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ObjectiveAlzheimer’s disease (AD) is characterized by loss of smell and olfactory system pathology that precedes the diagnosis of dementia. Understanding these early processes can potentially identify diagnostic and therapeutic targets to slow AD progression. Here we analyzed differential gene and protein expression in the olfactory bulb (OB) and olfactory tract (OT) of familial AD (FAD) individuals carrying the autosomal dominant presenilin 1 E280A paisa mutation and age-matched controls.MethodsFormalin-fixed, paraffin-embedded sections containing both the OB and OT from 6 FAD individuals and 6 age-matched controls were obtained. Tissue morphology and composition were characterized by immunohistochemistry using antibodies against the myelin marker proteolipid protein (PLP), amyloid-beta (Aβ), and microglia/macrophage markers Iba1 and CD68, respectively. OB and OT were analyzed separately by targeted RNA sequencing of the whole human transcriptome (BioSpyder TempO-Seq); ingenuity pathway analysis and R-computational program were used to identify differentially expressed genes and pathways between groups. The nanoString spatial proteomics assay for 88 proteins, including markers for AD and immune responses, was used to complement gene expression findings.ResultsCompared to control OT, FAD OT had significantly increased immunostaining for Aβ and CD68 in the high and low myelinated regions, as well as increased immunostaining for Iba1 in the high myelinated region only; both control and FAD OT samples had similar total area of high and low myelinated regions. In FAD samples, RNA sequencing showed a transcription profile consistent with: (1) viral infection in the OB; (2) inflammation in the OT that carries information via entorhinal cortex from the OB to hippocampus, a brain region essential for learning and memory; and (3) decreased oligodendrocyte deconvolved transcripts, indicating dysregulation of myelination. Interestingly, spatial proteomic analysis confirmed altered myelination in the OT of FAD individuals, implying dysfunction of communication between the OB and hippocampus.ConclusionsThese findings raise the possibility that viral infection and associated inflammation and dysregulation of myelination of the olfactory system may disrupt downstream hippocampal function, contributing to acceleration of FAD progression.

Hereditary ataxias are a group of devastating neurological disorders that affect coordination of gait and are often associated with poor coordination of hands, speech, and eye movements. Ataxia with Ocular Apraxia type 1 (AOA1) (OMIM: 606350.0006) is characterized by slowly progressive symptoms of childhood-onset and pathogenic mutations in APTX; the only known cause underpinning AOA1. APTX encodes the protein Aprataxin, composed of three domains sharing homology with proteins involved in DNA damage, signaling, and repair. We present four siblings from an endogamic family in a rural, isolated town of Colombia with ataxia and ocular apraxia of childhood-onset and confirmed molecular diagnosis of AOA1, homozygous for the W279* p.Trp279Ter mutation. We predicted the mutated APTX with Alpha Fold to demonstrate the effects of this stop-gain mutation that deletes three beta helices encoded by amino acid 270 to 339 rescinding the C2H2-type zinc fingers (Znf) (C2H2 Znf) DNA-binding and DNA-repair domain and the whole tridimensional structure of the APTX. All siblings exhibited different ages of onset (4, 6, 8, and 11 y/o) and heterogeneous patterns of dysarthria (ranging from absence to mild-moderate dysarthria). Neuropsychological evaluation showed no neurocognitive impairment in three siblings, but one sibling showed temporospatial disorientation, semantic and phonologic fluency impairment, episodic memory affection, constructional apraxia, moderate anomia, low executive function, and symptoms of depression. This heterogeneous phenotype suggests genetic interactions can shape the natural history of AOA1. To our knowledge, this report represents the most extensive series of siblings affected with AOA1 in Latin America, and the genetic analysis completed adds important knowledge to outline this family’s disease and general complex phenotype of hereditary ataxias.

SummaryOvine gammaherpesvirus 2 (OvHV-2), a member of the Macavirus genus, causes sheep-associated malignant catarrhal fever (SA-MCF), a fatal lymphoproliferative disease that affects a wide variety of ungulates in addition to horses.This study described an outbreak of SA-MCF that occurred in Mexico and the identification of the OvHV-2 virus through viral isolation and different laboratory techniques such as immunofluorescence (IF), immunoperoxidase (IP), immunohistochemistry (IHC), end point PCR and partial sequencing of the ORF75 gene. The animals involved in this outbreak showed head and eye clinical signs and lesions. Based on the clinical-pathological outcome, buffy coats were taken, and virus isolation was attempted on primary cell cultures of the rabbit testicle. Small clusters of refractile cytomegalic cells characterized the cytopathic effect between 48 and 72 hours postinfection. In addition, inclusion bodies were identified, and cytoplasmic immunoreactivity was observed in the infected cells. The sequences obtained were aligned with OvHV-2 sequences reported in GenBank and revealed a nucleotide identity higher than 98%. The results indicate that the outbreak was caused by OvHV-2 and the horses are susceptible to SA-MCF.

The present study aims to explore the association between the quality of life (QoL) score and the clinical and sociodemographic variables in patients with the PSEN1-E280A mutation. We also seek to evaluate the differences between the QoL reported by the patients (P-QoL) and the scores reported by the caregivers (C-QoL). An analysis of 75 patients with the PSEN1-E280A mutation with mild cognitive impairment and dementia was performed. We used the Quality of Life in Alzheimer Disease (QoL-AD) survey to evaluate QoL as an outcome and evaluated its association with sociodemographic, lifestyle, clinical, and past medical history variables. The largest difference in the median of the QoL-AD score was in those who needed help to eat, those with moderate or severe dementia, those classified as frail or pre-frail, those with moderate social risk, and those with depression. Also, C-QoL was lower than the P-QoL, and the QoL-AD of individuals with severe dementia was lower than for milder forms of the disease. Not needing help to eat, not having a stressful situation in the past 3 months, and the years of education were positively correlated with QoL-AD in the linear model. As studies in similar populations with AD, factors with more impact on QoL are those related to loss of functionality and independence. These factors are also associated with variables related to the current literature with the burden of the disease for the caregivers.

This article constructed two spatial indices to better understand the interactions between social sustainability (an important but poorly defined concept) and exposure to climatic and environmental risks. The indices, and the Choropleth maps used to represent them, can be combined and operationalized across different country contexts to yield insights into how climate change and social vulnerabilities intersect and can be jointly addressed. The two indices were here applied to Vietnam, a country particularly exposed to climate change. While Vietnam is well-known for its vulnerability to changing temperatures and rising sea levels, there was huge variation within and between regions for these two risks. The analysis also found enormous spatial variation within the risks from precipitation, drought, deforestation, and air pollution. Social inclusion generally outperformed resilience and social cohesion, as well as empowerment in Vietnam. Our findings were robust for choices of indicators, weights, and aggregation specifications.

Background: There are forms of Alzheimer’s disease (AD) that have an autosomal dominant inheritance pattern; one of them is caused by the E280A mutation in the gene that codes for Presenilin-1 (PSEN1). Studying families of people with this mutation allows the evaluation of characteristics of the subjects before cognitive decline begins. Objective: To determine whether having the mutation E280A in PSEN1 increases the risk of presenting mental disorders in adults under 30 years old who are in the preclinical stage of AD and may be eligible for primary prevention studies of AD. Methods: A psychiatric evaluation was made to 120 people belonging to families with a history of early onset AD. Of these, 62 carried the E280A mutation in PSEN1. The occurrence of mental disorders between carriers and non-carriers of the mutation was compared. Results: No statistically significant differences were found in the frequency of any mental disorder between the group of carriers and non-carriers of the mutation (Hazard Ratio: 0.80, 95% CI 0.49 to 1.31); nor were differences observed when evaluating specific disorders. Conclusion: The E280A mutation does not increase the risk of mental disorders before the age of 30 in the relatives of people affected by familial AD. Studies with larger sample sizes are required to assess the risk of low incidence mental disorders.

Introduction A small percentage of Alzheimer's disease (AD) cases are caused by genetic mutations with autosomal dominant inheritance. We report a family with a novel variant in PSEN1. Methods We performed clinical and genetic evaluation of 93 related individuals from a Colombian admixed population. 31 individuals had whole-genome sequencing. Results Genetic analysis revealed a missense variant in PSEN1 (NM_000021.3: c.1247T>C p.Ile416Thr), which originated on an African haplotype and segregated with AD logarithm of the odds score of 6. Their clinical phenotype is similar to sporadic AD except for earlier age at onset: the mean age at onset for mild cognitive impairment was 47.6 years (standard deviation 5.83) and for dementia 51.6 years (standard deviation 5.03). Discussion Ile416Thr is a novel pathogenic variant that causes AD in the sixth decade of life. The history of the region that included slave importation and admixtures within a confined geographic locale represents a "mini-population bottleneck" and subsequent emergence of a rare dominant mutation.

Blue eye disease (BED) in pigs is caused by Porcine orthorubulavirus (PRV) of the Paramyxoviridae family. It is an endemic disease in swine production in the central region of Mexico and causes nervous signs and high mortality in suckling pigs, pneumonia in growing pigs, orchitis in boars and mummification during gestation. PRV hemagglutinates most red blood cells (RBCs) of domestic species. For serological diagnosis, the hemagglutination inhibition test is used, and in this test, guinea pig, bovine and chicken RBCs have been commonly used. In this investigation, hemagglutination with PRV was evaluated using the RBCs of seven domestic species (chicken, bovine, horse, pig, dog, guinea pig and rabbit). In the hemagglutination test, the following parameters were evaluated: temperature (25 °C and 37 °C), bottoms of the wells (V and U), erythrocyte concentration (0.5%, 0.75%, and 1%), and reading time (15, 30, 45, 60 and 90 min). Significant differences (P 0.001) were found in most of the evaluated treatments. The best hemagglutination results were obtained with chicken, bovine and horse RBCs. The hemagglutination titer is higher (2 dilutions) when using chicken RBCs than when using bovine or horse RBCs. If chicken RBCs are used in the inhibition of hemagglutination, the test will be more sensitive, while it is more specific when bovine or horse RBCs are used. The hemagglutination readings are imprecise when using RBCs from dogs, pigs, guinea pigs and rabbits. RBCs from these species should not be used for the diagnosis or investigation of PRV.

The present study aims to explore the association between the quality of life (QoL) score and the clinical and sociodemographic variables in patients with the PSEN1-E280A mutation. We also seek to evaluate the differences between the QoL reported by the patients (P-QoL) and the scores reported by the caregivers (C-QoL).An analysis of 75 patients with the PSEN1-E280A mutation with mild cognitive impairment and dementia was performed. We used the Quality of Life in Alzheimer Disease (QoL-AD) survey to evaluate QoL as an outcome and evaluated its association with sociodemographic, lifestyle, clinical, and past medical history variables.The largest difference in the median of the QoL-AD score was in those who needed help to eat, those with moderate or severe dementia, those classified as frail or pre-frail, those with moderate social risk, and those with depression. Also, C-QoL was lower than the P-QoL, and the QoL-AD of individuals with severe dementia was lower than for milder forms of the disease. Not needing help to eat, not having a stressful situation in the past 3 months, and the years of education were positively correlated with QoL-AD in the linear model.As studies in similar populations with AD, factors with more impact on QoL are those related to loss of functionality and independence. These factors are also associated with variables related to the current literature with the burden of the disease for the caregivers.

Introduction Mild Cognitive Impairment (MCI) is common in Parkinson's Disease (PD). Few studies have compared the Health-Related Quality of Life (HRQoL) in patients with and without MCI due to PD (PD-MCI), and its correlation to patients’ subjective cognitive and communicative difficulties has not been explored. Objective We aimed to compare HRQoL in PD-MCI and PD without MCI (PD-nMCI), and explore its possible relationship to subjective cognitive and communicative complaints. Methods We included 29 PD-nMCI and 11 PD-MCI patients. The HRQoL was assessed with the Parkinson's Disease Questionnaire-39 (PDQ-39): its Cognition dimension was used as a measure of subjective cognitive complaints, its Communication dimension for subjective communicative complaints, and the summary index (PDQ-39 SI) as an indicator of HRQoL. Non-parametric partial correlations between the Cognition and Communication dimensions, and the adjusted PDQ-39 SI were conducted. Results PD-MCI patients had greater subjective cognitive and communicative complaints and worse HRQoL than PD-nMCI patients. In the PD-MCI group, both subjective cognitive and communicative complaints exhibited significant direct correlations with the adjusted HRQoL scores. Conclusions HRQoL seems to be affected in PD-MCI, and it might be influenced by greater subjective cognitive and communicative complaints. Including patient-reported outcome measures of HRQoL, and providing cognitive and speech rehabilitation, as well as psychotherapeutic strategies to face these deficits can enhance the patient-centred approach in PD.

Background Genetic associations with Alzheimer’s disease (AD) age at onset (AAO) have revealed genetic variants with the potential for therapeutic application. Such studies in late onset AD are limited by population heterogeneity and co-morbidities associated with aging. Studies to date in ADAD (autosomal dominant AD) have been limited by their small sample size. The large Colombian kindred presented here provides a unique opportunity to discover AAO genetic associations. Methods A genetic association study was conducted for AAO in 344 individuals with the PSEN1 E280A mutation via array imputation and whole genome sequencing in a subset of 80 individuals. Scrambled age conditions were used as a control, and replication was assessed using three studies on AD age of onset, age of onset survival, and meta-analysis. Results The proportion of variance explained (+/-95% CI) was 56% (+/-15%). 29 loci reached genome-wide significance, of which 23 had a GWAS hit from the NHGRI-EBI catalog within 500 kb relevant to neurodegeneration. Hits included a new variant in the CLU locus, rs35980966, (which replicated), a variant in a locus on a separate chromosome previously associated with plasma clusterin (rs138295139), and a missense variant in SORBS3 (rs34059820). Former GWAS index variants at the CLU locus also replicated in this cohort (rs4236673, rs9331896). APOE e4 (rs429358) and APOE e2 (rs7412)-associated variants exhibited modest (less than 3 years) associations with earlier and later age of dementia onset, respectively. Other nominal associations included coding variants in IL34 (rs4985556), TSPAN10 (rs6565617, rs7210026), STIM2 (rs1457401458), HTT (rs1473464204), and KCNT1 (rs557219607). Interpretation A large proportion of the variability in AAO was explained by genetic variation at numerous loci. The unique demography of this population as a tri-continental admixture that passed through a bottleneck about 500 years ago might predict that drift would uncover rare variants with a large effect size on AAO. Indeed, candidates for large contributions from rare alleles were observed. Common variation, presumably ancestral to the bottleneck, was also associated with AAO. The detection of these effects in the presence of a strong mutation for ADAD reinforce the potentially impactful role of the identified variants.

Introduction The Alzheimer's Prevention Initiative Colombia Trial is a collaborative project involving the Neurosciences Group of Antioquia, Genentech/Roche, and the Banner Alzheimer's Institute, studying whether crenezumab can delay or prevent the clinical onset of Alzheimer's disease in cognitively unimpaired individuals who carry the PSEN1 E280A mutation. In an effort to optimize participant compliance and adherence and maintain interest in the trial for its duration, the Neurosciences Group of Antioquia developed an “Adherence/Retention Plan.” This plan identifies potential barriers to trial adherence related to characteristics of the participants and study partners, protocol design, sponsors, investigators, environmental factors, and characteristics of this population in general and identifies potential solutions to these barriers. Methods Neurosciences Group of Antioquia designed and implemented a number of strategies including a) a prescreening process that emphasized detailed and staged informed consent involving the participant and family and/or friends, b) a schedule of visits and assessments designed to minimize burden while achieving the trial's aims, c) appointment reminders, d) reimbursement for transportation and missed work, e) meals during study visits, f) birthday cards, g) quarterly newsletters, h) annual in-person feedback meetings, i) a supplemental health plan to participants, and j) a social plan to support family members. All the methods used in this plan were approved by local ethics committees. Results By the end of the fourth year of the trial, participant retention was 94.0%, with most participants reporting that they felt “very satisfied” with their participation in the trial. Discussion The Adherence/Retention Plan plays a crucial role in maintaining adherence and compliance needed to achieve the ambitious goals of the Alzheimer's Prevention Initiative-Colombia Autosomal Dominant Alzheimer's Disease Trial and may offer guideposts for other prevention trials.

Blue eye disease (BED) of pigs was identified in the early 1980s in La Piedad, Michoacan, Mexico. The causal agent is Porcine orthorubulavirus (PRV), which affects pigs of all ages, producing nervous, respiratory, and reproductive disorders. BED is geographically endemic to the center of Mexico, where 75% of the country's swine industry is concentrated. Due to its adverse effects on the swine industry and the risk of dissemination to other countries, it is essential to have reliable diagnostic methods for BED. The objective of this study was to establish the optimal conditions for three serological tests, hemagglutination inhibition (HI), immunoperoxidase monolayer assay (IPMA), and serum neutralization (SN), and to compare their sensitivity, specificity, kappa coefficient, and predictive values. Twelve different HI protocols (9408 tests), one SN protocol and one IPMA protocol (784 tests, each) were evaluated. Forty-nine sera were analyzed, and thirty-seven sera showed true positive results, while twelve showed true negative results. The kappa coefficient was used to assess the variation in each test. The best HI protocol registered a sensitivity and specificity of 89 and 100%, respectively, the IPMA test showed values of 85 and 100%, and the SN test registered a sensitivity of 91% and a specificity of 96%. One of the disadvantages of the HI test is that when chicken red blood cells (RBCs) are used, elution occurs in a short incubation time, which would decrease the specificity. The use of bovine RBCs increases the specificity of the testy and makes it more stable, but it decreases the sensitivity. The results of HI and SN revealed the importance of eliminating the complement system of the serum and removing other inhibitors to avoid test nonspecificity. The IPMA test does not use an active virus; hence, it is considered safe and does not present any risk of disseminating PRV.

Summary The Colombian Alzheimer's Prevention Initiative (API) Registry is a collaborative project among the Neurosciences Group of Antioquia, the Banner Alzheimer's Institute, and Genentech. The main goal is to provide a source of interested research participants and data to support the API-Colombia Autosomal Dominant Alzheimer's Disease Trial and help find treatments to delay or prevent the clinical onset of Alzheimer's disease.

This analysis explores the determinants behind the unequal access to justice services among poor Indonesians. The study analyzes the stock of observed past disputes by socioeconomic group and the demand for conflict resolution services for unresolved conflicts or “trajectories.” It also models the hypothetical demand of justice services for future disputes. Results suggest that unequal access to justice might go beyond the financial costs of seeking justice and also depends on individual preferences and community infrastructure. These findings warn against focusing exclusively on formal justice costs to improve the equal access of the poor to conflict resolution services.

To identify a cognitive composite that is sensitive to tracking preclinical Alzheimer's disease decline to be used as a primary end point in treatment trials.We capitalized on longitudinal data collected from 1995 to 2010 from cognitively unimpaired presenilin 1 (PSEN1) E280A mutation carriers from the world's largest known early-onset autosomal dominant Alzheimer's disease kindred to identify a composite cognitive test with the greatest statistical power to track preclinical Alzheimer's disease decline and estimate the number of carriers age 30 years and older needed to detect a treatment effect in the Alzheimer's Prevention Initiative's (API) preclinical Alzheimer's disease treatment trial. The mean-to-standard-deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of 1 to 7 cognitive tests/subtests drawn from the neuropsychological test battery in cognitively unimpaired mutation carriers during a 2- and 5-year follow-up period (n = 78 and 57), using data from noncarriers (n = 31 and 56) during the same time period to correct for aging and practice effects. Combinations that performed well were then evaluated for robustness across follow-up years, occurrence of selected items within top-performing combinations, and representation of relevant cognitive domains.The optimal test combination included Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word List Recall, CERAD Boston Naming Test (high frequency items), Mini-Mental State Examination (MMSE) Orientation to Time, CERAD Constructional Praxis, and Raven's Progressive Matrices (Set A), with an MSDR of 1.62. This composite is more sensitive than using either the CERAD Word List Recall (MSDR = 0.38) or the entire CERAD-Col battery (MSDR = 0.76). A sample size of 75 cognitively normal PSEN1 E280A mutation carriers aged 30 years and older per treatment arm allows for a detectable treatment effect of 29% in a 60-month trial (80% power, P = .05).We have identified a composite cognitive test score representing multiple cognitive domains that, compared to the most sensitive single test item, has improved power to track preclinical Alzheimer's disease decline in autosomal dominant Alzheimer's disease mutation carriers and to evaluate preclinical Alzheimer's disease treatments. This API composite cognitive test score will be used as the primary end point in the first API trial in cognitively unimpaired autosomal dominant Alzheimer's disease carriers within 15 years of their estimated age at clinical onset. We have independently confirmed our findings in a separate cohort of cognitively healthy older adults who progressed to the clinical stages of late-onset Alzheimer's disease, described in a separate report, and continue to refine the composite in independent cohorts and compared with other analytic approaches.

This article analyses the distributional effects of education spending across regions of Thailand, a country that purportedly seeks to reduce regional welfare disparities through decentralisation. It finds that public expenditure on education is neither progressive nor pro-poor, although there are sizeable regional differences, driven by the pro-rich distributional profiles of public tertiary education spending and public transfers to private education. Policy-wise, these results suggest that the current decentralised allocation of educational spending is not consistent with an equity-enhancing goal.

Identifying genes that modify the age-at-onset (AAO) of Alzheimer disease and targeting them pharmacologically represent a potential treatment strategy. In this exploratory study, we sequenced the complete genomes of six individuals with familial Alzheimer disease due to the autosomal dominant mutation p.Glu280Ala in PSEN1 (MIM# 104311; NM_000021.3:c.839A>C). The disease and its age-at-onset are highly heritable, motivating our search for genetic variants that modulate AAO. The median AAO of dementia in carriers of the mutant allele is 49 years. Extreme phenotypic outliers for AAO in this genetically isolated population with limited environmental variance are likely to harbor onset-modifying genetic variants. A narrow distribution of AAO in this kindred suggests large effect sizes of genetic determinants of AAO in these outliers. Identity by Descent (IBD) analysis and a combination of bioinformatics filters have suggested several candidate variants for AAO modifiers. Future work and replication studies on these variants may provide mechanistic insights into the etiopathology of Alzheimer disease.

We identified several families in Antioquia, Colombia, with early-onset Alzheimer disease (AD) due to the mendelian autosomal dominant inheritance of a PSEN1 E280A gene mutation. Extended family members were interviewed and parish baptism certificates in Antioquian municipalities examined.1 The size of these extended families (including carriers and noncarriers) approaches 5,000 individuals. Full genomes in carriers proved a single founder.2 To support an AD prevention clinical trial, we established a registry in 2010 of all family members over age 8 years.3 Since then we genotyped 3,407 family members and identified 823 (24%) carriers of the PSEN1 E280A mutation. The Comite de Bioetica de la Sede de Investigacion Universitaria, SIU Universidad de Antioquia, approved this study. All participants provided written informed consent. Despite the size of this exceptionally large family and frequent consanguinity, homozygosity at this gene locus had not been reported. The apparent absence of homozygous PSEN1 mutations led to the speculation that E280A homozygosity could be lethal. Generally, homozygous dominant mutations are more severely affected than heterozygotes in both humans and model systems.4 However, human cases in which dominant point mutations are homozygous are rare.

© 2015 Macmillan Publishers Limited We have sequenced the complete genomes of 72 individuals affected with early-onset familial Alzheimer's disease caused by an autosomal dominant, highly penetrant mutation in the presenilin-1 (PSEN1) gene, and performed genome-wide association testing to identify variants that modify age at onset (AAO) of Alzheimer’s disease. Our analysis identified a haplotype of single-nucleotide polymorphisms (SNPs) on chromosome 17 within a chemokine gene cluster associated with delayed onset of mild-cognitive impairment and dementia. Individuals carrying this haplotype had a mean AAO of mild-cognitive impairment at 51.0±5.2 years compared with 41.1±7.4 years for those without these SNPs. This haplotype thus appears to modify Alzheimer's AAO, conferring a large (~10 years) protective effect. The associated locus harbors several chemokines including eotaxin-1 encoded by CCL11, and the haplotype includes a missense polymorphism in this gene. Validating this association, we found plasma eotaxin-1 levels were correlated with disease AAO in an independent cohort from the University of California San Francisco Memory and Aging Center. In this second cohort, the associated haplotype disrupted the typical age-associated increase of eotaxin-1 levels, suggesting a complex regulatory role for this haplotype in the general population. Altogether, these results suggest eotaxin-1 as a novel modifier of Alzheimer's disease AAO and open potential avenues for therapy.Molecular Psychiatry advance online publication, 1 September 2015; doi:10.1038/mp.2015.131.

It was hypothesized that subjective memory complaints represent the earliest sign of dementia in carriers of the presenilin-1 (PS1) mutation. A total of 122 subjects (44 males, 78 females) were included in this study. Forty of them were positive for the mutation in the PS1 gene (mutation positive, MP) whereas 82 showed negative results (mutation negative, MN). Subjects were active, functionally normal, even though some of them complained of memory difficulties. Two groups of neuropsychological instruments were administered: (a) The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological test battery (Morris et al., 1989), and (b) some additional neuropsychological tests (Raven Test, Wechsler Memory Scale, Rey-Osterrieth Complex Figure, Boston Naming Test, Naming of Categories, Boston Diagnostic Aphasia Examination, Memory of Three Phrases, Knopman Test, Digit Symbol, and Visual "A" Cancellation Test). Performance in both groups was quite similar. In a secondary analysis, the MP group was subdivided into two subgroups: without and with memory complaints. When comparing both subgroups, a better performance in the first subgroup was found throughout the different subtests. Statistically significant differences were observed in the following test scores: Mini-Mental State Examination, Naming Test (Low Frequency), Memory of Words Test, Recall of Drawings, Wechsler Memory Scale (Logical Memory, Associative Learning, and Total Score), Rey-Osterrieth Complex Figure (Immediate Recall Condition), Boston Diagnostic Aphasia Examination (Complex Ideational Material Subtest), Memory of Three Phrases Test, Serial Verbal Learning (maximum score and Delayed Recall), Knopman Test (First Trial, Second Trial, and Recall after 5 Minutes), Digit Symbol, and Visual "A" Cancellation Test (Additions). Results supported the hypothesis that memory complaints represent the earliest symptom of familial Alzheimer's disease. In addition to the memory difficulties, other minor cognitive impairments were also found, particularly, mild anomia, concentration difficulties and defects in the understanding of complex verbal material.

A single base substitution of a glutamic acid to an alanine codon 280 was found in the presenilin-1 (PS-1) gene on chromosome 14 in affected individuals in each of seven Colombian early-onset Alzheimer's disease (AD) kindreds. The mutation segregated with disease in kindreds tested. In the largest kindred (C2), the maximum two-point lod score between the mutation and AD was Z = 8.14 at θ = 0. The presence of a single mutation and the common geographic origin, with all families from the state of Antioquia, suggest a founder effect in this population. This finding is supported by the observation of a rare haplotype inherited with AD in all kindreds. These kindreds form the largest collection of AD cases with the same PS-1 mutation and the same educational, environmental, and ethnic background in which to study the phenotypic effect of putative risk factors, such as the ϵ4 allele of apolipoprotein E (ApoE) or head trauma. Of the few AD cases having a history of head trauma, the age of onset was not lowered. No effect of ApoE genotype on the age of onset was detected. Previous investigations of the effect of ApoE genotype on the age of onset were confounded by small patient numbers, familial clustering of ApoE genotypes, and combining data from unrelated families with different mutations. Hum Mutat 10:186–195, 1997. © 1997 Wiley-Liss, Inc.

Background A mutation in presenilin 1 (E280A) causes early-onset Alzheimer's disease. Understanding the origin of this mutation will inform medical genetics. Methods We sequenced the genomes of 102 individuals from Antioquia, Colombia. We applied identity-by-descent analysis to identify regions of common ancestry. We estimated the age of the E280A mutation and the local ancestry of the haplotype harboring this mutation. Results All affected individuals share a minimal haplotype of 1.8 Mb containing E280A. We estimate a time to most recent common ancestor of E280A of 10 (95% credible interval, 7.2–12.6) generations. We date the de novo mutation event to 15 (95% credible interval, 11–25) generations ago. We infer a western European geographic origin of the shared haplotype. Conclusions The age and geographic origin of E280A are consistent with a single founder dating from the time of the Spanish Conquistadors who began colonizing Colombia during the early 16th century.

Cockayne syndrome (CS) is an autosomal recessive disease associated with premature aging, progressive multiorgan degeneration, and nervous system abnormalities including cerebral and cerebellar atrophy, brain calcifications, and white matter abnormalities. Although several clinical descriptions of CS patients have reported developmental delay and cognitive impairment with relative preservation of social skills, no previous studies have carried out a comprehensive neuropsychological and social cognition assessment. Furthermore, no previous research in individuals with CS has examined the relationship between brain atrophy and performance on neuropsychological and social cognition tests. This study describes the case of an atypical late-onset type III CS patient who exceeds the mean life expectancy of individuals with this pathology. The patient and a group of healthy controls underwent a comprehensive assessment that included multiple neuropsychological and social cognition (emotion recognition, theory of mind, and empathy) tasks. In addition, we compared the pattern of atrophy in the patient to controls and to its concordance with ERCC8 gene expression in a healthy brain. The results showed memory, language, and executive deficits that contrast with the relative preservation of social cognition skills. The cognitive profile of the patient was consistent with his pattern of global cerebral and cerebellar loss of gray matter volume (frontal structures, bilateral cerebellum, basal ganglia, temporal lobe, and occipito-temporal/occipito-parietal regions), which in turn was anatomically consistent with the ERCC8 gene expression level in a healthy donor's brain. The study of exceptional cases, such as the one described here, is fundamental to elucidating the processes that affect the brain in premature aging diseases, and such studies provide an important source of information for understanding the problems associated with normal and pathological aging. Fil: Báez Buitrago, Sandra Jimena. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Diego Portales; Chile. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires"; Argentina. Universidad Favaloro; Argentina. Instituto de Neurología Cognitiva; Argentina Fil: Couto, Juan Blas Marcos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Favaloro; Argentina. Instituto de Neurología Cognitiva; Argentina Fil: Herrera, Eduar. Universidad Autónoma del Caribe; Colombia Fil: Bocanegra, Yamile. Universidad de Antioquia; Colombia. Universidad de San Buenaventura; Colombia Fil: Trujillo Orrego, Natalia. Universidad de Antioquia; Colombia Fil: Madriga Zapata, Lucia. Universidad de Antioquia; Colombia Fil: Cardona Londoño, Juan Felipe. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Favaloro; Argentina. Instituto de Neurología Cognitiva; Argentina Fil: Manes, Facundo Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Australian Government, Australian Research Council; Australia. Universidad Diego Portales; Chile. Universidad Favaloro; Argentina. Instituto de Neurología Cognitiva; Argentina Fil: Ibáñez Barassi, Agustín Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Diego Portales; Chile. Universidad Favaloro; Argentina. Instituto de Neurología Cognitiva; Argentina Fil: Villegas, Andres. Universidad de Antioquia; Colombia

Total factor productivity (TFP) in Latin America has declined relative to the US since the mid-1970s. This paper applies a comparable methodology to firm-level data of ten Latin American countries to quantify the heterogeneity of firm productivity and the extent to which resource misallocation can explain lower aggregate TFP. In general, productivity heterogeneity and resource misallocation are found to be much larger than in the US. Achieving an efficient allocation of resources could boost manufacturing TFP between 41% and 122% depending on the countries and years considered. We also find that difficulty in access to capital and restrictive labor regulations explain distortions faced by firms.

Total factor productivity (TFP) in Latin America has not increased since the mid- 1970s, and in many countries it has declined. Moreover, resource misallocation can lower aggregate TFP. This paper presents evidence based on firm-level data from 10 Latin American countries to quantify the heterogeneity of firm productivity and the degree of resource misallocation within countries. Productivity heterogeneity and resource misallocation are found to be much larger than in the United States. Achieving an efficient allocation of resources could boost manufacturing TFP between 45 percent and 127 percent depending on the countries and years considered.

This paper explores the reduction of food insecurity in Bolivia, adopting a supply side approach that analyzes the role of agricultural spending on vulnerability. Vulnerability to food insecurity is captured by a municipal level composite -- developed locally within the framework of World Food Program food security analysis -- that combines welfare outcomes, weather conditions and agricultural potential for all 327 municipalities in 2003, 2006 and 2007. Our econometric results indicate that levels of public agricultural spending are positively associated with high or very high vulnerability. The authors interpret this to indicate that agricultural spending allocation decisions are driven by high or very high vulnerability levels. In other words, more agricultural spending appears to be destined to where it is more needed in line with previous findings in other sectors in Bolivia. This is confirmed through a number of specifications, including contemporaneous and lagged relationships between spending and vulnerability. They also find evidence of public spending on infrastructure and research and extension services having a significant (but very small) effect towards reducing high vulnerability. This indicates the importance of the composition of public agricultural spending in shaping its relationship with vulnerability to food insecurity.

This paper investigates the relationship between part-time work and job satisfaction using a recent household survey from Honduras. In contrast to previous work for developed countries, this paper does not find a preference for part-time work among women. Instead, both women and men tend to prefer full- time work, although the preference for working longer hours is stronger for men. Consistent with an interpretation of working part-time as luxury consumption, the paper finds that partnered women with children, poor women or women working in the informal sector are more likely to prefer full-time work than single women, partnered women without children, non-poor women or women working in the formal sector. These results have important implications for the design of family and child care policies in low-income countries.

This paper investigates the relationship between part-time work and job satisfaction using a recent household survey from Honduras. In contrast to previous work for developed countries, this paper does not find a preference for part-time work among women. Instead, both women and men tend to prefer fulltime work, although the preference for working longer hours is stronger for men. Consistent with an interpretation of working part-time as luxury consumption, the paper finds that partnered women with children, poor women or women working in the informal sector are more likely to prefer full-time work than single women, partnered women without children, non-poor women or women working in the formal sector. These results have important implications for the design of family and child care policies in low-income countries.

Prevalence of late onset Alzheimer's disease (LOAD) both familial and sporadic is increasing with the raising proportion of third-age population. There are evidences either supporting or rejecting the existence of differences in the behavior of neuropsychological variables between familial and sporadic cases of LOAD.To identify neuropsychological variables discriminating between familial and sporadic cases of LOAD, in order to detect clinical manifestations that may provide information on the pathological process of the neurodegenerative process.Using sequential sampling, we selected individuals affected by LOAD according to the criteria of the DSM-IV and NINCS-ADRDA. The following neuropsychological protocol was used: CERAD, Wisconsin, Phonological Fluency, Rey's Figure, Raven, A Cancellation Test, WAIS (Arithmetic); also used were: Global Deterioration Scale, Functional Assessment Staging of Reisberg (FAST), Barthel and Yesavage. Parametrical and non-parametrical univariate, factorial (principal components) and discriminant analyses were performed. In total, 52 patients were analyzed (average age: 74.8 years; mean age at onset of the disease: 69 years; time of disease's evolution: 5.7 years; average of educational level: 6.4 years).No significant statistical differences were found in clinical or neuropsychological variables between familial and sporadic cases of LOAD. Additionally, neither variables nor models were detected discriminating significantly between them.Familial and sporadic cases of LOAD present the same clinical and neuropsychological phenotype which makes very probable that sporadic cases are low penetrance familial ones.

A single base substitution of a glutamic acid to an alanine codon 280 was found in the presenilin-1 (PS-1) gene on chromosome 14 in affected individuals in each of seven Colombian early-onset Alzheimer's disease (AD) kindreds. The mutation segregated with disease in kindreds tested. In the largest kindred (C2), the maximum two-point lod score between the mutation and AD was Z = 8.14 at theta = 0. The presence of a single mutation and the common geographic origin, with all families from the state of Antioquia, suggest a founder effect in this population. This finding is supported by the observation of a rare haplotype inherited with AD in all kindreds. These kindreds form the largest collection of AD cases with the same PS-1 mutation and the same educational, environmental, and ethnic background in which to study the phenotypic effect of putative risk factors, such as the epsilon4 allele of apolipoprotein E (ApoE) or head trauma. Of the few AD cases having a history of head trauma, the age of onset was not lowered. No effect of ApoE genotype on the age of onset was detected. Previous investigations of the effect of ApoE genotype on the age of onset were confounded by small patient numbers, familial clustering of ApoE genotypes, and combining data from unrelated families with different mutations.

Missense mutations in the presenilin 1 (PS1) gene cause the most common form of dominant early-onset familial Alzheimer's disease (FAD) and are associated with increased levels of amyloid beta-peptides (A beta) ending at residue 42 (A beta 42) in plasma and skin fibroblast media of gene carriers. A beta 42 aggregates readily and appears to provide a nidus for the subsequent aggregation of A beta 40 (ref. 4), resulting in the formation of innumerable neuritic plaques. To obtain in vivo information about how PS1 mutations cause AD pathology at such early ages, we characterized the neuropathological phenotype of four PS1-FAD patients from a large Colombian kindred bearing the codon 280 Glu to Ala substitution (Glu280Ala) PS1 mutation. Using antibodies specific to the alternative carboxy-termini of A beta, we detected massive deposition of A beta 42, the earliest and predominant form of plaque A beta to occur in AD (ref. 6-8), in many brain regions. Computer-assisted quantification revealed a significant increase in A beta 42, but not A beta 40, burden in the brains from 4 PS1-FAD patients compared with those from 12 sporadic AD patients. Severe cerebellar pathology included numerous A beta 42-reactive plaques, many bearing dystrophic neurites and reactive glia. Our results in brain tissue are consistent with recent biochemical evidence of increased A beta 42 levels in PS1-FAD patients and strongly suggest that mutant PS1 proteins alter the proteolytic processing of the beta-amyloid precursor protein at the C-terminus of A beta to favor deposition of A beta 42.

Genetic linkage studies place a gene causing early onset familial Alzheimer's disease (FAD) on chromosome 14q24.3 (refs 1–4). Five mutations within the S182 (Presenilin 1: PS–1) gene, which maps to this region, have recently been reported in several early onset FAD kindreds5. We have localized the PS-1 gene to a 75 kb region and present the structure of this gene, evidence for alternative splicing and describe six novel mutations in early onset FAD pedigrees all of which alter residues conserved in the STM26 (Presenilin 2: PS-2) gene.

INTRODUCTION Prevalence of late onset Alzheimer's disease (LOAD) both familial and sporadic is increasing with the raising proportion of third-age population. There are evidences either supporting or rejecting the existence of differences in the behavior of neuropsychological variables between familial and sporadic cases of LOAD. OBJECTIVE To identify neuropsychological variables discriminating between familial and sporadic cases of LOAD, in order to detect clinical manifestations that may provide information on the pathological process of the neurodegenerative process. PATIENTS AND METHODS Using sequential sampling, we selected individuals affected by LOAD according to the criteria of the DSM-IV and NINCS-ADRDA. The following neuropsychological protocol was used: CERAD, Wisconsin, Phonological Fluency, Rey's Figure, Raven, A Cancellation Test, WAIS (Arithmetic); also used were: Global Deterioration Scale, Functional Assessment Staging of Reisberg (FAST), Barthel and Yesavage. Parametrical and non-parametrical univariate, factorial (principal components) and discriminant analyses were performed. In total, 52 patients were analyzed (average age: 74.8 years; mean age at onset of the disease: 69 years; time of disease's evolution: 5.7 years; average of educational level: 6.4 years). RESULTS No significant statistical differences were found in clinical or neuropsychological variables between familial and sporadic cases of LOAD. Additionally, neither variables nor models were detected discriminating significantly between them. CONCLUSION Familial and sporadic cases of LOAD present the same clinical and neuropsychological phenotype which makes very probable that sporadic cases are low penetrance familial ones.