Failure to Recover from Proactive Semantic Interference Differentiates Amnestic Mild Cognitive Impairment and PreMCI from Normal Aging after Adjusting for Initial Learning Ability

Background: There is increasing evidence that the failure to recover from proactive semantic interference (frPSI) may be an early cognitive marker of preclinical Alzheimer’s disease (AD). However, it is unclear whether frPSI effects reflect deficiencies in an individual’s initial learning capacity versus the actual inability to learn new semantically related targets. Objective: The current study was designed to adjust for learning capacity and then to examine the extent to which frPSI, proactive semantic interference (PSI) and retroactive semantic interference (RSI) effects could differentiate between older adults who were cognitively normal (CN), and those diagnosed with either Pre-Mild Cognitive Impairment (PreMCI) or amnestic MCI (aMCI). Methods: We employed the LASSI-L cognitive stress test to examine frPSI, PSI and RSI effects while simultaneously controlling for the participant’s initial learning capacity among 50 CN, 35 aMCI, and 16 PreMCI participants who received an extensive diagnostic work-up. Results: aMCI and PreMCI participants showed greater frPSI deficits (50% and 43.8% respectively) compared to only 14% of CNparticipants. PSI effects were observed for aMCI but not PreMCI participants relative to their CN counterparts. RSI failed to differentiate between any of the study groups. Conclusion: By using participants as their own controls and adjusting for overall learning and memory, it is clear that frPSI deficits occur with much greater frequency in individuals at higher risk for Alzheimer’s disease (AD), and likely reflect a failure of brain compensatory mechanisms.Fil: Curiel, Rosie E.. University of Miami; Estados UnidosFil: Crocco, Elizabeth A.. University of Miami; Estados UnidosFil: Raffo, Arlene. University of Miami; Estados UnidosFil: Guinjoan, Salvador Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Nemeroff, Charles B.. University of Miami; Estados UnidosFil: Penate, Ailyn. Mount Sinai Medical Center; Estados Unidos. University of Miami; Estados UnidosFil: Piña, Daema. University of Miami; Estados UnidosFil: Loewenstein, David A.. Mount Sinai Medical Center; Estados Unidos. University of Miami; Estados Unido

Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

A novel Alzheimer disease locus located near the gene encoding tau protein

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordAPOE ε4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ε4+ (10 352 cases and 9207 controls) and APOE ε4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ε4 status. Suggestive associations (P<1 × 10-4) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ε4+: 1250 cases and 536 controls; APOE ε4-: 718 cases and 1699 controls). Among APOE ε4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10-9). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ε4+ subjects (CR1 and CLU) or APOE ε4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10-7) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P≤1.3 × 10-8), frontal cortex (P≤1.3 × 10-9) and temporal cortex (P≤1.2 × 10-11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10-6) and temporal cortex (P=2.6 × 10-6). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ε4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted

Research in Caregiving

Between 1950 and 2050, the proportion of those aged 65 years and older in the population will more than double (Himes, Elderly Americans, 2001). As the population ages, the likelihood of frailty, dementia, and disabling illness increases. This unprecedented growth in the elderly population in need of support presents multiple challenges for society and in particular, for families who are frequently called upon to act as caregivers for impaired spouses, parents, and siblings. A tremendous degree of burden and psychological distress are associated with the caregiving role (Schulz et al., Gerontologist 35:771–791, 1995). For this reason, research is essential to identify those caregivers who are most susceptible to adverse outcomes and to identify and alleviate the burden associated with different aspects of the caregiving experience. Furthermore, innovative caregiving research can lead to the development of constructive interventions that will aid families, older adults, and society at large

Psychiatric aspects of mild cognitive impairment

Mild cognitive impairment in the elderly may represent a transitional phase between normal aging and early Alzheimer's disease (AD). It recently has been recognized as a distinct clinical entity with potentially different cognitive subtypes and etiologies. Like AD, studies have shown that psychiatric symptoms are more common than in the cognitively normal geriatric population. Understanding these symptoms has been recognized as important not only because they may impair patient function and caregiver burden, but also these symptoms may be relevant to understanding the development of AD in general. This article presents current information on psychiatric symptoms in mild cognitive impairment, their suggested role in the pathophysiology of AD and future research considerations on the subject

Bipolar Disorder in the Elderly

Bipolar disorder in older individuals is becoming more relevant to clinicians due to the advent of the aging of the population. Geriatric patients in general are more complex, and the disease process is not simply an extension of the symptomatology observed in the younger cohort. The information derived from study data of younger adults as applied to geriatric psychiatric management is never ideal. Additionally, research and guidelines for evidencebased management and treatment of the elderly bipolar is extremely limited. This chapter presents the most recent data describing the clinical features, diagnosis, comorbidities, and treatment strategies (including lithium and anticonvulsants, antipsychotics, antidepressants, benzodiazepines, and ECT) for this complex bipolar subgroup

Depression and Risk for Alzheimer’s Disease: Systematic Review, Meta-Analysis, And Metaregression Analysis

Context: A history of depression may increase risk for developing Alzheimer disease (AD) later in life. Clarifying this relation might improve understanding of risk factors for and disease mechanisms in AD. Objective: To systematically review and complete a meta-analysis on the relation of depression and AD. Data sources: We conducted electronic bibliographic searches of MEDLINE, PsychLit, EMBASE, and BIOSIS using search terms sensitive to studies of etiology combined with searches on terms related to depression and AD and reviewed reference lists of articles. Study selection: Studies with data contrasting depressed vs non-depressed patients who did and did not later develop AD were included. Studies that related continuous measures of depression and cognitive status were excluded. Data extraction: Numerical data were independently extracted by 3 reviewers. They also rated studies on a scale that assessed quality indicators for observational studies. Data on the interval between observation of depression and the diagnosis of AD were collected when available. Data synthesis: Meta-analytic evaluation with random-effects models resulted in pooled odds ratios of 2.03 (95% confidence interval, 1.73-2.38) for case-control and of 1.90 (95% confidence interval, 1.55-2.33) for cohort studies. Findings of increased risk were robust to sensitivity analyses. Interval between diagnoses of depression and AD was positively related to increased risk of developing AD, suggesting that rather than a prodrome, depression may be a risk factor for AD. Conclusions: A history of depression may confer an increased risk for later developing AD. This relation may reflect an independent risk factor for the disease

Depression and Risk for Alzheimer’s Disease: Systematic Review, Meta-Analysis, And Metaregression Analysis

Context: A history of depression may increase risk for developing Alzheimer disease (AD) later in life. Clarifying this relation might improve understanding of risk factors for and disease mechanisms in AD. Objective: To systematically review and complete a meta-analysis on the relation of depression and AD. Data sources: We conducted electronic bibliographic searches of MEDLINE, PsychLit, EMBASE, and BIOSIS using search terms sensitive to studies of etiology combined with searches on terms related to depression and AD and reviewed reference lists of articles. Study selection: Studies with data contrasting depressed vs non-depressed patients who did and did not later develop AD were included. Studies that related continuous measures of depression and cognitive status were excluded. Data extraction: Numerical data were independently extracted by 3 reviewers. They also rated studies on a scale that assessed quality indicators for observational studies. Data on the interval between observation of depression and the diagnosis of AD were collected when available. Data synthesis: Meta-analytic evaluation with random-effects models resulted in pooled odds ratios of 2.03 (95% confidence interval, 1.73-2.38) for case-control and of 1.90 (95% confidence interval, 1.55-2.33) for cohort studies. Findings of increased risk were robust to sensitivity analyses. Interval between diagnoses of depression and AD was positively related to increased risk of developing AD, suggesting that rather than a prodrome, depression may be a risk factor for AD. Conclusions: A history of depression may confer an increased risk for later developing AD. This relation may reflect an independent risk factor for the disease

An evaluation of deficits in semantic cueing and proactive and retroactive interference as early features of Alzheimer\u27s Disease

OBJECTIVES: To determine the degree to which susceptibility to different types of semantic interference may reflect the initial manifestations of early Alzheimer\u27s disease (AD) beyond the effects of global memory impairment. METHODS: Normal elderly (NE) subjects (n = 47), subjects with amnestic mild cognitive impairment (aMCI; n = 34), and subjects with probable AD (n = 40) were evaluated by using a unique cued recall paradigm that allowed for evaluation of both proactive and retroactive interference effects while controlling for global memory impairment (i.e., Loewenstein-Acevedo Scales of Semantic Interference and Learning [LASSI-L] procedure). RESULTS: Controlling for overall memory impairment, aMCI subjects had much greater proactive and retroactive interference effects than NE subjects. LASSI-L indices of learning by using cued recall revealed high levels of sensitivity and specificity, with an overall correct classification rate of 90%. These measures provided better discrimination than traditional neuropsychological measures of memory function. CONCLUSIONS: The LASSI-L paradigm is unique and unlike other assessments of memory in that items posed for cued recall are explicitly presented, and semantic interference and cueing effects can be assessed while controlling for initial level of memory impairment. This is a powerful procedure that allows the participant to serve as his or her own control. The high levels of discrimination between subjects with aMCI and normal cognition that exceeded traditional neuropsychological measures makes the LASSI-L worthy of further research in the detection of early AD