ORCID Profile
0000-0002-0308-5156
Current Organisation
Monash University
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Pattern Recognition and Data Mining | Psychology | Computer-Human Interaction | Developmental Psychology and Ageing
Expanding Knowledge in Psychology and Cognitive Sciences | Expanding Knowledge in the Medical and Health Sciences | Expanding Knowledge in Technology |
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.BPSC.2016.08.006
Abstract: Hypothalamic-pituitary-adrenal axis dysregulation, which is typically assessed by measuring cortisol levels, is associated with cognitive dysfunction, hippoc al atrophy, and increased risk for mild cognitive impairment and Alzheimer's disease (AD). However, little is known about the role of hypothalamic-pituitary-adrenal axis dysregulation in moderating the effect of high levels of amyloid-β (Aβ+) on cognitive decline in the preclinical phase of AD, which is often protracted, and thus offers opportunities for prevention and early intervention. Using data from a 6-year multicenter prospective cohort study, we evaluated the relation between Aβ level, plasma cortisol level, and cognitive decline in 416 cognitively normal older adults. Results revealed that Aβ+ older adults experienced faster decline than Aβ- older adults in all cognitive domains (Cohen's d at 6-year assessment = 0.37-0.65). They further indicated a significant interaction between Aβ and cortisol levels for global cognition (d = 0.32), episodic memory (d = 0.50), and executive function (d = 0.59) scores, with Aβ+ older adults with high cortisol levels having significantly faster decline in these domains compared with Aβ+ older adults with low cortisol levels. These effects were independent of age, sex, APOE genotype, anxiety symptoms, and radiotracer type. In cognitively healthy older adults, Aβ+ is associated with greater cognitive decline and high plasma cortisol levels may accelerate the effect of Aβ+ on decline in global cognition, episodic memory, and executive function. These results suggest that therapies targeted toward lowering plasma cortisol and Aβ levels may be helpful in mitigating cognitive decline in the preclinical phase of AD.
Publisher: Oxford University Press (OUP)
Date: 03-04-2013
Abstract: Large prospective studies of Alzheimer's disease (AD) have sought to understand the pathological evolution of AD and factors that may influence the rate of disease progression. Estimates of rates of cognitive change are available for 12 or 24 months, but not for shorter time frames (e.g., 3 or 6 months). Most clinical drug trials seeking to reduce or modify AD symptoms have been conducted over 12- or 24-week periods. As such, we aimed to characterize the performance of a group of healthy older adults, adults with amnestic mild cognitive impairment (aMCI), and adults with AD on the CogState battery of tests over short test-retest intervals. This study recruited 105 healthy older adults, 48 adults with aMCI, and 42 adults with AD from the Australian Imaging, Biomarkers, and Lifestyle study and administered the CogState battery monthly over 3 months. The CogState battery of tests showed high test-retest reliability and stability in all clinical groups when participants were assessed over 3 months. When considered at baseline, the CogState battery of tests was able to detect AD-related cognitive impairment. The data provide important estimates of the reliability, stability, and variability of each cognitive test in healthy older adults, adults with aMCI, and adults with AD. This may potentially be used to inform future estimates of cognitive change in clinical trials.
Publisher: Wiley
Date: 15-10-2019
DOI: 10.1111/AJAG.12725
Abstract: To explore the perceived acceptability of the Volunteer Dementia and Delirium Care (VDDC)© program components from the perspective of key stakeholders in a metropolitan health network. A mixed-methods design was used. Surveys (nurses) and focus groups and interviews (hospital staff, volunteers, patients and caregivers) were conducted simultaneously. Descriptive statistics were used to profile the survey responses. The framework method was used to analyse the qualitative data. The majority of nurses identified that it is acceptable for volunteers to read to, and converse and play games with patients. Hospital staff perceived risk in volunteers assisting with feeding and mobilisation. Overall participants believed the VDDC was acceptable and would be of benefit to the patients. Key stakeholders have a favourable view of the VDDC© program. Strategies can be developed to address the identified issues, and components of the program may be amended to ensure that implementation is acceptable.
Publisher: Oxford University Press (OUP)
Date: 10-2019
Abstract: To prospectively examine 8-year risk of clinical disease progression to mild cognitive impairment (MCI)/dementia in older adults ≥60 with superior episodic memory (SuperAgers) compared to those cognitively normal for their age (CNFA). Additionally, to determine the extent to which SuperAgers were resilient to the negative effects of elevated amyloid-beta (Aβ+) on cognition. Participants were classified as SuperAgers based on episodic memory performance consistent with younger adults aged 30–44 and no impairment on non-memory tests (n = 179), and were matched with CNFA on age, sex, education, and follow-up time (n = 179). Subdistribution hazard models examined risk of clinical progression to MCI/dementia. Linear mixed models assessed the effect of Aβ on cognition over time. Prevalence of Aβ+ and APOE ε4 was equivalent between SuperAgers and CNFA. SuperAgers had 69%–73% reduced risk of clinical progression to MCI/dementia compared to CNFA (HR: 0.27–0.31, 95% CI: 0.11–0.73, p & .001). Aβ+ was associated with cognitive decline in verbal memory and executive function, regardless of SuperAger/CNFA classification. In the absence of Aβ+, equivalent age-related changes in cognition were observed between SuperAgers and CNFA. SuperAgers displayed resilience against clinical progression to MCI/dementia compared to CNFA despite equivalent risk for Alzheimer’s disease (AD) however, SuperAgers had no greater protection from Aβ+ than CNFA. The deleterious effects of Aβ on cognition persist regardless of baseline cognitive ability. Thus, superior cognitive performance does not reflect resistance against the neuropathological processes associated with AD, and the observed resilience for SuperAgers may instead reflect neuropsychological criteria for cognitive impairment.
Publisher: Wiley
Date: 06-11-2019
DOI: 10.1111/AJAG.12726
Abstract: To explore the perceived barriers and enablers to the implementation of the Volunteer Dementia and Delirium Focus groups and interviews with hospital staff, volunteers, patients and caregivers. Deductive analysis was conducted for the Behaviour Change Wheel (COM-B) domains, and inductive thematic analysis for emerging themes. Utilising the skills and knowledge of volunteers, making the program available to all patients, and recognising that volunteers will improve the care experience for patients were identified as enablers. Threats to volunteer safety, difficulty in defining roles and responsibilities of volunteers, volunteer attrition and availability and supervision of volunteers were perceived as barriers to implementation. To enhance the implementation of the program into a metropolitan setting, strategies addressing the identified barriers and enablers need to be developed.
Publisher: Wiley
Date: 02-10-2012
DOI: 10.1002/HUP.2263
Abstract: Alprazolam is a benzodiazepine that, when administered acutely, results in impairments in several aspects of cognition, including attention, learning, and memory. However, the profile (i.e., component processes) that underlie alprazolam-related decrements in visual paired associate learning has not been fully explored. In this double-blind, placebo-controlled, randomized cross-over study of healthy older adults, we used a novel, "process-based" computerized measure of visual paired associate learning to examine the effect of a single, acute 1-mg dose of alprazolam on component processes of visual paired associate learning and memory. Acute alprazolam challenge was associated with a large magnitude reduction in visual paired associate learning and memory performance (d = 1.05). Process-based analyses revealed significant increases in distractor, exploratory, between-search, and within-search error types. Analyses of percentages of each error type suggested that, relative to placebo, alprazolam challenge resulted in a decrease in the percentage of exploratory errors and an increase in the percentage of distractor errors, both of which reflect memory processes. Results of this study suggest that acute alprazolam challenge decreases visual paired associate learning and memory performance by reducing the strength of the association between pattern and location, which may reflect a general breakdown in memory consolidation, with less evidence of reductions in executive processes (e.g., working memory) that facilitate visual paired associate learning and memory.
Publisher: Wiley
Date: 11-02-2020
DOI: 10.1002/ALZ.12032
Publisher: Cambridge University Press (CUP)
Date: 18-07-2013
DOI: 10.1017/S1041610213001087
Abstract: To date evidence of the relationship between cognition and Aβ amyloid during the early stages of Alzheimer's Disease (AD) has been inconsistent. This study aimed to describe the nature and magnitude of the relationship between Aβ amyloid and cognitive performance of in iduals without dementia. Composite cognitive measures were developed from the Australian Imaging Biomarkers and Lifestyle study neuropsychological test battery using data from 768 healthy older adults and 133 adults with mild cognitive impairment (MCI). A subgroup of this s le (174 healthy, 53 MCI) underwent neuroimaging for Aβ amyloid. Within the MCI group in iduals with high Aβ amyloid showed selective impairment for memory compared with those with low Aβ amyloid however, this difference was not evident in the healthy group. The current findings provide further evidence of the relationship between Aβ amyloid and cognition, with memory impairment being the primary symptom of the underlying disease during the prodromal phases of AD.
Publisher: Wiley
Date: 12-12-2015
Publisher: Wiley
Date: 30-12-2015
DOI: 10.1016/J.JALZ.2015.09.005
Abstract: Three (18)F-labeled radiopharmaceuticals have been Food and Drug Administration-approved for the identification of cortical amyloidosis in clinical settings. Although there has been strong debate among professionals as to the ethical and social consequences of disclosing such information, increasing numbers of participants are being recruited into secondary prevention trials for which they are likely to, and/or desire to, receive their positron emission tomography (PET) imaging results. Healthy older adults (n = 63, mean age = 62 years) enrolled in a preclinical Alzheimer's disease (AD) biomarkers trial, and 11 requested disclosure of PET amyloid imaging results to their treating neurologist, per institutional review board-approved study protocol. These in iduals completed a follow-up psychoeducational program and structured interviews to assess impact of disclosure on several key psychological factors. Four of 11 subjects demonstrated increased amyloid aggregation and reported that they were not surprised, particularly given their family histories and subjective memory concerns. All indicated that they had shared this information with pertinent significant others they were satisfied with their level of social support, and the imaging results had motivated them to change their lifestyle by exercising more, changing their diet, and planning ahead. Amyloid-positive participants showed little change in levels of depressive, anxiety, and stress symptoms, subjective sense of memory impairment, or on measures of intrusion, avoidance, and hyperarousal, and reported risk of self-harm. Disclosure of PET amyloid status did not significantly impact mood, subjective sense of memory impairment, or perceived risk of developing AD nor was this associated with significant emotional impact, irrespective of actual amyloid burden status. Those subjects with increased amyloid burden were more likely than those without significant amyloidosis to make positive changes to their lifestyle (e.g., engaging in more exercise and changing their diet).
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.NEUROBIOLAGING.2018.06.005
Abstract: Cognitive decline is considered an inevitable consequence of aging however, estimates of cognitive aging may be influenced negatively by undetected preclinical Alzheimer's disease (AD). This study aimed to determine the extent to which estimates of cognitive aging were biased by preclinical AD. Cognitively normal older adults (n = 494) with amyloid-β status determined from positron emission tomography neuroimaging underwent serial neuropsychological assessment at 18-month intervals over 72 months. Estimates of the effects of age on verbal memory, working memory, executive function, and processing speed were derived using linear mixed models. The presence of preclinical AD and clinical progression to mild cognitive impairment or dementia during the study were then added to these models as covariates. Initially, age was associated with decline across all 4 cognitive domains. With the effects of elevated amyloid-β and clinical progression controlled, age was no longer associated with decline in verbal or working memory. However, the magnitude of decline was reduced only slightly for executive function and was unchanged for processing speed. Thus, considered together, the results of the study indicate that undetected preclinical AD negatively biases estimates of age-related cognitive decline for verbal and working memory.
Publisher: American Psychological Association (APA)
Date: 07-2023
DOI: 10.1037/NEU0000900
Publisher: Informa UK Limited
Date: 29-03-2019
Publisher: American Psychological Association (APA)
Date: 05-2013
DOI: 10.1037/A0032321
Abstract: It has been proposed that only mild cognitive impairment (MCI) with high Aβ amyloid is indicative of incipient Alzheimer's disease (AD), yet MCI with low Aβ amyloid may reflect other neurodegenerative processes. We aimed to determine the extent to which high Aβ amyloid influenced cognitive function in healthy older adults and adults with MCI. Healthy controls (HC n = 178) and adults with MCI (n = 56) enrolled in the Australian Imaging, Biomarkers, and Lifestyle study, underwent positron emission tomography neuroimaging for Aβ amyloid and completed an extensive neuropsychological battery, assessing the cognitive domains of verbal and visual episodic memory, executive function, visuoconstruction, attention and processing speed, and language at baseline. MCI with low Aβ performed worse than MCI with high Aβ on measures of executive function, attention, visuoconstruction and language. No differences were observed between HC high and low Aβ groups. When compared with HC with low Aβ, both MCI high and low Aβ groups performed worse on measures of episodic memory. However, only the MCI low Aβ group performed worse than HC low Aβ on measures of executive function, attention, visuoconstruction, and language. When compared with HC with low Aβ amyloid, MCI with high Aβ amyloid present with impairments restricted to episodic memory, and the episodic memory impairments in MCI with low Aβ amyloid were accompanied by impairments in executive function, attention, visuoconstruction, and language, suggesting that MCI with high Aβ amyloid reflects prodromal AD, although further longitudinal data is required to confirm this.
Publisher: American Medical Association (AMA)
Date: 03-2015
DOI: 10.1001/JAMAPSYCHIATRY.2014.2476
Abstract: Alzheimer disease (AD) is now known to have a long preclinical phase in which pathophysiologic processes develop many years, even decades, before the onset of clinical symptoms. Although the presence of abnormal levels of amyloid-β (Aβ) is associated with higher rates of progression to clinically classified mild cognitive impairment or dementia, little research has evaluated potentially modifiable moderators of Aβ-related cognitive decline, such as anxiety and depressive symptoms. To evaluate the association between Aβ status and cognitive changes, and the role of anxiety and depressive symptoms in moderating Aβ-related cognitive changes in the preclinical phase of AD. In this multicenter, prospective cohort study with baseline and 18-, 36-, and 54-month follow-up assessments, we studied 333 healthy, older adults at hospital-based research clinics. Carbon 11-labeled Pittsburgh Compound B (PiB)-, florbetapir F 18-, or flutemetamol F 18-derived measures of Aβ, Hospital Anxiety and Depression Scale scores, and comprehensive neuropsychological evaluation that yielded measures of global cognition, verbal memory, visual memory, attention, language, executive function, and visuospatial ability. A positive Aβ (Aβ+) status at baseline was associated with a significant decline in global cognition, verbal memory, language, and executive function, and elevated anxiety symptoms moderated these associations. Compared with the Aβ+, low-anxiety group, slopes of cognitive decline were significantly more pronounced in the Aβ+, high-anxiety group, with Cohen d values of 0.78 (95% CI, 0.33-1.23) for global cognition, 0.54 (95% CI, 0.10-0.98) for verbal memory, 0.51 (95% CI, 0.07-0.96) for language, and 0.39 (95% CI, 0.05-0.83) for executive function. These effects were independent of age, educational level, IQ, APOE genotype, subjective memory complaints, vascular risk factors, and depressive symptoms furthermore, depressive symptoms and subjective memory complaints did not moderate the association between Aβ and cognitive decline. These results provide additional support for the deleterious effect of elevated Aβ levels on cognitive function in preclinical AD. They further suggest that elevated anxiety symptoms moderate the effect of Aβ on cognitive decline in preclinical AD, resulting in more rapid decline in several cognitive domains. Given that there is currently no standard antiamyloid therapy and that anxiety symptoms are amenable to treatment, these findings may help inform risk stratification and management of the preclinical phase of AD.
Publisher: Springer Science and Business Media LLC
Date: 02-12-2022
DOI: 10.1007/S11065-022-09567-Y
Abstract: Psychological stress is a potential modifiable risk factor for cognitive decline. However, the extent to which self-reported psychological stress is differentially associated with decline in specific cognitive domains remains unclear. Differences may be due to heterogeneity in the aspects of psychological stress investigated, for ex le, neuroticism (which is linked to vulnerability to stress), perceived stress, or exposure to stressful life events. This review aims to establish the associations between these aspects of self-reported psychological stress and cognitive decline. PsychINFO, Embase and MEDLINE were searched from database inception to September 2021. Studies were included if they were observational, prospective, and if they investigated the association between self-reported psychological stress and cognitive decline in adults with a minimum mean age of 40 years at baseline. Thirty studies satisfied the inclusion criteria, with most examining neuroticism (n = 17) as a predictor of cognitive decline. Fewer examined perceived stress (n = 7) or stressful life events (n = 6). There was evidence of an association between neuroticism and cognitive decline, particularly in the domain of memory. Similarly, across studies, perceived stress was also associated with memory decline. Research investigating the relationship between stressful life events and cognitive decline had fewer outcomes to interpret. Overall, the findings highlight that memory may be particularly susceptible to high levels of neuroticism and perceived stress. We identified a lack of research into some cognitive domains, such as executive function, which should be addressed by future studies.
Publisher: Springer Science and Business Media LLC
Date: 09-2016
DOI: 10.1007/S12031-016-0822-8
Abstract: In a group of older adults with very mild dementia, we aimed to characterize the nature and magnitude of cognitive decline as measured by the Cogstate Brief Battery, in relation to Aβ levels and hippoc al volume. Participants were characterized according to their status on the Clinical Dementia Rating (CDR) scale. A total of 308 in iduals who were CDR 0 and had low cerebral Aβ levels (Aβ-), 32 in iduals who were Aβ- and CDR 0.5, and 43 in iduals who were Aβ+ and CDR 0.5 were included in this study. Participants completed the CogState brief battery at baseline, and at 18-, 36-, 54- and 72-month follow-up. Linear mixed model analyses indicated that relative to the Aβ- CDR 0 group, the Aβ+ CDR 0.5 group showed increased rates of memory decline and hippoc al volume loss. However, compared to the Aβ- CDR 0 group, the Aβ- CDR 0.5 group showed no changes in cognitive function or hippoc al volume over 72 months. The results of this study confirm that in in iduals with very mild dementia, who also have biomarker confirmation of Aβ+, changes in cognitive function manifest primarily as deterioration in memory processing, and this is associated with hippoc al volume loss. Conversely, the absence of any cognitive decline or loss in hippoc al volume in in iduals with very mild dementia but who are Aβ- suggests that some other non-AD disease process may underlie any static impairment in cognitive function.
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.NEUROBIOLAGING.2015.07.009
Abstract: Disruption in cholinergic neurotransmission is one of the earliest neuropathological changes in preclinical Alzheimer's disease (AD) and may be associated with abnormal beta-amyloid (Aβ) accumulation. Therefore, disruption of cholinergic neurotransmission with scopolamine may unmask otherwise undetectable cognitive deficits in preclinical AD. To compare the effects of low-dose (0.20 mg s.c.) scopolamine on cognition between Aβ+ and Aβ- cognitively normal (CN) older adults using the Groton Maze Learning Test (GMLT). CN older adults completed the GMLT predose and then received scopolamine (0.20 mg) subcutaneously. Participants were reassessed 1-, 3-, 5-, 7-, and 8-hours post dose. All participants underwent positron emission tomography neuroimaging for Aβ using (18)F-florbetapir within 6 weeks of their baseline visit. Rhode Island Hospital Clinical Research Center, Providence, USA. CN older adults (n = 63), with a family history of AD and subjective memory complaints were enrolled (15 were classified as Aβ+ and 48 were classified as Aβ-). Cognition was assessed using the computerized GMLT at all predose and post-dose time points. At 5-hours post dose, the Aβ+ group performed significantly worse than the Aβ- group on all measures of learning efficiency and working memory and/or executive function (Cohen's d = 1.13-1.56). When participants were classified as having an abnormal response to scopolamine (based on change score at 5-hours post dose >0), 100% were correctly classified as Aβ+ and 67% as Aβ-. The results of this study suggest that diminished cholinergic tone likely occurs in preclinical AD, and as such, the use of a cholinergic stress test to perturb an already compromised neurotransmitter system may be an effective way of identifying CN older adults who are in this preclinical stage of AD.
Publisher: Springer Science and Business Media LLC
Date: 27-02-2019
Publisher: Springer Science and Business Media LLC
Date: 11-2009
Publisher: Cambridge University Press (CUP)
Date: 19-07-2017
DOI: 10.1017/S1041610217001284
Abstract: The brain-derived neurotrophic factor ( BDNF ) Val66Met polymorphism Met allele exacerbates amyloid (Aβ) related decline in episodic memory (EM) and hippoc al volume (HV) over 36–54 months in preclinical Alzheimer's disease (AD). However, the extent to which Aβ+ and BDNF Val66Met is related to circulating markers of BDNF (e.g. serum) is unknown. We aimed to determine the effect of Aβ and the BDNF Val66Met polymorphism on levels of serum mBDNF, EM, and HV at baseline and over 18-months. Non-demented older adults ( n = 446) underwent Aβ neuroimaging and BDNF Val66Met genotyping. EM and HV were assessed at baseline and 18 months later. Fasted blood s les were obtained from each participant at baseline and at 18-month follow-up. Aβ PET neuroimaging was used to classify participants as Aβ– or Aβ+. At baseline, Aβ+ adults showed worse EM impairment and lower serum mBDNF levels relative to Aβ- adults. BDNF Val66Met polymorphism did not affect serum mBDNF, EM, or HV at baseline. When considered over 18-months, compared to Aβ– Val homozygotes, Aβ+ Val homozygotes showed significant decline in EM and HV but not serum mBDNF. Similarly, compared to Aβ+ Val homozygotes, Aβ+ Met carriers showed significant decline in EM and HV over 18-months but showed no change in serum mBDNF. While allelic variation in BDNF Val66Met may influence Aβ+ related neurodegeneration and memory loss over the short term, this is not related to serum mBDNF. Longer follow-up intervals may be required to further determine any relationships between serum mBDNF, EM, and HV in preclinical AD.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-03-2016
Publisher: Springer Science and Business Media LLC
Date: 12-2013
Publisher: Oxford University Press (OUP)
Date: 02-12-2015
Abstract: We investigated the extent to which decline in memory and working memory in beta-amyloid (Aβ) positive non-demented in iduals was related to hippoc al atrophy and Aβ accumulation over 36 months. Cognitively normal older adults (CN) (n = 178) and adults with mild cognitive impairment (MCI) (n = 49) underwent positron emission tomography neuroimaging, magnetic resonance imaging, and cognitive assessments at baseline, 18- and 36-months. Relative to Aβ- CNs, Aβ+ CNs and Aβ+ MCIs showed greater rates of cognitive decline, Aβ accumulation, and hippoc al atrophy. Analysis of interrelationships between these Alzheimer's disease markers in Aβ+ CNs and MCIs indicated that rate of Aβ accumulation was associated with rate of hippoc al atrophy (β = -0.05, p = .037), which was in turn associated independently with rate of decline in memory (β = -0.03, p = .032). This suggests that Aβ accumulation precedes any neurodegeneration or clinical symptoms, and that the relationship between Aβ and cognitive decline is mediated by hippoc al atrophy.
Publisher: Public Library of Science (PLoS)
Date: 02-10-2015
Publisher: Wiley
Date: 06-01-2020
Publisher: Oxford University Press (OUP)
Date: 30-10-2014
DOI: 10.1093/BRAIN/AWT286
Abstract: High amyloid has been associated with substantial episodic memory decline over 18 and 36 months in healthy older adults and in iduals with mild cognitive impairment. However, the nature and magnitude of amyloid-related memory and non-memory change from the preclinical to the clinical stages of Alzheimer's disease has not been evaluated over the same time interval. Healthy older adults (n = 320), in iduals with mild cognitive impairment (n = 57) and in iduals with Alzheimer's disease (n = 36) enrolled in the Australian Imaging, Biomarkers and Lifestyle study underwent at least one positron emission tomography neuroimaging scan for amyloid. Cognitive assessments were conducted at baseline, and 18- and 36-month follow-up assessments. Compared with amyloid-negative healthy older adults, amyloid-positive healthy older adults, and amyloid-positive in iduals with mild cognitive impairment and Alzheimer's disease showed moderate and equivalent decline in verbal and visual episodic memory over 36 months (d's = 0.47-0.51). Relative to amyloid-negative healthy older adults, amyloid-positive healthy older adults showed no decline in non-memory functions, but amyloid-positive in iduals with mild cognitive impairment showed additional moderate decline in language, attention and visuospatial function (d's = 0.47-1.12), and amyloid-positive in iduals with Alzheimer's disease showed large decline in all aspects of memory and non-memory function (d's = 0.73-2.28). Amyloid negative in iduals with mild cognitive impairment did not show any cognitive decline over 36 months. When non-demented in iduals (i.e. healthy older adults and adults with mild cognitive impairment) were further dichotomized, high amyloid-positive non-demented in iduals showed a greater rate of decline in episodic memory and language when compared with low amyloid positive non-demented in iduals. Memory decline does not plateau with increasing disease severity, and decline in non-memory functions increases in amyloid-positive in iduals with mild cognitive impairment and Alzheimer's disease. The combined detection of amyloid positivity and objectively-defined decline in memory are reliable indicators of early Alzheimer's disease, and the detection of decline in non-memory functions in amyloid-positive in iduals with mild cognitive impairment may assist in determining the level of disease severity in these in iduals. Further, these results suggest that grouping amyloid data into at least two categories of abnormality may be useful in determining the disease risk level in non-demented in iduals.
Publisher: Wiley
Date: 03-2014
DOI: 10.1016/J.JALZ.2014.01.009
Abstract: Abnormal β-amyloid (Aβ) is associated with deleterious changes in central acetylcholinergic tone in the very early stages of Alzheimer's disease (AD), which may be unmasked by a cholinergic antagonist. We aimed to establish an optimal "microdose" of scopolamine for the development of a "cognitive stress test." Healthy older adults (n = 26, aged 55-75 years) with two risk factors for AD, but with low cortical Aβ burden, completed the Groton Maze Learning Test (GMLT) at baseline and then received scopolamine (0.20 mg subcutaneously). Participants were reassessed at 1, 3, 5, 7, and 8 hours postinjection. There were significant differences, of a moderate magnitude, in performance between baseline and 3 hours postinjection for total errors, rule break errors, and the GMLT composite (d ≈ 0.50) that were all unrelated to body mass. A very low dose of scopolamine leads to reliable cognitive impairment at 3 hours postdose (Tmax) and full cognitive recovery within 5 hours, supporting its use as a prognostic test paradigm to identify in iduals with potential preclinical AD. This paradigm is being implemented in a larger cohort of healthy adults, with high or low Aβ, to identify pharmacodynamic differences between groups.
Publisher: Springer Science and Business Media LLC
Date: 24-12-2022
Publisher: Public Library of Science (PLoS)
Date: 27-01-2014
Publisher: Elsevier BV
Date: 03-2015
DOI: 10.1016/J.NEUROBIOLAGING.2014.12.015
Abstract: Memory changes in preclinical Alzheimer's disease (AD) are often characterized by heterogenous trajectories. However, data regarding the nature and determinants of predominant trajectories of memory changes in preclinical AD are lacking. We analyzed data from 333 cognitively healthy older adults who participated in a multicenter prospective cohort study with baseline and 18-, 36-, and 54-month follow-up assessments. Latent growth mixture modeling revealed 3 predominant trajectories of memory change: a below average, subtly declining memory trajectory (30.9%) a below average, rapidly declining memory trajectory (3.6%) and an above average, stable memory trajectory (65.5%). Compared with the stable memory trajectory, high Αβ (relative risk ratio [RRR] = 2.1), and lower Mini-Mental State Examination (RRR = 0.6) and full-scale IQ (RRR = 0.9) scores were independently associated with the subtly declining memory trajectory and high Αβ (RRR = 8.3), APOE ε4 carriage (RRR = 6.1), and greater subjective memory impairment (RRR = 1.2) were independently associated with the rapidly declining memory trajectory. Compared with the subtly declining memory trajectory group, APOE ε4 carriage (RRR = 8.4), and subjective memory complaints (RRR = 1.2) were associated with a rapidly declining memory trajectory. These results suggest that the preclinical phase of AD may be characterized by 2 predominant trajectories of memory decline that have common (e.g., high Αβ) and unique (e.g., APOE ε4 genotype) determinants.
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.JAD.2017.12.101
Abstract: Relationships between depression and Alzheimer's disease (AD) may become clearer if studied in preclinical AD where dementia is not present. The aim of this study was to evaluate prospectively, relationships between brain amyloid-β (Aβ), depressive symptoms and screen positive depression in cognitively normal (CN) older adults. Depressive symptoms were measured with the Geriatric Depression Inventory (GDS-15) in CN adults from the Australian Imaging Biomarkers and Lifestyle (AIBL) study without depression at baseline and classified as having abnormally high (Aβ+ n = 136) or low (Aβ- n = 449) Aβ according to positron emission tomography at 18-month intervals over 72 months. Incident cases of screen positive depression were not increased in Aβ+ CN adults although small increases in overall depressive symptoms severity (d = - 0.25 95% CI, - 0.45, - 0.05) and apathy-anxiety symptoms (d = - 0.28 95% CI - 0.48, - 0.08) were. As the AIBL s le is an experimental s le, no in iduals had severe medical illnesses or significant psychiatric disorders. Additionally, in iduals who had evidence of screen-positive depression at screening were excluded from enrolment in the AIBL study. Thus, the current data can be considered only as providing a foundation for understanding relationships between Aβ and depression in preclinical AD. These results suggest that the presence of a depressive disorder or even increased depressive symptoms are themselves unlikely to be a direct consequence of increasing Aβ. New depressive disorders presenting in CN older adults could therefore be investigated for aetiologies beyond AD.
Publisher: Informa UK Limited
Date: 13-09-2019
Publisher: Royal College of Psychiatrists
Date: 05-2014
DOI: 10.1192/BJP.BP.113.134239
Abstract: Although beta-amyloid, anxiety and depression have been linked cross-sectionally to reduced memory function in healthy older adults without dementia, prospective data evaluating these associations are lacking. Using data from an observational cohort study of 178 healthy older adults without dementia followed for 3 years, we found that anxiety symptoms significantly moderated the relationship between beta-amyloid level and decline in verbal (Cohen's d = 0.65) and episodic (Cohen's d = 0.38) memory. Anxiety symptoms were additionally linked to greater decline in executive function, irrespective of beta-amyloid and other risk factors. These findings suggest that interventions to mitigate anxiety symptoms may help delay memory decline in otherwise healthy older adults with elevated beta-amyloid.
Publisher: Wiley
Date: 2020
DOI: 10.1002/ALZ.12010
Publisher: Oxford University Press (OUP)
Date: 23-12-2011
Abstract: The International Shopping List Test (ISLT) is a measure of verbal learning and memory, developed specifically for use in people from different cultural and linguistic backgrounds. In this report, we describe two studies that examined the ISLT's ability to detect memory impairment and memory decline in patients with mild Alzheimer's disease (AD) from a range of cultural and linguistic backgrounds. In Study 1, the performance of Australian-English-speaking adults with mild AD was compared with that of native Australian-English- and Korean-speaking patients with mild AD. Compared with controls, patients with AD from both language groups showed large but equivalent impairments in total recall, delayed recall, rate of learning, and primacy and retention-weighted recall (RWR) measures on the ISLT. In Study 2, the rate of deterioration in verbal memory over 1 year was examined in groups of native Canadian-English, French, and Korean speakers with mild AD using the total recall, delayed recall, and RWR measures. Rates of change on all three measures were equivalent across the language groups, although the magnitude of deterioration was most pronounced for the total recall and RWR measures. Taken together, these results suggest that the ISLT is valid and reliable for the assessment of verbal learning and memory impairment and decline in patients with mild AD from erse language groups.
Publisher: Informa UK Limited
Date: 04-2012
DOI: 10.1080/13803395.2011.643227
Abstract: 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.
Publisher: American Medical Association (AMA)
Date: 04-2018
Publisher: Wiley
Date: 03-03-2014
DOI: 10.1016/J.JALZ.2013.11.005
Abstract: High β-amyloid (Aβ) is associated with faster memory decline in healthy in iduals 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. 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. 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. In healthy in iduals, 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.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-08-2017
DOI: 10.1212/WNL.0000000000004336
Abstract: To clarify associations between APOE ε4 allele and age on longitudinal rates of β-amyloid (Aβ) accumulation within Aβ+ and Aβ− older in iduals without dementia. We analyzed 595 older adults without dementia classified cross-sectionally as Aβ− (n = 325) and Aβ+ (n = 270) using longitudinal florbetapir PET. The influence of age and APOE genotype on longitudinal accumulation of Aβ was examined with linear mixed models. APOE ε4 and older age were associated with higher risk of being classified as Aβ+ at baseline. The annual rate of Aβ accumulation was significantly greater than zero for Aβ− ε3 (0.0021 ± 0.0007 standardized uptake value ratio [SUVR] units) and Aβ− ε4 (0.0044 ± 0.0010 SUVR units), as well as Aβ+ ε3 (0.0141 ± 0.0019 SUVR units) and Aβ+ ε4 (0.0126 ± 0.0018 SUVR units). Aβ accumulation was significantly faster in Aβ− ε4 compared to Aβ− ε3 and Aβ− ε2. Rates of Aβ accumulation did not differ significantly between Aβ+ APOE groups. Older age was associated with higher rates of Aβ accumulation in the Aβ− group. APOE ε4 carriage and older age were predictors of longitudinal Aβ accumulation within the Aβ− group but not the Aβ+ group. APOE ε2 carriage was protective against longitudinal Aβ accumulation within the Aβ− group. APOE genotype in conjunction with chronologic age may aid in participant selection for primary prevention trials aimed at halting Aβ accumulation before abnormal levels are reached.
Publisher: Wiley
Date: 18-10-2016
Publisher: Wiley
Date: 2016
DOI: 10.1016/J.DADM.2016.09.001
Abstract: In patients with Alzheimer's disease (AD) and mild cognitive impairment, structural changes in the retina (i.e., reduced thicknesses of the ganglion cell and retinal nerve fiber layers and inclusion bodies that appear to contain beta‐amyloid protein [Ab]) have been previously reported. We sought to explore whether anatomic retinal changes are detectable in the preclinical stage of AD. A cross‐sectional study (as part of an ongoing longitudinal cohort study) involving 63 cognitively normal adults, all of whom have a parent with AD and subjective memory complaints. We compared neocortical amyloid aggregation (florbetapir PET imaging) to retinal spectral domain optical coherence tomography (SD‐OCT) markers of possible disease burden. Retinal biomarkers, including the number and surface area of retinal inclusion bodies and the thickness of retinal neuronal layers, were compared across groups with high vs. low neocortical beta‐amyloid load. The surface area of inclusion bodies increased as a function of cortical amyloid burden. Additionally, there was a trend toward a selective volume increase in the inner plexiform layer (IPL a layer rich in cholinergic activity) of the retina in Aβ+ relative to Aβ− participants, and IPL volume was correlated with the surface area of retinal inclusion bodies. These initial results suggest that retinal imaging may be a potential cost‐effective and noninvasive technique that can be used to identify those at‐risk for AD. Layer‐specific changes in the IPL and their association with surface area of inclusion bodies are discussed as a possible reflection of early inflammatory processes associated with cholinergic disruption and concurrent Ab accumulation in the neocortex.
Publisher: Wiley
Date: 26-06-2018
DOI: 10.1002/ANA.25246
Publisher: American Psychological Association (APA)
Date: 10-2019
DOI: 10.1037/NEU0000561
Abstract: Previous studies have shown that paired associate learning (PAL), a type of episodic memory, is impaired in early Alzheimer's disease (AD). Such tasks require that a set of associations (e.g., pattern-location) be learned over several trials, and the objective is to reduce errors with each trial. Currently, the nature and magnitude of impairment and decline on PAL measures in cognitively normal (CN) older adults with elevated levels of beta-amyloid (Aβ+) is unknown. This study examined PAL errors in Aβ+ and Aβ - CN older adults, both within a single assessment and over time. Participants (210 Aβ - CN, 146 Aβ + CN) from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study underwent three assessments over 36-months (baseline, and 18- and 36-month follow-ups) using a computerized paired associate learning task (CPAL). Aβ status was determined by positron emission tomography (PET) neuroimaging. No significant group differences in PAL were evident at baseline. Significant groupxtime interactions were observed, with the Aβ - CN group, but not the Aβ + CN group, evidencing improvement over time (Cohen's d = 0.30 [0.08, 0.51]). Despite this, no group differences were evident at 36-months. Results suggest that PAL dysfunction is evident over time in Aβ + CNs. This indicates a lack of benefit from repeated exposure to the task over time associated with Aβ+, which is not the case for Aβ - CNs. Further, results suggest that assessing change in Aβ+ related cognition over time, rather than at a single assessment, provides greater understanding of dysfunction in early AD. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
Publisher: SAGE Publications
Date: 20-11-2015
Abstract: Depression has been shown to be a risk factor for Alzheimer’s disease (AD), and in older adults may provide a marker for the beginning of the prodromal phase of AD. The purpose of this systematic review is to examine the relationship between amyloid-β (Aβ), a key biomarker of AD, and depression in older adults. The literature search was limited to studies conducted from 2006 to 2014 that were published in English in peer-reviewed journals. Studies were selected if they included a group of older adults who either met established criteria for Major Depressive Disorder or Dysthymia or were assessed for depressive symptoms on a standardised measure. Studies were also required to include an outcome variable that was a direct measure of Aβ levels in either blood or cerebrospinal fluid (CSF) s les, or via neuroimaging techniques such as positron emission tomography (PET). Nineteen studies were identified, 15 of which found significant differences in Aβ levels between depressed and non-depressed older adults. However, studies were limited by their cross-sectional design, reliance on blood-based measures of Aβ, and potential s le bias. Future investigations should consider prospective longitudinal design using neuroimaging and CSF measures of Aβ.
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1016/J.NEUROBIOLAGING.2017.01.013
Abstract: Few studies have examined the relationship between CSF and structural biomarkers, and cognitive function in MCI. We examined the relationship between cognitive function, hippoc al volume and cerebrospinal fluid (CSF) Aβ
Publisher: Oxford University Press (OUP)
Date: 12-08-2016
DOI: 10.1093/BRAIN/AWW200
Publisher: Oxford University Press (OUP)
Date: 24-07-2017
DOI: 10.1093/BRAIN/AWX137
Abstract: See Derry and Kent (doi:10.1093/awx167) for a scientific commentary on this article.The large variance in cognitive deterioration in subjects who test positive for amyloid-β by positron emission tomography indicates that convergent pathologies, such as iron accumulation, might combine with amyloid-β to accelerate Alzheimer's disease progression. Here, we applied quantitative susceptibility mapping, a relatively new magnetic resonance imaging method sensitive to tissue iron, to assess the relationship between iron, amyloid-β load, and cognitive decline in 117 subjects who underwent baseline magnetic resonance imaging and amyloid-β positron emission tomography from the Australian Imaging, Biomarkers and Lifestyle study (AIBL). Cognitive function data were collected every 18 months for up to 6 years from 100 volunteers who were either cognitively normal (n = 64) or diagnosed with mild cognitive impairment (n = 17) or Alzheimer's disease (n = 19). Among participants with amyloid pathology (n = 45), higher hippoc al quantitative susceptibility mapping levels predicted accelerated deterioration in composite cognition tests for episodic memory [β(standard error) = -0.169 (0.034), P = 9.2 × 10-7], executive function [β(standard error) = -0.139 (0.048), P = 0.004), and attention [β(standard error) = -0.074 (0.029), P = 0.012]. Deteriorating performance in a composite of language tests was predicted by higher quantitative susceptibility mapping levels in temporal lobe [β(standard error) = -0.104 (0.05), P = 0.036] and frontal lobe [β(standard error) = -0.154 (0.055), P = 0.006]. These findings indicate that brain iron might combine with amyloid-β to accelerate clinical progression and that quantitative susceptibility mapping could be used in combination with amyloid-β positron emission tomography to stratify in iduals at risk of decline.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-10-2012
Publisher: Informa UK Limited
Date: 10-2012
DOI: 10.1080/13803395.2012.689815
Abstract: There is a need for culture neutral neuropsychological instruments. The International Shopping List Test (ISLT) is sensitive to memory impairment in Alzheimer's disease (AD) in different cultural groups, although its sensitivity to mild cognitive impairment (MCI) and ability to be given repeatedly at short retest intervals is unknown. Performance on the ISLT was compared between groups of healthy adults, MCI, and AD from the Australian Imaging Biomarkers and Lifestyle study of ageing. Subjects were assessed four times in three months. In each group, the ISLT performance measures had high test-retest reliability, and group means remained stable over time. There was no difference between groups on within-subject variability. These data suggest that in English-speaking s les, the ISLT is sensitive to MCI and can be given repeatedly in order to assess change in memory.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-02-2022
DOI: 10.1212/WNL.0000000000200118
Abstract: This prospective study sought to determine the association of modifiable/nonmodifiable components included in the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) risk score with hippoc al volume (HV) loss and episodic memory (EM) decline in cognitively normal (CN) older adults classified as brain β-amyloid (Aβ) negative (Aβ−) or positive (Aβ+). Australian Imaging, Biomarkers and Lifestyle study participants (age 58–91 years) who completed ≥2 neuropsychological assessments and a brain Aβ PET scan (n = 592) were included in this study. We computed the CAIDE risk score (age, sex, APOE ε4 status, education, hypertension, body mass index [BMI], hypercholesterolemia, physical inactivity) and a modifiable CAIDE risk score (CAIDE-MR education, hypertension, BMI, hypercholesterolemia, physical inactivity) for each participant. Aβ+ was classified using Centiloid . Linear mixed models assessed interactions between each CAIDE score, Aβ group, and time on HV loss and EM decline. Age, sex, and APOE ε4 were included as separate predictors in CAIDE-MR models to assess differential associations. Exploratory analyses examined relationships between in idual modifiable risk factors and outcomes in Aβ− cognitively normal (CN) adults. We observed a significant Aβ group × CAIDE × time interaction on HV loss (β [SE] = –0.04 [0.01] p 0.000) but not EM decline (β [SE] = –2.33 [9.96] p = 0.98). Decomposition revealed a significant CAIDE × time interaction in Aβ+ participants only. When modifiable/nonmodifiable CAIDE components were considered separately, we observed a significant Aβ group × CAIDE-MR × time interaction on EM decline only (β [SE] = 3.03 [1.18] p = 0.01). A significant CAIDE-MR score × time interaction was observed in Aβ− participants only. Significant interactions between APOE ε4 and age × time on HV loss and EM decline were observed in both groups. Exploratory analyses in Aβ− CN participants revealed a significant interaction between BMI × time on EM decline (β [SE] = –3.30 [1.43] p = 0.02). These results are consistent with studies showing that increasing age and APOE ε4 are associated with increased rates of HV loss and EM decline. In Aβ− CN adults, lower prevalence of modifiable cardiovascular risk factors was associated with less HV loss and EM decline over ∼10 years, suggesting interventions to reduce modifiable cardiovascular risk factors could be beneficial in this group.
Publisher: Elsevier BV
Date: 03-2015
DOI: 10.1016/J.NEUROBIOLAGING.2014.12.008
Abstract: The apolipoprotein E (APOE) ɛ4 allele and high levels of beta-amyloid (Aβ) are associated with episodic memory decline and risk for Alzheimer's disease. However, there is debate about independent or interactive effects of ɛ4 on Aβ-related memory decline in healthy older adults. Healthy older adults with high Aβ burden (n = 84) enrolled in Australian Imaging, Biomarkers, and Lifestyle Study were included in this study. Cognition was measured using the computerized Cogstate Brief Battery at baseline, 18-, 36-, and 54-month follow-ups. Mini Mental State Examination and Clinical Dementia Rating scales were also administered at baseline and each follow-up timepoint. Relative to Aβ+ ɛ4 noncarriers (n = 36), Aβ+ ɛ4 carriers (n = 48) showed significantly faster decline on memory tasks, which was by convention, moderate in magnitude (d = 0.40-0.47). Aβ positivity coupled with APOE ɛ4 was associated with moderately increased decline in memory over a 54-month assessment period, suggesting that, in the preclinical stages of Alzheimer's disease, the manifestation of memory decline in older adults with high Aβ is exacerbated by the presence of APOE ɛ4.
Publisher: Wiley
Date: 2017
Publisher: Wiley
Date: 12-08-2019
Publisher: MDPI AG
Date: 17-07-2022
DOI: 10.3390/IJMS23147867
Abstract: Alzheimer’s disease (AD) has shown altered immune responses in the periphery. We studied P2X7 (a proinflammatory receptor and a scavenger receptor) and two integrins, CD11b and CD11c, on the surface of circulating leukocytes and analysed their associations with Aβ-PET, brain atrophy, neuropsychological assessments, and cerebrospinal fluid (CSF) biomarkers. Total 287 age-matched, sex-balanced participants were recruited in a discovery cohort and two validation cohorts through the AIBL study and studied using tri-colour flow cytometry. Our results demonstrated reduced expressions of P2X7, CD11b, and CD11c on leukocytes, particularly monocytes, in Aβ +ve cases compared with Aβ −ve controls. P2X7 and integrin downregulation was observed at pre-clinical stage of AD and stayed low throughout disease course. We further constructed a polygenic risk score (PRS) model based on 12 P2RX7 risk alleles to assess the genetic impact on P2X7 function in AIBL and ADNI cohorts. No significant association was identified between the P2RX7 gene and AD, indicating that P2X7 downregulation in AD is likely caused by environmental changes rather than genetic factors. In conclusion, the downregulation of P2X7 and integrins at pre-clinical stage of AD indicates altered pro-inflammatory responses, phagocytic functions, and migrating capabilities of circulating monocytes in early AD pathogenesis. Our study not only improves our understanding of peripheral immune involvement in early stage of AD but also provides more insights into novel biomarker development, diagnosis, and prognosis of AD.
Publisher: Wiley
Date: 16-11-2013
DOI: 10.1016/J.JALZ.2012.07.004
Abstract: Only one study has investigated the relationship between cerebral β-amyloid (Aβ), apolipoprotein E (APOE) ε4 genotype, and cognition. Although significant relationships between cerebral Aβ and cognition were observed in ε4 carriers but not noncarriers, the magnitude of this relationship was not reported. Further, when demographic variables were controlled, the influence of APOE ε4 on the relationship between cerebral Aβ and cognition dissipated. In 144 healthy older adults who had undergone amyloid scanning and APOE ε4 genotyping in the Australian Imaging, Biomarkers, and Lifestyle (AIBL) Flagship Study of Ageing, correlations were conducted to determine the magnitude of relationship between cerebral Aβ and cognition in ε4 carriers and noncarriers. Fisher's Z was used to compare these correlations and Cohen's q determined the magnitude of difference between correlations. Cerebral Aβ was significantly associated with tasks of visual and verbal episodic memory in APOE ε4 carriers. This association was not observed in ε4 noncarriers. The relationship between cerebral Aβ and episodic memory in ε4 carriers was significantly different from that in ε4 noncarriers, and the magnitude of this difference was small to moderate. In APOE ε 4 carriers, there is a moderate negative relationship between cerebral Aβ and episodic memory. This suggests that increased cerebral Aβ may signify the onset of preclinical AD, especially in healthy older adults who are genetically at risk for AD.
Publisher: Oxford University Press (OUP)
Date: 08-12-2017
Abstract: The extent to which increasing age is associated with impairment in cognitive function, termed cognitive aging, may have been overestimated in prior studies. The inclusion of in iduals with severe or uncontrolled systemic medical illness or prodromal neurodegenerative disease in normal aging s les is likely to bias estimates toward lower cognitive performance and inflate estimates of variability. Unbiased estimates of cognitive aging in 658 adults aged 60-84, who underwent rigorous screening to ensure their general and cognitive health, were computed. The first study screened the psychometric properties of a battery of neuropsychological tests in order to identify those with optimal properties to evaluate cognitive aging. The second study used the selected tests to compare baseline performance within 5-year age bands from 60 to 84. The first study identified a battery of 12 tests that provided reliable measures of memory, psychomotor speed, attention, and executive function and were appropriate for investigating age-related cognitive changes. The second study observed moderate to large age-related impairment for performance on tests of complex psychomotor function, category fluency, verbal learning, and verbal and visual memory. No, or only small, age effects were observed for working memory, phonemic fluency, learning of visual information, and reaction time. These data suggested that while increasing age is associated with impairment in cognitive function, this impairment is less severe and is evident only on more complex neuropsychological tests than estimated previously in s les selected using less rigorous criteria to ensure cognitive health.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-07-2019
DOI: 10.1212/WNL.0000000000007831
Abstract: To determine the time required for a preclinical Alzheimer disease population to decline in a meaningful way, use estimates of decline to update previous clinical trial design assumptions, and identify factors that modify β-amyloid (Aβ)–related decline. In 1,120 cognitively unimpaired in iduals from 3 international cohorts, we estimated the relationship between Aβ status and longitudinal changes across multiple cognitive domains and assessed interactions between Aβ and baseline factors. Power analyses were performed to explore s le size as a function of treatment effect. Cognitively unimpaired Aβ+ participants approach mild cognitive impairment (MCI) levels of performance 6 years after baseline, on average. Achieving 80% power in a simulated 4-year treatment trial, assuming a 25% treatment effect, required 2,000 participants/group. Multiple factors interacted with Aβ to predict cognitive decline however, these findings were all cohort-specific. Despite design differences across the cohorts, with large s le sizes and sufficient follow-up time, the Aβ+ groups declined consistently on cognitive composite measures. A preclinical AD population declines to the cognitive performance of an early MCI population in 6 years. Slowing this rate of decline by 40%–50% delays clinically relevant impairment by 3 years—a potentially meaningful treatment effect. However, assuming a 40%–50% drug effect highlights the difficulties in preclinical AD trial design, as a more commonly assumed treatment effect of 25% results in a required s le size of 2,000/group. Designers of preclinical AD treatment trials need to prepare for larger and longer trials than are currently being considered. Interactions with Aβ status were inconsistent and not readily generalizable.
Publisher: Wiley
Date: 06-01-2021
DOI: 10.1111/GBB.12724
Abstract: The brain‐derived neurotrophic factor ( BDNF ) Val66Met (rs6265) polymorphism has been shown to moderate the extent to which memory decline manifests in preclinical Alzheimer's disease (AD). To date, no study has examined the relationship between BDNF and memory in in iduals across biologically confirmed AD clinical stages (i.e., Aβ+). We aimed to understand the effect of BDNF on episodic memory decline and clinical disease progression over 126 months in in iduals with preclinical, prodromal and clinical AD. Participants enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study who were Aβ + (according to positron emission tomography), and cognitively normal (CN n = 238), classified as having mild cognitive impairment (MCI n = 80), or AD (n = 66) were included in this study. Cognition was evaluated at 18 month intervals using an established episodic memory composite score over 126 months. We observed that in Aβ + CNs, Met66 was associated with greater memory decline with increasing age and were 1.5 times more likely to progress to MCI/AD over 126 months. In Aβ + MCIs, there was no effect of Met66 on memory decline or on disease progression to AD over 126 months. In Aβ + AD, Val66 homozygotes showed greater memory decline, while Met66 carriers performed at a constant and very impaired level. Our current results illustrate the importance of time and disease severity to clinicopathological models of the role of BDNF Val66Met in memory decline and AD clinical progression. Specifically, the effect of BDNF on memory decline is greatest in preclinical AD and reduces as AD clinical disease severity increases.
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.JAGP.2016.08.007
Abstract: To examine how β-amyloid (Aβ), APOE and BDNF genotypes, and cortisol relate to depressive and anxiety symptoms in cognitively normal older women and men. Cross-sectional data were analyzed from 423 older adults from the Australian Imaging Biomarkers and Lifestyle study. Analyses of covariance evaluated associations between Aβ, APOE and BDNF genotype, and cortisol in relation to severity of depressive and anxiety symptoms. Among Aβ+ older adults, APOE ε4 carriage was associated with greater severity of anxiety symptoms (d = 0.55) and in the full s le, APOE ε4 carriage was linked to greater severity of depressive (d = 0.26) and anxiety (d = 0.21) symptoms. Among Aβ+ women, ε4 carriers reported greater anxiety symptoms than non-ε4 carriers (d = 0.83), and female BDNF rs6265 Val66 Met allele carriers reported greater depressive symptoms (d = 0.29). Sex moderated the relationship between Aβ, APOE genotype, and BDNF genotype in predicting severity of anxiety and depressive symptoms in cognitively normal older adults.
Publisher: Springer Science and Business Media LLC
Date: 21-03-2019
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.NEUROBIOLAGING.2018.12.014
Abstract: The longevity gene Klotho (KL), specifically the functional KL-VS variant, has previously been associated with cognition and rates of cognitive decline. This study aimed to determine whether KL-VS associations with cognition were observable in preclinical Alzheimer's disease (AD). The study also aimed to determine whether there was a combined influence of KL-VS, neocortical amyloid-β (Aβ) burden, and carriage of the apolipoprotein E (APOE) ε4 allele on cognitive decline. This study involved 581 Aβ-imaged, cognitively normal older adults, enrolled in the Australian Imaging, Biomarkers and Lifestyle Study of Aging. Linear mixed effects models revealed no significant associations between KL-VS and cognitive decline independently or in combination with Aβ burden and APOE ε4 genotype. Overall, previous associations reported between KL-VS and cognitive decline are not observed at the preclinical stages of AD. Furthermore, the results do not support the hypothesis that KL-VS has a modifying effect on Aβ burden and APOE ε4-driven cognitive decline in preclinical AD.
Publisher: Frontiers Media SA
Date: 19-12-2018
Publisher: Wiley
Date: 24-05-2018
DOI: 10.1016/J.JALZ.2018.04.010
Abstract: Our objective was to investigate the effect of sex on cognitive decline within the context of amyloid β (Aβ) burden and apolipoprotein E genotype. We analyzed sex‐specific effects on Aβ‐positron emission tomography, apolipoprotein, and rates of change on the Preclinical Alzheimer Cognitive Composite‐5 across three cohorts, such as the Alzheimer's Disease Neuroimaging Initiative, Australian Imaging, Biomarker and Lifestyle, and Harvard Aging Brain Study (n = 755 clinical dementia rating = 0 age (standard deviation) = 73.6 (6.5) female = 55%). Mixed‐effects models of cognitive change by sex, Aβ‐positron emission tomography, and apolipoprotein ε4 were examined with quadratic time effects over a median of 4 years of follow‐up. Apolipoprotein ε4 prevalence and Aβ burden did not differ by sex. Sex did not directly influence cognitive decline. Females with higher Aβ exhibited faster decline than males. Post hoc contrasts suggested that females who were Aβ and apolipoprotein ε4 positive declined faster than their male counterparts. Although Aβ did not differ by sex, cognitive decline was greater in females with higher Aβ. Our findings suggest that sex may play a modifying role on risk of Alzheimer's disease–related cognitive decline.
Publisher: Wiley
Date: 25-04-2017
DOI: 10.1002/GPS.4489
Abstract: Several studies have reported that non-demented older adults with clinical depression show changes in amyloid-β (Aβ) levels in blood, cerebrospinal fluid and on neuroimaging that are consistent with those observed in patients with Alzheimer's disease. These findings suggest that Aβ may be one of the mechanisms underlying the relation between the two conditions. We sought to determine the relation between elevated cerebral Aβ and the presence of depression across a 54-month prospective observation period. Cognitively normal older adults from the Australian Imaging Biomarkers and Lifestyle study who were not depressed and had undergone a positron emission tomography scan to classify them as either high Aβ (n = 81) or low Aβ (n = 278) participated. Depressive symptoms were assessed using the Geriatric Depression Scale - Short Form at 18-month intervals over 54 months. Whilst there was no difference in probable depression between groups at baseline, incidence was 4.5 (95% confidence interval [CI] 1.3-16.4) times greater within the high Aβ group (9%) than the low Aβ group (2%) by the 54-month assessment. Results of this study suggest that elevated Aβ levels are associated with a 4.5-fold increased likelihood of developing clinically significant depressive symptoms on follow-up in preclinical Alzheimer's disease. This underscores the importance of assessing, monitoring and treating depressive symptoms in older adults with elevated Aβ. Copyright © 2016 John Wiley & Sons, Ltd.
Publisher: Wiley
Date: 25-08-2018
DOI: 10.1002/ANA.25299
Publisher: Wiley
Date: 12-2013
DOI: 10.1002/ANA.24040
Abstract: Biomarkers for Alzheimer disease (AD) can detect the disease pathology in asymptomatic subjects and in iduals with mild cognitive impairment (MCI), but their cognitive prognosis remains uncertain. We aimed to determine the prognostic value of β-amyloid imaging, alone and in combination with memory performance, hippoc al atrophy, and apolipoprotein E ε4 status in nondemented, older in iduals. A total of 183 healthy in iduals (age = 72.0 ± 7.26 years) and 87 participants with MCI (age = 73.7 ± 8.27) in the Australian Imaging, Biomarkers, and Lifestyle study of ageing were studied. Clinical reclassification was performed after 3 years, blind to biomarker findings. β-Amyloid imaging was considered positive if the (11) C-Pittsburgh compound B cortical to reference ratio was ≥1.5. Thirteen percent of healthy persons progressed (15 to MCI, 8 to dementia), and 59% of the MCI cohort progressed to probable AD. Multivariate analysis showed β-amyloid imaging as the single variable most strongly associated with progression. Of combinations, subtle memory impairment (Z score = -0.5 to -1.5) with a positive amyloid scan was most strongly associated with progression in healthy in iduals (odds ratio [OR] = 16, 95% confidence interval [CI] = 3.7-68 positive predictive value [PPV] = 50%, 95% CI = 19-81 negative predictive value [NPV] = 94%, 95% CI = 88-98). Almost all amnestic MCI subjects (Z score ≤ -1.5) with a positive amyloid scan developed AD (OR = ∞ PPV = 86%, 95% CI = 72-95 NPV = 100%, 95% CI = 80-100). Hippoc al atrophy and ε4 status did not add further predictive value. Subtle memory impairment with a positive β-amyloid scan identifies healthy in iduals at high risk for MCI or AD. Clearly amnestic patients with a positive amyloid scan have prodromal AD and a poor prognosis for dementia within 3 years.
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1016/J.NEUROBIOLAGING.2013.05.006
Abstract: 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, hippoc al 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 hippoc al atrophy over 36 months, compared with Val/Val homozygotes. BDNF Val66Met was not found to be related to rates of change in cognition or hippoc al 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 hippoc al degeneration in in iduals in the preclinical stage of AD.
Publisher: Wiley
Date: 24-07-2018
DOI: 10.1002/GPS.4761
Location: Australia
Start Date: 2019
End Date: 2022
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2016
End Date: 2020
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2017
End Date: 2020
Funder: Alzheimer's Association
View Funded ActivityStart Date: 2018
End Date: 2020
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 05-2023
End Date: 05-2028
Amount: $4,583,816.00
Funder: Australian Research Council
View Funded Activity