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This paper is the first to analyse the impact of free trade agreements (FTAs) and the harmonisation of rules of origin (RoO) on Middle East and North African (MENA) countries’ exports differentiating between final and in-termediate goods for a global sample of trade partners. Data on exports from four MENA countries (Egypt, Jordan, Morocco and Tunisia) to 61 destinations over the period 1995– 2016 are used to estimate a structural gravity model applying a Poisson Pseudo Maximum Likelihood (PPML) estimator. Moreover, the paper esti-mates the effect of the progressive adoption of the Pan- European- Mediterranean RoO. Results show that FTAs have been overall successful in increasing MENA ex-ports. This is particularly true for FTAs that eliminate protection on agricultural products. In contrast to the ex-isting literature, we find that the agreements concluded with European countries raise MENA exports, whereas no significant impact is found for the application of the Pan- European RoO.

espanolLas remesas que los inmigrantes envian a su pais de origen contribuyen a alcanzar los Objetivos de Desarrollo Sostenible (ODS), permitiendo que muchas familias salgan de la pobreza. Dichos envios han disminuido en la primera mitad de 2020 debido a la crisis de la COVID-19. Centrandonos en un grupo de paises de America Latina, en este articulo hacemos un analisis exploratorio sobre el efecto que la COVID-19 podria tener sobre las remesas a traves de la contraccion en el PIB y el empleo de los paises que las envian. Asi mismo, relacionamos dicho impacto con la rigurosidad de las medidas tomadas en cada pais y comparamos la evolucion observada hasta ahora con lo ocurrido tras la crisis financiera global de 2008. EnglishThe money immigrants send back to their countries –remittances– could contribute to achieve the Sustainable Development Goals (SDG) allowing many families to escape poverty. These remittances have decreased in the first half of 2020 due to the COVID-19 crisis. Focusing on a group of Latin American countries, we present an exploratory analysis of the effect that COVID-19 could have on remittances through the contraction in GDP and employment in the sending countries. Likewise, we relate this impact to the stringency of the lockdown measures taken in each country and compare the evolution observed so far with the aftermaths of the global financial crisis of 2008

This paper is the first to analyze the impact of free trade agreements (FTAs) and the harmonization of rules of origin (RoO) on Middle East and North African (MENA) countries’ exports differentiating between final and intermediate goods for a global sample of trade partners. Data on exports from four MENA countries (Egypt, Jordan, Morocco and Tunisia) to 61 destinations over the period 1995-2016 are used to estimate a structural gravity model applying a Poisson Pseudo Maximum Likelihood (PPML) estimator. Moreover, the paper estimates the effect of the progressive adoption of the Pan-European-Mediterranean RoO. Results show that FTAs have been overall successful in increasing MENA exports. This is particularly true for FTAs that eliminate protection on agricultural products. In contrast to the existing literature, we find that the agreements concluded with European countries raise MENA exports, whereas no significant impact is found for the application of the Pan-European RoO.

This paper uses the gravity model of trade to investigate the effect of foreign aid on exports of aid recipients to donor countries. Most of the theoretical work emphasises the possible negative impact of aid on recipient countries’ exports, primarily due to exchange rate appreciation, disregarding possible positive effects of aid in overcoming supply bottlenecks and promoting bilateral trade relations. Using non-stationary panel (cointegration) estimators to control for omitted variable and endogeneity bias, we find that the net effect of aid on recipient countries’ exports is insignificant, both for our sample (of 123 countries) as a whole and for important regional sub-samples. This finding is in line with the small or insignificant macroeconomic impact of aid found in earlier studies and also suggests that exporters in recipient countries are not benefiting from improved trade relations with donors.

Multiple system atrophy (MSA) is a Parkinson's Disease (PD)-like alpha-synucleinopathy clinically characterized by dysautonomia, parkinsonism, cerebellar ataxia, and pyramidal signs in any combination. We aimed to determine whether the clinical presentation of MSA as well as diagnostic and therapeutic strategies differ across Europe and Israel. In 19 European MSA Study Group centres all consecutive patients with a clinical diagnosis of MSA were recruited from 2001 to 2005. A standardized minimal data set was obtained from all patients. Four-hundred thirty-seven MSA patients from 19 centres in 10 countries were included. Mean age at onset was 57.8 years; mean disease duration at inclusion was 5.8 years. According to the consensus criteria 68% were classified as parkinsonian type (MSA-P) and 32% as cerebellar type (MSA-C) (probable MSA: 72%, possible MSA: 28%). Symptomatic dysautonomia was present in almost all patients, and urinary dysfunction (83%) more common than symptomatic orthostatic hypotension (75%). Cerebellar ataxia was present in 64%, and parkinsonism in 87%, of all cases. No significant differences in the clinical presentation were observed between the participating countries. In contrast, diagnostic work up and therapeutic strategies were heterogeneous. Less than a third of patients with documented orthostatic hypotension or neurogenic bladder disturbance were receiving treatment. This largest clinical series of MSA patients reported so far shows that the disease presents uniformly across Europe. The observed differences in diagnostic and therapeutic management including lack of therapy for dysautonomia emphasize the need for future guidelines in these areas. (C) 2010 Movement Disorder Society

The aim of the present study was to investigate whether cyclooxygenase-2 (COX-2) expression is involved in the pathogenesis of neurodegeneration in dementia with Lewy bodies (DLB) by measuring COX-2 mRNA and protein expression in frontal cortex and substantia nigra pars compacta of DLB and control human brains. DLB cases were classified as pure form or common form according to the absence or the presence of Alzheimer pathology including neurofibrillary tangles and amyloid deposits by Braak staging. Using Western Blot and Real-time Polymerase chain reaction (PCR) analysis, we have shown that cortical COX-2 protein levels were decreased in DLB cases (P < 0.01). However, no differences in nigral COX-2 mRNA expression were observed between control and DLB cases. In conclusion, the present results suggest that in DLB nigral COX-2 mRNA expression does not correlate with dopaminergic neurodegeneration and that the slight changes observed in the common type are probably due to the concomitant AD pathology.

The objective of this study was to investigate tolerability and possible neurotrophic effects of growth hormone (GH) in treatment of multiple system atrophy (MSA). In this double-blind pilot study, MSA patients were randomized to recombinant human growth hormone (r-hGH, n = 22), 1 mg every second day (6 months) followed by alternating daily injections of 1 mg and 0.5 mg (6 months), or matched placebo (n = 21). Safety analysis demonstrated no obvious between-group differences. In both groups, there was progressive worsening of Unified Parkinson's Disease Rating Scale total score, which tended to be less in r-hGH-treated patients (12.9% at 6 months, 25.3% at 12 months) than in placebo (17.0% and 35.7%). Similarly, there was a trend to less worsening in Unified MSA Rating Scale total score with r-hGH (13.2% and 21.2%) than with placebo (21.1% and 36.5%). Cardiovascular reflex autonomic testing also tended to show less deterioration with r-hGH than with placebo at 12 months. However, 95% CI did not indicate treatment differences for any efficacy measures. In conclusion, r-hGH administration in MSA patients for up to 1 year appears safe and might influence disease symptoms, signs and, possibly, progression. The results support further studies utilizing higher doses in more patients.

Sleep disturbances occur frequently in patients with Parkinson's disease (PD). The aim of this study was to investigate the effects of rotigotine on sleep fluctuations in a sample of PD patients with self-reported complaints of nocturnal awakenings. This prospective, open-label, observational, and multicenter study enrolled consecutive outpatients with PD and administered rotigotine (mean dose 8.9 mg/day) for 3 months. The primary endpoint was the change from baseline in sleep fragmentation, assessed using the sleep maintenance subscale score of the Parkinson's Disease Sleep Scale (PDSS). The newly designed Parkinson's Disease Sleep Fragmentation Questionnaire (PD-SFQ) was used to measure other sleep parameters. A total of 62 patients were enrolled (mean age 70.2 years; 66% male). At 3 months, rotigotine significantly improved sleep fragmentation from baseline on the PDSS-2 sleep maintenance subscale (from 3.4 +/- 0.9 to 1.9 +/- 1.4; P < 0.0001). Rotigotine also significantly improved nocturnal motor symptoms (P < 0.0001), restless legs-like symptoms (P < 0.005), and nocturia (P = 0.004). Rotigotine significantly improved self-reported complaints of sleep fragmentation in PD patients and could be a useful treatment to improve this specific sleep problem in PD. However, these results are based on a small and clinically heterogeneous sample so they must be taken cautiously., The authors wish to thank Simone Boniface of Springer Healthcare Communication and Raewyn Poole on behalf of Springer Healthcare Communications, for English editing and styling of the paper for submission. This assistance was funded by UCB Pharma, Spain. The study was funded by an unrestricted grant from UCB. UCB was not involved in the study design, the collection, analysis, and interpretation of the data gathered, the writing of the report, or the decision to submit the paper for publication.

Abnormal tau phosphorylation and deposition in neurones and glial cells is one of the major features in tau pathies. The present study examines the involvement of the Ras/MEK/ERK pathway of tau phosphorylation in Alzheimer disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), by Western blotting, single and double‐labelling immunohistochemistry, and p21Ras activation assay. Since this pathway is also activated in several paradigms of cell death and cell survival, activated ERK expression is also analysed with double‐labelling immunohistochemistry and in situ end‐labelling of nuclear DNA fragmentation to visualise activated ERK in cells with increased nuclear DNA vulnerability. The MEK1 antibody recognises one band of 45 kD that identifies phosphorylation‐independent MEK1, whose expression levels are not modified in diseased brains. The ERK antibody recognises one band of 42 kD corresponding to the molecular weight of phosphorylation‐independent ERK2; the expression levels, as well as the immunoreactivity of ERK in individual cells, is not changed in AD, PiD, PSP and CBD. The antibody MAPK‐P distinguishes two bands of 44 kD and 42 kD that detect phosphorylated ERK1 and ERK2. MAPK‐P expression levels, as seen with Western blotting, are markedly increased in AD, PiD, PSP and CBD. Moreover, immunohistochemistry discloses granular precipitates in the cytoplasm of neurones in AD, mainly in a subpopulation of neurones exhibiting early tau deposition, whereas neurones with developed neurofibrillary tangles are less commonly immunostained. MAPK‐P also decorates neurones with Pick bodies in PiD, early tau deposition in neurones in PSP and CBD, and cortical achromatic neurones in CBD. In addition, strong MAPK‐P immunoreactivity is found in large numbers of tau‐positive glial cells in PSP and CBD, as seen with double‐labelling immunohistochemistry. Yet no co‐localisation of enhanced phosphorylated ERK immunoreactivity and nuclear DNA fragmentation is found in AD, PiD, PSP and CBD. Finally, activated Ras expression levels are increased in AD cases when compared with controls. These results demonstrate increased phosphorylated (active) ERK expression in association with early tau deposition in neurones and glial cells in taupathies, and suggest activated Ras as the upstream activator of the MEK/ERK pathway of tau phosphorylation in AD.

The presence of neuronal intranuclear inclusions (NIIs) and neuronal mosaicism has been described in some autosomal dominant spinocerebellar ataxias (SCA), but their implication in neurodegenerative mechanisms still remains unclear. Objective: To investigate the correlation between neuronal loss and NIIs, and the size of CAG triplet expansion in selected areas of the CNS in two SCA3 patients. Material and methods: Postmortem neuropathological study was carried out, and the regional distribution of neuronal loss was compared with NIIs. CAG expansion was analysed by PCR amplification in the same regions. Results: Marked neuronal loss was seen in the anterior horn of the spinal cord, pontine nuclei and motor nuclei of the brain stem. Moderate neurone loss was found in the locus ceruleus, colliculus and substantia nigra. Loss of granule and Purkinje cells was found in the cerebellum, mainly in the vermis. NIIs were present in neurones of the involved nuclei of the anterior horn of the spinal cord, medulla oblongata and pons, but not in the locus ceruleus, substantia nigra and cerebellum. A few NIIs were found in the striatum. The number of CAG repeats was 27/70 in the first patient and 21/74 in the second patient. The variation of the expanded allele size among different cerebral areas was ±1–3 CAG repeats. Conclusion: The partial correlation between neuronal loss and NIIs suggests that other factors distinct from NII formation may be involved in the neuronal death. Moreover, the low degree of mosaicism between regions without neuronal loss and regions with marked neuronal loss points to the existence of selective cellular vulnerability to the genetic defect.

Hypocretin (orexin) cerebrospinal fluid (CSF) levels have been previously found normal or decreased in Dementia with Lewy bodies and Parkinson disease, two synucleinopathies commonly associated with excessive daytime sleepiness (EDS). We evaluated CSF hypocretin-1 levels in 15 patients with moderately severe multiple system atrophy (MSA), another synucleinopathy where sleep disorders occur frequently and EDS has been reported, performing additional electrophysiological studies in 5 of them to assess the presence of EDS and sleep onset REM (SOREM) periods. Despite relatively low sleep efficiencies in nocturnal sleep, mean sleep latencies in the Multiple Sleep Latency Test were normal with no SOREM periods. All patients had CSF hypocretin-1 levels in the normal range (>200 pg/mL) suggesting that the hypocretin system is not altered in MSA, at least in patients with a moderately severe disease.

Summary Background Multiple system atrophy (MSA) is a fatal and still poorly understood degenerative movement disorder that is characterised by autonomic failure, cerebellar ataxia, and parkinsonism in various combinations. Here we present the final analysis of a prospective multicentre study by the European MSA Study Group to investigate the natural history of MSA. Methods Patients with a clinical diagnosis of MSA were recruited and followed up clinically for 2 years. Vital status was ascertained 2 years after study completion. Disease progression was assessed using the unified MSA rating scale (UMSARS), a disease-specific questionnaire that enables the semiquantitative rating of autonomic and motor impairment in patients with MSA. Additional rating methods were applied to grade global disease severity, autonomic symptoms, and quality of life. Survival was calculated using a Kaplan-Meier analysis and predictors were identified in a Cox regression model. Group differences were analysed by parametric tests and non-parametric tests as appropriate. Sample size estimates were calculated using a paired two-group t test. Findings 141 patients with moderately severe disease fulfilled the consensus criteria for MSA. Mean age at symptom onset was 56·2 (SD 8·4) years. Median survival from symptom onset as determined by Kaplan-Meier analysis was 9·8 years (95% CI 8·1–11·4). The parkinsonian variant of MSA (hazard ratio [HR] 2·08, 95% CI 1·09–3·97; p=0·026) and incomplete bladder emptying (HR 2·10, 1·02–4·30; p=0·044) predicted shorter survival. 24-month progression rates of UMSARS activities of daily living, motor examination, and total scores were 49% (9·4 [SD 5·9]), 74% (12·9 [8·5]), and 57% (21·9 [11·9]), respectively, relative to baseline scores. Autonomic symptom scores progressed throughout the follow-up. Shorter symptom duration at baseline (OR 0·68, 0·5–0·9; p=0·006) and absent levodopa response (OR 3·4, 1·1–10·2; p=0·03) predicted rapid UMSARS progression. Sample size estimation showed that an interventional trial with 258 patients (129 per group) would be able to detect a 30% effect size in 1-year UMSARS motor examination decline rates at 80% power. Interpretation Our prospective dataset provides new insights into the evolution of MSA based on a follow-up period that exceeds that of previous studies. It also represents a useful resource for patient counselling and planning of multicentre trials. Funding Fifth Framework Programme of the European Union, the Oesterreichische Nationalbank, and the Austrian Science Fund.

The value of the Apgar score as an index of birth asphyxia has been recently questioned. The purpose of the present study is to evaluate the relationship between cord blood pH and Apgar score in term newborn infants.A cross-sectional study involving 76 term newborn infants was performed from March through September 1995 at the Obstetric Unit of Hospital de Clínicas de Porto Alegre. The blood samples were obtained from umbilical cord artery and vein at the moment of delivery. Infants were divided in three different groups according to the Apgar score: Group A (n=60):or=7 at one and five minutes; Group B (n=13):7 at one minute andor=7 at five minutes; Group C (n=3):7 at one and five minutes. The frequency of acidemia in Group A was 18.3% (11 newborn infants) considering arterial pH7.20 and 5% considering arterial pHor= 7.10. Three newborn infants (23%) of Group B had arterial pHor= 7.20 and nine (56.2%) had arterial pH7.10. None of the newborn infants in Group C had arterial pH7.10. The sensitivity and specificity values for Apgar score less than 7 at one minute for detection of fetal acidemia were, respectively, 54.1% and 94.1%. This study confirms a poor correlation between Apgar score and umbilical blood cord pH, even in a term newborn, and emphasizes the importance of obtaining umbilical cord pH to consider the diagnosis of perinatal asphyxia.

In order to recognize substantia nigra neuronal changes occurring in aging, 20 human control brains from 13 males and 7 females with a mean age of 61 years (range 20 to 93 years) without neurological disease were examined using the Golgi method. A quantitative study of dendrites and dendritic spines was performed as well as a statistical analysis of obtained data. Parallel sections to the impregnated material were histologically and immunohistologically studied with the aim to identify possible neuronal cytoskeletal abnormalities. Results were compared to changes of substantia nigra reported in other conditions such as Parkinson's disease (PD) and methyl-4-phenylpyridine (MPTP) experimental toxicity. Three different substantia nigra neuronal types were observed. Morphological changes during aging consisted of distorted profile of the cell body and swelling and beading of dendritic branches. The quantitative assessment of changes observed in neuronal types showed a significant loss of dendrites and dendritic spines, especially in the oldest cases. These findings were similar to those previously described in other cerebral areas during aging, but a specific vulnerability of the largest substantia nigra neuronal type could be observed. Nodulations and beaded aspects of dendrites are reminiscent of those changes previously described in MPTP toxicity. Dendritic varicosities found in the oldest cases have also been found in dendrites of large substantia nigra neurons in PD. Cytoskeletal abnormalities have been described in PD but were not found in the present study. Therefore, other pathophysiological mechanisms different from the cytoskeletal compromise occurring in some neurodegenerative diseases should be involved in aging.

In order to compare the recovery capacity of the nigrostriatal system between adult and old mice, MPTP hydrochloride was administered to 48 BL/C57 male mice, which were sacrificed 24 h or 10 d after the second dose. The animals were divided into four groups, based on age (adult or old) and moment of sacrifice (24 h or 10 d). The detailed morphology of the neurons and the cellular processes of the substantia nigra pars compacta and the striatum were studied using the Golgi method. Immunostaining with a polyclonal glial fibrillary acidic protein antiserum using the peroxidase-antiperoxidase technique was performed to study the glial response. Striatal catecholamines were determined to correlate the biochemical data with the morphological changes. Significant neuronal changes of cellular processes were observed in substantia nigra pars compacta from all MPTP-treated mice, consisting of swelling and distortion of cellular bodies, discontinuous thickness, and nodulations of dendrites with baded aspect. Axons showing focal swelling and nodulations were also found in the neuropil of silver impregnated striata. Marked gliosis with reactive astrocytes in substantia nigra and striatum from all the old treated mice was found. Recovery was only observed in adult mice sacrificed 10 d after withdrawal. At this time, all the old MPTP-treated mice showed marked neuronal changes and a persistent marked gliosis. As expected, 24 h after the MPTP treatment, a marked depletion of dopamine and its metabolites was found in all the animals; at 10 d, the depletion was partially reversed in the adult group. These data correlate well with the observed morphological changes. Our results suggest that, in mice, deterioration of dendritic and axonal neuropil constitutes a significant causal factor of the MPTP neurotoxicity. These features are related to the age of the animals and the integrity of the plasticity phenomena, which appear to be altered in old mice.

This paper uses the gravity model of trade to investigate the link between foreign aid and exports in recipient countries. Most of the theoretical work emphasizes the negative impact of aid on recipient countries’ exports primarily due to exchange rate appreciation, disregarding possible positive effects of aid in promoting bilateral trade relations. The empirical findings, in contrast, indicate that the net impact of aid on recipient countries’ exports is positive -even though the macroeconomic impact of aid is rather small- and that the average return for recipients’ exports is about 1.50 US$ for every aid dollar spent. We argue that “bilateral aid” seems to promote good bilateral trade relations, mutual trust and familiarity and that those factors reinforce bilateral trade, including recipient country exports. The paper also estimates the effect of different types of aid (bilateral aid versus multilateral aid flowing to a specific recipient) and studies aid’s contribution to an expansion of exports in different regions of the world. It is found that aid is strongly export-enhancing in Asia and Latin America, but not in Africa.

This paper investigates growth convergence across Colombian departments during the period of 1975 to 2000, following both the regression and the distributional approaches suggested in the literature, and using two income measures computed by Centro de Estudios Ganaderos (CEGA).We also discuss issues related to data provided by Departamento Administrativo Nacional de Estadısticas (DANE) used by previous convergence studies. Our results show no evidence supporting convergence using per capita gross departmental product, but rather persistence in the distribution. Using per capita gross household disposable income, we find convergence, but only at a low speed, close to one percent per year. Furthermore, we find no evidence of the existence of different steady states for the two variables considered.

This paper investigates convergence in social indicators among Colombian departments from 1973 to 2005. We use census data and apply both the regression approach and the distributional approach (univariate and bivariate kernel density estimators). Using literacy rate as a proxy for education, we find convergence between 1973 and 2005, but persistence in the distribution between 1975 and 2000, when we use the infant survival rate and life expectancy at birth as proxies for health. Additionally, using data from Demographic and Health Surveys, we find convergence in the rate of children that are well-nourished between 1995 and 2005.

In this paper, we analyze how the distribution of selected non-income welfare indicators changed between 1997 and 2003 in Colombia. We use multidimensional pro-poor growth measurement techniques and create indices for assets, health, education, and subjective welfare using two alternative weighing techniques: polychoric principal components and normatively selected weights. Results show that while income and expenditures fluctuated according to economic growth, reflecting the effects of the 1999 economic crisis, non-income indicators had minor changes. While income and expenditures decreased for all income percentiles, and relatively more for the richest, the non-income dimensions stagnated and remained in 2003 as unequally distributed as in 1997.

The aim of the present study was to investigate whether cyclooxygenase-2 (COX-2) expression is involved in the pathogenesis of neurodegeneration in dementia with Lewy bodies (DLB) by measuring COX-2 mRNA and protein expression in frontal cortex and substantia nigra pars compacta of DLB and control human brains. DLB cases were classified as pure form or common form according to the absence or the presence of Alzheimer pathology including neurofibrillary tangles and amyloid deposits by Braak staging. Using Western Blot and Real-time Polymerase chain reaction (PCR) analysis, we have shown that cortical COX-2 protein levels were decreased in DLB cases (P0.01). However, no differences in nigral COX-2 mRNA expression were observed between control and DLB cases. In conclusion, the present results suggest that in DLB nigral COX-2 mRNA expression does not correlate with dopaminergic neurodegeneration and that the slight changes observed in the common type are probably due to the concomitant AD pathology.

The clinical diagnosis Of Multiple system atrophy (MSA) is fraught with difficulty and there are no pathognomonic features to discriminate the parkinsonian variant (MSA-P) from Parkinson's disease (PD). Besides the poor response to levodopa, and the additional presence of pyramidal or cerebellar signs (ataxia) or autonomic failure as major diagnostic criteria, certain other clinical features known as "red flags" or warning signs may raise the clinical suspicion of MSA. To study the diagnostic role of these features in MSA-P versus PD patients, a standardized red flag check list (RFCL) developed by the European MSA Study Group (EMSA-SG) was administered to 57 patients with probable MSA-P and 116 patients with probable PD diagnosed according to established criteria. Those red flags with a specifity over 95% were selected for further analysis. Factor analysis was applied to reduce the number of red flags. The resulting set was then applied to 17 patients with possible MSA-P who on follow-up fulfilled criteria of probable MSA-P. Red flags were grouped into related categories. With two or more of six red flag categories present specificity was 98.3% and sensitivity was 84.2% in our cohort. When applying these criteria to patients with possible MSA-P, 76.5% of them would have been correctly diagnosed as probable MSA-P 15.9 (+/- 7.0) months earlier than with the Consensus criteria alone. We propose a combination of two out of six red flag categories as additional diagnostic criteria for probable MSA-P. (C) 2008 Movement Disorder Society.

Background The neuropathology associated with LRRK2 mutations is heterogeneous but Lewy body (LB) type pathology is the most common substrate encountered. While the prevalence of LRRK2 mutations has been extensively studied in Parkinson's disease (PD), limited information is available on the frequency of LRRK2 mutations in dementia with Lewy bodies (DLB) and in other pathological conditions associated with these mutations, such as non-specific nigral degeneration without LB, tau-immunopositive neurofibrillary tangle pathology, and ubiquitin-positive neuronal inclusions resembling those observed in a subtype of frontotemporal lobar degeneration (FTLD-U). Objective To further investigate the neuropathology associated with LRRK2 mutations. Methods We have screened for the LRRK2 G2019S and codon-1441 (R1441G/C/H) mutations in 110 cases from a Spanish Brain Bank, which include: 66 synucleinopathies (33 PD, 25 DLB and 8 multiple system atrophy cases), 29 tauopathies (21 progressive supranuclear palsy, 3 corticobasal degeneration and 5 tau-positive FTLD cases), 3 cases of non-specific nigral degeneration and 12 tau-negative FTLD (9 FTLD-U and 3 dementia lacking distinctive histology cases). Results The G2019S mutation was found in two cases: One case had a clinical and pathological diagnosis of PD and the other suffered from typical PD and on neuropathological examination had non-specific nigral degeneration without LB. A synonymous variant (R1441R; c.4323C>T) was detected in another PD case. Conclusions In this brain bank-based series, LRRK2 G2019S mutation occurred in patients with parkinsonism associated with either typical brainstem LB pathology or non-specific nigral degeneration. LRRK2 mutations were not encountered in other neurodegenerative disorders associated with synuclein and tau deposition.

The G2019S leucine-rich repeat kinase 2 gene (LRRK2) mutation has been identified in a significant proportion of familial and sporadic cases of Parkinson's disease (PD). Until now, information on the neuropathological changes associated with the G2019S LRRK2 mutation has been sparse. We report a 77-year-old patient who presented with a 14 year history of PD but, unexpectedly, histopathological examination disclosed mild neuronal loss in the substantia nigra without alpha-synuclein, tau or ubiquitin cytoplasmic inclusions. A G2019S LRRK2 mutation was eventually detected. The present case confirms that clinical PD caused by G2019S mutations can be associated with non-specific nigral degeneration without Lewy bodies.

Although multiple system atrophy (MSA) is a neurodegenerative disorder leading to progressive disability and decreased life expectancy, little is known about patients' own evaluation of their illness and factors associated with poor health-related quality of life (Hr-QoL). We, therefore, assessed Hr-QoL and its determinants in MSA. The following scales were applied to 115 patients in the European MSA-Study Group (EMSA-SG) Natural History Study: Medical Outcome Study Short Form (SF-36), EQ-5D, Beck Depression Inventory (BDI), Mini-Mental state examination (MMSE), Unified MSA Rating Scale (UMSARS), HoehnYahr (HY) Parkinson's disease staging scale, Composite Autonomic Symptom Scale (COMPASS), and Parkinson's Disease Sleep Scale (PDSS). Forty-six percent of patients had moderate to severe depression (BDIor = 17); Hr-QoL scores on the SF-36 and EQ-5D were significantly impaired. Pain, the only domain with similar scores in MSA and published PD patients, was reported more frequently in patients with MSA-P (predominantly parkinsonian motor subtype) than MSA-C (predominantly cerebellar motor subtype; 76% vs. 50%; P = 0.005). Hr-QoL scores correlated most strongly with UMSARS motor, COMPASS, and BDI scores but not with MMSE scores, age at onset, or disease duration. The COMPASS and UMSARS activities of daily living scores were moderate-to-strong predictors for the SF-36 physical summary score and the BDI and UMSARS motor scores for the SF-36 mental summary score. This report is the first study to show that Hr-QoL is significantly impaired in MSA. Although not all possible factors related to impaired Hr-QoL in MSA could be assessed, autonomic dysfunction, motor impairment, and depression were most closely associated with poor Hr-QoL, and therapeutic management, therefore, should concentrate upon these aspects of the disease.

The disease-specific Unified Multiple System Atrophy Rating Scale (UMSARS) has been developed recently and validated for assessing disease severity in multiple system atrophy (MSA). Here, we aimed at (1) assessing rates of disease progression in MSA and (2) validating UMSARS for sensitivity to change over time. Impairment was assessed at two time points 12 months apart using UMSARS Part I (historical review), UMSARS Part II (motor examination), as well as measures of global disease severity, including UMSARS Part IV, Hoehn and Yahr (HY) Parkinson's disease staging, Schwab England Activities of Daily Living (SE ADL), and a three-point global Severity Scale (SS3). Fifty patients (male:female ratio, 1:0.9; possible MSA, 16%; probable MSA, 84%; MSA-parkinsonian, 58%; MSA-cerebellar, 42%) were assessed twice with an interval of 12.3 months. UMSARS II scores progressed by 57.3% (P

Background The pathophysiology of white matter involvement in dentatorubropallidoluysian atrophy (DRPLA) is controversial. Moreover, the clinical repercussions and evolution of these lesions have not been well documented. Objective To describe a case of DRPLA with severe cerebellar white matter involvement. Design Case report. Patient A 62-year-old woman with DRPLA. Results When the genetic diagnosis was made, the patient manifested severe ataxia, slight dysarthria, and subcortical cognitive impairment. Cranial magnetic resonance imaging showed atrophy of the cerebellum and brainstem and moderate high-intensity signal alterations in the periventricular cerebral white matter in T2-weighted sequences. In the following 5 years, she developed uncontrolled head movements associated with severe bruxism and tetraparesis, and became deeply demented. New magnetic resonance imaging showed severe diffuse cerebral white matter alterations in T2 sequences with only slight progression of brainstem and cerebellar atrophy. After her death at 67 years of age, the autopsy study showed diffuse myelin pallor, axonal preservation, and reactive astrogliosis in the cerebral white matter, with only mild atherosclerotic changes, and moderate neuronal loss in the cerebellum and brainstem. Conclusions Leukoencephalopathy could be a prominent finding in some patients with DRPLA, explaining, at least in part, their clinical evolution. In our case, the disproportion between the severity of white matter damage and vascular changes does not support a cardinal role for ischemic mechanisms in leukoencephalopathy.

In view of reports on high frequencies of atypical parkinsonism from different parts of the world and in non-white communities in the United Kingdom, we have prospectively surveyed 1,000 consecutive patients with parkinsonism presenting to two European tertiary referral centres for movement disorders (London, UK, and Barcelona, Spain). The aims of our study were to assess in a cross-sectional, prospective manner the proportion of patients who could not be classified diagnostically, to identify the factors precluding classification, and to determine which diagnostic measures would increase the rate of classifiable cases. Diagnoses were established using published clinical diagnostic criteria for Parkinson's disease (PD) and for other conditions associated with parkinsonism. Twenty-nine patients in London and 25 in Barcelona were initially considered unclassifiable; nine could be classified after further investigations. Levodopa (L-dopa) responsiveness was found to have a pivotal role in establishing a clinical diagnosis in previously unclassifiable patients: In those 45 patients who remained unclassifiable, failure to respond to L-dopa without other exclusion criteria for PD was the most common finding in each centre. Our results show that 4.0 to 5.0% of parkinsonian patients presenting to specialist clinics in Western Europe cannot be categorised using currently available clinical diagnostic criteria for parkinsonian syndromes. Prolonged follow-up and neuropathological diagnosis will be needed to determine whether all these cases represent atypical presentations of established clinico-pathological entities or whether some represent unrecognised new disorders. (C) 2003 Movement Disorder Society.

The clinical, neuroradiological, neuropathological and biochemical findings in four patients with primary progressive aphasia and tauopathy are described. The aphasic syndrome preceded by several years the appearance of other symptoms in every case. Asymmetrical apraxia with alien hand phenomenon occurred in one case. Frontotemporal symptoms occurred in three cases, but progressed to dramatic cognitive devastation in only one of these. Generalized dementia consistent with probable Alzheimer's disease (AD) developed with time in another. Cerebral computer tomography scans, magnetic resonance imaging and SPECT studies revealed marked asymmetries in one case, and showed nonspecific cerebral atrophy in the remaining ones. The neuropathological examination revealed typical corticobasal degeneration (CBD) in one case; CBD and AD in another; and atypical CBD, argyrophilic grain disease (AGD) and alpha-synucleinopathy consistent with Parkinson's disease in a third. Unique neuropathological findings were found in the remaining case. This was characterized by severe cerebral atrophy, marked neuronal loss in the cerebral cortex and abnormal tau deposition in neurons of the cerebral cortex, diencephalon and brain stem. Ballooned neurons, Pick bodies, generalized cortical neurofibrillary tangles and astrocytic plaques were absent. However, massive globular inclusions, containing phospho-tau, occurred in glial cells, mainly oligodendrocytes, in the white matter. Biochemical studies of frontal homogenates revealed four bands of 73/74, 68, 64 and 60 kDa of phosphorylated tau (using antibodies recognizing phospho-tau Thr181, Ser262 and Ser422) in the patient with AD and CBD, suggesting a predominant AD pattern in this case. Two bands of 68 and 64 kDa of phospho-tau were recovered in the sarkosyl-insoluble fraction in the other three cases. This pattern is similar to that found in CBD, progressive supranuclear palsy and AGD. Taken together, the present series further supports pure and combined CBD as causes of primary progressive aphasia, and they extend the hypothesis that primary progressive aphasia may be the initial symptom of distinct tauopathies.

Aging is associated with a progressive impairment in motor function. This feature, together with the decline in mental function, could be considered as an aging syndrome which may finally compromise the ability of the elderly to maintain an active, independent life-style.

Day-care attendance accounts for an increased frequency of acute respiratory infections (ARI), in numbers of both episodes and hospitalizations. In addition to day-care exposure, risk factors include age, siblings, and crowding. The purpose of this study was to investigate a possible association between duration of day-care exposure and ARI. A cross-sectional study was carried out to compared ARI rates for children exposed to day care and children cared for at home. Children with at least one parent working in a hospital were sampled from the hospital-run day-care center and those cared for at home. An acute respiratory infection was defined as the presence of two or more signs or symptoms in the previous two weeks. Children exposed to the day-care center for 12 to 50 hours a week had a three to five times greater risk of developing ARI than those staying at home. This risk was assessed independently, taking socioeconomic status, age, and number of siblings into account. Risk of respiratory illness and day-care attendance has been described elsewhere, but this study presents original findings related to duration of exposure. With a view towards reducing risk of ARI, improvements should be made in institutional day-care centers in Brazil, where family day care is still not available. A freqüência à creche associa-se com maior número de episódios de infecção respiratória e hospitalizações. Além da creche, a idade, a presença de irmãos e a aglomeração do ambiente são outras características identificadas como fatores de risco. Neste estudo investigou-se a associação entre infecção aguda do trato respiratório (IRA) e o número de horas que a criança permanecia na creche. Investigou-se a prevalência de IRA entre crianças freqüentadoras da creche e entre aquelas cuidadas em casa através de um estudo transversal. Selecionou-se a amostra entre filhos de funcionários de um hospital com disponibilidade de creche. Infecção respiratória foi definida pela presença de pelo menos dois sinais ou sintomas ocorridos nas duas últimas semanas. Crianças expostas à creche por 12 a 50 horas semanais apresentaram um risco aproximadamente três a cinco vezes maior de ter uma infecção respiratória aguda. Este efeito mostrou-se independente do nível sócio-econômico dos pais, da presença de irmãos e da idade da criança. Outros estudos caracterizaram o risco decorrente da exposição à creche, contudo neste detectou-se o efeito relacionado a permanência prolongada. Alternativas como as creches familiares americanas são pouco difundidas em nosso meio, portanto, deve-se buscar meios de minimizar o risco de IRA nas instituições tradicionais.

Immunohistological findings in cerebral blood vessels of 4 cases with cerebral amyloid angiopathy (CAA) were compared with those of 4 Alzheimer's (AD) cases. A panel of antibodies against 2 neurofilament subunits (BF10 and RT97), a microtubule-associated protein (TAU) and ubiquitin were used. CAA cases showed a strong immunoreactivity for ubiquitin in blood vessel wall. Senile plaques (SPs) in CAA cases showed strong ubiquitin positivity but the central amyloid core was negative. AD brains showed immunoreactivity with all antibodies in SPs and neurofibrillary tangles (NFTs); blood vessels were consistently negative for ubiquitin. Control brains showed few SPs and NFTs; these were positive for ubiquitin, but blood vessels were negative. These results indicate that vascular amyloid deposition in CAA and AD may have different pathophysiological mechanisms.

The grumose degeneration observed in the dentate nuclei of 7 cases of progressive supranuclear palsy (PSP) was studied with a panel of antibodies which included 2 neurofilaments, Tau and ubiquitin. Dentate nucleus neurons were negative with all antibodies except ubiquitin which showed a slightly positive homogeneous pattern of staining. The amorphous material surrounding swollen or normal neurons was strongly positive for neurofilament and subunits and numerous torpedoes were observed in the granular layer of the cerebellar cortex. Our results confirm that grumose degeneration consists in degeneration of terminal axons of Purkinje cells in the dentate nucleus. The positivity of dentate nucleus neurons for ubiquitin may support the concept of synaptic dysfunction between Purkinje cells and dentate nucleus neurons.

Two cases with classical clinical manifestations of progressive supranuclear palsy (PSP) showed severe progressive dementia as an additional clinical feature. Neuropathological study demonstrated typical features of PSP in the brainstem. Additionally, histological criteria of Alzheimer's disease (AD) were observed. A topographic and immunohistological study (with neurofilament subunit and Tau and Ubiquitin antibodies) of the distribution of neurofibrillary tangles (NFTs) was performed in order to compare the characteristics of NFTs from cortex and brainstem. NFTs from cortex were positive with all antibodies used and were predominantly distributed in cortical layers III and V and affected medium size neurons. Brainstem NFTs were positive only for neurofilament subunits and Tau. Cortical and brainstem NFTs showed immunohistological differences. Cortical NFTs in our two cases had a similar distribution as in control AD cases. On the basis of our observations we believe (1) that cortical tangles in our PSP cases are related to Alzheimer's disease and (2) that the cortical NFTs of PSP and AD are morphologically and immunohistologically distinct. Mechanisms concerned with the production of cortical and brainstem NFTs in PSP and AD are discussed.