial skills occurs frequently in Parkinson disease (PD) even in the early stages of the disease. Although frank dementia (Parkinson disease dementia, PDD) is less frequent, risk for developing dementia is two to six times greater than the prevalence rate in general population and it increases in relation to disease duration. Clinically, dementia in PD is characterized by uninsidious onset and slowly progressive cognitive decline, with a predominant dysexecutive syndrome accompanied frequently by a variety of behavioral symptoms such as hallucinations, depression, anxiety, and excessive daytime sleepiness. Although the exact pathophysiology and neurobiological basis of PDD is not known, dementia in PD probably develops as a result of progressive involvement of subcortical and cortical structures by Lewy‐type pathology and associated Alzheimer‐like histological changes. Dysfunction of different monoamine transmitter has also been implicated in the cognitive deterioration of PD but reduced cholinergic activity in the cortex is thought to account for the strongest mechanism in the development of dementia. Recent evidence suggests that cholinesterase inhibitors are effective in the treatment of dementia and accompanying behavioral symptoms in PD.

Agomelatine for Depression in Parkinson Disease: Additional Effect on Sleep and Motor Dysfunction.

AbstractDepression and sleep disorders are among the most prevalent nonmotor symptoms of Parkinson disease (PD). Because agomelatine acts as a MT1 and MT2 agonist and as a 5HT2c antagonist, this study was designed to assess the efficacy of agomelatine in treating depressive symptoms in PD patients, and the potential changes both in sleep quality and motor symptoms. Depressed patients with PD were treated with agomelatine for 6 months, and they were evaluated with an array of scales. Completed nocturnal video-polysomnography was performed at baseline and week 12. The efficacy analysis population included 24 patients (12 men). The mean (SD) age was 75.2 (8.3) years. The mean (SD) daily dose of agomelatine was 25.00 (10.43) mg at 24 weeks. No changes in dopamine replacement therapy were made. There was a significant decrease in the 17-item Hamilton Depression Scale score over the course of the study (P < 0.0005). The Scales for Outcomes in Parkinson disease Sleep Questionnaire showed a statistically significant improvement over time in each of its subscales: nighttime sleep (P < 0.005), last month nighttime sleep (P < 0.0005), and daytime sleepiness (P < 0.0005). Surprisingly, changes over time in the motor subscale of Unified Parkinson Disease Rating Scale were statistically significant (P < 0.0005). Periodic limb movements and awakenings measured by polysomnography improved significantly (P < 0.005 and P < 0.05, respectively). We concluded that the use of agomelatine in PD depressed patients may have a considerable therapeutic potential because of its dual action for treating both symptoms of depression and disturbed sleep given its secondary beneficial effects regarding the reduction of extrapyramidal symptoms.

Cerebrospinal fluid levels of coenzyme Q10 are reduced in multiple system atrophy

INTRODUCTION The finding of mutations of the COQ2 gene and reduced coenzyme Q10 levels in the cerebellum in multiple system atrophy (MSA) suggest that coenzyme Q10 is relevant to MSA pathophysiology. Two recent studies have reported reduced coenzyme Q10 levels in plasma and serum (respectively) of MSA patients compared to Parkinsons disease and/or control subjects, but with largely overlapping values, limited comparison with other parkinsonisms, or dependence on cholesterol levels. We hypothesized that cerebrospinal fluid (CSF) is reliable to assess reductions in coenzyme Q10 as a candidate biomarker of MSA. METHODS In this preliminary cross-sectional study we assessed CSF coenzyme Q10 levels in 20 patients with MSA from the multicenter Catalan MSA Registry and of 15 PD patients, 10 patients with progressive supranuclear palsy (PSP), and 15 control subjects from the Movement Disorders Unit Biosample Collection of Hospital Clinic de Barcelona. A specific ELISA kit was used to determine CSF coenzyme Q10 levels. CSF coenzyme Q10 levels were compared in MSA vs. the other groups globally, pair-wise, and by binary logistic regression models adjusted for age, sex, disease severity, disease duration, and dopaminergic treatment. RESULTS CSF coenzyme Q10 levels were significantly lower in MSA than in other groups in global and pair-wise comparisons, as well as in multivariate regression models. Receiver operating characteristic curve analyses yielded significant areas under the curve for MSA vs. PD, PSP and controls. CONCLUSIONS These findings support coenzyme Q10 relevance in MSA. Low CSF coenzyme Q10 levels deserve further consideration as a biomarker of MSA.

MRI and transcranial sonography findings in Wilson's disease

This image (T2-weighted brain MRI sequences) corresponds to a 24-year old man with a 3-year history of rest and postural tremor starting in the right hand, subsequently extending to both arms. It shows bilateral and symmetric hyperintensities in the putamen, thalami, dorsal mesencephalic area, and pons involving corticospinal, dentatothalamic, and pontocerebellar tracts and periaqueductal gray regions (A). Involvement of white matter around the red nucleus shows the typical “face of the giant panda.” There is also mild corticosubcortical atrophy. Transcranial Doppler sonography (B) shows hyperechogenicity of the ventral tegmental and periaqueductal gray areas (arrows). Kayser– Fleischer rings at the outer margin of the cornea were confirmed by slit-lamp examination (C), representing copper deposits in Descemet’s membrane. Serum copper and ceruloplasmin levels were decreased, and 24-hour urinary copper excretion was significantly increased. A diagnosis of Wilson’s disease was made, and treatment with the copper chelator trientine and zinc was initiated. This led to marked clinical improvement 6 months later, although no change was evident on the repeat brain MRI scan. This observation supports the suggestion that transcranial sonography could be a promising tool to detect brain lesions related to copper deposition.

Discovering the 3′ UTR-mediated regulation of alpha-synuclein

Abstract Recent evidence indicates a link between Parkinsons Disease (PD) and the expression of a-synuclein (SNCA) isoforms with different 3′ untranslated regions (3′UTRs). Yet, the post-transcriptional mechanisms regulating SNCA expression are unknown. Using a large-scale in vitro /in silico screening we identified RNA-binding proteins (RBPs) that interact with SNCA 3′ UTRs. We identified two RBPs, ELAVL1 and TIAR, that bind with high affinity to the most abundant and translationally active 3′ UTR isoform (575 nt). Knockdown and overexpression experiments indicate that both ELAVL1 and TIAR positively regulate endogenous SNCA in vivo. The mechanism of regulation implies mRNA stabilization as well as enhancement of translation in the case of TIAR. We observed significant alteration of both TIAR and ELAVL1 expression in motor cortex of post-mortem brain donors and primary cultured fibroblast from patients affected by PD and Multiple System Atrophy (MSA). Moreover, trans expression quantitative trait loci (trans-eQTLs) analysis revealed that a group of single nucleotide polymorphisms (SNPs) in TIAR genomic locus influences SNCA expression in two different brain areas, nucleus accumbens and hippocampus. Our study sheds light on the 3′ UTR-mediated regulation of SNCA and its link with PD pathogenesis, thus opening up new avenues for investigation of post-transcriptional mechanisms in neurodegeneration.

Myoclonus-dominant corticobasal degeneration: Myoclonus-dominant CBD

Corticobasal degeneration (CBD) is a rare neurodegenerative four-repeat (4R) tauopathy with a wide clinical spectrum. Corticobasal syndrome (CBS) is characterized by highly asymmetric parkinsonism combined with dystonia, myoclonus, apraxia, cortical sensory deficits, or alien limb phenomena. Whereas asymmetric limb rigidity and bradykinesia are the most common motor features in cases of pathologically confirmed CBD presenting as CBS (CBD-CBS cases), myoclonus has been recently found to be much less prevalent than previously reported. Here, we describe a patient with CBD-CBS highlighting a myoclonuspredominant phenotype.

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.

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.

Freezing of Backward Gait

We aim to present a patient whose main complaint was a disturbance of backward gait. This 70-year-old male with no significant clinical or family history presented with a 12-month history of difficulty in walking backward, which had led to frequent falls. In addition, he also reported what he called “leg tremor” on gait initiation and on turning. On neurological examination (see Video), mild generalized symmetric bradykinesia, including minor hypomimia and hypophonia, was observed. The patient had no limb or axial rigidity. The first step forward or sideward was delayed, and took him some effort, but once forward gait was initiated it was normal, except for freezing episodes on turning. Passing through a narrow doorway or other usual maneuvers to explore freezing of gait (FOG) did not elicit freezing in forward progression. When the patient was asked to walk backward, it took him a significant effort to initiate a first stepping movement, and once backward gait started, he could only perform very small steps at a fast pace. On auditory command to raise his legs, this external stimulus enabled him to produce longer backward strides, although still below normal. Neuropsychological assessment with wide frontal evaluation showed preserved overall cognition with normal executive function. Levodopa was started and increased up to 600 mg/ day, eliciting no response. Serum ferritin and ceruloplasmine levels were normal. An electromyography registry showed no tremor at rest or at forward gait initiation, but a 5to 6-Hz bilateral leg tremor in backward gait onset was observed. A brain MRI showed bilateral iron deposits in both SN and globus pallidus (GP), whereas I-FP-CIT single-photon emission CT (SPECT) brain imaging uptake was bilaterally abnormal (Fig. 1). Genetic testing for neuroferritinopathy (ferritin light chain 1 [FTL1] gene), pantothenate kinase (PANK)-associated neurodegeneration (PANK2 gene) and phospholipase A2, group VI (PLA2G6)-associated neurodegeneration (PLA2G6 gene) was negative. After 3 years of follow-up, the patient had not developed apparent freezing of forward gait or any other new neurological symptoms, and his backward freezing is clinically stable. No change was evident on the repeat MRI scan. Several genes have been described to cause neurodegeneration with brain iron accumulation (NBIA): FTL1, PANK2, PLA2G6, ATP13A2 (PARK9), fatty acid 2-hydroxylase (FA2H; FA2H-associated neurodegeneration), CP (aceruloplasminemia), WDR45 (X-linked dominant NBIA), and C19orf12 (mitochondrial membrane protein-associated neurodegeneration). As mentioned above, we ruled out the first three of the former entities. The remaining conditions usually present, unlike our patient, as progressive broader neurodegenerative syndromes with childhood or young-adult onset. Aceruloplasminemia can start in the elderly, but is usually accompanied by serum abnormalities such as undetectable ceruloplasmine or elevation of ferritin, which were not found. Therefore, thus far we consider our patient to be affected by an unclassified late-onset form of NBIA, which can account for 50% of all cases. We would like to stress the semiologic interest of the case, because we consider that our patient’s disturbance in walking backward agrees, except for the direction of progression, with the working definition of FOG proposed by the International Parkinson and Movement Disorder Society: “brief, episodic absence or marked reduction of forward progression of the feet despite having the intention to walk.” The experts highlighted that “focused attention and external stimuli (cues) can overcome the episode.” Thus, our patient’s problem with backward gait overlaps with the description of “forward FOG,” including the ability to overcome freezing using an auditory cue; consequently, we conclude that our patient suffered from primary backward FOG, a clinical feature, to our knowledge, not previously described in the literature as the main complaint. In our experience backward FOG can frequently be observed on pull testing, in patients who suffer from forward FOG, but we have not remarked on such a disassociation with backward freezing and frequent backward falls being so prominent, in comparison to forward FOG. FOG, in the context of a loss of psychic autoactivation, is a typical feature of bilateral pallidal lesions with patients having no rigidity and relatively little akinesia. The GP internus (GPi), together with the SN reticulata, represent the basal ganglia output to the mesencephalic locomotor region, a midbrain area involved in locomotion and step eliciting. Our patient has damage of these output structures related to iron