Service and clinical impacts of reader bias in breast cancer screening: a retrospective study.

OBJECTIVES: To determine factors influencing reader agreement in breast screening and investigate the relationship between agreement level and patient outcomes. METHODS: Reader pair agreement for 83 265 sets of mammograms from the Scottish Breast Screening service (2015-2020) was evaluated using Cohen's kappa statistic. Each mammography examination was read by two readers, per routine screening practice, with the second initially blinded but able to choose to view the first reader's opinion. If the two readers disagreed, a third reader arbitrated. Variation in reader agreement was examined by: whether the reader acted as the first or second reader, reader experience, and recall, cancer detection and arbitration recall rate. RESULTS: Readers' opinions varied by whether they acted as the first or second reader. Furthermore, reader 2 was more likely to agree with reader 1 if reader 1 was more experienced than they were, and less likely to agree if they themselves were more experienced than reader 1 (P < .001). Agreement was not significantly associated with cancer detection rate, overall recall rate or arbitration recall rates (P > .05). Lower agreement between readers led to a higher arbiter workload (P < .001). CONCLUSIONS: In mammography screening, the second reader's opinion is influenced by the first reader's opinion, with the degree of influence dependent on the readers' relative experience levels. ADVANCES IN KNOWLEDGE: While less-experienced readers relied on their more experienced reading partner, no adverse impact on service outcomes was observed. Allowing access to the first reader's opinion may benefit newly qualified readers, but reduces independent evaluation, which may lower cancer detection rates.

Brain PET and SPECT imaging and quantification: a survey of the current status in the UK.

OBJECTIVES: With disease-modifying therapies in development for neurological disorders, quantitative brain imaging techniques become increasingly relevant for objective early diagnosis and assessment of response to treatment. The aim of this study was to evaluate the use of Brain SPECT and PET scans in the UK and explore drivers and barriers to using quantitative analysis through an online survey. METHODS: A web-based survey with 27 questions was used to capture a snapshot of brain imaging in the UK. The survey included multiple-choice questions assessing the availability and use of quantification for DaTscan, Perfusion SPECT, FDG PET and Amyloid PET. The survey results were reviewed and interpreted by a panel of imaging experts. RESULTS: Forty-six unique responses were collected and analysed, with 84% of responses from brain imaging sites. Within these sites, 88% perform DaTscan, 50% Perfusion SPECT, 48% FDG PET, and 33% Amyloid PET, while a few sites use other PET tracers. Quantitative Brain analysis is used in 86% of sites performing DaTscans, 40% for Perfusion SPECT, 63% for FDG PET and 42% for Amyloid PET. Commercial tools are used more frequently than in-house software. CONCLUSION: The survey showed variations across the UK, with high availability of DaTscan imaging and quantification and lower availability of other SPECT and PET scans. The main drivers for quantification were improved reporting confidence and diagnostic accuracy, while the main barriers were a perception of a need for an appropriate database of healthy controls and a lack of training, time, and software availability.

Impact of Different Mammography Systems on Artificial Intelligence Performance in Breast Cancer Screening.

Artificial intelligence (AI) tools may assist breast screening mammography programs, but limited evidence supports their generalizability to new settings. This retrospective study used a 3-year dataset (April 1, 2016-March 31, 2019) from a U.K. regional screening program. The performance of a commercially available breast screening AI algorithm was assessed with a prespecified and site-specific decision threshold to evaluate whether its performance was transferable to a new clinical site. The dataset consisted of women (aged approximately 50-70 years) who attended routine screening, excluding self-referrals, those with complex physical requirements, those who had undergone a previous mastectomy, and those who underwent screening that had technical recalls or did not have the four standard image views. In total, 55 916 screening attendees (mean age, 60 years ± 6 [SD]) met the inclusion criteria. The prespecified threshold resulted in high recall rates (48.3%, 21 929 of 45 444), which reduced to 13.0% (5896 of 45 444) following threshold calibration, closer to the observed service level (5.0%, 2774 of 55 916). Recall rates also increased approximately threefold following a software upgrade on the mammography equipment, requiring per-software version thresholds. Using software-specific thresholds, the AI algorithm would have recalled 277 of 303 (91.4%) screen-detected cancers and 47 of 138 (34.1%) interval cancers. AI performance and thresholds should be validated for new clinical settings before deployment, while quality assurance systems should monitor AI performance for consistency. Keywords: Breast, Screening, Mammography, Computer Applications-Detection/Diagnosis, Neoplasms-Primary, Technology Assessment Supplemental material is available for this article. © RSNA, 2023.

AI in breast screening mammography: breast screening readers' perspectives.

OBJECTIVES: This study surveyed the views of breast screening readers in the UK on how to incorporate Artificial Intelligence (AI) technology into breast screening mammography. METHODS: An online questionnaire was circulated to the UK breast screening readers. Questions included their degree of approval of four AI implementation scenarios: AI as triage, AI as a companion reader/reader aid, AI replacing one of the initial two readers, and AI replacing all readers. They were also asked to rank five AI representation options (discrete opinion; mammographic scoring; percentage score with 100% indicating malignancy; region of suspicion; heat map) and indicate which evidence they considered necessary to support the implementation of AI into their practice among six options offered. RESULTS: The survey had 87 nationally accredited respondents across the UK; 73 completed the survey in full. Respondents approved of AI replacing one of the initial two human readers and objected to AI replacing all human readers. Participants were divided on AI as triage and AI as a reader companion. A region of suspicion superimposed on the image was the preferred AI representation option. Most screen readers considered national guidelines (77%), studies using a nationally representative dataset (65%) and independent prospective studies (60%) as essential evidence. Participants' free-text comments highlighted concerns and the need for additional validation. CONCLUSIONS: Overall, screen readers supported the introduction of AI as a partial replacement of human readers and preferred a graphical indication of the suspected tumour area, with further evidence and national guidelines considered crucial prior to implementation.

Sexual dimorphism in the relationship between brain complexity, volume and general intelligence (g): a cross-cohort study.

Changes in brain morphology have been reported during development, ageing and in relation to different pathologies. Brain morphology described by the shape complexity of gyri and sulci can be captured and quantified using fractal dimension (FD). This measure of brain structural complexity, as well as brain volume, are associated with intelligence, but less is known about the sexual dimorphism of these relationships. In this paper, sex differences in the relationship between brain structural complexity and general intelligence (g) in two diverse geographic and cultural populations (UK and Indian) are investigated. 3D T1-weighted magnetic resonance imaging (MRI) data and a battery of cognitive tests were acquired from participants belonging to three different cohorts: Mysore Parthenon Cohort (MPC); Aberdeen Children of the 1950s (ACONF) and UK Biobank. We computed MRI derived structural brain complexity and g estimated from a battery of cognitive tests for each group. Brain complexity and volume were both positively corelated with intelligence, with the correlations being significant in women but not always in men. This relationship is seen across populations of differing ages and geographical locations and improves understanding of neurobiological sex-differences.

The Role of redo-Sentinel Lymph Node Biopsy in Patients With Prior Ipsilateral Breast Cancer Surgery.

BACKGROUND: Sentinel Lymph Node Biopsy (SLNB) is used to stage the axilla, but there is limited data in patients with prior ipsilateral breast cancer. This study compares redo-SLNB (reSLNB) and Axillary node sample (ANS) in this sub-cohort of patients. MATERIALS AND METHODS: This is a retrospective study looking at patients with a new ipsilateral primary or recurrence with history of breast-conserving surgery. Planned and performed surgery, patient demographics and previous treatments were recorded. Node positivity and success rate of reSLNB was analyzed. RESULTS: A total of 86 patients were identified that had mastectomy for ipsilateral recurrent disease with radiologically negative axilla. Out of the 48 that had reSLNB, 35(72.9%) were successful. Nineteen percent of the reSLNB had positive axillae and 20% of the ANS patients. reSLNB success rate was significantly lower amongst patients with previous axillary surgery (P = .014) and previous positive nodes(P = .001). CONCLUSION: reSLNB should be considered to restage the axilla in patients with previous history of ipsilateral cancer especially that there is growing evidence showing good identification rate.

Cognitive Test Scores and Progressive Cognitive Decline in the Aberdeen 1921 and 1936 Birth Cohorts.

The Aberdeen birth cohorts of 1921 and 1936 (ABC21 and ABC36) were subjected to IQ tests in 1932 or 1947 when they were aged about 11y. They were recruited between 1997-2001 among cognitively healthy community residents and comprehensively phenotyped in a long-term study of brain aging and health up to 2017. Here, we report associations between baseline cognitive test scores and long-term cognitive outcomes. On recruitment, significant sex differences within and between the ABC21 and ABC36 cohorts supported advantages in verbal ability and learning among the ABC36 women that were not significant in ABC21. Comorbid physical disorders were self-reported in both ABC21 and ABC36 but did not contribute to differences in terms of performance in cognitive tests. When used alone without other criteria, cognitive tests scores which fell below the -1.5 SD criterion for tests of progressive matrices, namely verbal learning, digit symbol and block design, did not support the concept that Mild Cognitive Impairment (MCI) is a stable class of acquired loss of function with significant links to the later emergence of a clinical dementia syndrome. This is consistent with many previous reports. Furthermore, because childhood IQ-type data were available, we showed that a lower cognitive performance at about 64 or 78 y than that predicted by IQ at 11 ± 0.5 y did not improve the prediction of progress to MCI or greater cognitive loss. We used binary logistic regression to explore how MCI might contribute to the prediction of later progress to a clinical dementia syndrome. In a fully adjusted model using ABC21 data, we found that non-amnestic MCI, along with factors such as female sex and depressive symptoms, contributed to the prediction of later dementia. A comparable model using ABC36 data did not do so. We propose that (1) MCI criteria restricted to cognitive test scores do not improve the temporal stability of MCI classifications; (2) pathways towards dementia may differ according to age at dementia onset and (3) the concept of MCI may require measures (not captured here) that underly self-reported subjective age-related cognitive decline.

Degeneration of basal and limbic networks is a core feature of behavioural variant frontotemporal dementia.

The behavioural variant of frontotemporal dementia is a clinical syndrome characterized by changes in behaviour, cognition and functional ability. Although atrophy in frontal and temporal regions would appear to be a defining feature, neuroimaging studies have identified volumetric differences distributed across large parts of the cortex, giving rise to a classification into distinct neuroanatomical subtypes. Here, we extended these neuroimaging studies to examine how distributed patterns of cortical atrophy map onto brain network hubs. We used baseline structural magnetic resonance imaging data collected from 213 behavioural variant of frontotemporal dementia patients meeting consensus diagnostic criteria and having definite evidence of frontal and/or temporal lobe atrophy from a global clinical trial conducted in 70 sites in Canada, United States of America, Australia, Asia and Europe. These were compared with data from 244 healthy elderly subjects from a well-characterized cohort study. We have used statistical methods of hierarchical agglomerative clustering of 68 regional cortical and subcortical volumes (34 in each hemisphere) to determine the reproducibility of previously described neuroanatomical subtypes in a global study. We have also attempted to link the structural findings to clinical features defined systematically using well-validated clinical scales (Addenbrooke's Cognitive Examination Revised, the Mini-Mental Status Examination, the Frontotemporal Dementia Rating Scale and the Functional Assessment Questionnaire) and subscales derived from them. Whilst we can confirm that the subtypes are robust, they have limited value in explaining the clinical heterogeneity of the syndrome. We have found that a common pattern of degeneration affecting a small number of subcortical, limbic and frontal nodes within highly connected networks (most previously identified as rich club members or functional binding nodes) is shared by all the anatomical subtypes. Degeneration in these core regions is correlated with cognitive and functional impairment, but less so with behavioural impairment. These findings suggest that degeneration in highly connected basal, limbic and frontal networks is a core feature of the behavioural variant of frontotemporal dementia phenotype irrespective of neuroanatomical and clinical heterogeneity, and may underly the impairment of integration in cognition, function and behaviour responsible for the loss of insight that characterizes the syndrome.

Long-Term Hydromethylthionine Treatment Is Associated with Delayed Clinical Onset and Slowing of Cerebral Atrophy in a Pre-Symptomatic P301S MAPT Mutation Carrier.

One of the mutations in the microtubule-associated protein tau, P301S, is causative for dominantly inherited frontotemporal dementia characterized by extensive tau pathology for which no licensed treatment is available. Hydromethylthionine is a potent tau aggregation inhibitor. We report treatment of an asymptomatic carrier of the P301S mutation using hydromethylthionine over a 5-year period beginning at the mean age of onset of clinical decline in the family. During the period of treatment, the rates of progression of cerebral atrophy were reduced by 61%-66% in frontal and temporal lobes, and the patient remained clinically asymptomatic.

Detectability of small objects in PET/computed tomography phantom images with Bayesian penalised likelihood reconstruction.

OBJECTIVES: This study investigated the subcentimetre lesion detection gains of a Bayesian penalised likelihood reconstruction (BPLR) (Q.Clear, GE Healthcare, Milwaukee, USA) in PET/computed tomography (CT) phantom images and compares observer performance with ordered subset expectation maximisation (OSEM) reconstruction images (VUE Point HD, GE Healthcare). METHODS: Images were presented to three blinded experienced observers to identify lesions and assign confidence ratings. Responses were analysed using jackknife alternative free receiver operator characteristic (JAFROC) software. Phantom lesions (active and nonactive) were constructed using putty. Seventy nonactive and 93 (F) active lesions, with diameters of 3, 5 or 7 mm were suspended in active backgrounds at varying contrast ratios (2:1-32:1) within an National Electrical Manufacturers Association 2012 phantom. PET/CT images were acquired with a GE Discovery 710 and reconstructed using both BPLR (penalisation coefficient 400) and high-definition attenuation corrected (HDAC) OSEM (2 iterations, 24 subsets). RESULTS: Small but significant (P = 0.009) visual detection gains were seen for active lesions with BPLR [weighted JAFROC figure of merit (wJAFROC FOM) = 0.77] over OSEM (FOM = 0.74). When split by subset, these improvements were significant for 5 mm and lesion to background ratio of 8:1. No significant (P = 0.514) differences were seen for the identification of nonactive lesions of any size (BPLR FOM = 0.74 and OSEM FOM = 0.73). CONCLUSIONS: Significant detection gains were demonstrated for small active lesions with BPLR over OSEM. Coupled with the significant increase in contrast-to-noise ratio, these results support the use of BPLR in the imaging of small active (≤7 mm) lesions but show no improvement with BPLR in the identification of true negative lesions.

Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia.

BACKGROUND: Hydromethylthionine is a potent inhibitor of pathological aggregation of tau and TDP-43 proteins. OBJECTIVE: To compare hydromethylthionine treatment effects at two doses and to determine how drug exposure is related to treatment response in bvFTD. METHODS: We undertook a 52-week Phase III study in 220 bvFTD patients randomized to compare hydromethylthionine at 200 mg/day and 8 mg/day (intended as a control). The principal outcomes were change on the Addenbrookes Cognitive Examination - Revised (ACE-R), the Functional Activities Questionnaire (FAQ), and whole brain volume. Secondary outcomes included Modified Clinical Global Impression of Change (Modified-CGIC). A population pharmacokinetic exposure-response analysis was undertaken in 175 of the patients with available blood samples and outcome data using a discriminatory plasma assay for the parent drug. RESULTS: There were no significant differences between the two doses as randomized. There were steep concentration-response relationships for plasma levels in the range 0.3-0.6 ng/ml at the 8 mg/day dose on clinical and MRI outcomes. There were significant exposure-dependent differences at 8 mg/day for FAQ, Modified-CGIC, and whole brain atrophy comparing patients with plasma levels greater than 0.346 ng/ml with having minimal drug exposure. The exposure-response is biphasic with worse outcomes at the high concentrations produced by 200 mg/day. CONCLUSIONS: Hydromethylthionine has a similar concentration-response profile for effects on clinical decline and brain atrophy at the 8 mg/day dose in bvFTD as recently reported in AD. Treatment responses in bvFTD are predicted to be maximal at doses in the range 20-60 mg/day. A confirmatory placebo-controlled trial is now planned.

Motion During Acquisition is Associated With fMRI Brain Entropy.

Measures of fMRI brain entropy have been used to investigate age and disease related neural changes. However, it is unclear if movement in the scanner is associated with brain entropy after geometric correction for movement. As age and disease can affect motor control, quantifying and correcting for the influence of movement will avoid false findings. This paper examines the influence of head motion on fMRI brain entropy. Resting-state and task-based fMRI data from 281 individuals born in Aberdeen between 1950 and 1956 were analyzed. The images were realigned, followed by nuisance regression of the head motion parameters. The images were either high-pass filtered (0.008 Hz) or band-pass (0.008-0.1 Hz) filtered in order to compare the two methods; fuzzy approximate entropy and fuzzy sample entropy were calculated for every voxel. Motion was quantified as the mean displacement and mean rotation in three dimensions. Greater mean motion was correlated with decreased entropy for all four methods of calculating entropy. Different movement characteristics produce different patterns of associations, which appear to be artefact. However, across all motion metrics, entropy calculation methods, and scan conditions, a number of regions consistently show a significant negative association: the right cerebellar crus, left precentral gyrus (primary motor cortex), the left postcentral gyrus (primary somatosensory cortex), and the opercular part of the left inferior frontal gyrus. The robustness of our findings at these locations suggests that decreased entropy in specific brain regions may be a marker for decreased motor control.

Klotho gene polymorphism, brain structure and cognition in early-life development.

Variation in the klotho gene is linked to differences in health outcomes: klotho allele KL-VS heterozygosity is associated with longevity, better cognition and greater right frontal grey matter volume in late life. Contradicting reports, however, suggest that KL-VS's effect on health might be age-dependent. Here we examine the relationship between KL-VS genotype, cognition and brain structure in childhood and adolescence. We hypothesized that KL-VS has early influences on cognitive and brain development. We investigated the associations of KL-VS carrier status with cognition and brain morphology in a cohort of 1387 children and adolescents aged 3-21 years, examining main effects and interactions between age, sex and socioeconomic circumstance. KL-VS had no main effect on either cognition or brain structure, though there was a significant KL-VS × age interaction for cognition (specifically executive function, attention, episodic memory, and general cognition), total grey matter and total brain volume. KL-VS heterozygotes had better cognition than non-carriers before age 11, but lower cognition after age 11. Heterozygotes had smaller brains than non-carriers did in early childhood. Sex moderated the association between KL-VS and white matter volume. Among girls, KL-VS heterozygotes had smaller white matter volumes than non-carriers. Among boys, heterozygotes had greater white matter volumes than non-carriers. However, a replication in a cohort of 2306 children aged 6-12 years showed no significant associations. In contrast to findings in late life, these results show that KL-VS does not have a main effect on cognition and brain structure. Furthermore, KL-VS's influence may depend on age and sex.

Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer's Disease.

BACKGROUND: Although hydromethylthionine is a potent tau aggregation inhibitor, no difference was found in either of two Phase III trials in mild to moderate Alzheimer's disease (AD) comparing doses in the range 150-250 mg/day with 8 mg/day intended as a control. OBJECTIVE: To determine how drug exposure is related to treatment response. METHODS: A sensitive plasma assay for the drug was used in a population pharmacokinetic analysis of samples from 1,162 of the 1,686 patients who participated in either of the Phase III trials with available samples and efficacy outcome data. RESULTS: There are steep concentration-response relationships for steady state plasma levels in the range 0.3-0.8 ng/ml at the 8 mg/day dose. Using a threshold based on the lower limit of quantitation of the assay on Day 1, there are highly significant differences in cognitive decline and brain atrophy in patients with above threshold plasma levels, both for monotherapy and add-on therapy, but with effect sizes reduced by half as add-on. Plasma concentrations in the range 4-21 ng/ml produced by the high doses are not associated with any additional benefit. CONCLUSIONS: Hydromethylthionine has pharmacological activity on brain structure and function at the 8 mg/day dose as monotherapy or as add-on to symptomatic treatments. This combined with a plateau at higher doses is consistent with the lack of dose-response seen in the Phase III trials. Treatment benefit is predicted to be maximal at 16 mg/day as monotherapy. A placebo-controlled trial in mild/moderate AD is now ongoing to confirm efficacy at this dose.

What are the earlier life contributions to reserve and resilience?

The brain's structures and functions arise from a combination of developmental processes and interaction with environmental experiences, beginning in utero and continuing throughout the lifespan. Broadly, the process that we think of as "successful aging" likely has its foundation in early life and is continuously shaped as life experiences are programmed into the brain in response to a changing environment. Thus, individual lifestyle choices and interventions aimed at increasing cognitive reserve and resilience could change the course of cognitive aging. To determine the relative efficacy of these approaches, we will need to understand how the timing of these interventions (e.g., age, duration, frequency) influences cognitive capacity through the lifespan. Although analysis of age-related changes in cognitive function reveals a general decline at the population level, it has become clear that there is great individual variance in the extent to which cognitive function changes with advanced age. The factors responsible for the individual differences in cognitive decline are unclear, but uncovering them with new analytical tools, epigenetic approaches, and subpopulation studies will provide a roadmap toward enhancing reserve and resilience in the population at large and preserving cognitive function in a greater number of aging individuals.

Cortical Thickness and Surface Area Networks in Healthy Aging, Alzheimer's Disease and Behavioral Variant Fronto-Temporal Dementia.

Models of the human brain as a complex network of inter-connected sub-units are important in helping to understand the structural basis of the clinical features of neurodegenerative disorders. The aim of this study was to characterize in a systematic manner the differences in the structural correlation networks in cortical thickness (CT) and surface area (SA) in Alzheimer's disease (AD) and behavioral variant Fronto-Temporal Dementia (bvFTD). We have used the baseline magnetic resonance imaging (MRI) data available from a large population of patients from three clinical trials in mild to moderate AD and mild bvFTD and compared this to a well-characterized healthy aging cohort. The study population comprised 202 healthy elderly subjects, 213 with bvFTD and 213 with AD. We report that both CT and SA network architecture can be described in terms of highly correlated networks whose positive and inverse links map onto the intrinsic modular organization of the four cortical lobes. The topology of the disturbance in structural network is different in the two disease conditions, and both are different from normal aging. The changes from normal are global in character and are not restricted to fronto-temporal and temporo-parietal lobes, respectively, in bvFTD and AD, and indicate an increase in both global correlational strength and in particular nonhomologous inter-lobar connectivity defined by inverse correlations. These inverse correlations appear to be adaptive in character, reflecting coordinated increases in CT and SA that may compensate for corresponding impairment in functionally linked nodes. The effects were more pronounced in the cortical thickness atrophy network in bvFTD and in the surface area network in AD. Although lobar modularity is preserved in the context of neurodegenerative disease, the hub-like organization of networks differs both from normal and between the two forms of dementia. This implies that hubs may be secondary features of the connectivity adaptation to neurodegeneration and may not be an intrinsic property of the brain. However, analysis of the topological differences in hub-like organization CT and SA networks, and their underlying positive and negative correlations, may provide a basis for assisting in the differential diagnosis of bvFTD and AD.

Intellectual engagement and cognitive ability in later life (the "use it or lose it" conjecture): longitudinal, prospective study.

OBJECTIVES: To examine the association between intellectual engagement and cognitive ability in later life, and determine whether the maintenance of intellectual engagement will offset age related cognitive decline. DESIGN: Longitudinal, prospective, observational study. SETTING: Non-clinical volunteers in late middle age (all born in 1936) living independently in northeast Scotland. PARTICIPANTS: Sample of 498 volunteers who had taken part in the Scottish Mental Health Survey of 1947, from one birth year (1936). MAIN OUTCOME MEASURES: Cognitive ability and trajectory of cognitive decline in later life. Typical intellectual engagement was measured by a questionnaire, and repeated cognitive measurements of information processing speed and verbal memory were obtained over a 15 year period (recording more than 1200 longitudinal data points for each cognitive test). RESULTS: Intellectual engagement was significantly associated with level of cognitive performance in later life, with each point on a 24 point scale accounting for 0.97 standardised cognitive performance (IQ-like) score, for processing speed and 0.71 points for memory (both P<0.05). Engagement in problem solving activities had the largest association with life course cognitive gains, with each point accounting for 0.43 standardised cognitive performance score, for processing speed and 0.36 points for memory (both P<0.05). However, engagement did not influence the trajectory of age related decline in cognitive performance. Engagement in intellectual stimulating activities was associated with early life ability, with correlations between engagement and childhood ability and education being 0.35 and 0.22, respectively (both P<0.01). CONCLUSION: These results show that self reported engagement is not associated with the trajectory of cognitive decline in late life, but is associated with the acquisition of ability during the life course. Overall, findings suggest that high performing adults engage and those that engage more being protected from relative decline.

Potential of Low Dose Leuco-Methylthioninium Bis(Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimer's Disease: Cohort Analysis as Modified Primary Outcome in a Phase III Clinical Trial.

BACKGROUND: LMTM is being developed as a treatment for AD based on inhibition of tau aggregation. OBJECTIVES: To examine the efficacy of LMTM as monotherapy in non-randomized cohort analyses as modified primary outcomes in an 18-month Phase III trial in mild AD. METHODS: Mild AD patients (n = 800) were randomly assigned to 100 mg twice a day or 4 mg twice a day. Prior to unblinding, the Statistical Analysis Plan was revised to compare the 100 mg twice a day as monotherapy subgroup (n = 79) versus 4 mg twice a day as randomized (n = 396), and 4 mg twice a day as monotherapy (n = 76) versus 4 mg twice a day as add-on therapy (n = 297), with strong control of family-wise type I error. RESULTS: The revised analyses were statistically significant at the required threshold of p < 0.025 in both comparisons for change in ADAS-cog, ADCS-ADL, MRI atrophy, and glucose uptake. The brain atrophy rate was initially typical of mild AD in both add-on and monotherapy groups, but after 9 months of treatment, the rate in monotherapy patients declined significantly to that reported for normal elderly controls. Differences in severity or diagnosis at baseline between monotherapy and add-on patients did not account for significant differences in favor of monotherapy. CONCLUSIONS: The results are consistent with earlier studies in supporting the hypothesis that LMTM might be effective as monotherapy and that 4 mg twice a day may serve as well as higher doses. A further suitably randomized trial is required to test this hypothesis.

Klotho, APOEε4, cognitive ability, brain size, atrophy, and survival: a study in the Aberdeen Birth Cohort of 1936.

A single copy of klotho allele KL-VS is associated with longevity, better health, increased cognition, and bigger regional brain volume. However, its longitudinal effects on cognition and brain volumes, both global and regional, in late life are unclear. In this study we show that, relative to noncarriers, KL-VS heterozygotes had (1) shorter survival; (2) smaller white matter volumes; (3) slower cognitive decline; and (4) greater right frontal lobe volumes. The KL-VS heterozygote survival and white matter volume disadvantages were unexpected. A possible explanation for these results in the context of the literature is a potential interaction between the environment and/or age of the participants, leading to a heterozygote disadvantage. The longitudinal cognitive trajectories indicate that heterozygotes would have an advantage in very late life. Collectively these results suggest that the genotype-survival advantage of the KL-VS allele is age-dependent and possibly mediated through differential cognition and brain volume.