Up to 60% of the patients with Alzheimer’s disease (AD) can have cortical or brainstem Lewy bodies (LB), and extrapyramidal signs (EPS) have been found to be associated with LB in AD patients. However, the relationship between EPS and brain volumes has not been studied in the LB variant of AD using structural magnetic resonance imaging (MRI). The purpose of this study was to determine the relationship between patterns of brain atrophy and clinical EPS in patients with pathologically confirmed AD. We compared gray matter structure using voxel-based morphometry in 29 Definite AD cases, 16 (55%) of whom also had LBs identified with α-synuclein immunohistochemistry. Multivariate models analyzed brain volume at a voxel level accounting for subject group, Mini-Mental State Examination (MMSE), EPS, total brain volume, and the time from MRI scan to death. There was no significant difference in gray matter volume in the Definite AD patients as a function of LB. There was a significant association between gray matter volumes and the MMSE in AD patients, both with and without LBs. There was a significant correlation between gray matter volume and EPS only in the group of AD patients with LBs, and not in those with pure AD. These findings suggest that that the etiology of EPS in patients with the LB variant of AD is associated with neuronal loss in the nigrostriatal tracts. By contrast, the source of the EPS in AD alone appears to be less well localized.

Amyloid-β (Aβ) deposits are detectable in the brain in vivo using positron emission tomography (PET) and [C-11]-labeled Pittsburgh Compound B ([C-11]PiB); however, the sensitivity of this technique is not well understood. In this study, we examined Aβ pathology in an individual who had clinical diagnoses of probable dementia with Lewy bodies and possible Alzheimer’s disease (AD) but with no detectable [C-11]PiB PET retention ([C-11]PiB(−)) when imaged 17 months prior to death. Brain samples were processed in parallel with region-matched samples from an individual with a clinical diagnosis of probable AD and a positive [C-11]PiB PET scan ([C-11]PiB(+)) when imaged 10 months prior to death. In the [C-11]PiB(−) case, Aβ plaques were sparse, occupying less than 2% cortical area, and were weakly labeled with 6-CN-PiB, a highly fluorescent derivative of PiB. In contrast, Aβ plaques occupied up to 12% cortical area in the [C-11]PiB(+) case, and were intensely labeled with 6-CN-PIB. The [C-11]PiB(−) case had low levels of [H-3]PiB binding (<100 pmol/g) and Aβ1–42 (<500 pmol/g) concentration except in the frontal cortex where Aβ1–42 values (788 pmol/g) approached cortical values in the [C-11]PiB(+) case (800–1,700 pmol/g). In several cortical regions of the [C-11]PiB(−) case, Aβ1–40 levels were within the range of cortical Aβ1–40 values in the [C-11]PiB(+) case. Antemortem [C-11]PiB DVR values correlated well with region-matched postmortem measures of Aβ1–42 and Aβ1–40 in the [C-11]PiB(+), and with Aβ1–42 only in the [C-11]PiB(−) case. The low ratios of [H-3]PiB binding levels to Aβ concentrations and 6-CN-PiB to Aβ plaque loads in the [C-11]PiB(−) case indicate that Aβ pathology in the brain may be associated with low or undetectable levels of [C-11]PiB retention. Studies in greater numbers of [C-11]PiB PET autopsy cases are needed to define the Aβ concentration and [H-3]PiB binding levels required to produce a positive [C-11]PiB PET signal.

Blast-induced traumatic brain injury (TBI) has been a major cause of morbidity and mortality in the conflicts in Iraq and Afghanistan. How the primary blast wave affects the brain is not well understood. In particular, it is unclear whether blast injures the brain through mechanisms similar to those found in non-blast closed impact injuries (nbTBI). The β-amyloid (Aβ) peptide associated with the development of Alzheimer’s disease is elevated acutely following TBI in humans as well as in experimental animal models of nbTBI. We examined levels of brain Aβ following experimental blast injury using enzyme-linked immunosorbent assays for Aβ 40 and 42. In both rat and mouse models of blast injury, rather than being increased, endogenous rodent brain Aβ levels were decreased acutely following injury. Levels of the amyloid precursor protein (APP) were increased following blast exposure although there was no evidence of axonal pathology based on APP immunohistochemical staining. Unlike the findings in nbTBI animal models, levels of the β-secretase, β-site APP cleaving enzyme 1, and the γ-secretase component presenilin-1 were unchanged following blast exposure. These studies have implications for understanding the nature of blast injury to the brain. They also suggest that strategies aimed at lowering Aβ production may not be effective for treating acute blast injury to the brain.

Psychotic symptoms occur in approximately 40% of subjects with Alzheimer’s disease (AD) and are associated with more rapid cognitive decline and increased functional deficits. They show heritability up to 61% and have been proposed as a marker for a disease subtype suitable for gene mapping efforts. We undertook a combined analysis of three genome-wide association studies (GWAS) to identify loci that a) increase susceptibility to an AD and subsequent psychotic symptoms; or b) modify risk of psychotic symptoms in the presence of neurodegeneration caused by AD. 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD−P) and 5659 controls were drawn from GERAD1, the NIA-LOAD family study and the University of Pittsburgh ADRC GWAS. Unobserved genotypes were imputed to provide data on > 1.8 million SNPs. Analyses in each dataset were completed comparing a) AD+P to AD−P cases, and b) AD+P cases with controls (GERAD1, ADRC only). Aside from the APOE locus, the strongest evidence for association was observed in an intergenic region on chromosome 4 (rs753129; ‘AD+PvAD−P’ P=2.85 × 10−7; ‘AD+PvControls’ P=1.11 × 10−4). SNPs upstream of SLC2A9 (rs6834555, P=3.0×10−7) and within VSNL1 (rs4038131, P=5.9×10−7) showed strongest evidence for association with AD+P when compared to controls. These findings warrant further investigation in larger, appropriately powered samples in which the presence of psychotic symptoms in AD has been well characterised.

Objective

Persons with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) are at heightened risk for future decisional incapacity. We sought to characterize advance care planning (ACP) rates over time in individuals who had no advance directives (living will or durable power of attorney) in place when they initially presented for a cognitive evaluation.

Design

Retrospective analysis of data that had been prospectively collected.

Setting

Alzheimer’s Disease Research Center memory disorders clinic.

Participants

Persons (N=127) with a diagnosis of MCI or early AD (n = 72) or moderate to severe AD (n = 55) and no advance directives upon initial presentation for a cognitive evaluation.

Measurements

Extraction of responses to items pertaining to advance care planning assessed during annual semi-structured interviews.

Results

By 5 years of follow-up, 39% of the sample had initiated ACP, with little difference by baseline diagnosis. Younger subjects (under 65 years old) were significantly more likely to initiate advance directives (43%) than were older subjects (37%). This age effect was more pronounced in men than women as well as in married subjects, those with a family history of dementia, no depressive disorder, and subjects with moderate to severe AD (versus those with MCI or early AD) at baseline.

Conclusion

Only a minority of subjects initiated ACPs. The findings suggest the need for interventions aimed at enhancing ACP completion rates, particularly among older adults with cognitive impairment since these individuals may have a timed-limited opportunity to plan for future medical, financial, and other major life decisions.

The National Institute on Aging and the Alzheimer’s Association charged a workgroup with the task of developing criteria for the symptomatic predementia phase of Alzheimer’s disease (AD), referred to in this article as mild cognitive impairment due to AD. The workgroup developed the following two sets of criteria: (1) core clinical criteria that could be used by healthcare providers without access to advanced imaging techniques or cerebrospinal fluid analysis, and (2) research criteria that could be used in clinical research settings, including clinical trials. The second set of criteria incorporate the use of biomarkers based on imaging and cerebrospinal fluid measures. The final set of criteria for mild cognitive impairment due to AD has four levels of certainty, depending on the presence and nature of the biomarker findings. Considerable work is needed to validate the criteria that use biomarkers and to standardize biomarker analysis for use in community settings.

Objective

To evaluate the cause of diagnostic errors in the visual interpretation of positron emission tomography scans with 18F-fluorodeoxyglucose (FDG-PET) in patients with frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD).

Design

Twelve trained raters unaware of clinical and autopsy information independently reviewed FDG-PET scans and provided their diagnostic impression and confidence of either FTLD or AD. Six of these raters also recorded whether metabolism appeared normal or abnormal in 5 predefined brain regions in each hemisphere – frontal cortex, anterior cingulate cortex, anterior temporal cortex, temporoparietal cortex and posterior cingulate cortex. Results were compared to neuropathological diagnoses.

Setting

Academic medical centers

Patients

45 patients with pathologically confirmed FTLD (n=14) or AD (n=31)

Results

Raters had a high degree of diagnostic accuracy in the interpretation of FDG-PET scans; however, raters consistently found some scans more difficult to interpret than others. Unanimity of diagnosis among the raters was more frequent in patients with AD (27/31, 87%) than in patients with FTLD (7/14, 50%) (p = 0.02). Disagreements in interpretation of scans in patients with FTLD largely occurred when there was temporoparietal hypometabolism, which was present in 7 of the 14 FTLD scans and 6 of the 7 lacking unanimity. Hypometabolism of anterior cingulate and anterior temporal regions had higher specificities and positive likelihood ratios for FTLD than temporoparietal hypometabolism had for AD.

Conclusions

Temporoparietal hypometabolism in FTLD is common and may cause inaccurate interpretation of FDG-PET scans. An interpretation paradigm that focuses on the absence of hypometabolism in regions typically affected in AD before considering FTLD is likely to misclassify a significant portion of FTLD scans. Anterior cingulate and/or anterior temporal hypometabolism indicates a high likelihood of FTLD, even when temporoparietal hypometabolism is present. Ultimately, the accurate interpretation of FDG-PET scans in patients with dementia cannot rest on the presence or absence of a single region of hypometabolism, but must take into account the relative hypometabolism of all brain regions.

Mild cognitive impairment (MCI) is rapidly becoming one of the most common clinical manifestations affecting the elderly. The pathologic and molecular substrate of people diagnosed with MCI is not well established. Since MCI is a human specific disorder and neither the clinical nor the neuropathological course appears to follows a direct linear path, it is imperative to characterize neuropathology changes in the brains of people who came to autopsy with a well-characterized clinical diagnosis of MCI. Herein, we discuss findings derived from clinical pathologic studies of autopsy cases with various subtypes of MCI antemortem. The heterogeneity of clinical MCI imparts significant challenges to any review of this subject. The pathologic substrate of MCI is equally complex and must take into account not only conventional plaque and tangle pathology but also a wide range of cellular biochemical and molecular deficits many of which relate to cognitive decline as well as compensatory responses to the progressive disease process. The multifaceted nature of the neuronal disconnection syndrome associated with MCI, suggests that there is no single event, which precipitates this prodromal stage of AD. In fact, it can be argued that neuronal degeneration initiated at different levels of the central nervous system drive cognitive decline as a final common pathway at this stage of the dementing disease process.

The amyloid cascade hypothesis suggests that the aggregation and deposition of amyloid-β protein is an initiating event in Alzheimer's disease (AD). Using amyloid imaging technology, such as the positron emission tomography (PET) agent Pittsburgh compound-B (PiB), it is possible to explore the natural history of preclinical amyloid deposition in people at high risk for AD. With this goal in mind, asymptomatic (n = 5) and symptomatic (n = 5) carriers of presenilin-1 (PS1) mutations (C410Y or A426P) that lead to early-onset AD and noncarrier controls from both kindreds (n = 2) were studied with PiB–PET imaging and compared with sporadic AD subjects (n = 12) and controls from the general population (n = 18). We found intense and focal PiB retention in the striatum of all 10 PS1 mutation carriers studied (ages 35–49 years). In most PS1 mutation carriers, there also were increases in PiB retention compared with controls in cortical brain areas, but these increases were not as great as those observed in sporadic AD subjects. The two PS1 mutation carriers with a clinical diagnosis of early-onset AD did not show the typical regional pattern of PiB retention observed in sporadic AD. Postmortem evaluation of tissue from two parents of PS1C410Y subjects in this study confirmed extensive striatal amyloid deposition, along with typical cortical deposition. The early, focal striatal amyloid deposition observed in these PS1 mutation carriers is often is not associated with clinical symptoms.

Dual process theories of recognition memory posit that recollection and familiarity represent dissociable processes. Animal studies and human functional imaging experiments support an anatomic dissociation of these processes in the medial temporal lobes (MTL). By this hypothesis, recollection may be dependent on the hippocampus; while familiarity appears to rely on extrahippocampal MTL (ehMTL) structures, particularly perirhinal and lateral entorhinal cortices. Despite these findings, the dual process model and these anatomic mappings remain controversial, in part because the study of patients with lesions to the MTL has been limited and has revealed predominantly single dissociations. We examined measures of recollection and familiarity in three groups (normal older adults, amnesic-Mild Cognitive Impairment, Alzheimer’s Disease) in which these memory measures and the relative integrity of MTL structures are variable, thus enhancing our power to detect MTL-memory relationships. Recollection and familiarity and volumes of hippocampus and ehMTL, defined as a region including entorhinal/perirhinal cortices and parahippocampus, were measured. Regression analyses revealed a stronger relationship of recollection with the hippocampus compared to ehMTL, while familiarity was more highly related to ehMTL compared to hippocampus. These results are consistent with a division of labor in the MTL and the dual process model.

Immunohistochemical characterization of the distribution of GABAA receptor subunits γ 1/3 and 2 in the hippocampus relative to neurofibrillary tangle (NFT) pathology staging was performed in cognitively normal subjects (Braak stage I/II, n=4) and two groups of Alzheimer’s disease (AD) patients (Braak stage III/IV, n=4; Braak stage V/VI, n=8). In both Braak groups of AD patients, neuronal γ1/3 and γ2 immunoreactivity was preserved in all hippocampal subfields. However, compared to normal controls neuronal γ1/3 immunoreactivity was more intense in several end-stage AD subjects. Despite increased NFT pathology in the Braak V/VI AD group, GABAAγ 1/3 and γ2 immunoreactivitydid not co-localize with markers of NFT. These results suggest that upregulating or preserving GABAAγ 1/3 and γ2 receptors may protect neurons against neurofibrillary pathology in AD.

Context

Cognitive impairment in late-life depression is a core feature of the illness.

Objective

to test whether donepezil + antidepressant is superior to placebo + antidepressant in (1) improving cognitive performance and instrumental activities of daily living and (2) reducing recurrences of depression over two years of maintenance treatment.

Design

Randomized, double-blind, placebo controlled maintenance trial.

Setting

university clinic

Main Outcome Measures

global neuropsychological performance, cognitive instrumental ADL, and recurrent depression.

Results

Donepezil + antidepressant temporarily improved global cognition (treatment by time interaction F = 3.78, df = 2, 126, p = .03), but effect sizes were small (Cohen’s d = 0.27: group difference at 1 year). A marginal benefit to cognitive instrumental ADL was also observed (treatment by time interaction; F = 2.94; df = 2, 137, p = 0.06). The donepezil group was more likely to experience recurrent major depression: 35% [95% CI: 24%, 46%] versus 19% [95% CI: 9%, 29%] (log rank chi squared = 3.97, p = .05); hazard ratio = 2.09 [95% CI: 1.00, 4.41]. Post-hoc subgroup analyses showed that, of 57 participants with mild cognitive impairment, 3/30 on donepezil (10%; 95% CI: 0, 21%) and 9/27 on placebo (33%; 95% CI: 16%, 51%) converted to dementia over two years (Fisher exact p = 0.05). The MCI subgroup had a 44 percent recurrence rate of major depression on donepezil verses 12% on placebo (LR=4.91, p=.03). The subgroup with normal cognition (n = 73) showed no benefit on donepezil or increase in recurrence of major depression.

Conclusion

Whether ChEI should be used as augmentation in the maintenance treatment of late-life depression depends upon a careful weighing of risks and benefits in those with MCI. In cognitively intact patients, donepezil appears to have no clear benefit for preventing progression to MCI/dementia or recurrence of depression.

The calcium-sensing receptor (CASR) is a G-protein coupled, transmembrane receptor that responds to changes in Ca2+ levels. We hypothesized that the CASR could have a role in Alzheimer disease (AD) given expression of the CASR in brain, knowledge that calcium dysregulation promotes susceptibility to neuronal cell damage, the important role that the CASR plays in calcium regulation, and the fact that systemic calcium homeostasis and G-protein signal transduction are altered in AD patients. To investigate the association of CASR variation in AD susceptibility, we genotyped a polymorphic dinucleotide repeat marker within intron 4, one SNP within the promoter region and three non-synonymous SNPs within exon 7 of the CASR gene and tested for association analysis, using a well-characterized cohort of AD cases (n = 692) and controls (n = 435). The dinucleotide repeat polymorphism was significantly associated with AD status (OR = 1.62; 95% CI: 1.27–2.07, P = 0.00037, Bonferroni corrected P = 0.0011) and the three non-synonymous SNP haplotype was boarderline associated with AD status (P = 0.032, Bonferroni corrected P = 0.096). Stratifying by APOE4 allele carrier status revealed that the significant association was only in non-APOE4 carriers (OR of 1.90; 95% CI: 1.37–2.62, P = 0.0001). We also investigated whether apoE or βamyloid could activate the calcium-sensing receptor. The receptor activation assays revealed that apoE as well as βamyloid activated the CASR and that the level of activation appeared to be isoform dependent for apoE. These data support our hypothesis that the CASR has a role in AD susceptibility, particularly in individuals without an APOE4 allele.

Background

Late-onset Alzheimer disease (LOAD) is a clinically heterogeneous complex disease defined by progressively disabling cognitive impairment. Psychotic symptoms which affect approximately one-half of LOAD subjects have been associated with more rapid cognitive decline. However, the variety of cognitive trajectories in LOAD, and their correlates have not been well defined. We therefore used latent class modeling to characterize trajectories of cognitive and behavioral decline in a cohort of AD subjects.

Methods

201 Caucasian subjects with possible or probable AD were evaluated for cognitive and psychotic symptoms at regular intervals for up to 13.5 years. Cognitive symptoms were evaluated serially with the Mini-Mental State Examination (MMSE), and psychotic symptoms were rated using the CERAD behavioral rating scale (CBRS). Analyses undertaken were latent class mixture models of quadratic trajectories including a random intercept, with initial MMSE score, age, gender, education, and APOE ε4 count modeled as concomitant variables. In a secondary analysis, psychosis status was also included.

Results

AD subjects showed six trajectories with significantly different courses and rates of cognitive decline. The concomitant variables included in the best latent class trajectory model were initial MMSE and age. Greater burden of psychotic symptoms increased the probability of following a trajectory of more rapid cognitive decline in all age and initial MMSE groups. APOE ε4 was not associated with any trajectory.

Conclusion

Trajectory modeling of longitudinal cognitive and behavioral data may provide enhanced resolution of phenotypic variation in Alzheimer disease.

Since previous observations indicated that the urea cycle may have a role in the Alzheimer’s disease (AD) process, we set out to quantify the expression of each gene involved in the urea cycle in control and AD brains and establish whether these genes could be genetic determinants of AD. We first confirmed that all the urea cycle enzyme genes are expressed in the AD brain. The expression of arginase 2 was greater in the AD brain than in the control brain. The presence of the rare arginase 2 allele rs742869 was associated with an increase in the risk of AD in men and with an earlier age at onset for both genders. None of the other genes in the pathway appeared to be differentially expressed in the AD brain or act as genetic determinants of the disease.

The only established genetic determinant of non-Mendelian forms of Alzheimer’s disease (AD) is the ε4 allele of the apolipoprotein E gene (APOE). Recently, it has been reported that the P86L polymorphism of the calcium homeostasis modulator 1 gene (CALHM1) is associated with the risk of developing AD. In order to independently assess this association, we performed a meta-analysis of 7,873 AD cases and 13,274 controls of Caucasian origin (from a total of 24 centres in Belgium, Finland, France, Italy, Spain, Sweden, the UK and the USA). Our results indicate that the CALHM1 P86L polymorphism is likely not a genetic determinant of AD but may modulate age at onset by interacting with the effect of the ε4 allele of the APOE gene.

Context

The herbal product Ginkgo biloba is taken frequently with the intention of improving cognitive health in aging. However, evidence from adequately powered clinical trials is lacking regarding its effect on long-term cognitive functioning.

Objective

To determine whether G biloba slows the rates of global or domain-specific cognitive decline in older adults.

Design, Setting, and Participants

The Ginkgo Evaluation of Memory (GEM) study, a randomized, double-blind, placebo-controlled clinical trial of 3069 community-dwelling participants aged 72 to 96 years, conducted in 6 academic medical centers in the United States between 2000 and 2008, with a median follow-up of 6.1 years.

Intervention

Twice-daily dose of 120-mg extract of G biloba (n=1545) or identical-appearing placebo (n=1524).

Main Outcome Measures

Rates of change over time in the Modified Mini-Mental State Examination (3MSE), in the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog), and in neuropsychological domains of memory, attention, visual-spatial construction, language, and executive functions, based on sums of z scores of individual tests.

Results

Annual rates of decline in z scores did not differ between G biloba and placebo groups in any domains, including memory (0.043; 95% confidence interval [CI], 0.034-0.051 vs 0.041; 95% CI, 0.032-0.050), attention (0.043; 95% CI, 0.037-0.050 vs 0.048; 95% CI, 0.041-0.054), visuospatial abilities (0.107; 95% CI, 0.097-0.117 vs 0.118; 95% CI, 0.108-0.128), language (0.045; 95% CI, 0.037-0.054 vs 0.041; 95% CI, 0.033-0.048), and executive functions (0.092; 95% CI, 0.086-0.099 vs 0.089; 95% CI, 0.082-0.096). For the 3MSE and ADAS-Cog, rates of change varied by baseline cognitive status (mild cognitive impairment), but there were no differences in rates of change between treatment groups (for 3MSE, P=.71; for ADAS-Cog, P=.97). There was no significant effect modification of treatment on rate of decline by age, sex, race, education, APOE*E4 allele, or baseline mild cognitive impairment (P>.05).

Conclusion

Compared with placebo, the use of G biloba, 120 mg twice daily, did not result in less cognitive decline in older adults with normal cognition or with mild cognitive impairment.

Trial Registration

clinicaltrials.gov Identifier: NCT00010803

Recently genetic variation in the DAPK1 and ABCA2 genes has been reported to be associated with late-onset and early-onset Alzheimer’s disease (AD), respectively. We examined the most significant two single-nucleotide polymorphisms (SNPs) in DAPK1 in a large case–control cohort of late-onset subjects and matched controls and one of the most significiant SNPs in ABCA2 in a small set of early-onset subjects as well. We did not detect associations with AD for any variation.

Objective

To compare rates of Mild Cognitive Impairment (MCI) and rates of progression to dementia, using different MCI diagnostic systems

Methods

MCI was investigated at baseline in 3063 community-dwelling non-demented elderly in the Ginkgo Evaluation of Memory (GEM) study who were evaluated every six months to identify presence of dementia. Overall MCI frequency was determined using (1) Clinical Dementia Rating (CDR) score of 0.5 and (2) neuropsychological (NP) criteria, defined by impairment on standard cognitive tests.

Results

40.2% of participants met CDR MCI criteria and 28.2% met NP MCI criteria (amnestic-MCI=16.6%). 15.7% were classified as MCI by both criteria and 47.4% as Normal by both. Discordant diagnoses were observed in 24.5% who met NP Normal/CDR MCI; and 12.4% who met NP MCI/CDR Normal. Factors associated with CDR MCI among NP Normal included, lower education, lower NP scores, more IADL impairment, greater symptoms of depression and subjective health problems. Individuals meeting NP MCI/CDR normal were significantly more likely to develop dementia over the median follow up of 6.1 years than those meeting NP Normal/CDR MCI.

Conclusions

Different criteria produce different MCI rates and different conversion rates to dementia. Although a higher percentage of MCI was identified by CDR than NP, a higher percentage of NP MCI progressed to dementia. These findings suggest that the CDR is sensitive to subtle changes in cognition not identified by NP algorithm but is also sensitive to demographic and clinical factors probably leading to a greater number of false positives. These results suggest that identifying all individuals with CDR scores of 0.5 as Alzheimer's disease is not advisable.

Alzheimer's disease (AD) is a complex and multifactorial disease with the possible involvement of several genes. With the exception of the APOE gene as a susceptibility marker, no other genes have been shown consistently to be associated with late-onset AD (LOAD). A recent genome-wide association study of 17,343 gene-based putative functional single nucleotide polymorphisms (SNPs) found 19 significant variants, including 3 linked to APOE, showing association with LOAD (Hum Mol Genet 2007; 16:865–873). We have set out to replicate the 16 new significant associations in a large case-control cohort of American Whites. Additionally, we examined six variants present in positional and/or biological candidate genes for AD. We genotyped the 22 SNPs in up to 1,009 Caucasian Americans with LOAD and up to 1,010 age-matched healthy Caucasian Americans, using 5′ nuclease assays. We did not observe a statistically significant association between the SNPs and the risk of AD, either individually or stratified by APOE. Our data suggest that the association of the studied variants with LOAD risk, if it exists, is not statistically significant in our sample.

SUMMARY

Background

While the deleterious psychosocial and mental health effects of dementia caregiving are firmly established, very little is known about the burdens or psychiatric outcomes of providing care to a spouse with less severe cognitive impairment, such as mild cognitive impairment (MCI). We characterized the nature and level of caregiver burden and psychiatric morbidity in spouses of persons diagnosed with MCI.

Methods

Interview assessments were completed on a cohort of 27 spouses of persons with a recent diagnosis of MCI. Patient medical records were reviewed to collect information regarding the MCI patient’s medical history.

Results

Respondents endorsed elevated levels of both task-related responsibilities and subjective caregiver burden. Depression and anxiety symptom levels also showed some elevations. Measures of caregiver burden were significantly associated with depression and anxiety levels. In particular, even after controlling for demographic risk factors for distress, nursing task burden was correlated with elevated depressive symptoms, and greater lifestyle constraints were correlated with higher anxiety levels.

Conclusion

Although caregiver burden and psychiatric morbidity levels were lower than those typically observed in family dementia caregiving samples, our findings suggest that MCI caregivers have already begun to experience distress in association with elevated caregiving burden. These individuals may be ideal targets for selective preventive interventions to maximize their psychological well-being as caregiving burdens related to their spouses’ cognitive impairment increase.

Inverse correlations between amyloid-β (Aβ) load measured by Pittsburgh Compound-B (PiB) positron emission tomography (PET) and cerebral metabolism using [18F]fluoro-2-deoxy-D-glucose (FDG) in Alzheimer’s disease (AD) patients, suggest local Aβ-induced metabolic insults. However, this relationship has not been well studied in mild cognitive impairment (MCI) or amyloid-positive controls. Here, we explored associations of Aβ deposition with metabolism via both region-of-interest-based and voxel-based analyses in amyloid-positive control subjects and patients with MCI or AD. Metabolism in parietal and precuneus cortices of AD patients was negatively correlated with PiB retention locally, and more distantly with PiB retention in frontal cortex. In amyloid-positive controls, no clear patterns in correlations were observed. In MCI patients, there were essentially no significant, negative correlations, but there were frequent significant positive correlations between metabolism and PiB retention. Metabolism in anterior cingulate showed positive correlations with PiB in most brain areas in MCI, and metabolism and PiB retention were positively correlated locally in precuneus/parietal cortex. However, there was no significant increase in metabolism in MCI compared to age-matched controls, negating the possibility that Aβ deposition directly caused reactive hypermetabolism. This suggests that, in MCI, higher basal metabolism could either be exacerbating Aβ deposition or increasing the level of Aβ necessary for cognitive impairment sufficient for the clinical diagnosis of AD. Only after extensive Aβ deposition has been present for longer periods of time does Aβ become the driving force for decreased metabolism in clinical AD and, only in more vulnerable brain regions such as parietal and precuneus cortices.

There is a strong association between late-life depression, cognitive impairment, cerebrovascular disease, and poor cognitive outcomes, including progressive dementia, especially Alzheimer’s disease. While neuroimaging evidence suggests that cerebrovascular disease plays a prominent role, it seems that depression alone may also confer substantial risk for developing Alzheimer’s disease. The relationships between the prominent cerebrovascular changes, other structural abnormalities, specific forms of cognitive dysfunction, and increased risk for developing Alzheimer’s disease among those with late-life depression have been difficult to reconcile. The varied findings suggest that there are likely multiple pathways to poor cognitive outcomes. We present a framework outlining multiple, non-mutually exclusive etiologic links between depression, cognitive impairment, and progressive decline, including dementia. Importantly, the model is both testable and falsifiable. Going forward, using models such as this to inform research should accelerate knowledge acquisition on the depression/dementia relationship that may be useful for dementia prevention, monitoring the impact of depression treatment on clinical status and course of illness.

The behavioral changes in people with dementia often negatively affect marital relationships. Yet little is known about how the marital relationship is affected when the care recipient has mild cognitive impairment (MCI). This study characterizes marital quality among adults who live with a spouse with MCI. Data were drawn from interviews with 27 spouses of people with a recent diagnosis of MCI. Even at early stages of MCI, many spouses report the frequent occurrence of distressing behaviors. This study demonstrates that MCI may degrade the quality of the marital relationship. These results have implications for clinical practice and the delivery of health care and social services to these families. It is important to develop interventions to address the needs of these individuals and their caregivers. Results of this study suggest the need for mental health interventions designed to preserve the quality of these marital relationships.