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Cerebral multi-morbidity is common in older people with dementia, including people with dementia with Lewy bodies (DLB). We describe the first Australian-based, longitudinal observational biomarker study of DLB.
To investigate the frequency and influence of Alzheimer’s disease (AD) pathology (amyloid-β and tau) and cerebrovascular disease on clinical symptoms and disease outcome in DLB.
The study will recruit 100 people with mild to moderate probable DLB, who will undergo comprehensive clinical and cognitive assessments. Scales targeting DLB-specific clinical features (such as cognitive fluctuations and rapid eye movement sleep behaviour disorder) are administered. Biomarker protocols incorporate blood sampling (including ApoE genotyping and systemic inflammatory markers), molecular imaging (amyloid-β [18F-NAV 4694], tau [18F-MK6240], VMAT2 [18F-AV133] PET scans), 3-tesla magnetic resonance imaging and optional lumbar puncture. Clinical assessments are completed 6 - monthly and imaging 18-monthly. Participants are also invited to register for post-mortem brain tissue donation.
Thirty participants with probable DLB have been enrolled to date (mean age 75.4 years, range 64-82; 87% male). All participants have mild to moderate cognitive impairment (mean MMSE 25, range 17-30). Approximately 64% of the participants were amyloid-β positive. Study procedure tolerability has been excellent with no adverse events reported.
There is significant overlap of AD-related proteinopathies in people with DLB. Understanding the impact of multi-morbidity is essential in the development of effective treatment strategies. This study supports the feasibility of intensive, longitudinal biomarker studies in DLB in the Australian setting.
The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism Met allele exacerbates amyloid (Aβ) related decline in episodic memory (EM) and hippocampal 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 samples 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.
Autobiographical memory (ABM), personal semantic memory (PSM), and autonoetic consciousness are affected in individuals with mild cognitive impairment (MCI) but their relationship with Alzheimer's disease (AD) biomarkers are unclear.
Forty-five participants (healthy controls (HC) = 31, MCI = 14) completed the Episodic ABM Interview and a battery of memory tests. Thirty-one (HC = 22, MCI = 9) underwent β-amyloid positron emission tomography (PET) and magnetic resonance (MR) imaging. Fourteen participants (HC = 9, MCI = 5) underwent one imaging modality.
Unlike PSM, ABM differentiated between diagnostic categories but did not relate to AD biomarkers. Personal semantic memory was related to neocortical β-amyloid burden after adjusting for age and apolipoprotein E (APOE) ɛ4. Autonoetic consciousness was not associated with AD biomarkers, and was not impaired in MCI.
Autobiographical memory was impaired in MCI participants but was not related to neocortical amyloid burden, suggesting that personal memory systems are impacted by differing disease mechanisms, rather than being uniformly underpinned by β-amyloid. Episodic and semantic ABM impairment represent an important AD prodrome.
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.
The Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing is a prospective study of 1,112 individuals (211 with Alzheimer's disease (AD), 133 with mild cognitive impairment (MCI), and 768 healthy controls (HCs)). Here we report diagnostic and cognitive findings at the first (18-month) follow-up of the cohort. The first aim was to compute rates of transition from HC to MCI, and MCI to AD. The second aim was to characterize the cognitive profiles of individuals who transitioned to a more severe disease stage compared with those who did not.
Eighteen months after baseline, participants underwent comprehensive cognitive testing and diagnostic review, provided an 80 ml blood sample, and completed health and lifestyle questionnaires. A subgroup also underwent amyloid PET and MRI neuroimaging.
The diagnostic status of 89.9% of the cohorts was determined (972 were reassessed, 28 had died, and 112 did not return for reassessment). The 18-month cohort comprised 692 HCs, 82 MCI cases, 197 AD patients, and one Parkinson's disease dementia case. The transition rate from HC to MCI was 2.5%, and cognitive decline in HCs who transitioned to MCI was greatest in memory and naming domains compared to HCs who remained stable. The transition rate from MCI to AD was 30.5%.
There was a high retention rate after 18 months. Rates of transition from healthy aging to MCI, and MCI to AD, were consistent with established estimates. Follow-up of this cohort over longer periods will elucidate robust predictors of future cognitive decline.
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 individuals 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 sample (174 healthy, 53 MCI) underwent neuroimaging for Aβ amyloid.
Within the MCI group individuals 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.
Molecular neuroimaging techniques such as PET are proving valuable in the early and differential diagnosis of Alzheimer's disease (AD). With the advent of new therapeutic strategies aimed at reducing β-amyloid (Aβ) burden in the brain to potentially prevent or delay functional and irreversible cognitive loss, there is increased interest in developing agents that allow assessment of Aβ burden in vivo.
Amyloid imaging with PET has proven useful in the discrimination of dementias, showing significantly higher Aβ burden in the gray matter of AD patients when compared with healthy controls or patients with frontotemporal dementia. ApoE ɛ4 carriers, independent of diagnosis or disease severity, present with higher Aβ burden than non-ɛ4 carriers. Amyloid imaging matches histopathological reports in aging and dementia, reflecting the true regional density of Aβ plaques in cortical areas. It also appears to be more sensitive than FDG-PET for the diagnosis of AD.
In healthy older people there is an increasing prevalence of amyloid positive scans with age, rising from 20% in the seventh decade to 60% in the ninth decade. Of people with mild cognitive impairment (MCI), 40–60% present with detectable cortical Aβ deposition. In both groups, Aβ deposition is associated with a higher risk for cognitive decline and dementia due to AD. These observations suggest that Aβ deposition is not part of normal aging, supporting the hypothesis that it occurs well before the onset of symptoms and is likely to represent preclinical AD in asymptomatic persons and prodromal AD in MCI. Further longitudinal observations, coupled with different disease-specific tracers and biomarkers, are required to confirm this hypothesis and further elucidate the precise role of Aβ deposition in the course of AD.
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