Christopher C. Rowe

Background: The introduction of therapeutics for Alzheimer's disease has led to increased interest in precisely quantifying amyloid-β (Aβ) burden for diagnosis, treatment monitoring, and further clinical research. Recent positron emission tomography (PET) hardware innovations including digital detectors have led to superior resolution and sensitivity, improving quantitative accuracy. However, the effect of PET scanner on Centiloid remains relatively unexplored and is assumed to be minimized by harmonizing PET resolutions. Objective: To quantify the differences in Centiloid between scanners in a paired cohort. Methods: 36 participants from the Australian Imaging, Biomarker and Lifestyle study (AIBL) cohort were scanned within a year on two scanners. Each participant underwent 18F-NAV4694 imaging on two of the three scanners investigated, the Siemens Vision, the Siemens mCT and the Philips Gemini. We compared Aβ Centiloid quantification between scanners and assessed the effectiveness of post-reconstruction PET resolution harmonization. We further compared the scanner differences in target sub-regions and with different reference regions to assess spatial variability. Results: Centiloid from the Vision camera was found to be significantly higher compared to the Gemini and mCT; the difference was greater at high-Centiloid levels. Post-reconstruction resolution harmonization only accounted for and corrected ∼20% of the Centiloid (CL) difference between scanners. We further demonstrated that residual differences have effects that vary spatially between different subregions of the Centiloid mask. Conclusions: We have demonstrated that the type of PET scanner that a participant is scanned on affects Centiloid quantification, even when scanner resolution is harmonized. We conclude by highlighting the need for further investigation into harmonization techniques that consider scanner differences.

Interventions that substantially slow neurodegeneration are needed to address the growing burden of Alzheimer disease (AD) to societies worldwide. Elevated brain iron observed in AD has been associated with accelerated cognitive decline and may be a tractable drug target. To investigate whether the brain-permeable iron chelator deferiprone slows cognitive decline in people with AD. This phase 2, double-masked, placebo-controlled randomized clinical trial of 12-month duration was conducted at 9 sites in Australia between August 2, 2018, and April 1, 2023. Patients older than 54 years with amyloid-confirmed mild cognitive impairment or early AD (a Mini-Mental State Examination score of 20 or higher) were screened. Randomization was 2:1 and masked to participants and all study staff. Deferiprone 15 mg/kg twice a day or placebo administered orally for 12 months. The primary outcome was a composite cognitive measure assessed at baseline, 6 months, and 12 months using a neuropsychological test battery (NTB) of memory, executive function, and attention tasks. Secondary outcomes included change in brain iron burden measured by quantitative susceptibility mapping (QSM) magnetic resonance imaging (target engagement), brain volume changes (secondary efficacy measure), and adverse events (safety analysis). Of 167 patients screened for eligibility, 81 were included, with 53 randomly assigned to the deferiprone group (mean [SD] age, 73.0 [8.0] years; 29 male [54.7%]) and 28 to the placebo group (mean [SD] age, 71.6 [7.2] years; 17 male [60.7%]); 54 participants completed the study (7 [25.0%] withdrew from the placebo group and 20 [37.7%] from the deferiprone group). In an intention-to-treat analysis, participants in the deferiprone group showed accelerated cognitive decline on the NTB primary outcome (β for interaction = -0.50; 95% CI, -0.80 to -0.20) compared with placebo (change in NTB composite z score for deferiprone, -0.80 [95% CI, -0.98 to -0.62]; for placebo, -0.30 [95% CI, -0.54 to -0.06]). Secondary analysis revealed that this result was driven by worsening performance on executive function tests. The QSM confirmed that deferiprone decreased iron in the hippocampus compared with placebo (change in hippocampal QSM for deferiprone, -0.36 ppb [95% CI, -0.76 to 0.04 ppb]; for placebo, 0.32 ppb [95% CI, -0.12 to 0.75 ppb]; β for interaction = -0.68 [95% CI, -1.27 to -0.09]). Longitudinal hippocampal volume loss was not affected by deferiprone, but exploratory analysis of other brain regions revealed increased volume loss with deferiprone in frontal areas. The frequency of the adverse effect of neutropenia (4 participants [7.5%] in the deferiprone group) was higher than in similar studies (1.6%-4.4%). These trial findings show that deferiprone 15 mg/kg twice a day decreased hippocampal QSM and accelerated cognitive decline in patients with amyloid-confirmed early AD, suggesting that lowering iron with deferiprone is detrimental to patients with AD. ClinicalTrials.gov Identifier: NCT03234686.

Since 2018, a movement has emerged to define Alzheimer disease (AD) as a purely biological entity based on biomarker findings. The recent revision of the Alzheimer's Association (AA) criteria for AD furthers this direction. However, concerns about a purely biological definition of AD being applied clinically, the understanding of AD by society at large, and the translation of blood-based biomarkers into clinical practice prompt these International Working Group (IWG) updated recommendations. To consider the revised AA criteria and to offer an alternative definitional view of AD as a clinical-biological construct for clinical use. The recommendations of the 2021 IWG diagnostic criteria are updated for further elaborating at-risk and presymptomatic states. PubMed was searched for articles published between July 1, 2020, and March 1, 2024, using the terms "biomarker" OR "amyloid" OR "tau" OR "neurodegeneration" OR "preclinical" OR "CSF" OR "PET" OR "plasma" AND "Alzheimer's disease." The references of relevant articles were also searched. In the new AA diagnostic criteria, AD can be defined clinically as encompassing cognitively normal people having a core 1 AD biomarker. However, recent literature shows that the majority of biomarker-positive cognitively normal individuals will not become symptomatic along a proximate timeline. In the clinical setting, disclosing a diagnosis of AD to cognitively normal people with only core 1 AD biomarkers represents the most problematic implication of a purely biological definition of the disease. The ultimate aim of the field was to foster effective AD treatments, including preventing symptoms and dementia. The approach of diagnosing AD without a clinical and biological construct would be unwarranted and potentially concerning without a clear knowledge of when or whether symptoms will ever develop. It is recommended that those who are amyloid-positive only and, more generally, most biomarker-positive cognitively normal individuals, should not be labeled as having AD. Rather, they should be considered as being at risk for AD. The expansion of presymptomatic AD is viewed as a better diagnostic construct for those with a specific pattern of biomarkers, indicating that they are proximate to the expression of symptoms in the near future.

Background: Dietary nitrate, as a nitric oxide (NO) precursor, may support brain health and protect against dementia. Objective: Our primary aim was to investigate whether dietary nitrate is associated with neuroimaging markers of brain health linked with Alzheimer's disease (AD). Methods: Study participants were cognitively unimpaired individuals from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing (AIBL) who had β-amyloid positron emission tomography (PET) scans (n = 554) and magnetic resonance imaging (MRI) scans (n = 335) and had completed a Food Frequency Questionnaire at baseline. Methods: Source-specific nitrate intakes were estimated using comprehensive nitrate food composition databases. Rates of cerebral β-amyloid (Aβ) deposition, measured using PET, and rates of brain atrophy, measured using MRI, were assessed between baseline and 126-months follow-up, at intervals of 18 months. Multivariable-adjusted linear mixed effect models were used to examine associations between baseline source-specific nitrate intake and rates of (i) cerebral Aβ deposition and (ii) brain atrophy, over the 126 months of follow-up. Analyses were carried out following stratification of the sample by established dementia Alzheimer's disease (AD) risk factors including sex and presence or absence of the apolipoprotein E (APOE) ε4 allele. Results: In women carriers of the APOE ε4 allele, higher plant sourced nitrate intake (median intake 121 mg/day), was associated with a slower rate of cerebral Aβ deposition [β: 4.47 versus 8.99 Centiloid (CL) /18 months, p < 0.05] and right hippocampal atrophy [-0.01 versus -0.03 mm3 /18 months, p < 0.01], after multivariable adjustments. Moderate intake showed protective associations in men carriers and in both men and women non-carriers of APOE ε4. Conclusions: Associations were observed between plant-derived nitrate intake and cerebral Aβ deposition, particularly in high-risk populations (women and APOE ε4 carriers). Associations were also observed for brain volume atrophy, however these exhibited subgroup variability without clear patterns relative to sex and APOE ε4 allele carriage. These findings suggest a potential link between plant-sourced nitrate and AD related neuroimaging markers of brain health improved brain health, but further validation in larger studies is required.

Background: Treatment options for low-risk differentiated thyroid cancer (DTC) include active surveillance (AS), hemithyroidectomy (HT), or total thyroidectomy (TT). Improved understanding of patient values and preferences is required to inform shared decision-making. This study examined factors influencing patient treatment preferences and trade-offs for low-risk DTC. Methods: Adult participants with benign thyroid nodules or low-risk DTC completed an online discrete choice experiment (DCE). Utilizing the scenario of a 50-year-old person with a small solitary DTC, participants chose between three unlabeled treatment options (representing AS, HT, and TT). Risk profiles varied across 5 domains: voice change, thyroid hormone supplementation, hypocalcaemia, chance of future thyroid surgery, and 10-year risk of cancer recurrence. Participants self-reported demographics, disease factors, and answered a decisional regret scale. A conditional logit model was utilized. Results: The DCE was completed by 143 patients across three sites. The conditional logit model demonstrated that participants preferred AS (49%) over TT (29%) or HT (22%). All five domains influenced choices (all p < 0.001), but perceived risk of cancer recurrence exerted most influence. Cancer survivors chose AS less often than those with benign disease (46% vs. 57%), driven by perceived risks of further surgery and cancer recurrence. As the perceived risk of cancer recurrence increased, more participants preferred HT over AS. Conclusions: This study demonstrates that when blinded to the actual treatment, patients prefer the trade-offs associated with AS rather than TT or HT. Perceived risk of cancer recurrence exerted the greatest influence. Accurate risk stratification for cancer recurrence is critical to shared decision-making.