Antonia Campolongo

Dementia risk in Parkinson disease: disentangling the role of MAPT haplotypes.

BACKGROUND Dementia in Parkinson disease (PD) causes nursing home placement, caregiver distress, higher health care burden, and increased mortality. OBJECTIVE To determine whether the microtubule-associated protein tau (MAPT) H1 haplotype and MAPT subhaplotypes play a role in the risk of PD and Parkinson disease-dementia (PDD) complex. DESIGN Case-control genetic analysis. SETTING Movement Disorders and Memory Units, Hospital de Sant Pau, Barcelona, Spain. PARTICIPANTS Two hundred two patients with PD (48 of whom developed dementia>2 years after disease onset), 41 patients with Lewy body dementia (LBD, pathologically confirmed in 17), 164 patients with Alzheimer disease (AD), and 374 controls. METHODS The MAPT haplotype was determined by testing for a 238-base pair deletion between exons 9 and 10, which is characteristic of the H2 haplotype. Haploview was used to visualize linkage disequilibrium relationships between all genetic variants (5 single-nucleotide polymorphisms and the del-In9 variant) within and surrounding the MAPT region. RESULTS The H1 haplotype was significantly overrepresented in PD patients compared with controls (P=.001). Stratifying the PD sample by the presence of dementia revealed a stronger association in PDD patients (sex- and age-adjusted odds ratio, 3.73; P=.002) than in PD patients without dementia (sex- and age-adjusted odds ratio, 1.89; P=.04). Examination of specific subhaplotypes showed that a rare version of the H1 haplotype (named H1p) was overrepresented in PDD patients compared with controls (2.3% vs 0.1%; P=.003). No positive signals for any of the MAPT variants or H1 subhaplotypes were found in AD or LBD. CONCLUSIONS Our data confirm that MAPT H1 is associated with PD and has a strong influence on the risk of dementia in PD patients. Our results also suggest that none of the MAPT subhaplotypes play a significant role in other neurodegenerative diseases, such as LBD or AD.

Glucocerebrosidase mutations confer a greater risk of dementia during Parkinson's disease course.

Mutations in the glucocerebrosidase gene are associated with Parkinsons disease and Lewy body dementia. However, whether these alterations have any effect on the clinical course of Parkinsons disease is not clear. The glucocerebrosidase coding region was fully sequenced in 225 Parkinsons disease patients, 17 pathologically confirmed Lewy body dementia patients, and 186 controls from Spain. Twenty‐two Parkinsons disease patients (9.8%) and 2 Lewy body dementia patients (11.8%) carried mutations in the glucocerebrosidase gene, compared with only 1 control (0.5%); P = .016 and P = .021 for Parkinsons disease and Lewy body dementia, respectively. The N370S and the L444P mutations represented 50% of the alterations. Two novel variants, L144V and S488T, and 7 previously described alterations were also found. Alterations in glucocerebrosidase were associated with a significant risk of dementia during the clinical course of Parkinsons disease (age at onset, years of evolution, and sex‐adjusted odds ratio, 5.8; P = .001). Mutation carriers did not show worse motor symptoms, had good response to L‐dopa, and tended to present the intermediate parkinsonian phenotype. Our findings suggest that mutations in the glucocerebrosidase gene not only increase the risk of both Parkinsons disease and Lewy body dementia but also strongly influence the course of Parkinsons disease with respect to the appearance of dementia.

Tremor dominant parkinsonism: Clinical description and LRRK2 mutation screening

Tremor dominant parkinsonism (TDP) is characterized by initial prominent resting and action tremor, mild parkinsonism, unpredictable response to medication, and a better prognosis than idiopathic Parkinsons disease (PD). We report on clinical features and longitudinal course of 26 patients suffering from TDP. Mean disease duration was 6.5 ± 3 years, 61.5% of patients had a positive family history of tremor, 73% did not need drug treatment, performance of 123I‐Ioflupane SPECT showed reduced striatal tracer uptake in 65.4% of patients, and odor identification testing was pathologic in all the patients tested (n = 22). Co‐occurrence of action and resting tremor were the most annoying and disabling symptoms in all the patients, whereas rigidity and/or bradykinesia were clinically irrelevant in most of them. We also sequenced the full coding region of the Leucine‐rich repeat kinase 2 gene (LRRK2) in all patients. We found a novel Val2390Met mutation that was not found in 864 chromosomes. Our results suggest a broader clinical heterogeneity related to LRRK2 mutations and points towards TDP as a subtype within the spectrum of PD, in which disabling tremor but otherwise mild parkinsonian signs and a better prognosis are the main characteristics.

Long-term response to continuous duodenal infusion of levodopa/ carbidopa gel in patients with advanced Parkinson disease: The Barcelona registry

INTRODUCTION Continuous infusion of levodopa/carbidopa intestinal gel (LCIG) is an effective treatment for patients with advanced Parkinson Disease (PD) that cannot be further improved by oral therapy. METHODS We conducted an observational, prospective, and multicenter study to collect, in a large sample of PD treated with LCIG, long-term information about the outcome and safety of the treatment. The assessments were performed before LCIG, 1, 3, 6 months after, and ever since, every 6 months. RESULTS We studied 72 patients with a mean observation time of 22 months and a maximum of 48 months. During follow-up 28 patients discontinued the treatment, especially for lack of efficacy or adverse events related to the drug. We obtained a significant improvement of motor and non-motor fluctuations, mean off time and some non-motor symptoms. A significant increase in the percentage of time with dyskinesias was found in patients having less than 50% of the day with dyskinesias before LCIG. However, patients having already many dyskinesias before LCIG experienced a significant decrease of the troublesome dyskinesias, meaning that outcomes might be different depending on specific clinical characteristics. Adverse effects were in general minor but one case of intestinal perforation and one of abdominal cellulite were observed. CONCLUSIONS We confirmed that LCIG is a very effective treatment option for advanced PD; however considering the findings that dyskinesia can increase and the potential for serious side effects, we suggest the necessity for development of guidelines that better define the profile of responders.

Levodopa and executive performance in Parkinson's disease: a randomized study.

Parkinsons disease (PD) patients may experience fluctuations in executive performance after oral levodopa (LD). Their relationship with the pharmacokinetic profile of LD and with distinct cognitive processes associated with frontal-basal ganglia circuits is not well understood. In this randomized, double-blind, crossover study we plotted acute cognitive changes in 14 PD patients challenged with faster (immediate-release, IR) versus slower (controlled-release, CR) increases in LD plasma concentrations. We monitored motor status, LD plasma levels, and performance on four tasks of executive function (Wisconsin Card Sorting Test-WCST, Sternberg test, Stroop and Tower of Hanoi), 1 hr before and over +6 hr after IR and CR-LD dose. Analysis of variance demonstrated significant but divergent changes in the Sternberg (6-digit but not 2- and 4-digit) test: improvement after CR-LD and worsening after IR-LD. Marginal improvement (p = .085) was observed with CR-LD in the WCST, while no significant differences were seen for the Stroop or Tower of Hanoi tests. Executive-related performance after LD challenge may differ depending on the LD time-to-peak plasma concentration and specific task demands. A slower rise in LD levels appears to have a more favorable impact on more difficult working memory tests. These results require replication to determine their generalization.

Neuropsychiatric symptoms are very common in premanifest and early stage Huntington's Disease.

BACKGROUND Neuropsychiatric symptoms are common features of Huntingtons disease (HD). Whereas most studies have focused on cognitive and neuroimaging markers of disease progression, little is known about the prevalence of neuropsychiatric symptoms in premanifest mutation carriers far-from and close-to disease onset. METHODS We obtained neurological, cognitive and behavioral data from 230 participants classified as premanifest far-from (preHD-A) and close-to (preHD-B) motor-based disease onset, early-symptomatic (early-HD), and healthy controls. Frequency and severity of neuropsychiatric symptoms were assessed with the short Problem Behaviors Assessment for HD (PBA-s). The odds-ratio (OR) to present symptoms in the clinical range was calculated using the control group as reference. Logistic regression analysis was used to explore relationships between neuropsychiatric symptoms and medication use. RESULTS Prevalence of depression was similar in all groups. Apathy was already present in 32% of preHD-A increasing to 62% of early-HD patients. The probability of presenting apathetic symptoms was 15-88 times higher in preHD-A and preHD-B respectively than in healthy controls. Irritability and executive dysfunction were present in both preHD-B and early-HD. CONCLUSION Neuropsychiatric symptoms are highly prevalent in HD, already in the premanifest stage, with increasing prevalence of irritability, apathy and executive dysfunction closer to onset. Compared to controls, HD mutation carriers have the highest probability to develop apathy, with an increasing prevalence along disease stages. Our findings confirm the high prevalence of neuropsychiatric symptoms in HD, already many years before the onset of motor symptoms, with apathy as an early manifestation and core neuropsychiatric feature of the disease.

Parkinson's disease-cognitive rating scale: Psychometrics for mild cognitive impairment

Lack of validated data on cutoff scores for mild cognitive impairment (MCI) and sensitivity to change in predementia stages of Parkinsons disease (PD) limit the utility of instruments measuring global cognition as screening and outcome measures in therapeutic trials. Investigators who were blinded to PD‐Cognitive Rating Scale (PD‐CRS) scores classified a cohort of prospectively recruited, nondemented patients into a PD with normal cognition (PD‐NC) group and a PD with MCI (PD‐MCI) group using Clinical Dementia Rating (CDR) and the Mattis Dementia Rating Scale‐2 (MDRS‐2). The discriminative power of the PD‐CRS for PD‐MCI was examined in a representative sample of 234 patients (145 in the PD‐NC group; 89 in the PD‐MCI group) and in a control group of 98 healthy individuals. Sensitivity to change in the PD‐CRS score (the minimal clinically important difference was examined with the Clinical Global Impression of Change scale and was calculated with a combination of distribution‐based and anchor‐based approaches) was explored in a 6‐month observational multicenter trial involving a subset of 120 patients (PD‐NC, 63; PD‐MCI, 57). Regression analysis demonstrated that PD‐CRS total scores (P < 0.001) and age (P = 0.01) independently differentiated PD‐NC from PD‐MCI. Area under the receiver operating characteristic curve (AUC) analysis (AUC, 0.85; 95% confidence interval, 0.80–0.90) indicated that a score ≤81 of 134 was the optimal cutoff point on the total score for the PD‐CRS (sensitivity, 79%; specificity, 80%; positive predictive value, 59%; negative predictive value, 91%). A range of change from 10 to 13 points on the PD‐CRS total score was indicative of clinically significant change. These findings suggest that the PD‐CRS is a useful tool to identify PD‐MCI and to track cognitive changes in nondemented patients with PD.

Mendelian genes for Parkinson's disease contribute to the sporadic forms of the disease

Parkinsons disease (PD) can be divided into familial (Mendelian) and sporadic forms. A number of causal genes have been discovered for the Mendelian form, which constitutes 10-20% of the total cases. Genome-wide association studies have successfully uncovered a number of susceptibility loci for sporadic cases but those only explain a small fraction (6-7%) of PD heritability. It has been observed that some genes that confer susceptibility to PD through common risk variants also contain rare causing mutations for the Mendelian forms of the disease. These results suggest a possible functional link between Mendelian and sporadic PD and led us to investigate the role that rare and low-frequency variants could have on the sporadic form. Through a targeting approach, we have resequenced at 49× coverage the exons and regulatory regions of 38 genes (including Mendelian and susceptibility PD genes) in 249 sporadic PD patients and 145 unrelated controls of European origin. Unlike susceptibility genes, Mendelian genes show a clear general enrichment of rare functional variants in PD cases, observed directly as well as with Tajimas D statistic and several collapsing methods. Our findings suggest that rare variation on PD Mendelian genes may have a role in the sporadic forms of the disease.

Detection of genomic rearrangements from targeted resequencing data in Parkinson's disease patients

The analysis of coverage depth in next‐generation sequencing data allows the detection of gene dose alterations. We explore the frequency of such structural events in a Spanish cohort of sporadic PD cases.

Short-lasting episodes of prosopagnosia in Parkinson's disease

BACKGROUND Prosopagnosia, the selective inability to recognize known faces, has been described in Alzheimers disease and fronto-temporal dementia but is not expected to occur in Parkinsons disease (PD). METHODS AND RESULTS We report three PD patients who developed recurrent, paroxysmal and short-lasting episodes of prosopagnosia, before progressing to PD dementia (PDD). Hallucinations and other higher-order visual deficits - such as optic ataxia and micro/macropsia - were also seen. CONCLUSION Progressive signs of temporal and parietal dysfunction have been suggested to herald dementia in PD. The observation of prosopagnosia and other higher-order visuoperceptive defects in the transition to dementia, reinforce the importance of posterior-cortical deficit in PD.