Javier Pagonabarraga

Favorable Outcome of Ischemic Stroke in Patients Pretreated with Statins

Background and Purpose— Statins may be beneficial for patients with acute ischemic stroke. We tested the hypothesis that patients pretreated with statins at the onset of stroke have less severe neurological effects and a better outcome. Methods— We prospectively included consecutive patients with ischemic stroke of <4-hour duration. We recorded demographic data, vascular risk factors, Oxfordshire Classification, National Institutes of Health Stroke Scale (NIHSS) score, admission blood glucose and body temperature, cause (Trial of Org 10172 in Acute Treatment [TOAST] criteria), neurological progression at day 3, previous statin treatment, and outcome at 3 months. We analyzed the data using univariate methods and a logistic regression with the dependent variable of good outcome (modified Rankin Scale [mRS] 0 to 1, Barthel Index [BI] 95 to 100). Results— We included 167 patients (mean age 70.7±12 years, 94 men). Thirty patients (18%) were using statins when admitted. In the statin group, the median NIHSS score was not significantly lower and the risk of progression was not significantly reduced. Favorable outcomes at 3 months were more frequent in the statin group (80% versus 61.3%, P =0.059 with the mRS; 76.7% versus 51.8%, P =0.015 with the BI). Predictors of favorable outcome with the BI were: NIHSS score at admission (OR: 0.72; CI: 0.65 to 0.80; P <0.0001), age (OR: 0.96; CI: 0.92 to 0.99; P =0.017), and statin group (OR: 5.55; CI: 1.42 to 17.8; P =0.012). Conclusions— Statins may provide benefits for the long-term functional outcome when administered before the onset of cerebral ischemia. However, randomized controlled trials will be required to evaluate the validity of our results.

Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families

Within the past few years, there has been a significant change in identifying and characterizing the FMR1 premutation associated phenotypes. The premutation has been associated with elevated FMR1 mRNA levels and slight to moderate reductions in FMRP levels. Furthermore, it has been established that ∼20% of female premutation carriers present primary ovarian insufficiency (POI) and that fragile X-associated tremor/ataxia syndrome (FXTAS) occurs in one-third of all male premutation carriers older than 50 years. Besides POI and FXTAS, new disorders have recently been described among individuals (especially females) with the FMR1 premutation. Those pathologies include thyroid disease, hypertension, seizures, peripheral neuropathy, and fibromyalgia. However there are few reports related to FXTAS penetrance among female premutation carriers or regarding these disorders recently associated to the FMR1 premutation. Therefore, we have evaluated 398 fragile X syndrome (FXS) families in an attempt to provide an estimation of the premutation associated phenotypes penetrance. Our results show that signs of FXTAS are detected in 16.5% of female premutation carriers and in 45.5% of premutated males older than 50 years. Furthermore, among females with the FMR1 premutation, penetrance of POI, thyroid disease and chronic muscle pain is 18.6, 15.9 and 24.4%, respectively. The knowledge of this data might be useful for accurate genetic counselling as well as for a better characterization of the clinical phenotypes of FMR1 premutation carriers.

Parkinson's disease-cognitive rating scale: a new cognitive scale specific for Parkinson's disease.

Cognitive defects associated with cortical pathology may be a marker of dementia in Parkinsons disease (PD). There is a need to improve the diagnostic criteria of PD dementia (PDD) and to clarify the cognitive impairment patterns associated with PD. Current neuropsychological batteries designed for PD are focused on fronto‐subcortical deficits but are not sensitive for cortical dysfunction. We developed a new scale, the Parkinsons Disease‐Cognitive Rating Scale (PD‐CRS), that was designed to cover the full spectrum of cognitive defects associated with PD. We prospectively studied 92 PD patients [30 cognitively intact (CogInt), 30 mild cognitive impairment (MCI), 32 PDD] and 61 matched controls who completed the PD‐CRS and neuropsychological tests assessing the cognitive domains included in the PD‐CRS. Acceptability, construct validity, reliability, and the discriminative properties of the PD‐CRS were examined. The PD‐CRS included items assessing fronto‐subcortical defects and items assessing cortical dysfunction. Construct validity, test‐retest and inter‐rater reliability of PD‐CRS total scores showed an intraclass correlation coefficient >0.70. The PD‐CRS showed an excellent test accuracy to diagnose PDD (sensitivity 94%, specificity 94%). The PD‐CRS total scores and confrontation naming item scores‐assessing “cortical” dysfunction—independently differentiated PDD from non‐demented PD. Alternating verbal fluency and delayed verbal memory independently differentiated the MCI group from both controls and CogInt. The PD‐CRS appeared to be a reliable and valid PD‐specific battery that accurately diagnosed PDD and detected subtle fronto‐subcortical deficits. Performance on the PD‐CRS showed that PDD is characterized by the addition of cortical dysfunction upon a predominant and progressive fronto‐subcortical impairment.

Apathy in Parkinson's disease: clinical features, neural substrates, diagnosis, and treatment

Normal maintenance of human motivation depends on the integrity of subcortical structures that link the prefrontal cortex with the limbic system. Structural and functional disruption of different networks within these circuits alters the maintenance of spontaneous mental activity and the capacity of affected individuals to associate emotions with complex stimuli. The clinical manifestations of these changes include a continuum of abnormalities in goal-oriented behaviours known as apathy. Apathy is highly prevalent in Parkinsons disease (and across many neurodegenerative disorders) and can severely affect the quality of life of both patients and caregivers. Differentiation of apathy from depression, and discrimination of its cognitive, emotional, and auto-activation components could guide an individualised approach to the treatment of symptoms. The opportunity to manipulate dopaminergic treatment in Parkinsons disease allows researchers to study a continuous range of motivational states, from apathy to impulse control disorders. Parkinsons disease can thus be viewed as a model that provides insight into the neural substrates of apathy.

Prevalence and correlates of neuropsychiatric symptoms in Parkinson's disease without dementia.

A cross‐sectional study of the profile of psychiatric symptoms and their relationships to medications, executive performance, and excessive daytime somnolence (EDS) was conducted on 1351 consecutive Parkinsons disease patients without dementia (PD‐ND). Ratings were: neuropsychiatric inventory (NPI); hospital anxiety and depression scale (HADS); executive performance (semantic, phonemic, and alternating verbal fluencies); and the Epworth sleepiness scale (ESS). Eighty‐seven percent of the subjects reported at least one psychiatric symptom. The most common were depression (70%), anxiety (69%), apathy (48%), and irritability (47%). Fifty percent of the patients had HADS‐depression scores ranging from possible (8–10; 22%) to probable (≥11; 28%) depression. Executive impairment was found in 41% and EDS in 26% of subjects. All considered variables were significantly more common with longer duration and more severe disease. Only depression appeared to be influenced by type of medication, being less prevalent among patients treated with DAs. Five NPI clusters were identified among patients scoring ≥1 on the NPI (87.3%): patients exhibiting predominantly apathy (12.7%), psychosis (3%), depression (13%), anxiety (15.6%), and “low‐total NPI” (43.2%). Neuropsychiatric symptoms are common in nondemented PD patients suggesting that they are an integral part of PD from the beginning of the disease and appears more related to disease progression than to the type of antiparkinsonian medication. Apathy emerged as an independent construct in PD‐ND, indicating the need to address specific therapeutical approaches targeted toward this particular symptom.

Cognitive impairment and dementia in Parkinson's disease.

Relatively subtle cognitive disturbances may be present from the initial stages of Parkinsons disease (PD) that progress in many patients to a more severe cognitive impairment and dementia. Several of the initial deficits are ascribed to failure in the frontal-striatal basal ganglia circuits and involve executive defects in planning, initiation, monitoring of goal-directed behaviors and working-memory. Other non-demented PD patients also exhibit visuospatial and memory deficits more representative of posterior cortical functioning and fail performing naming or copying tasks. Major differences in the overall rate of cognitive decline among PD patients support the co-existence of at least two patterns of involution, differentiating a relatively slow decline of fronto-striatal deficits from a more rapid decline of posterior-cortical deficits, with different pathophysiological substrates, genetics, prognosis and response to drugs used to treat the motor symptoms of PD.

Cognitive impairment in Parkinson's disease: tools for diagnosis and assessment.

Cognitive impairment (CI) and dementia are frequent and debilitating features associated with Parkinsons disease (PD). Formal neuropsychological examination is required to ascertain the degree and pattern of CI over the course of the disease. The use of different tools may explain heterogeneous data obtained from studies to date. Normative data for extensively used scales [Mattis Dementia Rating Scale (MDRS), Mini‐Mental State Examination (MMSE)] is incomplete in PD populations. According to sample characteristics, statistical analyses, and methodological quality, 33 studies using scales not specific to PD (MDRS, MMSE, Cambridge Cognitive Assessment, FAB) or PD‐specific scales (Mini‐Mental Parkinson, Scales for Outcomes of Parkinsons disease—Cognition, Parkinsons Disease—Cognitive Rating Scale, and Parkinson Neuropsychometric Dementia Assessment) were eligible for the critical analysis of their appropriateness to assess cognition in PD. Of the four scales specifically designed for PD, the SCOPA‐COG and the PD‐CRS have undergone extensive and rigorous validation processes. While the SCOPA‐COG mainly assesses “frontal‐subcortical” cognitive defects, the PD‐CRS also assesses “instrumental‐cortical” functions, allowing better characterization of the different patterns of CI that may be present in PD from the earliest stages. The MMP and PANDA scales were designed as brief screening tests for CI and have not yet been subjected to extensive clinimetric evaluations. Further research on PD‐specific tools seems mandatory to help establish accurate cut‐off scores for the diagnosis of mild PDD, detect cognitive profiles more prone to the future development of dementia, and allow comparisons between different descriptive or interventional studies.

Controlled study of decision‐making and cognitive impairment in Parkinson's disease

Impulse control disorders (ICD) related to reward‐processing dysfunction have been reported in Parkinsons disease (PD). The relationship between clinical markers of limbic dysfunction with demographic variables and cognitive status of PD is incompletely known. Our objective was to further characterize the relationship between limbic and cognitive dysfunction in a representative sample of nondemented PD patients without antecedents of ICD, as assessed by a risk‐taking test of decision‐making and a comprehensive neuropsychological battery. Prospective, controlled study of 35 nondemented PD patients and 31 matched controls who received the Iowa gambling task (IGT), the Mattis Dementia Rating Scale (MDRS) and verbal fluencies for global cognitive function, the Stroop and digit span tests for executive function, and the Rey Auditory Verbal Learning Test for memory. Compared to controls, PD patients performed significantly worse on the IGT. No clear relationship with demographic variables including dopaminergic treatment and motor response to levodopa (stable or fluctuating) emerged. Performance on the IGT was not related to executive function. In contrast, an inverse relationship was found between the IGT and memory and global cognitive performance, with patients with the better MDRS and memory scores performing significantly worse on the IGT. Our results confirm subclinical dysfunction of the limbic system in nondemented PD patients. Although impaired decision‐making appears unrelated to executive dysfunction, patients with the better cognitive status appears more prone to assume risky behaviors.

Cut‐off score of the Mattis Dementia Rating Scale for screening dementia in Parkinson's disease

The prevalence of dementia in Parkinsons disease (PD) is close to 30%, and its incidence is 4 to 6 times higher than in age‐matched general population. PD with dementia (PDD) is mainly characterized by a predominant and progressive frontal‐subcortical impairment. The Mattis Dementia Rating Scale (MDRS) is a commonly used screening test that sensitively measures the degree of frontal‐subcortical defects. Although the MDRS has been validated as a screening test of cognitive dysfunction in nondemented PD patients (PD‐ND), its utility for screening dementia in PD is unknown. In order to validate the MDRS for diagnosis of PDD it was prospectively administered to 92 PD patients (57 PD‐ND, 35 PDD) fulfilling UK‐PDSBB criteria. Dementia was diagnosed according to DSM‐IV‐TR and a Clinical Dementia Rating (CDR) scale score ≥1. Univariate, logistic regression, and ROC curve analysis were carried out to measure the discriminative power of MDRS in PDD. Regression analysis showed MDRS total scores to independently differentiate PD‐ND from PDD (P < 0.001). Age and education did not predict the presence of dementia. ROC curve analysis showed a cut‐off score of ≤123 on the MDRS total scores to yield high sensitivity (92.65%), specificity (91.4%), positive and negative predictive values (PPV 83.3%, NPV 96.4%). A brief version of the MDRS obtained by the addition of the memory, initiation/perseveration, and conceptualization subscores yielded similar discriminant properties. The MDRS has an excellent discriminant ability to diagnose dementia in PD and provides an objective measure to distinguish PD‐ND from PDD.

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.