Psychiatry - Research Publications

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    Trajectories of depressive and anxiety symptoms in older adults: a 6-year prospective cohort study
    Holmes, SE ; Esterlis, I ; Mazure, CM ; Lim, YY ; Ames, D ; Rainey-Smith, S ; Fowler, C ; Ellis, K ; Martins, RN ; Salvado, O ; Dore, V ; Villemagne, VL ; Rowe, CC ; Laws, SM ; Masters, CL ; Pietrzak, RH ; Maruff, P (WILEY, 2018-02-01)
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    Cerebrovascular disease, Alzheimer's disease biomarkers and longitudinal cognitive decline
    Yates, PA ; Villemagne, VL ; Ames, D ; Masters, CL ; Martins, RN ; Desmond, P ; Burnham, S ; Maruff, P ; Ellis, KA ; Rowe, CC (WILEY-BLACKWELL, 2016-06-01)
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    Amyloid burden and incident depressive symptoms in cognitively normal older adults
    Harrington, KD ; Gould, E ; Lim, YY ; Ames, D ; Pietrzak, RH ; Rembach, A ; Rainey-Smith, S ; Martins, RN ; Salvado, O ; Villemagne, VL ; Rowe, CC ; Masters, CL ; Maruff, P (WILEY, 2017-04-01)
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    Association of Plasma A beta Peptides with Blood Pressure in the Elderly
    Lambert, J-C ; Dallongeville, J ; Ellis, KA ; Schraen-Maschke, S ; Lui, J ; Laws, S ; Dumont, J ; Richard, F ; Cottel, D ; Berr, C ; Ames, D ; Masters, CL ; Rowe, CC ; Szoeke, C ; Tzourio, C ; Dartigues, J-F ; Buee, L ; Martins, R ; Amouyel, P ; Gravenor, MB (PUBLIC LIBRARY SCIENCE, 2011-04-15)
    BACKGROUND: Aß peptides are often considered as catabolic by-products of the amyloid ß protein precursor (APP), with unknown physiological functions. However, several biological properties have been tentatively attributed to these peptides, including a role in vasomotion. We assess whether plasma Aß peptide levels might be associated with systolic and diastolic blood pressure values (SBP and DBP, respectively). METHODOLOGY/PRINCIPAL FINDINGS: Plasma Aß(1-40) and Aß(1-42) levels were measured using an xMAP-based assay in 1,972 individuals (none of whom were taking antihypertensive drugs) from 3 independent studies: the French population-based 3C and MONA-LISA (Lille) studies (n = 627 and n = 769, respectively) and the Australian, longitudinal AIBL study (n = 576). In the combined sample, the Aß(1-42)/ Aß(1-40) ratio was significantly and inversely associated with SBP (p = 0.03) and a similar trend was observed for DBP (p = 0.06). Using the median age (69) as a cut-off, the Aß(1-42)/Aß(1-40) ratio was strongly associated with both SBP and DBP in elderly individuals (p = 0.002 and p = 0.03, respectively). Consistently, a high Aß(1-42)/ Aß(1-40) ratio was associated with a lower risk of hypertension in both the combined whole sample (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.56-0.90) and (to an even greater extent) in the elderly subjects (OR, 0.53; 95% CI, 0.37-0.75). Lastly, all these associations appeared to be primarily driven by the level of plasma Aß(1-40). CONCLUSION: The plasma Aß(1-42)/Aß(1-40) ratio is inversely associated with SBP, DBP and the risk of hypertension in elderly subjects, suggesting that Aß peptides affect blood pressure in vivo. These results may be particularly relevant in Alzheimer's disease, in which a high Aß(1-42)/Aß(1-40) plasma ratio is reportedly associated with a decreased risk of incident disease.
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    APOE and BDNF polymorphisms moderate amyloid beta-related cognitive decline in preclinical Alzheimer's disease
    Lim, YY ; Villemagne, VL ; Laws, SM ; Pietrzak, RH ; Snyder, PJ ; Ames, D ; Ellis, KA ; Harrington, K ; Rembach, A ; Martins, RN ; Rowe, CC ; Masters, CL ; Maruff, P (NATURE PUBLISHING GROUP, 2015-11-01)
    Accumulation of β-amyloid (Aβ) in the brain is associated with memory decline in healthy individuals as a prelude to Alzheimer's disease (AD). Genetic factors may moderate this decline. We examined the role of apolipoprotein E (ɛ4 carrier[ɛ4(+)], ɛ4 non-carrier[ɛ4(-)]) and brain-derived neurotrophic factor (BDNF(Val/Val), BDNF(Met)) in the extent to which they moderate Aβ-related memory decline. Healthy adults (n=333, Mage=70 years) enrolled in the Australian Imaging, Biomarkers and Lifestyle study underwent Aβ neuroimaging. Neuropsychological assessments were conducted at baseline, 18-, 36- and 54-month follow-ups. Aβ positron emission tomography neuroimaging was used to classify participants as Aβ(-) or Aβ(+). Relative to Aβ(-)ɛ4(-), Aβ(+)ɛ4(+) individuals showed significantly faster rates of cognitive decline over 54 months across all domains (d=0.40-1.22), while Aβ(+)ɛ4(-) individuals showed significantly faster decline only on verbal episodic memory (EM). There were no differences in rates of cognitive change between Aβ(-)ɛ4(-) and Aβ(-)ɛ4(+) groups. Among Aβ(+) individuals, ɛ4(+)/BDNF(Met) participants showed a significantly faster rate of decline on verbal and visual EM, and language over 54 months compared with ɛ4(-)/BDNF(Val/Val) participants (d=0.90-1.02). At least two genetic loci affect the rate of Aβ-related cognitive decline. Aβ(+)ɛ4(+)/BDNF(Met) individuals can expect to show clinically significant memory impairment after 3 years, whereas Aβ(+)ɛ4(+)/BDNF(Val/Val) individuals can expect a similar degree of impairment after 10 years. Little decline over 54 months was observed in the Aβ(-) and Aβ(+) ɛ4(-) groups, irrespective of BDNF status. These data raise important prognostic issues in managing preclinical AD, and should be considered in designing secondary preventative clinical trials.
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    Alterations in dorsal and ventral posterior cingulate connectivity in APOE epsilon 4 carriers at risk of Alzheimer's disease
    Kerestes, R ; Phal, PM ; Steward, C ; Moffat, BA ; Salinas, S ; Cox, KL ; Ellis, KA ; Cyarto, EV ; Ames, D ; Martins, RN ; Masters, CL ; Rowe, CC ; Sharman, MJ ; Salvado, O ; Szoeke, C ; Lai, M ; Lautenschlager, NT ; Desmond, PM (ROYAL COLL PSYCHIATRISTS, 2015-10-01)
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    Sensitivity of composite scores to amyloid burden in preclinical Alzheimer's disease: Introducing the Z-scores of Attention, Verbal fluency, and Episodic memory for Nondemented older adults composite score.
    Lim, YY ; Snyder, PJ ; Pietrzak, RH ; Ukiqi, A ; Villemagne, VL ; Ames, D ; Salvado, O ; Bourgeat, P ; Martins, RN ; Masters, CL ; Rowe, CC ; Maruff, P (Wiley, 2016)
    INTRODUCTION: Cognitive composite scores developed for preclinical Alzheimer's disease (AD) often consist of multiple cognitive domains as they may provide greater sensitivity to detect β-amyloid (Aβ)-related cognitive decline than episodic memory (EM) composite scores alone. However, this has never been empirically tested. We compared the rate of cognitive decline associated with high Aβ (Aβ+) and very high Aβ (Aβ++) in cognitively normal (CN) older adults on three multidomain cognitive composite scores and one single-domain (EM) composite score. METHODS: CN older adults (n = 423) underwent Aβ neuroimaging and completed neuropsychological assessments at baseline, and at 18-, 36-, 54-, and 72-month follow-ups. Four cognitive composite scores were computed: the ADCS-PACC (ADCS-Preclinical Alzheimer Cognitive Composite), ADCS-PACC without the inclusion of the mini-mental state examination (MMSE), an EM composite, and the Z-scores of Attention, Verbal fluency, and Episodic memory for Nondemented older adults (ZAVEN) composite. RESULTS: Compared with Aβ+ CN older adults, Aβ++ CN older adults showed faster rates of decline across all cognitive composites, with the largest decline observed for ZAVEN composite (d = 1.07). Similarly, compared with Aβ- CN older adults, Aβ+ CN older adults also showed faster rates of cognitive decline, but only for the ADCS-PACC no MMSE (d = 0.43), EM (d = 0.53), and ZAVEN (d = 0.50) composites. DISCUSSION: Aβ-related cognitive decline is best detected using validated neuropsychological instruments. Removal of the MMSE from the ADCS-PACC and replacing it with a test of executive function (verbal fluency; i.e., the ZAVEN) rendered this composite more sensitive even in detecting Aβ-related cognitive decline between Aβ+ and Aβ++ CN older adults.
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    A 'Disease Severity Index' to identify individuals with Subjective Memory Decline who will progress to mild cognitive impairment or dementia
    Ferreira, D ; Falahati, F ; Linden, C ; Buckley, RF ; Ellis, KA ; Savage, G ; Villemagne, VL ; Rowe, CC ; Ames, D ; Simmons, A ; Westman, E (NATURE PUBLISHING GROUP, 2017-03-13)
    Subjective memory decline (SMD) is a heterogeneous condition. While SMD might be the earliest sign of Alzheimer's disease (AD), it also occurs in aging and various neurological, medical, and psychiatric conditions. Identifying those with higher risk to develop dementia is thus a major challenge. We tested a novel disease severity index generated by multivariate data analysis with numerous structural MRI measures as input. The index was used to identify SMD individuals with high risk of progression to mild cognitive impairment (MCI) or AD. A total of 69 healthy controls, 86 SMD, 45 MCI, and 38 AD patients were included. Subjects were followed up for 7.5 years. Clinical, cognitive, PET amyloid imaging and APOE ε4 data were used as outcome variables. The results showed that SMD evidenced cognitive performance intermediate between healthy controls and MCI. The disease severity index identified eleven (13%) SMD individuals with an AD-like pattern of brain atrophy. These individuals showed lower cognitive performance, increased CDR-SOB, higher amyloid burden and worse clinical progression (6.2 times higher likelihood to develop MCI, dementia or die than healthy controls). The current disease severity index may have relevance for clinical practice, as well as for selecting appropriate individuals for clinical trials.
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    Evaluation of Cholinergic Deficiency in Preclinical Alzheimer's Disease Using Pupillometry
    Frost, S ; Robinson, L ; Rowe, CC ; Ames, D ; Masters, CL ; Taddei, K ; Rainey-Smith, SR ; Martins, RN ; Kanagasingam, Y (HINDAWI LTD, 2017-01-01)
    Cortical cholinergic deficiency is prominent in Alzheimer's disease (AD), and published findings of diminished pupil flash response in AD suggest that this deficiency may extend to the visual cortical areas and anterior eye. Pupillometry is a low-cost, noninvasive technique that may be useful for monitoring cholinergic deficits which generally lead to memory and cognitive disorders. The aim of the study was to evaluate pupillometry for early detection of AD by comparing the pupil flash response (PFR) in AD (N = 14) and cognitively normal healthy control (HC, N = 115) participants, with the HC group stratified according to high (N = 38) and low (N = 77) neocortical amyloid burden (NAB). Constriction phase PFR parameters were significantly reduced in AD compared to HC (maximum acceleration p < 0.05, maximum velocity p < 0.0005, average velocity p < 0.005, and constriction amplitude p < 0.00005). The high-NAB HC subgroup had reduced PFR response cross-sectionally, and also a greater decline longitudinally, compared to the low-NAB subgroup, suggesting changes to pupil response in preclinical AD. The results suggest that PFR changes may occur in the preclinical phase of AD. Hence, pupillometry has a potential as an adjunct for noninvasive, cost-effective screening for preclinical AD.
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    Amyloid β-associated cognitive decline in the absence of clinical disease progression and systemic illness.
    Harrington, KD ; Lim, YY ; Ames, D ; Hassenstab, J ; Laws, SM ; Martins, RN ; Rainey-Smith, S ; Robertson, J ; Rowe, CC ; Salvado, O ; Doré, V ; Villemagne, VL ; Snyder, PJ ; Masters, CL ; Maruff, P (Wiley, 2017)
    INTRODUCTION: High levels of amyloid β (Aβ) are associated with cognitive decline in cognitively normal (CN) older adults. This study investigated the nature of cognitive decline in healthy individuals who did not progress to mild cognitive impairment or dementia. METHOD: Cognition was measured over 72 months and compared between low (Aβ-) and high (Aβ+) CN older adults (n = 335) who did not progress to mild cognitive impairment or dementia and who remained free of severe or uncontrolled systemic illness. RESULTS: Compared to the Aβ- group, the Aβ+ group showed no cognitive impairment at baseline but showed substantial decline in verbal learning, episodic memory, and attention over 72 months. DISCUSSION: Moderate cognitive decline, particularly for learning and memory, was associated with Aβ+ in CN older adults in the absence of clinical disease progression and uncontrolled or serious comorbid illness.