Hamid R. Sohrabi

Background
Neuroinflammation and activation of innate immunity such as activated microglia are early events in neurodegenerative diseases including Alzheimer's disease (AD). Recently, a rare mutation in the Triggering receptor expressed on myeloid cells 2 (TREM2) gene has been associated with increased risk of late onset AD. Its product of proteolytic processing and shedding, soluble TREM2 (sTREM2), can be measured in the cerebrospinal fluid (CSF) and serum and is a surrogate marker of TREM2-mediated microglia function. CSF and serum sTREM2 have been documented to increase at different clinical stages of AD, however, alterations with respect to Neocortical Amyloid-β Load (NAL) remains unclear.

Methods
Plasma sTREM2 concentrations were measured employing the sTREM2 Meso Scale Discovery (MSD) assay in participants from the Kerr Anglican Retirement Village Initiative in Ageing Health cohort, aged 65–90 years. Participants underwent a battery of neuropsychological testing to evaluate cognitive performance and were categorized as low NAL (NAL-, n = 65) and high NAL (NAL+, n = 35) as assessed by PET imaging.

Results
No significant difference in plasma sTREM2 level was observed between NAL+ and NAL- participants; however, within APOE ε4 carriers, higher NAL was observed in individuals with higher sTREM2 concentrations within quartiles 4 (versus quartile 1). Furthermore, plasma sTREM2 level was positively correlated with NAL within the NAL+ participants only. No significant correlation with cognitive performance. Additionally, plasma sTREM2 was positively correlated with serum kynurenine pathway metabolites (inflammation-related markers).

Conclusions
The current findings indicate that increases in the level of NAL positivity are reflected by increased plasma sTREM2 levels in pre-clinical AD.

Background
Elevated blood neurofilament light chain (NFL) concentrations are indicative of neurodegeneration, while elevated kynurenine pathway (KP) metabolites are indicative of neuroinflammation. NFL and KP metabolites have independently been reported to be associated with neurodegenerative diseases, however the association between NFL and the KP metabolites have not been investigated previously. Therefore, the current study aimed to investigate whether an association between NFL and KP metabolites was present in elderly individuals to provide insight on the association between blood markers of neurodegeneration and neuroinflammation.

Methods
Plasma NFL concentrations were correlated with KP metabolites using Pearson's correlation coefficient in elderly individuals, aged 65–90 years, with normal global cognition (Mini Mental State Examination Score≥26) from the Kerr Anglican Retirement Village Initiative in Ageing Health cohort.

Results
A significant association between NFL and kynurenine to tryptophan ratio, reflecting 2,3-indoleamine dioxygenase activity was observed (K/T, r=.451, p<.0001). A positive correlation was also observed between NFL and kynurenine (r=.364, p<.0005), kynurenic acid (r=.384, p<.0001), 3-hydroxykynurenine (r=.246, p=.014), anthranilic acid (r=.311, p=.002) and quinolinic acid (r=.296, p=.003).

Conclusions
Observations from the current study suggest that an association between neurodegeneration and neuroinflammation manifests in the periphery.

Background
Genetic variation in Spondin-1 (SPON1), specifically rs11023139, has been associated with reduced rates of cognitive decline in individuals with Alzheimer's disease. The aim of this study was to assess whether the association was present in cognitively normal (CN) older adults.

Methods
Longitudinal cognitive decline was investigated using linear mixed modelling in a cohort of 590 CN older adults enrolled in the Australian Imaging, Biomarkers and Lifestyle Study.

Results
No independent effect of rs11023139 on cognitive decline was observed. However, significant associations were observed for the interaction between APOE ε4 and rs11023139 in individuals with high Aβ-amyloid burden. APOE ε4/rs11023139-A carriers declined significantly faster than APOE ε4/rs11023139-G_G carriers in measures of global cognition (p=0.011) and verbal episodic memory (p=0.020).

Conclusions
These results suggest that carriage of the SPON1 rs11023139-A allele significantly contributes to a worsening of cognitive performance in APOE ε4 CN older adults with a high neocortical Aβ-amyloid burden.

Background
There has been increased interest in the role of dietary patterns and future risk of Alzheimer's disease (AD). However, the specific relationship between protein and fibre intake on cognitive function in older adults at higher risk of AD remains to be determined. This study investigated the association of protein and fibre intake, with cognition using data from the Australian Imaging, Biomarkers and Lifestyle study of ageing (AIBL) cohort.

Methods
Neuropsychological data derived from AIBL (734) were grouped into two cognitive domains (PACC and the Boston non-memory score). Composite scores, calculated by averaging the normalised individual cognitive measure Z scores, were assessed between levels of fibre and protein intake (binary, below/above the recommended daily intake (RDI) age, gender, APOE e4 allele status, total energy intake, education and BMI.

Results
Average values for the AIBL Study Preclinical Alzheimer cognitive (AIBL PACC) score (but not the non-memory) were significantly higher in participants with high protein intake (PACC:0.11 vs PACC:0.68, p=0.046) but not for those with high fibre intake (PACC:0.51 vs PACC:0.53, p>0.05). Adjusted for all confounding variables, this difference was abrogated (p>0.05). Given the level of education as a covariate was strongly related to the PACC score (p<0.0001), we further tested the interaction between education level (<12/12+ years) with low/high protein and fibre intakes. We saw a significant interaction for both protein and fibre groups with education level for the PACC score (education*protein: p=0.014, education*fibre: p=0.051), with those participants with high protein/fibre intakes and 12+ years of education having higher PACC scores as compared to those with <12 years of education and low protein/fibre intakes. Combining both fibre and protein in one three level variable (0=low fibre/low protein, 1=at least 1 fibre/protein high, and 2=both high fibre and protein) identified a significant association with the PACC score (p=0.007), with those participants in the low group and with <12 years of education performing worse for the PACC score as compared with those in the high group with 12+years of education.

Conclusions
This study highlights the importance of adequate protein and fibre intake on cognitive performance in an elderly cognitively normal population.

Background
Olfactory episodic memory (OEM) could provide more valuable diagnostic information for the detection of Alzheimer's Disease than either olfactory identification or episodic memory alone (Croy et al., 2015; Murphy, Nordin & Acosta, 1997). However, very few validated tests of OEM are available which assess learning and memory characteristics. The present study aims to validate a newly developed Western Australia Olfactory Memory Test (WAOMT) in older adults which measures learning and memory characteristics of OEM.

Methods
A final sample of 181 participants were recruited from the Western Australia Memory Study (WAMS). Nine target odours were presented over 3 learning trials and participants named as many odours at the end of each trial, followed by a distractor list, short-delay free recall (SDFR) and short-delay cued recall. Long-delay free (LDFR) and cued recall (LDCR), and recognition (Y/N) was administered after a 20 minute delay. A liberal scoring criteria was used. Convergent validity was examined between OEM and conceptually similar constructs of verbal and visual episodic memory, and odour identification. Divergent validity was examined between executive functioning and visual-spatial abilities. Test re-test reliability was examined with 12 participants between 7 to 28 days.

Results
Test re-test reliability was adequate for learning trials, LDFR & d’ (r=.67 to .73; p<.05). Analysis revealed significant inter-correlations between learning and memory scores (r=.33 to .93), components of WAOMT and odour identification (r=.15 to .21), verbal episodic memory (r =.17 to .26) and visual episodic memory (r = .16 to .27). Females performed better than males on Trial 3 F(1,113) = 4.49, p = .4 and recognition hits F(1,113) = 6.24, p = .14, controlling for MoCA scores. Performance decreased with age (r = -.13 to -.20).

Conclusions
Relationships were found between conceptually similar constructs of verbal and visual episodic memory and odour identification. Performance was found to decrease with age, and females demonstrated an advantage overall males in learning trial 3 and recognition hits. The WAOMT presents a reliable, valid and simple test of odour episodic memory. Future research implications include examining the longitudinal relationship between OEM and cognitive decline.

Background
Brain damage in Alzheimer's disease (AD) begins up to 20 years before the onset of disease symptoms and it is this ‘pre-symptomatic/clinical’ phase that provides the best opportunity for an effective, early intervention in AD. Hyperspectral retinal imaging has the potential to identify biomarkers that could reflect the build-up of brain amyloid load and thereby, could prove to be a valuable tool for mass population screening in preclinical AD.

Methods
Hyperspectral retinal imaging was completed in n=10 participants (of the planned 50 participants that will be completed by April 2018) recruited from one of our study cohorts (n=105, 60 years and above) that had completed brain amyloid imaging. After performing a thorough ophthalmic evaluation, hyperspectral retinal measurements were obtained in the reflectance mode with spectral range 450-900 nm and in the fluorescence mode. Image analysis will be performed to quantify the spectral signature of retinal features which are of interest and their association with brain amyloid load (participants with positive versus negative brain amyloid load) will be determined.

Results
Hyperspectral retinal imaging will be completed for the remaining n=40 participants, aged 60 years and above. Data will be analysed via image processing and preliminary findings presented at the conference.

Conclusions
Successful validation of hyperspectral retinal imaging will serve as an early, non-invasive and economical diagnostic tool for preclinical AD.

Background

The kynurenine pathway (KP), generating the essential co-factor nicotinamide adenine dinucleotide, is dysregulated in several neurodegenerative and neuropsychiatric disorders including Alzheimer's disease (AD). However, alterations in the KP have not been investigated in the preclinical phase of AD, characterized by high neocortical amyloid-β load (NAL), prior to cognitive impairment.

Methods

Serum concentrations of KP metabolites including tryptophan, kynurenine, 3-hydroxykynurenine, anthranilic acid, 3-hydroxyanthranilic acid, picolinic acid and quinolinic acid were measured using UHPLC and GCMS in elderly individuals, aged 65-90 years, with normal global cognition (Mini Mental State Examination Score≥26) from the Kerr Anglican Retirement Village Initiative in Ageing Health cohort. Participants were categorised into low NAL (NAL-, n=65) and high NAL (NAL+, n=35) using a standard uptake value ratio cut-off = 1.35.

Results

Higher kynurenine (p=.0004 unadjusted, p=.004 adjusted for age and APOE ε4 carriage) and anthranilic acid (p=.0001 unadjusted, p=.001 adjusted for age and APOE ε4 carriage) concentrations in NAL+ versus NAL- participants were observed in the female subset of the cohort but not in the male subset (NAL by sex interaction p=0.001, 0.038, respectively for kynurenine and anthranilic acid). On evaluating the potential of kynurenine or/and anthranilic acid as biomarkers for NAL+ in females, logistic regressions with NAL+/- as outcome were carried out. Areas under the receiver operating characteristic curves were 0.794 using age and APOE ε4 as predictors, 0.844 when kynurenine was added, 0.866 when anthranilic acid was added, and 0.871 when both were added, such that kynurenine and anthranilic acid were individually and jointly significant predictors (p=0.007, 0.005, 0.0004, respectively).

Conclusions

Findings from the current study exhibit increased anthranilic acid and kynurenine, in NAL+ females and highlights their potential as blood biomarkers for preclinical AD. Additionally, the current study also provides insight into the influence of gender in AD pathogenesis. Further studies measuring the KP enzyme activities are underway. Additionally, longitudinal studies are required to provide further insight into the current findings.

Background
Executive functions (EF) decline during typical aging and are affected in age-related neurodegenerative conditions. These functions have long been associated with the integrity of the frontal lobe. While neuroimaging studies have frequently reported correlations between objective lab-based EF tasks and activity in diverse brain structures, the relationship between everyday naturalistic EF and regional brain activity has been less well-studied. We aim to evaluate the relationships between naturalistic “real-world” behavioral ratings of EF and resting state regional brain activity.

Methods
Participants were 80 (26M) healthy older adults (average 69.13, SD 8.70) and their informants (usually their spouse). We used Frontal Systems Behavioral Scale (FrSBe) to obtain ratings of subjects’ EF dysfunction symptoms from the informant, which produces three subscales of EF syndromes (the Apathic, Disinhibited, Dysexecutive syndromes). [18F]-FDG PET imaging quantified regional glucose metabolism, with regional standard uptake value ratio (SUVr) calculated using the CapAIBL platform1,2. In addition, participants completed a battery of cognitive tests including the Montreal Cognitive Assessment (MoCA), Digit Span Backwards, Trail Making Test B (Trails B), the Controlled Word Association Test (COWA), and 21-item version of the Depression Anxiety Stress Scales (DASS-21).

Results
Partial correlations controlling for APOE ε4 allele status and DASS-21 depression scale revealed that greater informant-reported EF dysfunction (total FrsBe score) was associated with lower levels of brain activity in the dorsolateral prefrontal (r=-0.28, p=0.025), orbitofrontal (r=0.28, p=0.026), and anterior cingulate (r=-0.39, p=0.001). These relationships appear to be driven by the Dysexecutive syndrome subscale (prefrontal r=-0.35, p=0.005; orbitofrontal r=-0.34, p=0.007, anterior cingulate r=-0.44, p<0.001). Conversely, greater everyday EF problems were not significantly correlated with other brain regions such as the temporal or parietal lobe, and measures such as MoCA, Digit span backwards, Trails B, and COWA verbal fluency were not significantly correlated with prefrontal metabolism.

Conclusions
We are able to specifly the link between EF and the frontal lobe by using FrSBe, a naturalistic behavioral rating, and the resting state glucose metabolism by FDG PET imaging. 1Zhou et al., PLOS ONE, 9:e84777 (2014). 2Bourgeat et al., Neurobiology of Aging, 36 Suppl 1:S159–66 (2015).

Background
Current pharmacological interventions for Alzheimer’s disease (AD) target its cognitive and behavioural symptoms, but do not impede disease pathogenesis. Furthermore, the lack of efficacy of disease modifying agents is conceivably attributable to administration of interventions too late in the disease process. Consequently, we have identified cognitively normal individuals in the preclinical stage of AD by assessing their brain beta-amyloid (Aβ) load via Positron Emission Tomography (PET), to investigate the therapeutic efficacy of curcumin.

Methods
Participants living within independent living units, at the Anglican Retirement Villages (ARV), Sydney Australia, were recruited to establish the McCusker Kerr Anglican Retirement Village Initiative in Ageing Health (McCusker KARVIAH) cohort. All eligible participants were 65-90 years of age, had subjective memory complaints (no dementia), stable health, and considered ‘at risk’ of AD. At baseline participants underwent physical health and lifestyle assessments (exercise, nutrition and sleep), blood draw for biochemical analysis, comprehensive neuropsychological assessment, and neuroimaging (PET using 18F-Florbetaben; 18F-Fluorodeoxyglucose; and magnetic resonance imaging). Following, a double blind placebo controlled, 12 month intervention using oral curcumin (BCM-95™, 1.5mg daily) with scheduled completion due in October, 2016, all participants will be re-assessed for the aforementioned parameters.

Results
Thirty-four percent of cohort participants (N=105) PET imaged using ligand 18F-Florbetaben had high amyloid load (defined as neocortical SUVR>1.35). Further within the cohort APOE ε4 carriers (N=24) were observed to have significantly elevated brain amyloid load compared to non- ε4 carriers (N=81; p<0.000). No significant difference was present between high and low amyloid load participants in age, gender and education. The therapeutic efficacy of curcumin will be assessed based on findings obtained at the 6 month (blood chemistry only) and 12 month time points.

Conclusions
While the anti-oxidative and anti-inflammatory properties of curcumin have been established from findings reported in in vitro and in vivostudies, its benefits in clinical AD pathology have not been confirmed. Limitations identified in earlier studies, including the low bioavailability of curcumin and the use of interventions too late in the disease process, have been addressed in our study, thus providing the best opportunity to elucidate the full potential of curcumin as a nutraceutical for AD prevention.

Background
Testosterone replacement therapy (TRT) has been investigated in older men as a preventative treatment against Alzheimer's disease (AD) and dementia. However, previous studies have produced inconsistent results. The inconsistencies may have arisen from differences in study design, dosage, treatment duration, and/or target population selection.

Methods
We designed a double blind, randomized, cross-over, placebo-controlled study to assess the physiological and clinical consequences of TRT in 44 older men (aged 61 + 7.7 years) with subjective memory complaints (SMC) in Indonesia. Participants were randomized into 2 groups, one group received 50 mg of transdermal testosterone daily for 24 weeks, followed by a 4 week washout period, then 24 weeks of placebo treatment; the other group received the reverse treatment (i.e. placebo, washout, then testosterone). Blood biomarkers were evaluated every 4 weeks in the first treatment period and every 8 weeks in the cross-over period.

Results
Significant increases in total testosterone, free (calculated) testosterone, dihydrotestosterone, and a decrease in luteinising hormone (LH) levels were observed (p<0.001) following TRT. Although there were significant increases in red blood cell counts, hemoglobin and prostate specific antigen (PSA) levels following TRT, they remained within normal ranges; an increased risk of prostate cancer or atherosclerosis would only have been indicated by much higher changes. No significant differences in estradiol, sex hormone binding globulin (SHBG), insulin levels, body fat percentage, or BMI were detected.

Conclusions
This first hospital-based study on elderly Indonesian men with SMC provides valuable insight into the role of TRT in terms of safety and its potential to prevent AD.