The Measurement of Everyday Cognition (ECog): Revisions and Updates.

INTRODUCTION: The Everyday Cognition scale (ECog), a measure of everyday functioning developed in 2008, is sensitive to early detection and progression of neurodegenerative disease. The goal was to update ECog item content to ensure relevancy to contemporary older adults from diverse backgrounds. METHODS: Participants included 44 culturally diverse older adults (18 with normal cognition, 11 with mild cognitive impairment) and their study partners. Item understandability and relevance was evaluated using iterative interviewing methods that were analyzed using standard qualitative methods. On the basis of this information, items were modified, deleted, or developed as needed. RESULTS: Of the 39 original items, 19 were revised, 3 new items were added (primarily to cover contemporary activities such as the use of technology), and 1 was deleted. The revised version (ECog-II) includes 41 items. DISCUSSION: To ensure strong psychometric properties, and to facilitate harmonization of previously collected data, we preserved well over half of the items. Future work will validate the revised ECog by measuring associations with neuropsychological performance, external measures of disease, and other functional measures. Overall, the revised ECog will continue to be a useful tool for measuring cognitively relevant everyday abilities in clinical settings and intervention clinical trials.

Neurodegeneration and the Intersubjectivities of Care.

Caring for a family member or friend with a serious health condition is a common feature of social life. Often, such care is framed as a burden, an unwelcome rupture in the fabric of everyday life. We draw on research conducted in Australia and the UK to examine care in the everyday lives of people living with and caring for neurodegenerative diseases and to trouble care as a burden. Participants in our studies mobilized practices of care to collaboratively produce a "good life". We argue that above all, care is a relational, enacted practice requiring examination in its local context.

SERCA stimulation: A potential approach in therapeutics.

sarco-endoplasmic reticulum Ca-ATPase (SERCA) is the major transporter present in sarco-endoplasmic reticulum (SR/ER), transporting calcium back into SR/ER from cytosol. The calcium-sequestering activity of SERCA facilitates relaxation in both cardiac and skeletal tissue. ER stress is one of the etiological factors in various diseases such as neurodegenerative diseases and diabetes. Disrupted calcium handling can cause ER stress. In the cardiac tissue, impairment of systolic and diastolic function can cause various cardiovascular diseases. SERCA ensures the proper calcium handling in cells and may act as a therapeutic target for the disease associated with dysregulation of calcium ions. This review examines the principle of calcium ion handling through SERCA and its role in various diseases.

Consanguinity and Inbreeding in Health and Disease in North African Populations.

North Africa is defined as the geographical region separated from the rest of the continent by the Sahara and from Europe by the Mediterranean Sea. The main demographic features of North African populations are their familial structure and high rates of familial and geographic endogamy, which have a proven impact on health, particularly the occurrence of genetic diseases, with a greater effect on the frequency and spectrum of the rarest forms of autosomal recessive genetic diseases. More than 500 different genetic diseases have been reported in this region, most of which are autosomal recessive. During the last few decades, there has been great interest in the molecular investigation of large consanguineous North African families. The development of local capacities has brought a substantial improvement in the molecular characterization of these diseases, but the genetic bases of half of them remain unknown. Diseases of known molecular etiology are characterized by their genetic and mutational heterogeneity, although some founder mutations are encountered relatively frequently. Some founder mutations are specific to a single country or a specific ethnic or geographic group, and others are shared by all North African countries or worldwide. The impact of consanguinity on common multifactorial diseases is less evident.

Surveillance for variant CJD: should more children with neurodegenerative diseases have autopsies?

OBJECTIVES: To report investigations performed in children with progressive neurodegenerative diseases reported to this UK study. DESIGN: Since 1997 paediatric surveillance for variant Creutzfeldt-Jakob disease (vCJD) has been performed by identifying children aged less than 16 years with progressive intellectual and neurological deterioration (PIND) and searching for vCJD among them. SETTING: The PIND Study obtains case details from paediatricians who notify via the British Paediatric Surveillance Unit. PARTICIPANTS: Between May 1997 and October 2017, a total of 2050 cases meeting PIND criteria had been notified and investigated. RESULTS: Six children had vCJD. 1819 children had other diagnoses, made in 12 cases by antemortem brain biopsy and in 15 by postmortem investigations. 225 children were undiagnosed: only 3 had antemortem brain biopsies and only 14 of the 108 who died were known to have had autopsies; postmortem neuropathological studies were carried out in just 10% (11/108) and only two had prion protein staining of brain tissue. Of the undiagnosed cases 43% were known to come from Asian British families. CONCLUSIONS: Most of the notified children had a diagnosis other than vCJD to explain their neurological deterioration. None of the undiagnosed cases had the clinical phenotype of vCJD but brain tissue was rarely studied to exclude vCJD. Clinical surveillance via the PIND Study remains the only practical means of searching for vCJD in UK children.

Non-musculoskeletal benefits of vitamin D.

The aim of this study is to determine and critically evaluate the plausible relationships of vitamin D with extra-skeletal tissues in humans. Severe vitamin D deficiency results in rickets in children and osteomalacia in adults; these beneficial effects in the musculoskeletal system and certain physiological functions are well understood. Nevertheless, mounting reports support additional beneficial effects of vitamin D, outside the musculoskeletal system. This review explores the recent advances in knowledge about the non-skeletal effects of vitamin D. Peer-reviewed papers were extracted from research databases using key words, to assess correlations between vitamin D and extra-skeletal diseases and conditions. As per the guidelines of the Preferred Reporting Items for Systematic Reviews (PRISMA); general interpretations of results are included; taking into consideration the broader evidence and implications. This review summarizes current knowledge of the effects of vitamin D status on extra-skeletal tissues with special attention given to relationships between vitamin D status and various diseases commonly affecting adults; the effects of intervention with vitamin D and exposure to sunlight. Evidence suggests that vitamin D facilitates the regulation of blood pressure; and cardiac; endothelial; and smooth muscle cell functions; playing an important role in cardiovascular protection. In addition; 1,25(OH)2D improves immunity; subdues inflammation; and reduces the incidence and severity of common cancers; autoimmune diseases and infectious diseases. Almost all adequately powered; epidemiological and biological studies that use; adequate doses of vitamin D supplementation in D-deficient populations have reported favorable outcomes. These studies have concluded that optimizing 25(OH)D status improves the functionality of bodily systems; reduces comorbidities; improves the quality of life; and increases survival. Although accumulating evidence supports biological associations of vitamin D sufficiency with improved physical and mental functions; no definitive evidence exists from well-designed; statistically powered; randomized controlled clinical trials. Nevertheless, most studies point to significant protective effects of vitamin D in humans when the minimum 25(OH)D serum level exceeds 30ng/mL and is maintained throughout the year.

Intermediate C9orf72 alleles in neurological disorders: does size really matter?

C9orf72 repeat expansions is a major cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) worldwide. Sizes of <20 hexanucleotide repeats are observed in controls, while up to thousands associate with disease. Intermediate C9orf72 repeat lengths, however, remain uncertain. We systematically reviewed the role of intermediate C9orf72 alleles in C9orf72-related neurological disorders. We identified 49 studies with adequate available data on normal or intermediate C9orf72 repeat length, involving subjects with FTD, ALS, Parkinson's disease (PD), atypical parkinsonism, Alzheimer's disease (AD) and other aetiologies. We found that, overall, normal or intermediate C9orf72 repeat lengths are not associated with higher disease risk across these disorders, but intermediate allele sizes appear to associate more frequently with neuropsychiatric phenotypes. Intermediate sizes were detected in subjects with personal or family history of FTD and/or psychiatric illness, parkinsonism complicated by psychosis and rarely in psychiatric cohorts. Length of the hexanucleotide repeat may be influenced by ethnicity (with Asian controls displaying shorter normal repeat lengths compared with Caucasians) and underlying haplotype, with more patients and controls carrying the 'risk' haplotype rs3849942 displaying intermediate alleles. There is some evidence that intermediate alleles display increased methylation levels and affect normal transcriptional activity of the C9orf72 promoter, but the 'critical' repeat size required for initiation of neurodegeneration remains unknown and requires further study. In common neurological diseases, intermediate C9orf72 repeats do not influence disease risk but may associate with higher frequency of neuropsychiatric symptoms. This has important clinical relevance as intermediate carriers pose a challenge for genetic counselling.

Current Issues in Randomized Clinical Trials of Neurodegenerative Disorders at Enrolment and Reporting: Diagnosis, Recruitment, Representativeness of Patients, Ethnicity, and Quality of Reporting.

BACKGROUND: The investigator is faced with several challenges when planning a randomized clinical trial (RCT). In the early phase, issues are particularly challenging for RCTs in neurodegenerative disorders (NDD). SUMMARY: At the time of inclusion in the study, an early and accurate diagnosis is mandatory. Variability of diagnostic criteria, mostly based on clinical grounds, lag time between onset and enrolment, and phenotypic heterogeneity are the main drivers of diagnostic complexity. High-quality data in terms of diagnostic reliability, phenotypic description, follow-up, and evaluation of outcomes are key determinants and are highly conditioned by the expertise of the investigators and center recruitment rate. Representativeness of NDD patients is mandatory to postulate the generalizability of the results of RCTs. There is, however, a systematic selection bias in terms of age (more likely to be younger), sex (more likely to be male), ethnicity (more likely to be of European/Caucasian origin), and other prognostic factors (more likely to be favorable). In the publication phase, researchers need to report properly all of the main features of the RCT. Consolidated Standards of Reporting Trials (CONSORT) facilitates the report and interpretation of RCTs, but adherence to these guidelines needs to be improved. KEY MESSAGES: Several issues discussed in this review may alter the internal and external validity of an RCT. To date, the impact on phenotype at study entry has often been overlooked. A differential effect of the selection of subjects and of specific clinical and nonclinical features needs to be systematically explored in the RCT planning phase.

Polarization of the effects of autoimmune and neurodegenerative risk alleles in leukocytes.

To extend our understanding of the genetic basis of human immune function and dysfunction, we performed an expression quantitative trait locus (eQTL) study of purified CD4(+) T cells and monocytes, representing adaptive and innate immunity, in a multi-ethnic cohort of 461 healthy individuals. Context-specific cis- and trans-eQTLs were identified, and cross-population mapping allowed, in some cases, putative functional assignment of candidate causal regulatory variants for disease-associated loci. We note an over-representation of T cell-specific eQTLs among susceptibility alleles for autoimmune diseases and of monocyte-specific eQTLs among Alzheimer's and Parkinson's disease variants. This polarization implicates specific immune cell types in these diseases and points to the need to identify the cell-autonomous effects of disease susceptibility variants.

Analysis of the CTAGE5 P521A variation with the risk of familial idiopathic basal ganglia calcification in an Iranian population.

Familial idiopathic basal ganglia calcification (IBGC) is a rare neurodegenerative syndrome with an autosomal dominant pattern of inheritance which is characterized by deposition of calcium in the basal ganglia and other brain regions. Linkage studies demonstrated its genetic heterogeneity; however, the responsible genes are unknown. Recently, a heterozygous variation (C>G, P521A) at exon 20 of the human cutaneous T cell lymphoma-associated antigen 5 (CTAGE5) gene was found in all patients of the affected large American family linked to IBGC1 (14q11.2-21.3). However, no carrier was detected in the two affected Brazilian families. This study was performed to investigate whether the CTAGE5 P521A variation is associated with the IBGC in an affected Iranian family. Genotyping of the CTAGE5 P521A variation was determined using PCR-RFLP. Totally, 22 members of an affected Iranian family as well as 100 normal people as control group were screened. All the samples including 22 members of the affected family as well as all control people had normal CC genotype and no GC carrier was found. Our result is similar to a Brazilian study but contrary to an American report, strengthening genetic heterogeneity of this syndrome. It seems that additional studies are necessary to confirm the pathogenicity of this rare mutation.

Comparison of 24-h volume and creatinine-corrected total urinary polyphenol as a biomarker of total dietary polyphenols in the Invecchiare InCHIANTI study.

Polyphenols have beneficial effects on several chronic diseases but assessing polyphenols intake from self-reported dietary questionnaires tends to be inaccurate and not very reliable. A promising alternative is to use urinary excretion of polyphenols as a proxy measure of intake. The best method to assess urinary excretion is to collect 24-h urine. However, since collecting 24-h urine method is expensive, time consuming and may be difficult to implement in large population-based studies, measures obtained from spot urine normalized by creatinine are commonly used. The purpose of the study was to evaluate the correlation between polyphenols dietary intake and total urinary polyphenol excretion (TPE), expressed by both 24-h volume and urinary creatinine normalization in 928 participants from the InCHIANTI study. Dietary intake data were collected using a validated food frequency questionnaire. Urinary TPE was analyzed by Folin-Ciocalteau assay. Both urinary TPE expression models were statistically correlated (r=0.580), and the partial correlation coefficient improved (pr=0.722) after adjusting for the variables that modify the urinary creatinine excretion (i.e. gender, age, BMI, physical activity and renal function). In crude models, polyphenol intake was associated with TPE corrected by 24-h volume (r=0.211; P<0.001), but not with creatinine normalization (r=0.014; P=0.692). However, urinary TPE expressed by creatinine correction was significantly correlated with dietary polyphenols after adjusting for covariates (pr=0.113; P=0.002). We conclude that urinary TPE expressed by 24-h volume is a better biomarker of polyphenol dietary intake than by urinary creatinine normalization. After covariate adjustment, both can be used for studying the relationships between polyphenol intake and health in large-scale epidemiological studies.

Ecodevelopmental contexts for preventing type 2 diabetes in Latino and other racial/ethnic minority populations.

Diabetes is the sixth leading cause of death in the United States and it is now cited along with obesity as a global epidemic. Significant racial/ethnic disparities exist in the prevalence of diabetes within the US, with racial and ethnic minorities disproportionately affected by type 2 diabetes and its complications. Racial/ethnic and socioeconomic factors influence the development and course of diabetes at multiple levels, including genetic, individual, familial, community and national. From an ecodevelopmental perspective, cultural variables assessed at one level (e.g., family level dietary practices) may interact with other types of variables examined at other levels (e.g., the availability of healthy foods within a low-income neighborhood), thus prompting the need for a clear analysis of these systemic relationships as they may increase risks for disease. Therefore, the need exists for models that aid in "mapping out" these relationships. A more explicit conceptualization of such multi-level relationships would aid in the design of culturally relevant interventions that aim to maximize effectiveness when applied with Latinos and other racial/ethnic minority groups. This paper presents an expanded ecodevelopmental model intended to serve as a tool to aid in the design of multi-level diabetes prevention interventions for application with racial/ethnic minority populations. This discussion focuses primarily on risk factors and prevention intervention in Latino populations, although with implications for other racial/ethnic minority populations that are also at high risk for type 2 diabetes.

The architecture of the tau haplotype block in different ethnicities.

We have assessed the pattern of the extended haplotype block over the tau gene which covers a region of approximately 2 Mb in different ethnicities. This analysis shows that the pattern of linkage disequilibrium over the tau region is shared by different ethnic groups indicating that haplotype structure in human is ancient. We discuss this observation in terms of the establishment of the haplotype structure and the possible impact of the tau haplotype on neurodegeneration in humans.

The validity and reliability of chinese frontal assessment battery in evaluating executive dysfunction among Chinese patients with small subcortical infarct.

OBJECTIVES: Frontal Assessment Battery (FAB) is a valid and reliable screening test for evaluating executive dysfunction among whites with frontal and subcortical degenerative lesions. We studied the properties of a Chinese version of FAB (CFAB) in evaluating executive dysfunction among Chinese stroke patients with small subcortical infarct. METHODS: Concurrent validity was evaluated using Wisconsin Card Sorting Tst (WCST) and Mattis Dementia Rating Scale-Initiation/Perseveration Subset (MDRS I/P) among 41 controls and 30 stroke patients with small subcortical infarct. Discriminant validities of CFAB and its subitems were compared with those of Mini-Mental State Examination (MMSE). Internal consistency, test-retest, and interrater reliability of CFAB were evaluated. RESULTS: The CFAB had low to good correlation with various executive measures: MDRS I/P (r = 0.63, p < 0.001), number of category completed (r = 0.45, p < 0.001), and number of perseverative errors (r = -0.37, p < 0.01) of WCST. Among the executive measures, only number of category completed had significant but small contribution (6.5%, p = 0.001) to the variance of CFAB. A short version of CFAB using three items yielded higher overall classification accuracy (86.6%) than that of CFAB full version (80.6%) and MMSE (77.6%). Internal consistency (alpha = 0.77), test-retest reliability (rho = 0.89, p < 0.001), and interrater reliability (rho = 0.85, p < 0.001) of CFAB were good. CONCLUSION: Although CFAB is reliable, it is only moderately valid in evaluating executive dysfunction among Chinese stroke patients with small subcortical infarct. The clinical use of CFAB in the evaluation of executive dysfunction among this group of patients cannot be recommended at this stage.

Apolipoprotein epsilon4 allele frequency in young Africans of Ugandan descent versus African Americans.

Through its role in lipid metabolism, Apolipoprotein epsilon4 (ApoE4) may affect "brain repair" in stroke, brain hemorrhage, Alzheimer's disease, and other brain injury syndromes for which African Americans may have greater morbidity and mortality. Cross-cultural evaluations of these and other genetic factors may provide insight on possible ethnic differences in risk of morbidity to acute central nervous system (CNS) injury and chronic neurodegenerative processes. As an initial step toward expanding knowledge of ApoE allele frequencies for persons of African descent, we compared ApoE genotype of a group of 70 young Ugandans to 59 (subset of a larger group of 342 African Americans of all ages) age-matched African Americans and to published frequencies for Caucasians and Asians. We found that the ApoE4 and epsilon2 alleles are more frequent in Ugandans (U) than Caucasians (C) or Asians (A) with corresponding alleles showing significant elevations of epsilon2 (U 15.71%, C 8.40%, A 4.20%) and 14 (U 25%, C 13.70%, A 8.90%) (p < .001). Comparing the differences between Ugandans and age-appropriate African Americans (AA) was not statically significant, but this outcome may be due to small sample size. These results provide the only published ApoE frequencies for Ugandans and the complete set of data provides the largest published community group of ApoE frequencies for African Americans.