Faculty Bibliography
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A RETROGENIC MODEL FOR DETECTING ABUSE OF INSTITUTIONALIZED PEOPLE WITH ALZHEIMER'S DISEASE
Several studies draw attention to the fact that elder abuse is a complex and multi-dimensional social problem. It has been noticed that institutionalization and disturbing behaviors that result from dementia represent risk factors for mistreatment. In this regard, we have tested if an adapted version of Child Abuse and Trauma Scale can efficiently assess different types of abuse on people with Alzheimer's disease (AD) living in institutional settings. Our choice of an instrument that would ordinarily be used to measure abuse in childhood and adolescence is based on the concept of retrogenesis. This term refers to the process of AD degenerative reversal recapitulation of human ontogenic acquisition patterns. In the present study, we have found that the chosen scale is a reliable screening tool for different forms of abuse in institutionalized AD subjects, providing both a useful, ethically and humanely relevant assessment instrument, and additional evidence for the retrogenesis process. With respect to the frequency of occurrence, neglect and emotional abuse were the most common forms of abuse reported by the study participants, followed by punishment and physical abuse, while sexual abuse was the least reported. Women questioned in this study were found to be more predisposed than men to sexual abuse, while the men were found to be more predisposed to physical abuse. Moreover, the subjects with mild AD reported lower levels of punishment, neglect and emotional abuse when compared to the other AD institutional residents included in this study. In conclusion, our findings will hopefully contribute to the more widespread identification of abuse in persons with dementia, as well as to the development of prevention and intervention strategies
ISI:000290178500002
ISSN: 1583-5170
CID: 133323
Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease
The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 x 10(-9), joint analysis P (P(J)) = 1.7 x 10(-9); stages 1, 2 and 3, P(M) = 8.2 x 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 x 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 x 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 x 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 x 10(-10), P(J) = 5.2 x 10(-11)), CLU (rs1532278; P(M) = 8.3 x 10(-8), P(J) = 1.9 x 10(-8)), BIN1 (rs7561528; P(M) = 4.0 x 10(-14), P(J) = 5.2 x 10(-14)) and PICALM (rs561655; P(M) = 7.0 x 10(-11), P(J) = 1.0 x 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility
PMCID:3090745
PMID: 21460841
ISSN: 1546-1718
CID: 134258
The fast: A brief, practical, comprehensive, valid functional assessment for alzheimer's disease staging, diagnosis and differential diagnosis in the primary care setting [Meeting Abstract]
Background: Impairment in functional capacities is an integral domain in AD presentation, diagnosis and progression. Among many functional scales for AD assessment, the Functional Assessment Staging scale (FAST) (Table 1) uniquely: (1) charts the entire course of AD, from normal aging to most severe AD; (2) has relevance for AD diagnosis and differential diagnosis; and (3) is brief and easy to utilize. Methods: Reliability, validity, and utility of the FAST have been documented in worldwide studies and clinical settings. Results: The FAST has excellent reliability (e.g., Foster et al., Int J Geriatr. Psychiatry,1988; Sclan and Reisberg, Int. Psychogeriatr., 1992). Concurrent validity has been demonstrated with: cognitive assessments across the severity spectrum (e.g., Reisberg, et al., Int. Psychogeriatr., 1992; Shimada, et al., Psychogeriatrics, 2003; Auer et al., JAGS, 1994); other dementia scales (Na et al., JAD, 2010); and neurologic assessments (Franssen and Reisberg, Int. Psychogeriatr., 1997). Criterion validity investigations have indicated superiority of the FAST in comparison with the MMSE, in tracking the course of AD. E.g., in a 5 year prospective longitudinal study of AD course, the FAST accounted for w 2x the temporal variance of the MMSE (Reisberg, et al., Int. Psychogeriatr., 1996). Also, in a range where the MMSE is zero, the FAST demonstrated very robust relationships to AD neuropathology (e.g., r = 0.9 [p 0.01], with hippocampal cornu ammonis neuronal loss), (Bobinski, et al., J. Neuropathol. Exp. Neurol., 1997). Additionally, in a pivotal trial, associated with worldwide approvals of memantine for AD treatment, FAST scores were sensitive to the intervention, MMSE change was not (Reisberg, et al., N Engl J Med., 2003). The FAST has shown widespread utility (e.g., usage mandated by U.S.A. Medicare since 1998, and the U.S.A. Veterans Administration System, since 2008). Conclusions: As noted in a Korean publication, the FAST is a rapid and easy to use staging tool with excellent validity. it. successfully measure[ s] detailed function throughout the entire course of AD. the FAST is composed of simple . and easy to understand sentences
EMBASE:70500916
ISSN: 1552-5260
CID: 136973
Alzheimer's disease
New York : Springer, c2011
pp. 25-64
ISBN: 0826127843
CID: 5782
THE CONCEPT OF RETROGENESIS IN ALZHEIMER'S DISEASE: ETHICAL AND FORENSIC IMPLICATIONS
The concept of retrogenesis has been documented by several studies as the process by which degenerative mechanisms in Alzheimer's disease (AD) reverse the order of acquisition in normal human development. The objective of the present study is to offer expert opinion on the possible ethical and forensic implications of retro genesis. In this regard, we constructed a six-item instrument called 'Questionnaire regarding possible ethical and forensic implications of retrogenesis', which we applied to three professional groups that are directly involved in clinical and forensic evaluation of AD persons, namely, psychiatrists, psychologists and forensic pathologists. The majority of experts questioned in this survey considered it ethical to start from the concept of retrogenesis when approaching AD. Moreover, most of the study participants agreed that it would be ethical to use psychometric tests and programs of cognitive stimulation for the child in the patient with AD. It can also be noted that more than half of the professionals involved in our study considered it ethical to apply child abuse evaluation tests to the AD patients. Furthermore, 61.2% of the opinion survey respondents agreed that it would be necessary to use the concept of retrogenesis for assessing mental capacity in these patients. In addition, most professionals surveyed herein pointed out that it would be necessary to enact legislative proposals on the protection of the patient with AD which would be adapted from the model of the current child protection legislation. This study appears to represent the first expert opinion survey that concerns the ethical and forensic implications of the concept of retrogenesis in AD
ISI:000296480200002
ISSN: 1583-5170
CID: 141093
Journal of neuropathology & experimental neurology. 2011:70(1):36-50.DOI: 10.1097/NEN.0b013e318202bfa1
Link between DYRK1A overexpression and several-fold enhancement of neurofibrillary degeneration with 3-repeat tau protein in Down syndrome
Triplication of chromosome 21 in Down syndrome (DS) results in overexpression of the minibrain kinase/dual-specificity tyrosine phosphorylated and regulated kinase 1A gene (DYRK1A). DYRK1A phosphorylates cytoplasmic tau protein and appears in intraneuronal neurofibrillary tangles (NFTs). We have previously shown significantly more DYRK1A-positive NFTs in DS brains than in sporadic Alzheimer disease (AD) brains. This study demonstrates a gene dosage-proportional increase in the level of DYRK1A in DS in the cytoplasm and the cell nucleus, and enhanced cytoplasmic and nuclear immunoreactivity of DYRK1A in DS. The results suggest that overexpressed DYRK1A may alter both phosphorylation of tau and alternative splicing factor (ASF). Two-dimensional electrophoresis revealed modification of ASF phosphorylation in DS/AD and AD in comparison to controls. Altered phosphorylation of ASF by overexpressed nuclear DYRK1A may contribute to the alternative splicing of the tau gene and an increase by 2.68 x of the 3R/4R ratio in DS/AD, and a several-fold increase in the number of 3R tau-positive NFTs in DS/AD subjects compared with that in sporadic AD subjects. These data support the hypothesis that phosphorylation of ASF by overexpressed DYRK1A may contribute to alternative splicing of exon 10, increased expression of 3R tau, and early onset of neurofibrillary degeneration in DS
PMCID:3083064
PMID: 21157379
ISSN: 0022-3069
CID: 134289
Functional, global and cognitive decline correlates to accumulation of Alzheimer's pathology in MCI and AD
BACKGROUND:Cognitive, global and functional instruments have been extensively investigated for correlations with neuropathological changes such as neurofibrillary tangles (NFTs), plaques, and synapse loss in the brain. OBJECTIVE:Our objective is to correlate the functional, global and cognitive decline assessed clinically with the neuropathological changes observed in a large prospectively characterized cohort of mild cognitive impairment (MCI) and Alzheimer's disease (AD). METHODS:We examined 150 subjects (16 MCI and 134 AD) that were prospectively assessed and longitudinally followed to autopsy. MCI subjects clinically met Petersen criteria for single or multi-domain amnestic MCI. AD subjects clinically met NINCDS-ADRDA criteria for probable or possible AD. All subjects received the Functional Assessment Staging (FAST), the Global Deterioration Scale (GDS), and the Mini Mental State Examination (MMSE) ante-mortem. Plaque and tangle counts were gathered for hippocampus, entorhinal cortex, frontal, temporal and parietal cortices. Braak staging was performed as well. RESULTS:The GDS, FAST and MMSE correlated with plaque counts in all regions. The GDS, FAST and MMSE correlated with tangle counts in in all regions. The three instruments also correlated with the Braak score. The MMSE and GDS correlate better than the FAST in most regions. CONCLUSIONS:Accumulation of neuropathology appears to correlate with functional, global, and cognitive decline as people progress from MCI through AD.
PMCID:3138789
PMID: 19715548
ISSN: 1875-5828
CID: 3890222
Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes
OBJECTIVES: To determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer disease (AD) and whether risk for AD associated with these genes is influenced by apolipoprotein E (APOE) genotypes. DESIGN: Association study of AD and CLU, PICALM, CR1, and APOE genotypes. SETTING: Academic research institutions in the United States, Canada, and Israel. PARTICIPANTS: Seven thousand seventy cases with AD, 3055 with autopsies, and 8169 elderly cognitively normal controls, 1092 with autopsies, from 12 different studies, including white, African American, Israeli-Arab, and Caribbean Hispanic individuals. RESULTS: Unadjusted, CLU (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.85-0.96 for single-nucleotide polymorphism [SNP] rs11136000), CR1 (OR, 1.14; 95% CI, 1.07-1.22; SNP rs3818361), and PICALM (OR, 0.89; 95% CI, 0.84-0.94, SNP rs3851179) were associated with AD in white individuals. None were significantly associated with AD in the other ethnic groups. APOE epsilon4 was significantly associated with AD (ORs, 1.80-9.05) in all but 1 small white cohort and in the Arab cohort. Adjusting for age, sex, and the presence of at least 1 APOE epsilon4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, presence or absence of APOE epsilon4, and an interaction term showed significant interaction between presence or absence of APOE epsilon4 and PICALM. CONCLUSIONS: We confirm in a completely independent data set that CR1, CLU, and PICALM are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE epsilon4-positive subjects. Thus, APOE and PICALM synergistically interact.
PMCID:3048805
PMID: 20697030
ISSN: 0003-9942
CID: 627192
Cognition and behavioral changes occur prior to subjective cognitive impairment (SCI) in the evolution of brain aging and alzheimer's disease (AD): >25 years prior to the advent of mild dementia [Meeting Abstract]
EMBASE:70807767
ISSN: 0893-133x
CID: 174188
Nonpharmacological therapies in Alzheimer's disease: a systematic review of efficacy
INTRODUCTION: Nonpharmacological therapies (NPTs) can improve the quality of life (QoL) of people with Alzheimer's disease (AD) and their carers. The objective of this study was to evaluate the best evidence on the effects of NPTs in AD and related disorders (ADRD) by performing a systematic review and meta-analysis of the entire field. METHODS: Existing reviews and major electronic databases were searched for randomized controlled trials (RCTs). The deadline for study inclusion was September 15, 2008. Intervention categories and outcome domains were predefined by consensus. Two researchers working together detected 1,313 candidate studies of which 179 RCTs belonging to 26 intervention categories were selected. Cognitive deterioration had to be documented in all participants, and degenerative etiology (indicating dementia) had to be present or presumed in at least 80% of the subjects. Evidence tables, meta-analysis and summaries of results were elaborated by the first author and reviewed by author subgroups. Methods for rating level of evidence and grading practice recommendations were adapted from the Oxford Center for Evidence-Based Medicine. RESULTS: Grade A treatment recommendation was achieved for institutionalization delay (multicomponent interventions for the caregiver, CG). Grade B recommendation was reached for the person with dementia (PWD) for: improvement in cognition (cognitive training, cognitive stimulation, multicomponent interventions for the PWD); activities of daily living (ADL) (ADL training, multicomponent interventions for the PWD); behavior (cognitive stimulation, multicomponent interventions for the PWD, behavioral interventions, professional CG training); mood (multicomponent interventions for the PWD); QoL (multicomponent interventions for PWD and CG) and restraint prevention (professional CG training); for the CG, grade B was also reached for: CG mood (CG education, CG support, multicomponent interventions for the CG); CG psychological well-being (cognitive stimulation, multicomponent interventions for the CG); CG QoL (multicomponent interventions for PWD and CG). CONCLUSION: NPTs emerge as a useful, versatile and potentially cost-effective approach to improve outcomes and QoL in ADRD for both the PWD and CG
PMID: 20838046
ISSN: 1421-9824
CID: 138218
