Environmental risk factors for dementia: a systematic review

Background - Dementia risk reduction is a major and growing public health priority. While certain modifiable risk factors for dementia have been identified, there remains a substantial proportion of unexplained risk. There is evidence that environmental risk factors may explain some of this risk. Thus, we present the first comprehensive systematic review of environmental risk factors for dementia. Methods - We searched the PubMed and Web of Science databases from their inception to January 2016, bibliographies of review articles, and articles related to publically available environmental data. Articles were included if they examined the association between an environmental risk factor and dementia. Studies with another outcome (for example, cognition), a physiological measure of the exposure, case studies, animal studies, and studies of nutrition were excluded. Data were extracted from individual studies which were, in turn, appraised for methodological quality. The strength and consistency of the overall evidence for each risk factor identified was assessed. Results - We screened 4784 studies and included 60 in the review. Risk factors were considered in six categories: air quality, toxic heavy metals, other metals, other trace elements, occupational-related exposures, and miscellaneous environmental factors. Few studies took a life course approach. There is at least moderate evidence implicating the following risk factors: air pollution; aluminium; silicon; selenium; pesticides; vitamin D deficiency; and electric and magnetic fields. Conclusions - Studies varied widely in size and quality and therefore we must be circumspect in our conclusions. Nevertheless, this extensive review suggests that future research could focus on a short list of environmental risk factors for dementia. Furthermore, further robust, longitudinal studies with repeated measures of environmental exposures are required to confirm these associations

Systematic Review of Potential Health Risks Posed by Pharmaceutical, Occupational and Consumer Exposures to Metallic and Nanoscale Aluminum, Aluminum Oxides, Aluminum Hydroxide and Its Soluble Salts

Aluminum (Al) is a ubiquitous substance encountered both naturally (as the third most abundant element) and intentionally (used in water, foods, pharmaceuticals, and vaccines); it is also present in ambient and occupational airborne particulates. Existing data underscore the importance of Al physical and chemical forms in relation to its uptake, accumulation, and systemic bioavailability. The present review represents a systematic examination of the peer-reviewed literature on the adverse health effects of Al materials published since a previous critical evaluation compiled by Krewski et al. (2007). Challenges encountered in carrying out the present review reflected the experimental use of different physical and chemical Al forms, different routes of administration, and different target organs in relation to the magnitude, frequency, and duration of exposure. Wide variations in diet can result in Al intakes that are often higher than the World Health Organization provisional tolerable weekly intake (PTWI), which is based on studies with Al citrate. Comparing daily dietary Al exposures on the basis of “total Al”assumes that gastrointestinal bioavailability for all dietary Al forms is equivalent to that for Al citrate, an approach that requires validation. Current occupational exposure limits (OELs) for identical Al substances vary as much as 15-fold. The toxicity of different Al forms depends in large measure on their physical behavior and relative solubility in water. The toxicity of soluble Al forms depends upon the delivered dose of Al+ 3 to target tissues. Trivalent Al reacts with water to produce bidentate superoxide coordination spheres [Al(O2)(H2O4)+ 2 and Al(H2O)6 + 3] that after complexation with O2•−, generate Al superoxides [Al(O2•)](H2O5)]+ 2. Semireduced AlO2• radicals deplete mitochondrial Fe and promote generation of H2O2, O2 • − and OH•. Thus, it is the Al+ 3-induced formation of oxygen radicals that accounts for the oxidative damage that leads to intrinsic apoptosis. In contrast, the toxicity of the insoluble Al oxides depends primarily on their behavior as particulates. Aluminum has been held responsible for human morbidity and mortality, but there is no consistent and convincing evidence to associate the Al found in food and drinking water at the doses and chemical forms presently consumed by people living in North America and Western Europe with increased risk for Alzheimer\u27s disease (AD). Neither is there clear evidence to show use of Al-containing underarm antiperspirants or cosmetics increases the risk of AD or breast cancer. Metallic Al, its oxides, and common Al salts have not been shown to be either genotoxic or carcinogenic. Aluminum exposures during neonatal and pediatric parenteral nutrition (PN) can impair bone mineralization and delay neurological development. Adverse effects to vaccines with Al adjuvants have occurred; however, recent controlled trials found that the immunologic response to certain vaccines with Al adjuvants was no greater, and in some cases less than, that after identical vaccination without Al adjuvants. The scientific literature on the adverse health effects of Al is extensive. Health risk assessments for Al must take into account individual co-factors (e.g., age, renal function, diet, gastric pH). Conclusions from the current review point to the need for refinement of the PTWI, reduction of Al contamination in PN solutions, justification for routine addition of Al to vaccines, and harmonization of OELs for Al substances

C9ORF72 repeat expansion in Australian and Spanish frontotemporal dementia patients

A hexanucleotide repeat expansion in C9ORF72 has been established as a common cause of frontotemporal dementia (FTD). However, the minimum repeat number necessary for disease pathogenesis is not known. The aims of our study were to determine the frequency of the C9ORF72 repeat expansion in two FTD patient collections (one Australian and one Spanish, combined n = 190), to examine C9ORF72 expansion allele length in a subset of FTD patients, and to examine C9ORF72 allele length in ‘non-expansion’ patients (those with <30 repeats). The C9ORF72 repeat expansion was detected in 5–17% of patients (21–41% of familial FTD patients). For one family, the expansion was present in the proband but absent in the mother, who was diagnosed with dementia at age 68. No association was found between C9ORF72 non-expanded allele length and age of onset and in the Spanish sample mean allele length was shorter in cases than in controls. Southern blotting analysis revealed that one of the nine ‘expansion-positive’ patients examined, who had neuropathologically confirmed frontotemporal lobar degeneration with TDP-43 pathology, harboured an ‘intermediate’ allele with a mean size of only ~65 repeats. Our study indicates that the C9ORF72 repeat expansion accounts for a significant proportion of Australian and Spanish FTD cases. However, C9ORF72 allele length does not influence the age at onset of ‘non-expansion’ FTD patients in the series examined. Expansion of the C9ORF72 allele to as little as ~65 repeats may be sufficient to cause disease.Carol Dobson-Stone, Marianne Hallupp, Clement T. Loy, Elizabeth M. Thompson, Eric Haan, Carolyn M. Sue, Peter K. Panegyres, Cristina Razquin, Manuel Seijo-Martínez, Ramon Rene, Jordi Gascon, Jaume Campdelacreu, Birgit Schmoll, Alexander E. Volk, William S. Brooks, Peter R. Schofield, Pau Pastor, John B. J. Kwo

Parkinson's disease and Alzheimer disease: environmental risk factors

Introduction: The purpose of this review is to update and summarise available evidence on environmental risk factors that have been associated with risk of Parkinson's disease (PD) or Alzheimer disease (AD) and to discuss their potential mechanisms. Development: Evidence consistently suggests that a higher risk of PD is associated with pesticides and that a higher risk of AD is associated with pesticides, hypertension and high cholesterol levels in middle age, hyperhomocysteinaemia, smoking, traumatic brain injury and depression. There is weak evidence suggesting that higher risk of PD is associated with high milk consumption in men, high iron intake, chronic anaemia and traumatic brain injury. Weak evidence also suggests that a higher risk of AD is associated with high aluminium intake through drinking water, excessive exposure to electromagnetic fields from electrical grids, DM and hyperinsulinaemia, obesity in middle age, excessive alcohol consumption and chronic anaemia. Evidence consistently suggests that a lower risk of PD is associated with hyperuricaemia, tobacco and coffee use, while a lower risk of AD is associated with moderate alcohol consumption, physical exercise, perimenopausal hormone replacement therapy and good cognitive reserve. Weak evidence suggests that lower risk of PD is associated with increased vitamin E intake, alcohol, tea, NSAIDs, and vigorous physical exercise, and that lower risk of AD is associated with the Mediterranean diet, coffee and habitual NSAID consumption. Conclusions: Several environmental factors contribute significantly to risk of PD and AD. Some may already be active in the early stages of life, and some may interact with other genetic factors. Population-based strategies to modify such factors could potentially result in fewer cases of PD or AD. Resumen: Introducción: Esta revisión pretende actualizar y resumir la evidencia disponible sobre los factores de riesgo ambientales que se han asociado a riesgo de enfermedad de Parkinson (EP) o de Alzheimer (EA) y discutir sus posibles mecanismos. Desarrollo: Hay evidencia consistente de mayor riesgo de EP asociado a pesticidas y de mayor riesgo de EA asociado a pesticidas, hipertensión y colesterol en edad media, hiperhomocistei-nemia, tabaco, traumatismo craneoencefálico grave y depresión. Hay evidencia débil de mayor riesgo de EP asociado a consumo elevado de leche en hombres, ingesta alta de hierro, ane-mia crónica y traumatismo craneoencefálico grave, y de mayor riesgo de EA asociado a ingesta elevada de aluminio en agua potable, alta exposición a redes eléctricas, DM e hiperinsuline-mia, obesidad en edad media, consumo excesivo de alcohol y anaemia crónica. Hay evidencia consistente de menor riesgo de EP asociado a hiperuricemia, tabaco y café, y de menor riesgo de EA asociado a consumo moderado de alcohol, ejercicio físico, terapia hormonal sustitutiva perimenopáusica y buena reserva cognitiva; hay evidencia débil de menor riesgo de EP asociado a mayor consumo de vitamina E, alcohol, té y AINE y a ejercicio físico vigoroso, y de menor riesgo de EA asociado a dieta mediterránea, café y consumo crónico de AINE. Conclusiones: Diversos factores ambientales contribuyen significativamente al riesgo de EP y EA. Algunos de ellos podrían actuar ya desde etapas tempranas de la vida o interaccionar con otros factores genéticos. Estrategias poblacionales de modificación de estos factores podrían potencialmente evitar algunos casos de EP o de EA. Keywords: Environmental risk factors, Protective factors, Environmental toxins, Parkinson's disease, Alzheimer disease, Interaction, Palabras clave: Factores de riesgo ambientales, Factores protectores, Tóxicos ambientales, Enfermedad de Parkinson, Enfermedad de Alzheimer, Interacció

Enfermedad de Parkinson y enfermedad de Alzheimer: factores de riesgo ambientales

Resumen: Introducción: Esta revisión pretende actualizar y resumir la evidencia disponible sobre los factores de riesgo ambientales que se han asociado a riesgo de enfermedad de Parkinson (EP) o de Alzheimer (EA) y discutir sus posibles mecanismos. Desarrollo: Hay evidencia consistente de mayor riesgo de EP asociado a pesticidas y de mayor riesgo de EA asociado a pesticidas, hipertensión y colesterol en edad media, hiperhomocisteinemia, tabaco, traumatismo craneoencefálico grave y depresión. Hay evidencia débil de mayor riesgo de EP asociado a consumo elevado de leche en hombres, ingesta alta de hierro, anemia crónica y traumatismo craneoencefálico grave, y de mayor riesgo de EA asociado a ingesta elevada de aluminio en agua potable, alta exposición a redes eléctricas, DM e hiperinsulinemia, obesidad en edad media, consumo excesivo de alcohol y anemia crónica. Hay evidencia consistente de menor riesgo de EP asociado a hiperuricemia, tabaco y café, y de menor riesgo de EA asociado a consumo moderado de alcohol, ejercicio físico, terapia hormonal sustitutiva perimenopáusica y buena reserva cognitiva; hay evidencia débil de menor riesgo de EP asociado a mayor consumo de vitamina E, alcohol, té y AINE y a ejercicio físico vigoroso, y de menor riesgo de EA asociado a dieta mediterránea, café y consumo crónico de AINE. Conclusiones: Diversos factores ambientales contribuyen significativamente al riesgo de EP y EA. Algunos de ellos podrían actuar ya desde etapas tempranas de la vida o interaccionar con otros factores genéticos. Estrategias poblacionales de modificación de estos factores podrían potencialmente evitar algunos casos de EP o de EA. Abstract: Introduction: The purpose of this review is to update and summarise available evidence on environmental risk factors that have been associated with risk of Parkinson disease (PD) or Alzheimer disease (AD) and discuss their potential mechanisms. Development: Evidence consistently suggests that a higher risk of PD is associated with pesticides and that a higher risk of AD is associated with pesticides, hypertension and high cholesterol levels in middle age, hyperhomocysteinaemia, smoking, traumatic brain injury and depression. There is weak evidence suggesting that higher risk of PD is associated with high milk consumption in men, high iron intake, chronic anaemia and traumatic brain injury. Weak evidence also suggests that a higher risk of AD is associated with high aluminium intake through drinking water, excessive exposure to electromagnetic fields from electrical grids, DM and hyperinsulinaemia, obesity in middle age, excessive alcohol consumption and chronic anaemia. Evidence consistently suggests that a lower risk of PD is associated with hyperuricaemia, tobacco and coffee use, while a lower risk of AD is associated with moderate alcohol consumption, physical exercise, perimenopausal hormone replacement therapy and good cognitive reserve. Weak evidence suggests that lower risk of PD is associated with increased vitamin E intake, alcohol, tea, NSAIDs, and vigorous physical exercise, and that lower risk of AD is associated with the Mediterranean diet, coffee and habitual NSAID consumption. Conclusions: Several environmental factors contribute significantly to risk of PD and AD. Some may already be active in the early stages of life, and some may interact with other genetic factors. Population-based strategies to modify such factors could potentially result in fewer cases of PD or AD. Palabras clave: Factores de riesgo ambientales, Factores protectores, Tóxicos ambientales, Enfermedad de Parkinson, Enfermedad de Alzheimer, Interacción, Keywords: Environmental risk factors, Protective factors, Environmental toxins. Parkinson disease, Alzheimer disease, Interactio

Relative high frequency of the c.255delA parkin gene mutation in Spanish patients with autosomal recessive parkinsonism

Objectives: To search for the presence of parkin gene mutations in Spanish patients with Parkinson's disease (PD) and characterise the phenotype associated with these mutations. Methods: Thirty seven PD patients with either early onset or autosomal recessive pattern of inheritance were selected for genetic study. Results: Mutations were identified in seven index patients (19%). Homozygous mutations were detected in six patients and a heterozygous mutation in one. The age at onset was lower in patients with mutations than in patients without mutations. Dystonia at onset was present in two patients with parkin gene mutations. The disease began in two patients with postural tremor in the upper limbs mimicking essential tremor. Four patients exhibited a long term response to dopamine agonists. The c.255delA mutation was identified in four unrelated families. This is a frameshift mutation leading to protein truncation. Conclusions: Parkin gene mutations are present in Spanish patients with early onset and/or an autosomal recessive parkinsonism. The c.255delA is the most frequent mutation found, suggesting a relative high prevalence in the Spanish population

Splenectomy for refractory Evans' syndrome associated with antiphospholipid antibodies: report of two cases

The main haematological manifestations seen in patients with antiphospholipid antibodies (aPL) are thrombocytopenia, usually mild, and haemolytic anaemia with a positive Coombs test. Owing to the shared characteristics with idiopathic thrombocytopenic purpura, similar rules are followed in the treatment of these cytopenias. Two patients with severe aPL associated cytopenias, who required splenectomy after being refractory to steroids, immunosuppressive agents, and other treatments (intravenous gammaglobulin, danazol), are described, and previously reported cases are reviewed.