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Introduction: The objective of this study was to determine the utility of subjective memory decline (SMD) to predict episodic memory change and rates of clinical progression in cognitively normal older adults with evidence of high β-amyloid burden (CN Aβ+)., Methods: Fifty-eight CN Aβ+ participants from the Australian Imaging, Biomarkers, and Lifestyle study responded to an SMD questionnaire and underwent comprehensive neuropsychological assessments. Participant data for three follow-up assessments were analyzed., Results: In CN Aβ+, subjects with high SMD did not exhibit significantly greater episodic memory decline than those with low SMD. High SMD was related to greater rates of progression to mild cognitive impairment or Alzheimer's disease (AD) dementia (hazard ratio = 5.1; 95% confidence interval, 1.4-20.0, P = .02) compared with low SMD. High SMD was associated with greater depressive symptomatology and smaller left hippocampal volume., Discussion: High SMD is a harbinger of greater rates of clinical progression in preclinical AD. Although SMD reflects broader diagnostic implications for CN Aβ+, more sensitive measures may be required to detect early subtle cognitive change., (Copyright © 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Background: Postoperative cognitive dysfunction (POCD) affects 16 to 21% of the elderly 3 months after anesthesia and surgery and is associated with adverse outcomes. The exact cause of POCD remains unknown. The authors hypothesized that elderly individuals with Alzheimer disease (AD) neuropathology, identified by cerebrospinal fluid (CSF) analysis, would have increased the risk for POCD., Methods: CSF samples were collected from 59 patients 60 yr or older who received combined spinal and general anesthesia for elective total hip replacement. Patients underwent neuropsychological testing preoperatively and at 7 days, 3 months, and 12 months postoperatively. POCD at 3 months and cognitive decline at 12 months were calculated by using the reliable change index. CSF amyloid β1-42 (Aβ1-42), total-tau, phosphorylated-tau, and neurofilament light were assayed with enzyme-linked immunosorbent assay methods., Results: POCD was identified in 5 of 57 patients (8.8%) at 3 months. For Aβ1-42, 11 patients were below the cut-point for AD neuropathology of whom 3 were classified with POCD (27.3%; 95% CI, 6.0 to 61%), whereas of the 46 patients above the cut-point, 2 were classified with POCD (4.3%; 95% CI, 0.5 to 14.8%) (P = 0.01). There was no significant difference in the incidence of POCD in relation to the cut-points for any of the other analytes., Conclusions: Low CSF Aβ1-42 may be a significant predictor of POCD at 3 months. This indicates that patients with AD neuropathology even in the absence of clinically detectable AD symptoms may be susceptible to POCD.

Background: APOEɛ4 genotype and aging have been identified as risk factors for Alzheimer's disease (AD). In addition, subjective memory complaints (SMC) might be a first clinical expression of the effect of AD pathology on cognitive functioning., Objective: To assess whether APOEɛ4 genotype, age, SMC, and episodic memory are risk factors for high amyloid-β (Aβ) burden in cognitively normal elderly., Methods: 307 cognitively normal participants (72.7 ± 6.8 years, 53% female, 55% SMC) from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study underwent amyloid PET and APOE genotyping. Logistic regression analyses were performed to determine the association of APOEɛ4 genotype, age, SMC, and episodic memory with Aβ pathology., Results: Odds of high Aβ burden were greater at an older age (OR = 3.21; 95% CI = 1.68-6.14), when SMC were present (OR = 1.90; 95% CI = 1.03-3.48), and for APOEɛ4 carriers (OR = 7.49; 95% CI = 3.96-14.15), while episodic memory was not associated with odds of high Aβ burden. Stratified analyses showed that odds of SMC for high Aβ burden were increased in specifically APOEɛ4 carriers (OR = 4.58, 95% CI = 1.83-11.49) and younger participants (OR = 3.73, 95% CI = 1.39-10.01)., Conclusion: Aging, APOEɛ4 genotype, and SMC were associated with high Aβ burden. SMC were especially indicative of high Aβ burden in younger participants and in APOEɛ4 carriers. These findings suggest that selection based on the presence of SMC, APOEɛ4 genotype and age may help identify healthy elderly participants with high Aβ burden eligible for secondary prevention trials.

Background: There has been limited research into potentially inappropriate medication (PIM) use and anticholinergic burden in patients attending memory clinics., Objectives: The aim of this study was to explore the use of PIMs related to cognitive impairment (PIMcog), anticholinergic cognitive burden (ACB) and concomitant use of anticholinergic medications with cholinesterase inhibitors (ChEIs) in patients attending memory clinics., Methods: Cross-sectional analysis of baseline data from the Prospective Research In MEmory clinics (PRIME) study was performed. Participants were community-dwelling patients who attended nine memory clinics and had a diagnosis of mild cognitive impairment or dementia. PIMcog were defined as any medication considered potentially inappropriate for patients with cognitive impairment according to the Beers or STOPP criteria. Clinically significant ACB was defined as total score of ≥3 on the ACB scale., Results: A total of 964 patients, mean age 77.6 years, were included. PIMcog were used by 206 (21.4%) patients. Anticholinergics and sedatives were the most common PIMcog. PIMcog use was associated with higher number of medications (adjusted OR 1.26; 95% CI 1.19-1.33) and with not having completed secondary level education (adjusted OR 1.71; 95% CI 1.01-2.89). One hundred and thirteen (11.7%) patients had a clinically significant ACB score (≥3). ChEIs were used by 575 patients and 65 (11.3%) of these had an ACB score ≥3. There was no statistically significant difference in ChEI use between patients with and without an ACB score ≥3., Conclusion: PIMcog use, clinically significant anticholinergic burden, and concurrent use of anticholinergics with ChEIs were prevalent in patients attending memory clinics. Efforts are needed to improve prescribing for people with cognitive impairment.

Accumulation of β-amyloid (Aβ) in the brain is associated with memory decline in healthy individuals as a prelude to Alzheimer's disease (AD). Genetic factors may moderate this decline. We examined the role of apolipoprotein E (ɛ4 carrier[ɛ4(+)], ɛ4 non-carrier[ɛ4(-)]) and brain-derived neurotrophic factor (BDNF(Val/Val), BDNF(Met)) in the extent to which they moderate Aβ-related memory decline. Healthy adults (n=333, Mage=70 years) enrolled in the Australian Imaging, Biomarkers and Lifestyle study underwent Aβ neuroimaging. Neuropsychological assessments were conducted at baseline, 18-, 36- and 54-month follow-ups. Aβ positron emission tomography neuroimaging was used to classify participants as Aβ(-) or Aβ(+). Relative to Aβ(-)ɛ4(-), Aβ(+)ɛ4(+) individuals showed significantly faster rates of cognitive decline over 54 months across all domains (d=0.40-1.22), while Aβ(+)ɛ4(-) individuals showed significantly faster decline only on verbal episodic memory (EM). There were no differences in rates of cognitive change between Aβ(-)ɛ4(-) and Aβ(-)ɛ4(+) groups. Among Aβ(+) individuals, ɛ4(+)/BDNF(Met) participants showed a significantly faster rate of decline on verbal and visual EM, and language over 54 months compared with ɛ4(-)/BDNF(Val/Val) participants (d=0.90-1.02). At least two genetic loci affect the rate of Aβ-related cognitive decline. Aβ(+)ɛ4(+)/BDNF(Met) individuals can expect to show clinically significant memory impairment after 3 years, whereas Aβ(+)ɛ4(+)/BDNF(Val/Val) individuals can expect a similar degree of impairment after 10 years. Little decline over 54 months was observed in the Aβ(-) and Aβ(+) ɛ4(-) groups, irrespective of BDNF status. These data raise important prognostic issues in managing preclinical AD, and should be considered in designing secondary preventative clinical trials.

Background: Information provided by an informant about a patient with cognitive change is an essential component of clinical history taking. How an informant's report relates to the patient's phenomenological experience of memory loss is yet to be understood. The aim was to examine patterns of relationships between self and informant reports from a phenomenological perspective., Methods: Forty-three healthy non-memory complainers (HC-NMC), 37 healthy subjective memory complainers (HC-SMC) and 43 individuals with mild cognitive impairment (MCI) were administered a semi-structured interview, which measured their concerns of frequency of memory lapses and impact on mood. Informants responded to questionnaires., Results: Self-reported concerns of increasing frequency and impacted mood related to informant concerns in HC-SMCs. MCI with lower informant concern showed a similar pattern to HC-SMCs on complaints of increasing frequency. In those with higher informant concern, self-reports markedly separated from informant concern. The MCI group with greater informant concern performed comparatively poor on verbal and non-verbal memory measures., Conclusions: Our results suggest that the association between self-reported and informant memory concerns is moderated by MCI severity. Self and informant reports of increasing memory lapse frequency aligned in HC-SMC and MCIs with low informant concern, suggesting a similar dyadic experience of memory change. In MCIs with greater informant concern, the pattern changed exposing a changing insight with advancing memory impairment. These individuals are potentially reflecting a 'forgetting that they forget' phenomenon in elements of their concern., (© The Author 2015. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The aim of this paper was to investigate the association of three well-recognised dietary patterns with cognitive change over a 3-year period. Five hundred and twenty-seven healthy participants from the Australian Imaging, Biomarkers and Lifestyle study of ageing completed the Cancer Council of Victoria food frequency questionnaire at baseline and underwent a comprehensive neuropsychological assessment at baseline, 18 and 36 months follow-up. Individual neuropsychological test scores were used to construct composite scores for six cognitive domains and a global cognitive score. Based on self-reported consumption, scores for three dietary patterns, (1) Australian-style Mediterranean diet (AusMeDi), (2) western diet and (3) prudent diet were generated for each individual. Linear mixed model analyses were conducted to examine the relationship between diet scores and cognitive change in each cognitive domain and for the global score. Higher baseline adherence to the AusMeDi was associated with better performance in the executive function cognitive domain after 36 months in apolipoprotein E (APOE) ɛ4 allele carriers (P<0.01). Higher baseline western diet adherence was associated with greater cognitive decline after 36 months in the visuospatial cognitive domain in APOE ɛ4 allele non-carriers (P<0.01). All other results were not significant. Our findings in this well-characterised Australian cohort indicate that adherence to a healthy diet is important to reduce risk for cognitive decline, with the converse being true for the western diet. Executive function and visuospatial functioning appear to be particularly susceptible to the influence of diet.

Background: This study investigated the prevalence of cognitive impairment in elderly noncardiac surgery patients and any association between preoperative cognitive impairment and postoperative cognitive dysfunction (POCD). Additionally, the incidence of cognitive decline at 12 months after surgery was identified., Methods: Three hundred patients for hip joint replacement and 51 nonsurgical controls aged 60 yr or older were studied in a prospective observational clinical trial. All study participants and controls completed a battery of eight neuropsychological tests before surgery and at 7 days, 3 months, and 12 months afterwards. Preoperative cognitive status was assessed using preexisting cognitive impairment (PreCI) defined as a decline of at least 2 SD on two or more of seven neuropsychological tests compared to population norms. POCD and cognitive decline were assessed using the reliable change index utilizing the results of the control group., Results: PreCI was classified in 96 of 300 (32%) patients (95% CI, 23 to 43%). After surgery, 49 of 286 (17%) patients (95% CI, 13 to 22%) and 27 of 284 (10%) patients (95% CI, 6 to 13%) demonstrated POCD at 7 days and 3 months, respectively, while 7 of 271 (3%) patients (95% CI, 1 to 4%) demonstrated cognitive decline at 12 months. Patients with PreCI had a significantly increased incidence of POCD at 7 days and 3 months and cognitive decline at 12 months., Conclusions: Patients with PreCI have an increased incidence of POCD and cognitive decline. PreCI is a good predictor of subsequent POCD and cognitive decline. The incidence of cognitive decline after 12 months in this group of patients is low.

Objectives: Patients with dementia experience a wide range of neuropsychiatric symptoms. These symptoms often cause considerable distress to patients and caregivers, and often contribute to institutionalization. The current study examined the prevalence and course of neuropsychiatric symptoms in a large sample of patients with dementia attending memory clinics., Design: Three-year nonprescriptive, observational study examining relationships between predictors and outcome variables in patients with dementia., Setting: Nine memory clinics around Australia., Participants: Of 970 patients recruited, 779 patients had dementia at baseline., Measurements: Over 3 years, patients were rated on 6 occasions on the 12-item Neuropsychiatric Inventory and measures of cognition, dementia severity, function, and medication use. Analyses focused on the 514 patients with dementia who completed the Neuropsychiatric Inventory on 4 or more occasions., Results: Overall levels of neuropsychiatric symptoms increased over the 3 years. In particular, delusions, hallucinations, agitation, anxiety, apathy, disinhibition, irritability, and aberrant motor behavior increased over the 3 years. Depression, euphoria, night time behavior, and appetite did not significantly increase over this period. Severity of dementia, male sex, and frontotemporal dementia were associated with greater levels of neuropsychiatric symptoms at baseline. Dementia with Lewy bodies was associated with more hallucinations and less appetite disturbances, and Alzheimer's disease was associated with lower levels of neuropsychiatric symptoms than other types of dementia at baseline., Conclusions: The findings confirm that different symptoms have different trajectories and that baseline characteristics of patients, including sex and dementia type, predict the subsequent course of symptoms. The findings also highlight the association between dementia severity and neuropsychiatric symptoms, indicating the need to control for this variable when examining their longitudinal trajectories., (Copyright © 2015 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

Background: High β-amyloid (Aβ) is associated with faster memory decline in healthy individuals and adults with mild cognitive impairment (MCI). However, longer prospective studies are required to determine if Aβ-related memory decline continues and whether it is associated with increased rate of disease progression., Methods: Healthy controls (HCs; n = 177) and adults with MCI (n = 48) underwent neuroimaging for Aβ and cognitive assessment at baseline. Cognition was reassessed 18 and 36 months later., Results: Compared with low-Aβ HCs, high-Aβ HC and MCI groups showed moderate decline in episodic and working memory over 36 months. Those with MCI with low Aβ did not show any cognitive decline. Rates of disease progression were increased in the high-Aβ HC and MCI groups., Conclusions: In healthy individuals, high Aβ likely indicates that Alzheimer's disease (AD)-related neurodegeneration has begun. Once commenced, the rate of decline in cognitive function remains constant across the preclinical and prodromal stages of AD., (Copyright © 2014. Published by Elsevier Inc.)

Introduction: There is increasing evidence to support the benefits of physical activity on cognition in older adults. This paper describes (i) the attitudes, beliefs and barriers towards physical activity of older adults with and without cognitive impairment and (ii) their opinion of the attributes of the ideal physical activity program., Methods: Thematic analysis of focus groups and individual interviews with 50 older adults with no cognitive impairment, subjective memory complaints, mild cognitive impairment and Alzheimer's disease was performed., Results: Consistent with previous research in cognitively intact older adults, most participants, irrespective of cognitive status, had a positive attitude towards physical activity and believed it was beneficial both generally and for cognition. There was a preference for physical activity programs to be suggested by advertising and general practitioners (GPs), undertaken in a group setting, and beliefs that they should be tailored to individual's needs and preferences, and should be affordable according to their income. Participants with cognitive impairment cited specific barriers including "memory" and "lack of companion" as well as preferring "accessible" settings and "simple/light/safe" activities., Discussion: These findings provide useful data, particularly from participants with cognitive impairment, with whom there has been little research to date. This could contribute to efforts to translate the growing research evidence of the benefits of physical activity for brain health into effective community programs., (Copyright © 2012 Wiley Publishing Asia Pty Ltd.)

Background: Folate fortification of food aims to reduce the number of babies born with neural tube defects, but has been associated with cognitive impairment when vitamin B12 levels are deficient. Given the prevalence of low vitamin B12 levels among the elderly, and the global deployment of food fortification programs, investigation of the associations between cognitive impairment, vitamin B12, and folate are needed., Objective: To investigate the associations of serum vitamin B12, red cell folate, and cognitive impairment., Methods: Data were collected on 1,354 subjects in two studies investigating cognitive impairment, and from patients attending for assessment or management of memory problems in the Barwon region of south eastern Australia between 2001 and 2011. Eligible subjects who had blood measurements of vitamin B12 and red cell folate taken within six months of cognitive testing were included. Subjects with stroke or neurodegenerative diseases other than Alzheimer's disease were excluded. A Mini-Mental State Examination score of <24 was used to define impaired cognitive function., Results: Participants with low serum vitamin B12 (<250 pmol/L) and high red cell folate (>1,594 nmol/L) levels were more likely to have impaired cognitive performance (adjusted odds ratio (AOR) 3.45, 95% confidence interval (CI): 1.60-7.43, p = 0.002) when compared to participants with biochemical measurements that were within the normal ranges. Participants with high folate levels, but normal serum vitamin B12, were also more likely to have impaired cognitive performance (AOR 1.74, 95% CI: 1.03-2.95, p = 0.04)., Conclusions: High folate or folic acid supplements may be detrimental to cognition in older people with low vitamin B12 levels. This topic is of global significance due to the wide distribution of food fortification programs, so prospective studies should be a high priority.

Background: We evaluated the utility of longitudinal measures of plasma amyloid-β (Aβ) as a means to identify pre-symptomatic cognitive decline in Alzheimer's disease (AD) when coupled to neuroimaging and neuropsychological parameters., Methods: Participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were grouped based upon cognitive change and changes in measurable levels of neocortical amyloid over 36 months. Participants were classified as those who transitioned for cognitive decline and change in neocortical amyloid, those healthy controls that did not transition, and stable AD participants over 36 months., Results: Comparisons of plasma Aβ levels between the transition and non-transitional groups showed Aβ1-42 and the Aβ1-42/Aβ1-40 ratio were significantly decreased at baseline (p = 0.008 and p = 0.002, respectively) and at 18 months (p = 0.003 and p = 0.004, respectively). Both measures of neocortical amyloid and two previously published composite scores validated the creation of the novel transitional grouping (p < 0.0001). In addition Aβn-42 performed well as a longitudinal prognostic indicator of transition toward cognitive decline, with a significant decrease in the transition group at the 18 month time point (p = 0.01)., Conclusion: We demonstrated that baseline plasma Aβ1-42 and the Aβ1-42/Aβ1-40 ratio were putative biomarkers indicative of cognitive decline and validated this result using 18 month data. We created a novel transitional grouping and validated this measure using published measures of neocortical amyloid and composite memory scores. These findings suggest that longitudinal plasma Aβ could contribute to a pre-symptomatic biomarker panel for AD.

Background: The rate of cognitive decline in Alzheimer's disease (AD) varies considerably between individuals. Predicting rapid cognitive decline might help clinicians provide prognostic information, select subjects for trial intervention and/or reduce costs., Methods: PubMed and PsycINFO were searched for all the English written studies published until the end of 2010 on rapid cognitive decline in AD and factors associated with it., Results: More than 300 individual articles were retrieved. We selected 82 relevant studies. The main findings of these papers are that younger, more educated and more impaired patients are more likely to show rapid cognitive decline. ApoE alleles seem not to modify the velocity of clinical progression of dementia, or at most could have a very small effect. No inference can be made for all the other variables analysed., Conclusions: There are many studies on rapid cognitive decline. Results are heterogeneous and often contradictory. No reliable conclusions about factors that may be associated with rapid cognitive decline can yet be drawn.

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has previously been implicated in Alzheimer's disease (AD)-related cognitive impairment. We aimed to determine the relationship between BDNF Val66Met and beta-amyloid (Aβ) on cognitive decline, hippocampal atrophy, and Aβ accumulation over 36 months in 165 healthy adults enrolled in the Australian Imaging, Biomarkers and Lifestyle study. In healthy adults with high Aβ, Met carriers showed significant and moderate-to-large declines in episodic memory, executive function, and language, and greater hippocampal atrophy over 36 months, compared with Val/Val homozygotes. BDNF Val66Met was not found to be related to rates of change in cognition or hippocampal volume in healthy adults with low Aβ. BDNF Val66Met did not relate to the amount of Aβ or to the rate of Aβ accumulation in either group. High Aβ levels coupled with Met carriage may be useful prognostic markers of accelerated cognitive decline and hippocampal degeneration in individuals in the preclinical stage of AD., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: To investigate the associations of metformin, serum vitamin B12, calcium supplements, and cognitive impairment in patients with diabetes., Research Design and Methods: Participants were recruited from the Primary Research in Memory (PRIME) clinics study, the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, and the Barwon region of southeastern Australia. Patients with Alzheimer disease (AD) (n=480) or mild cognitive impairment (n=187) and those who were cognitively intact (n=687) were included; patients with stroke or with neurodegenerative diseases other than AD were excluded. Subgroup analyses were performed for participants who had either type 2 diabetes (n=104) or impaired glucose tolerance (n=22)., Results: Participants with diabetes (n=126) had worse cognitive performance than participants who did not have diabetes (n=1,228; adjusted odds ratio 1.51 [95% CI 1.03-2.21]). Among participants with diabetes, worse cognitive performance was associated with metformin use (2.23 [1.05-4.75]). After adjusting for age, sex, level of education, history of depression, serum vitamin B12, and metformin use, participants with diabetes who were taking calcium supplements had better cognitive performance (0.41 [0.19-0.92])., Conclusions: Metformin use was associated with impaired cognitive performance. Vitamin B12 and calcium supplements may alleviate metformin-induced vitamin B12 deficiency and were associated with better cognitive outcomes. Prospective trials are warranted to assess the beneficial effects of vitamin B12 and calcium use on cognition in older people with diabetes who are taking metformin.

Background: Similar to most chronic diseases, Alzheimer's disease (AD) develops slowly from a preclinical phase into a fully expressed clinical syndrome. We aimed to use longitudinal data to calculate the rates of amyloid β (Aβ) deposition, cerebral atrophy, and cognitive decline., Methods: In this prospective cohort study, healthy controls, patients with mild cognitive impairment (MCI), and patients with AD were assessed at enrolment and every 18 months. At every visit, participants underwent neuropsychological examination, MRI, and a carbon-11-labelled Pittsburgh compound B ((11)C-PiB) PET scan. We included participants with three or more (11)C-PiB PET follow-up assessments. Aβ burden was expressed as (11)C-PiB standardised uptake value ratio (SUVR) with the cerebellar cortex as reference region. An SUVR of 1·5 was used to discriminate high from low Aβ burdens. The slope of the regression plots over 3-5 years was used to estimate rates of change for Aβ deposition, MRI volumetrics, and cognition. We included those participants with a positive rate of Aβ deposition to calculate the trajectory of each variable over time., Findings: 200 participants (145 healthy controls, 36 participants with MCI, and 19 participants with AD) were assessed at enrolment and every 18 months for a mean follow-up of 3·8 (95% CI CI 3·6-3·9) years. At baseline, significantly higher Aβ burdens were noted in patients with AD (2·27, SD 0·43) and those with MCI (1·94, 0·64) than in healthy controls (1·38, 0·39). At follow-up, 163 (82%) of the 200 participants showed positive rates of Aβ accumulation. Aβ deposition was estimated to take 19·2 (95% CI 16·8-22·5) years in an almost linear fashion-with a mean increase of 0·043 (95% CI 0·037-0·049) SUVR per year-to go from the threshold of (11)C-PiB positivity (1·5 SUVR) to the levels observed in AD. It was estimated to take 12·0 (95% CI 10·1-14·9) years from the levels observed in healthy controls with low Aβ deposition (1·2 [SD 0·1] SUVR) to the threshold of (11)C-PiB positivity. As AD progressed, the rate of Aβ deposition slowed towards a plateau. Our projections suggest a prolonged preclinical phase of AD in which Aβ deposition reaches our threshold of positivity at 17·0 (95% CI 14·9-19·9) years, hippocampal atrophy at 4·2 (3·6-5·1) years, and memory impairment at 3·3 (2·5-4·5) years before the onset of dementia (clinical dementia rating score 1)., Interpretation: Aβ deposition is slow and protracted, likely to extend for more than two decades. Such predictions of the rate of preclinical changes and the onset of the clinical phase of AD will facilitate the design and timing of therapeutic interventions aimed at modifying the course of this illness., Funding: Science and Industry Endowment Fund (Australia), The Commonwealth Scientific and Industrial Research Organisation (Australia), The National Health and Medical Research Council of Australia Program and Project Grants, the Austin Hospital Medical Research Foundation, Victorian State Government, The Alzheimer's Drug Discovery Foundation, and the Alzheimer's Association., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

We aimed to characterize the nature and magnitude of cognitive decline in a group of adults with amnestic mild cognitive impairment (aMCI) with high and low levels of amyloid-β (Aβ) in relation to healthy older adults with low Aβ levels. Healthy older adults and adults with aMCI enrolled in the Australian Imaging, Biomarker, and Lifestyle study, completed the CogState brief battery at baseline and 18 months, and underwent positron emission tomography neuroimaging for Aβ at baseline. In this study, we included adults with MCI who had been classified as having high and low levels of Aβ and healthy older adults who had been classified as having low levels of Aβ. Linear model analyses adjusted for baseline cognitive function indicated that relative to healthy older adults with low Aβ, adults with aMCI and high Aβ showed greater decline in working memory and in verbal and visual episodic memory at 18 months. Adults with aMCI and low Aβ also showed greater decline in working memory; however they did not evidence any decline in episodic memory at 18 months. The results of our study suggests that relative to healthy older adults and adults with aMCI with low Aβ, adults with aMCI and high levels of Aβ showed faster rates of decline on measures of episodic memory over 18 months, and this was approximately twice that observed previously for healthy older adults with high Aβ levels.

We aimed to characterize the nature and magnitude of cognitive decline in a group of healthy older adults with high and low levels of amyloid-β (Aβ) and who were APOE ε4 carriers and non-carriers. Healthy older adults underwent positron emission tomography neuroimaging for Aβ, APOE genotyping, and cognitive and clinical assessment as part of their baseline assessment in the Australian Imaging, Biomarker, and Lifestyle study. Cognitive function and clinical ratings were reassessed 18 months later. Linear mixed model analyses adjusted for baseline cognitive function indicated that relative to healthy older adults with low Aβ, healthy older adults with high Aβ showed greater decline in episodic memory and language at 18 months. No decline on any measure of executive function, attention, or clinical rating was observed for healthy older adults with high Aβ levels. Compared to non-carriers, APOE ε4 carriers showed a greater decline only on the task of visual memory at the 18 month assessment. Importantly though, no interaction between APOE ε4 and Aβ was observed on any measure of cognitive function. The results of this study suggest that high Aβ load was associated with greater decline in episodic memory and language, that the magnitude of this decline was moderate and equivalent across both domains, and that APOE ε4 carriage did not moderate the relationship between Aβ and decline in memory and language functions.

Objective: Although the APOE ε4 allele is associated with more rapid decline in memory in healthy older adults, the significance of elevated cerebral β-amyloid (Aβ) load for longitudinal changes in cognition is unclear., Methods: Healthy and cognitively normal older adults (n = 141; mean age 76 years) underwent PET neuroimaging for cerebral Aβ, APOE genotyping, and cognitive assessment as part of their baseline assessment in the Australian Imaging Biomarkers and Lifestyle study. Cognitive function was reassessed 18 months later., Results: Linear mixed-model analyses adjusted for baseline cognitive function indicated that, relative to individuals with low cerebral Aβ, individuals with high cerebral Aβ showed significantly greater decline in working memory and verbal and visual episodic memory at 18 months. Compared with noncarriers, APOE ε4 carriers showed a greater decline in visual memory at the 18-month assessment. No interaction between APOE ε4 and cerebral Aβ load was observed for any measure of cognitive function., Conclusions: In this prospective study of healthy older adults, high cerebral Aβ load was associated with greater decline in episodic and working memory over 18 months. The APOE ε4 genotype was also associated with a decline in visual memory, although the effect was less than that observed for cerebral Aβ load.

Background: This review examines the associations between low vitamin B12 levels, neurodegenerative disease, and cognitive impairment. The potential impact of comorbidities and medications associated with vitamin B12 derangements were also investigated. In addition, we reviewed the evidence as to whether vitamin B12 therapy is efficacious for cognitive impairment and dementia., Methods: A systematic literature search identified 43 studies investigating the association of vitamin B12 and cognitive impairment or dementia. Seventeen studies reported on the efficacy of vitamin B12 therapy for these conditions., Results: Vitamin B12 levels in the subclinical low-normal range (<250 ρmol/L) are associated with Alzheimer's disease, vascular dementia, and Parkinson's disease. Vegetarianism and metformin use contribute to depressed vitamin B12 levels and may independently increase the risk for cognitive impairment. Vitamin B12 deficiency (<150 ρmol/L) is associated with cognitive impairment. Vitamin B12 supplements administered orally or parenterally at high dose (1 mg daily) were effective in correcting biochemical deficiency, but improved cognition only in patients with pre-existing vitamin B12 deficiency (serum vitamin B12 levels <150 ρmol/L or serum homocysteine levels >19.9 μmol/L)., Conclusion: Low serum vitamin B12 levels are associated with neurodegenerative disease and cognitive impairment. There is a small subset of dementias that are reversible with vitamin B12 therapy and this treatment is inexpensive and safe. Vitamin B12 therapy does not improve cognition in patients without pre-existing deficiency. There is a need for large, well-resourced clinical trials to close the gaps in our current understanding of the nature of the associations of vitamin B12 insufficiency and neurodegenerative disease.

The aim of this study was to validate the CogState Brief Battery, which assesses psychomotor, attentional, working memory, and visual learning functions, in healthy older people and in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD), enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. In healthy older adults, weak relationships between demographic variables (e.g., education, depression) and cognitive performance were observed. In AD and MCI groups, the magnitude of impairment was greatest for tasks of working memory and memory, with a negative influence of apolipoprotein E ϵ4 status on learning but not working memory. These results suggest that the CogState Brief Battery can be used to screen for AD-related cognitive changes.

The 'preclinical' phase of Alzheimer's disease is a future target for treatment, but additional research is essential to understand the relationship between β-amyloid burden and cognition during this time. We investigated this relationship using a large sample of apparently healthy older adults (N=177), which also enabled examination of whether the relationship differed according to age, gender, years of education, apolipoprotein E status, and the presence of subjective memory complaints. In addition to episodic memory, a range of cognitive measures (global cognition, semantic memory, visuospatial performance, and executive function) were examined. Participants were aged over 60 years with no objective cognitive impairment and came from the imaging arm of the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study of ageing. (11)C-PiB PET was used to measure β-amyloid burden and a PiB 'cut-off' level of 1.5 was used to separate participants with low PiB retention from those with high PiB retention. Thirty-three percent of participants had a PiB positive scan. PiB positive participants were 5 years older, twice as likely to carry an apolipoprotein E ɛ4 allele, and their composite episodic memory was 0.26 SD worse than PiB negative volunteers. Linear regressions with β-amyloid burden as a dichotomous predictor, revealed an interaction between β-amyloid burden and gender, as well as age and education effects, in predicting episodic memory and visuospatial performance. In females, but not in males, increased β-amyloid was related to worse episodic memory and visuospatial performance. Furthermore, an interaction between β-amyloid burden and APOE status was found in predicting visuospatial performance, whereby there was a trend for increased β-amyloid to relate to worse visuospatial performance for those without an APOE ɛ4 allele. There were no other main or interaction effects of β-amyloid on any of the other composite cognitive measures. These cross-sectional findings suggest that β-amyloid burden does not have a large effect on cognition in this subset of apparently healthy older people. The finding of gender differences deserves further research to answer definitively the important question of gender susceptibility to adverse cognitive effects from β-amyloid., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: The prevalence of preexisting cognitive impairment (PreCI) is documented before cardiac surgery, but there is less information before noncardiac surgery. In addition, the prevalence of mild cognitive impairment, defined by different cognitive criteria and subjective complaints, and which may progress to Alzheimer disease, is unknown in these subjects. Because anesthesia and surgery have been implicated in Alzheimer disease pathology, we prospectively measured PreCI and mild cognitive impairment in subjects scheduled for total hip joint replacement surgery in an observational study., Methods: One hundred fifty-two subjects 60 y of age and older who were scheduled for total hip joint replacement surgery underwent assessment, including neuropsychologic testing, 1 week before surgery. Test results were compared with published norms. PreCI was defined as impairment in two or more of seven cognitive tests, for which impairment in an individual test was defined as ≥ 2 SD below norms for that test. Amnestic mild cognitive impairment (aMCI) was defined as impairment ≥1.5 SD below norms for results of the immediate and/or delayed Auditory Verbal Learning Test plus a subjective complaint., Results: Subjects performed worse compared with normative data on five of seven neuropsychologic tests. Thirty (20% [95% CI, 13-26%]) subjects were classified as having PreCI. Thirty-four (22% [95% CI, 16-29%]) were classified as having aMCI. Ten (7%) subjects were classified as having both PreCI and aMCI, representing 33% of the 30 subjects with PreCI., Conclusions: The prevalence of aMCI in subjects scheduled for total hip joint replacement surgery is similar to that in the general community. PreCI and aMCI tend to identify different subjects. Because aMCI is known to progress to Alzheimer disease, future studies that track cognition before and after anesthesia and surgery should document the presence or absence of aMCI so that the rate of conversion to Alzheimer disease after anesthesia and surgery can be compared with the rate in the nonsurgical population.

Objective: There is mounting evidence for the contribution of apoE to the pathophysiology of Alzheimer disease (AD). Studies also indicate that plasma apoE levels may reflect disease status, suggesting that apoE is a potential AD biomarker. However, while some studies of apoE levels in plasma have presented correlations with AD pathology, others have not. Thus, there is a lack of consensus as to the suitability of plasma apoE as an AD biomarker. The major objective of this cross-sectional study was to investigate total plasma apoE as well as levels of the apoE4 form in a large, highly characterized cohort which included both healthy controls and participants with early-stage AD., Methods: Total apoE and apoE4 were measured in 1,079 individuals drawn from the highly characterized Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Total and isoform-specific plasma apoE levels were then compared with cerebral Aβ load, as assessed by PET using Pittsburgh compound B (PiB)., Results: Total apoE and apoE4 levels were found to be significantly lower in patients with AD in the entire cohort, and decrease with Aβ load in the PiB-PET subset. ApoE levels were significantly lower among ε4 homozygous individuals. In APOE ε3/ε4 heterozygote carriers, apoE4 levels decrease, indicating that apoE3 levels increase with disease., Conclusion: Analysis of cross-sectional data from the AIBL study indicates that plasma apoE levels are altered in AD and correlate with AD pathology level. The significance of these findings will be determined in the AIBL longitudinal study of aging., (© 2011 by AAN Enterprises, Inc.)

A decline in cognition greater than expected with ageing and accompanied by subjective cognitive concerns or functional changes may be indicative of a dementing disorder. The capacity to correctly identify cognitive decline relies on comparisons with normative data from a suitably matched healthy reference group with relatively homogeneous demographic features. Formal assessment of cognition is usually performed by specialist neuropsychologists trained in administration and interpretation of psychometric tests. With a scarcity of normative data from large cohorts of older adults, Australian neuropsychologists commonly use representative data from small international studies. Data from 727 healthy older Australians participating in the Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing have been used to create a normative dataset. A web-based calculator was developed to simplify the time-consuming process of comparing cognitive performance scores with these representative data.

Objective: Assess Aβ deposition longitudinally and explore its relationship with cognition and disease progression., Methods: Clinical follow-up was obtained 20 ± 3 months after [¹¹C]Pittsburgh compound B (PiB)-positron emission tomography in 206 subjects: 35 with dementia of the Alzheimer type (DAT), 65 with mild cognitive impairment (MCI), and 106 age-matched healthy controls (HCs). A second PiB scan was obtained at follow-up in 185 subjects and a third scan after 3 years in 57., Results: At baseline, 97% of DAT, 69% of MCI, and 31% of HC subjects showed high PiB retention. At 20-month follow-up, small but significant increases in PiB standardized uptake value ratios were observed in the DAT and MCI groups, and in HCs with high PiB retention at baseline (5.7%, 2.1%, and 1.5%, respectively). Increases were associated with the number of apolipoprotein E ε4 alleles. There was a weak correlation between PiB increases and decline in cognition when all groups were combined. Progression to DAT occurred in 67% of MCI with high PiB versus 5% of those with low PiB, but 20% of the low PiB MCI subjects progressed to other dementias. Of the high PiB HCs, 16% developed MCI or DAT by 20 months and 25% by 3 years. One low PiB HC developed MCI., Interpretation: Aβ deposition increases slowly from cognitive normality to moderate severity DAT. Extensive Aβ deposition precedes cognitive impairment, and is associated with ApoE genotype and a higher risk of cognitive decline in HCs and progression from MCI to DAT over 1 to 2 years. However, cognitive decline is only weakly related to change in Aβ burden, suggesting that downstream factors have a more direct effect on symptom progression., (Copyright © 2010 American Neurological Association.)

Background/aims: The nature and extent of adverse cognitive effects due to the prescription of anticholinergic drugs in older people with and without dementia is unclear., Methods: We calculated the anticholinergic load (ACL) of medications taken by participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing, a cohort of 211 Alzheimer's disease (AD) patients, 133 mild cognitive impairment (MCI) patients and 768 healthy controls (HC) all aged over 60 years. The association between ACL and cognitive function was examined for each diagnostic group (HC, MCI, AD)., Results: A high ACL within the HC group was associated with significantly slower response speeds for the Stroop color and incongruent trials. No other significant relationships between ACL and cognition were noted., Conclusion: In this large cohort, prescribed anticholinergic drugs appeared to have modest effects upon psychomotor speed and executive function, but not on other areas of cognition in healthy older adults., (Copyright © 2011 S. Karger AG, Basel.)

Background: The Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging aimed to recruit 1000 individuals aged over 60 to assist with prospective research into Alzheimer's disease (AD). This paper describes the recruitment of the cohort and gives information about the study methodology, baseline demography, diagnoses, medical comorbidities, medication use, and cognitive function of the participants., Methods: Volunteers underwent a screening interview, had comprehensive cognitive testing, gave 80 ml of blood, and completed health and lifestyle questionnaires. One quarter of the sample also underwent amyloid PET brain imaging with Pittsburgh compound B (PiB PET) and MRI brain imaging, and a subgroup of 10% had ActiGraph activity monitoring and body composition scanning., Results: A total of 1166 volunteers were recruited, 54 of whom were excluded from further study due to comorbid disorders which could affect cognition or because of withdrawal of consent. Participants with AD (211) had neuropsychological profiles which were consistent with AD, and were more impaired than participants with mild cognitive impairment (133) or healthy controls (768), who performed within expected norms for age on neuropsychological testing. PiB PET scans were performed on 287 participants, 100 had DEXA scans and 91 participated in ActiGraph monitoring., Conclusion: The participants comprising the AIBL cohort represent a group of highly motivated and well-characterized individuals who represent a unique resource for the study of AD. They will be reassessed at 18-month intervals in order to determine the predictive utility of various biomarkers, cognitive parameters and lifestyle factors as indicators of AD, and as predictors of future cognitive decline.

Beta-amyloid (Abeta) deposition is one of the neuropathological hallmarks of Alzheimer's disease (AD), Abeta burden can be quantified using (11)C PiB PET. Neuropathological studies have shown that the initial plaques are located in the temporal and orbitofrontal cortices, extending later to the cingulate, frontal and parietal cortices (Braak and Braak, 1997). Previous studies have shown an overlap in (11)C PiB PET retention between AD, mild cognitive impairment (MCI) patients and normal elderly control (NC) participants. It has also been shown that there is a relationship between Abeta deposition and memory impairment in MCI patients. In this paper we explored the variability seen in 15 AD, 15 MCI and 18 NC by modeling the voxel data from spatially and uptake normalized PiB images using principal component analysis. The first two principal components accounted for 80% of the variability seen in the data, providing a clear separation between AD and NC, and allowing subsequent classification. The MCI cases were distributed along an apparent axis between the AD and NC group, closely aligned with the first principal component axis. The NC cases that were PiB(+) formed a distinct cluster that was between, but separated from the AD and PiB(-) NC clusters. The PiB(+) MCI were found to cluster with the AD cases, and exhibited a similar deposition pattern. The primary principal component score was found to correlate with episodic memory scores and mini mental status examination and it was observed that by varying the first principal component, a change in amyloid deposition could be derived that is similar to the expected progression of amyloid deposition observed from post mortem studies.

The role of working memory, specifically the episodic buffer, in the learning performance of patients with very mild (n = 18) and mild (n = 12) Alzheimer's disease as compared with healthy older adults (n = 29) was investigated using a series of word-lists that were manipulated (clustered, unclustered) to explore the impact of strategic organizational skills under varying attention conditions (full, divided). Results indicated that the learning performance for all three groups under full attention was better than that under divided attention, but only for the clustered word-lists. Moreover, in contrast to the mild Alzheimer's disease group, both the healthy older controls and the very mild Alzheimer's disease group demonstrated better performance on clustered word-lists than on unclustered lists, suggesting active strategic organizational skills, even at delayed free recall. The overall pattern of results indicates a staging of working-memory impairment in early Alzheimer's disease.

Objectives: To investigate whether the presence of hippocampal atrophy (HCA) on MRI in Alzheimer's disease (AD) leads to a more rapid decline in cognitive function. To investigate whether cognitively unimpaired controls and depressed subjects with HCA are at higher risk than those without HCA of developing dementia., Design: A prospective follow-up of subjects from a previously reported MRI study., Setting: Melbourne, Australia., Participants: Five controls with HCA and five age-matched controls without HCA, seven depressed subjects with HCA and seven without HCA, and 12 subjects with clinically diagnosed probable AD with HCA and 12 without HCA were studied. They were followed up at approximately 2 years with repeat cognitive testing, blind to initial diagnosis and MRI result., Measures: HCA was rated by two radiologists blind to cognitive test score results. Cognitive assessment was by the Cambridge Cognitive Examination (CAMCOG)., Results: No significant differences in rate of cognitive decline, mortality or progression to dementia were found between subjects with or without HCA., Conclusions: HCA was not found to be a predictor of subsequent cognitive decline in this series.

The aim of this study was to determine the effect cognitive impairment has on direct and indirect costs to elderly people, their carers and the community over one year, by following prospectively a cohort of elderly people referred to an aged care assessment team. The 78 subjects were drawn from a random sample of people referred to the NorthWest Hospital team, and validated tools were used to assess their cognitive state. Outcome measures included total costs of community services, residential care, hospital bed use, carer burden and psychological morbidity. A comparison of outcome measures was made between those with cognitive impairment and those without. Use of community services and hospital beds was high overall. Those with cognitive impairment were substantially greater users of residential care, accounting for the higher expenditure in this group. Psychological morbidity and burden remain high in carers of those with cognitive impairment despite a high rate of institutionalisation in this group. The total costs for those referred to aged care assessment teams with cognitive impairment are double those seen for those with normal cognition.

Background: To investigate an association between HPA axis dysfunction, depression and cognitive impairment, we assessed subjects with mild Alzheimer's disease (AD).Method: Sixteen non-depressed subjects with AD according to NINCDS/ADRDA criteria and 18 normal controls underwent the insulin hypoglycaemia (IH) test and the dexamethasone suppression test (DST).Results: The AD subjects showed a blunted response of adrenocorticotrophic hormone (ACTH) to IH compared with controls (P = 0.019). ACTH response (area under curve) correlated with a score for cognitive ability (CAMCOG) (r = 0.64, P < 0.01). AD subjects had a shorter time to peak cortisol level than controls (P = 0.004), although total cortisol response was normal.Conclusions: The AD subjects show evidence of adrenal hyper-responsiveness and normal immediate (rate-sensitive) glucocorticoid feedback. An association between HPA axis dysfunction and organic brain pathology in AD subjects may be mediated by cell loss in the hippocampus. [ABSTRACT FROM AUTHOR]