Authors: Elias, Alby | Woodward, Michael | Rowe, Christopher C.
Article Type: Research Article
Abstract: Background: 2-[18F]fluoro-2-Deoxy-D-glucose (FDG) positron emission tomography (PET) may assist the diagnosis of dementia but it is an expensive investigation. Objective: To obtain management impact data for FDG-PET in dementia. Methods: This was a prospective study of 194 consecutive patients referred from a memory clinic for FDG-PET at the discretion of the dementia specialists. Diagnosis and management plans formulated at a multidisciplinary patient review meeting were compared before and after the release of PET findings. Results: FDG-PET had moderate to high impact on the diagnosis and management in 85 (44%) participants. Diagnosis changed from probable neurodegenerative disease in 27 patients to …a non-degenerative diagnosis and vice versa in 12 patients. PET changed the type of dementia in another 29 (15%) participants and prescription of cholinesterase inhibitors in 33 patients (17%). Number of uncertain diagnoses reduced from 58 to 35 (p < 0.001, χ2 = 15.12), differential diagnoses reduced from 127 to 55 (p = 0.003) and very probable diagnoses increased from 5 to 42 (p ≤ 0.001, χ2 = 1.01). Mini-Mental State Examination score was higher in those where PET had high diagnostic impact (26.3 ± 3.1 versus 23.9 ± 5.1, p ≤ 0.05). The degree of impact correlated with the pre-scan level of diagnostic uncertainty (ρ = −0.258, p < 0.001). Discussion: The management impact was higher in those with greater diagnostic uncertainty and in those with less severe cognitive impairment. The findings suggest that FDG-PET is a useful adjunct for the management of suspected dementing disorders in appropriately selected patients. Show more
Keywords: Alzheimer's disease, diagnostic impact, FDG-PET, memory clinic
DOI: 10.3233/JAD-132729
Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 885-892, 2014
Authors: Villemagne, Victor L. | Rowe, Christopher C.
Article Type: Review Article
Abstract: The introduction of radiotracers for the non-invasive in vivo quantification of amyloid-β (Aβ) burden in the brain has revolutionized the approach to the evaluation of Alzheimer's disease (AD). Aβ burden as measured by positron emission tomography (PET) matches histopathological reports of Aβ distribution in aging and dementia. It appears more accurate than FDG for the diagnosis of AD, and is an excellent aid in the differential diagnosis of AD from frontotemporal lobar degeneration. Apolipoprotein E ε4 carriers, independent of diagnosis or disease severity, present with higher Aβ burden than non-ε4 carriers. As new therapies enter clinical trials, the role of …Aβ imaging in vivo is becoming increasingly crucial. Aβ imaging allows the in vivo assessment of brain Aβ pathology and its changes over time, providing highly accurate, reliable, and reproducible quantitative statements of regional or global Aβ burden in the brain, essential for therapeutic trial recruitment and for the evaluation of anti-Aβ treatments. Although Aβ burden as assessed by PET does not strongly correlate with cognitive impairment in AD, it does correlate with memory impairment and a higher risk for cognitive decline in the aging population and mild cognitive impairment (MCI) subjects. This correlation with memory impairment, one of the earliest symptoms of AD, suggests that Aβ deposition is not part of normal aging, supporting the hypothesis that Aβ deposition occurs well before the onset of symptoms and likely represents preclinical AD in asymptomatic individuals and prodromal AD in MCI. Further longitudinal observations, coupled with different disease-specific biomarkers to assess potential downstream effects of Aβ, are required to confirm this hypothesis and further elucidate the role of Aβ deposition in the course of AD. Show more
Keywords: Alzheimer's disease, amyloid-β, brain imaging, dementia, positron emission tomography
DOI: 10.3233/JAD-2012-129034
Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S349-S359, 2013
Authors: Liang, Yulin | Doré, Vincent | Rowe, Christopher C. | Krishnadas, Natasha
Article Type: Systematic Review
Abstract: Background: Alzheimer’s disease (AD) is the most common cause of dementia. While preclinical studies have shown benefits of glucagon-like peptide 1 receptor agonists (GLP-1 RA) in targeting core AD pathology, clinical studies are limited. Objective: A systematic review was performed to evaluate GLP-1 RAs in AD for their potential to target core AD pathology and improve cognition. Methods: Searches were conducted via three different databases (PubMed, Embase, and Cochrane Library). Search terms included Medical Subject Headings (MeSH) terms: ‘glucagon-like peptide 1 receptor agonist’ and ‘Alzheimer’s disease’, as well as entry terms ‘GLP-1 RA’, ‘AD’, and three types of GLP-1 RA: …‘liraglutide’, ‘exenatide’, and ‘lixisenatide’. Results: A total of 1,444 studies were screened. Six articles that met criteria were included (four randomized control trials [RCTs] and two protocol studies). Two RCTs with amyloid-β and tau biomarker endpoints did not observe an end of treatment difference between the placebo and treated groups. In three RCTs with cognitive endpoints, there was no end of treatment difference between placebo and treated groups. GLP-1 RA showed metabolic benefits, such as lower body mass index and improved glucose levels on oral glucose tolerance tests in treated groups. GLP-1 RA may mitigate the decline in cerebral glucose metabolism and show enhanced blood-brain glucose transport capacity using 18 F-FDG PET, however, more data is needed. Conclusions: GLP-1 RA therapy did not alter amyloid-β and tau biomarkers nor show improvements in cognition but showed potential metabolic and neuroprotective benefits. Show more
Keywords: Alzheimer’s disease, amyloid, cognition, glucagon-like peptide 1, tau protein
DOI: 10.3233/ADR-230181
Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 777-789, 2024
Authors: Woodward, Michael C. | Rowe, Christopher C. | Jones, Gareth | Villemagne, Victor L. | Varos, Tammie A.
Article Type: Research Article
Abstract: Background: Alzheimer's disease (AD) can present with behavioral changes with this syndrome described as frontal variant AD (FvAD). Excess frontal pathology may explain this presentation. Neuroimaging with fluoro-deoxy-glucose positron emission tomography (FDG- PET) can be used to examine the effects of pathology in FvAD. Methods: We administered an assessment scale for frontal behavioral impairment, the Frontal Behavioral Inventory (FBI), to 53 patients with AD. Scores in the top quartile were defined as FvAD. FDG- PET was analyzed in 8 frontal regions. Results: The Z (SD) score for metabolism was significantly higher (indicating greater hypometabolism) in the FvAD group than the …remaining AD group for combined left and right orbitofrontal regions (2.64 (SD 0.99) versus 2.11 (1.22), p < 0.03)) and combined left and right medial frontal regions (2.38 (0.63) versus 1.82 (0.88) p < 0.003) but insignificantly different in combined lateral frontal and superior frontal regions. Statistical parametric mapping revealed these frontal regions to be the only brain regions with significantly different metabolism between the FvAD and the remainder of the AD groups. Conclusions: Medial and orbital frontal hypometabolism is greater in AD patients presenting with more frontal/behavioral features, likely reflecting a greater pathological load in these brain regions in FvAD patients. These frontal regions may be more linked to behavioral features than other frontal brain regions. Show more
Keywords: Alzheimer's disease, behavioral features versus hypometabolism, degree of hypometabolism, Frontal Behavioral Inventory, frontal variant Alzheimer's disease, FDG- PET, statistical parametric mapping
DOI: 10.3233/JAD-141110
Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 233-242, 2015
Authors: Villemagne, Victor L. | Pike, Kerryn | Pejoska, Svetlana | Boyd, Alison | Power, Margaret | Jones, Gareth | Masters, Colin L. | Rowe, Christopher C.
Article Type: Short Communication
Abstract: Brain amyloid imaging is becoming an essential tool for the pre-mortem evaluation of Alzheimer's disease (AD). This study explores the pattern of 11 C-PiB retention in a subject with Worster-Drought syndrome (WDS). A 55 year-old male carrier of the WDS gene mutation with mild signs of ataxia and subtle cognitive impairment underwent MRI and 11 C-PiB-PET studies. Brain PiB regional distribution was compared to those from cohorts of healthy controls and AD patients. While no significant cortical 11 C-PiB retention was present, a high degree of cerebellar 11 C-PiB retention was observed in a genetically confirmed carrier of the WDS …gene. We speculate that the sparsity of ABri plaques in the neocortex together with its high deposition in the cerebellum, might explain the observed pattern of 11 C-PiB retention. Show more
Keywords: Amyloid, brain imaging, Familial British Dementia, PiB, positron emission tomography, Worster-Drought syndrome
DOI: 10.3233/JAD-2010-1241
Citation: Journal of Alzheimer's Disease, vol. 19, no. 2, pp. 423-428, 2010
Authors: Bahar-Fuchs, Alex | Villemagne, Victor | Ong, Kevin | Chetélat, Gaël | Lamb, Fiona | Reininger, Cornelia B. | Woodward, Michael | Rowe, Christopher C.
Article Type: Research Article
Abstract: Assessment of disease biomarkers, particularly the in vivo assessment of amyloid-β (Aβ) burden with positron emission tomography (PET), is gradually becoming central to the diagnosis of mild cognitive impairment (MCI) due to Alzheimer's disease (AD). However, the incorporation of biomarker evidence to the diagnostic process is currently restricted mainly to research settings. The identification of memory measures that are associated with Aβ is of clinical relevance as this may enhance the confidence in making a diagnosis of MCI due to AD in clinical settings. Forty one persons with amnestic MCI underwent Aβ imaging with 18 F-Florbetaben PET, magnetic resonance imaging, …and a comprehensive neuropsychological assessment. All measures of episodic memory were significantly correlated with Aβ burden, but regression analyses revealed a strong and selective association between story recall and Aβ over and beyond the effects of age, education, global cognition, hippocampal volume, or other memory tests. Analyses of sensitivity and specificity of memory measures to detect high versus low Aβ scans suggested that word-list recall performed better when high sensitivity was preferred, whereas story recall performed better when high specificity was preferred. In conclusion, a measure of story recall may increase the confidence in making a diagnosis of MCI due to AD in clinical settings. Show more
Keywords: Aging, Alzheimer's disease, amyloid imaging, 18F Florbetaben PET, memory, mild cognitive impairment
DOI: 10.3233/JAD-2012-121315
Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 451-462, 2013
Authors: Ramanan, Siddharth | Flanagan, Emma | Leyton, Cristian E. | Villemagne, Victor L. | Rowe, Christopher C. | Hodges, John R. | Hornberger, Michael
Article Type: Research Article
Abstract: Diagnostic distinction of primary progressive aphasias (PPA) remains challenging, in particular for the logopenic (lvPPA) and nonfluent/agrammatic (naPPA) variants. Recent findings highlight that episodic memory deficits appear to discriminate these PPA variants from each other, as only lvPPA perform poorly on these tasks while having underlying amyloid pathology similar to that seen in amnestic dementias like Alzheimer’s disease (AD). Most memory tests are, however, language based and thus potentially confounded by the prevalent language deficits in PPA. The current study investigated this issue across PPA variants by contrasting verbal and non-verbal episodic memory measures while controlling for their performance on …a language subtest of a general cognitive screen. A total of 203 participants were included (25 lvPPA; 29 naPPA; 59 AD; 90 controls) and underwent extensive verbal and non-verbal episodic memory testing, with a subset of patients (n = 45) with confirmed amyloid profiles as assessed by Pittsburgh Compound B and PET. The most powerful discriminator between naPPA and lvPPA patients was a non-verbal recall measure (Rey Complex Figure delayed recall), with 81% of PPA patients classified correctly at presentation. Importantly, AD and lvPPA patients performed comparably on this measure, further highlighting the importance of underlying amyloid pathology in episodic memory profiles. The findings demonstrate that non-verbal recall emerges as the best discriminator of lvPPA and naPPA when controlling for language deficits in high load amyloid PPA cases. Show more
Keywords: Logopenic progressive aphasia, memory, Pittsburgh Compound B, primary progressive aphasia, progressive nonfluent aphasia
DOI: 10.3233/JAD-150752
Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 367-376, 2016
Authors: Lim, Nastasia K.-H. | Villemagne, Victor L. | Soon, Cynthia P.W. | Laughton, Katrina M. | Rowe, Christopher C. | McLean, Catriona A. | Masters, Colin L. | Evin, Genevieve | Li, Qiao-Xin
Article Type: Research Article
Abstract: Pathological changes in the Alzheimer's disease (AD) brain include amyoid-β (Aβ) plaques, and neurofibrillary tangles, as well as neuronal death and synaptic loss. Matrix metalloproteinases MMP-2 and MMP-9 are known to degrade Aβ, and their expressions are increased in the AD brain, in particular in the astrocytes surrounding amyloid plaque. To investigate a possible association between plasma metalloproteinases and AD, we quantified MMP-2 and MMP-9 activities in the plasma of healthy controls (HC, n = 56), cases with mild cognitive impairment (MCI, n = 45), and AD (n = 50). All cases had previously been imaged with Pittsburgh compound B …(PiB) and had a Mini-Mental Status Examination (MMSE) assessment. MMP-2 and MMP-9 activity was determined using gelatine-zymography. There was a significant 1.5-fold decrease in MMP-2 activity in the AD group compared to HC (p < 0.001) and a 1.4-fold decrease compared to MCI (p < 0.01). There was no difference in MMP-9 levels between the three groups. A positive correlation was identified between MMP-2 plasma activity and MMSE score (r = 0.16, p < 0.05), but there was no association with PiB. This is the first report of a change in MMP-2 activity in AD plasma and these findings may provide some insight into AD pathogenesis. Show more
Keywords: Alzheimer's disease, matrix metalloproteinase-2, matrix metalloproteinase-9, mild cognitive impairment, Pittsburgh compound B, plasma biomarker
DOI: 10.3233/JAD-2011-101974
Citation: Journal of Alzheimer's Disease, vol. 26, no. 4, pp. 779-786, 2011
Authors: Watt, Andrew D. | Perez, Keyla A. | Faux, Noel G. | Pike, Kerryn E. | Rowe, Christopher C. | Bourgeat, Pierrick | Salvado, Olivier | Masters, Colin L. | Villemagne, Victor L. | Barnham, Kevin J.
Article Type: Research Article
Abstract: Diagnostic measures for Alzheimer's disease (AD) commonly rely on evaluating the levels of amyloid-β (Aβ) peptides within the cerebrospinal fluid (CSF) of affected individuals. These levels are often combined with levels of an additional non-Aβ marker to increase predictive accuracy. Recent efforts to overcome the invasive nature of CSF collection led to the observation of Aβ species within the blood cellular fraction, however, little is known of what additional biomarkers may be found in this membranous fraction. The current study aimed to undertake a discovery-based proteomic investigation of the blood cellular fraction from AD patients (n = 18) and healthy …controls (HC; n = 15) using copper immobilized metal affinity capture and Surface Enhanced Laser Desorption/Ionisation Time-Of-Flight Mass Spectrometry. Three candidate biomarkers were observed which could differentiate AD patients from HC (ROC AUC > 0.8). Bivariate pairwise comparisons revealed significant correlations between these markers and measures of AD severity including; MMSE, composite memory, brain amyloid burden, and hippocampal volume. A partial least squares regression model was generated using the three candidate markers along with blood levels of Aβ. This model was able to distinguish AD from HC with high specificity (90%) and sensitivity (77%) and was able to separate individuals with mild cognitive impairment (MCI) who converted to AD from MCI non-converters. While requiring further characterization, these candidate biomarkers reaffirm the potential efficacy of blood-based investigations into neurodegenerative conditions. Furthermore, the findings indicate that the incorporation of non-amyloid markers into predictive models, function to increase the accuracy of the diagnostic potential of Aβ. Show more
Keywords: Amyloid-β, biomarkers, blood, copper, diagnostics, SELDI-TOF-MS
DOI: 10.3233/JAD-2010-101722
Citation: Journal of Alzheimer's Disease, vol. 24, no. 1, pp. 47-59, 2011
Authors: Villemagne, Victor L. | Doré, Vincent | Chong, Lee | Kassiou, Michael | Mulligan, Rachel | Feizpour, Azadeh | Taylor, Jack | Roesner, Miriam | Miller, Tamara | Rowe, Christopher C.
Article Type: Research Article
Abstract: Background: 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates intracellular cortisol and its inhibition by the small molecule inhibitor, Xanamem™, may provide a disease-modifying strategy for Alzheimer’s disease (AD). Animal models suggest a range of 30–60% enzyme inhibition may suffice to provide neuroprotection. Objective: To determine the regional brain occupancy of 11β-HSD1 by Xanamem™ in cognitively normal participants (CN) and mild cognitive impairment (MCI)/mild AD patients to investigate potential dosing ranges for future efficacy studies. Methods: Seventeen MCI/AD and 23 CN were included. Regional brain time-activity curves (TAC), standardized uptake values (SUV40–60 ) and volume of distribution (VT ) from Logan plot …with image derived input function from 11 C-TARACT positron emission tomography (PET) were used to assess the degree of 11β-HSD1 occupancy by increasing doses of Xanamem™ (5 mg, 10 mg, 20 mg or 30 mg daily for 7 days). Results: All measures showed high 11β-HSD1 occupancy with Xanamem to similar degree in CN and MCI/AD. The dose-response relationship was relatively flat above 5 mg. Respective median (interquartile range [Q1-Q3]) 11β-HSD1 occupancy in the MCI/AD and CN groups after treatment with 10 mg Xanamem were 80% [79–81%] and 75% [71–76%] in the neocortex, 69% [64–70%] and 61% [52–63%] in the medial temporal lobe, 80% [79–80%] and 73% [68–73%] in the basal ganglia, and 71% [67–75%] and 66% [62–68%] in the cerebellum. Conclusions: TAC, SUV40–60 , and VT measures indicate Xanamem achieves high target occupancy levels with near saturation at 10 mg daily. These data support exploration of doses of≤10 mg daily in future clinical studies. Show more
Keywords: Alzheimer’s disease, 11beta-hydroxysteroid dehydrogenase type 1, cortisol, drug development, positron emission tomography, target occupancy
DOI: 10.3233/JAD-220542
Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1463-1475, 2024
