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Background: The identification of people at risk of cognitive impairment is essential for improving recruitment in secondary prevention trials of Alzheimer's disease. We aimed to test and qualify a biomarker risk assignment algorithm (BRAA) to identify participants at risk of developing mild cognitive impairment due to Alzheimer's disease within 5 years, and to evaluate the safety and efficacy of low-dose pioglitazone to delay onset of mild cognitive impairment in these at-risk participants. Methods: In this phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled cognitively healthy, community living participants aged 65–83 years from 57 academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. By use of the BRAA, participants were grouped as high risk or low risk. Participants at high risk were randomly assigned 1:1 to receive oral pioglitazone (0·8 mg/day sustained release) or placebo, and all low-risk participants received placebo. Study investigators, site staff, sponsor personnel, and study participants were masked to genotype, risk assignment, and treatment assignment. The planned study duration was the time to accumulate 202 events of mild cognitive impairment due to Alzheimer's disease in White participants who were at high risk (the population on whom the genetic analyses that informed the BRAA development was done). Primary endpoints were time-to-event comparisons between participants at high risk and low risk given placebo (for the BRAA objective), and between participants at high risk given pioglitazone or placebo (for the efficacy objective). The primary analysis included all participants who were randomly assigned, received at least one dose of study drug, and had at least one valid post-baseline visit, with significance set at p=0·01. The safety analysis included all participants who were randomly assigned and received at least one dose of study medication. An efficacy futility analysis was planned for when approximately 33% of the anticipated events occurred in the high-risk, White, non-Hispanic or Latino group. This trial is registered with ClinicalTrials.gov, NCT01931566. Findings: Between Aug 28, 2013, and Dec 21, 2015, we enrolled 3494 participants (3061 at high risk and 433 at low risk). Of those participants, 1545 were randomly assigned to pioglitazone and 1516 to placebo. 1104 participants discontinued treatment (464 assigned to the pioglitazone group, 501 in the placebo high risk group, and 139 in the placebo low risk group). 3399 participants had at least one dose of study drug or placebo and at least one post-baseline follow-up visit, and were included in the efficacy analysis. 3465 participants were included in the safety analysis (1531 assigned to the pioglitazone group, 1507 in the placebo high risk group, and 427 in the placebo low risk group). In the full analysis set, 46 (3·3%) of 1406 participants at high risk given placebo had mild cognitive impairment due to Alzheimer's disease, versus four (1·0%) of 402 participants at low risk given placebo (hazard ratio 3·26, 99% CI 0·85–12·45; p=0·023). 39 (2·7%) of 1430 participants at high risk given pioglitazone had mild cognitive impairment, versus 46 (3·3%) of 1406 participants at high risk given placebo (hazard ratio 0·80, 99% CI 0·45–1·40; p=0·307). In the safety analysis set, seven (0·5%) of 1531 participants at high risk given pioglitazone died versus 21 (1·4%) of 1507 participants at high risk given placebo. There were no other notable differences in adverse events between groups. The study was terminated in January, 2018, after failing to meet the non-futility threshold. Interpretation: Pioglitazone did not delay the onset of mild cognitive impairment. The biomarker algorithm demonstrated a 3 times enrichment of events in the high risk placebo group compared with the low risk placebo group, but did not reach the pre-specified significance threshold. Because we did not complete the study as planned, findings can only be considered exploratory. The conduct of this study could prove useful to future clinical development strategies for Alzheimer's disease prevention studies. Funding: Takeda and Zinfandel.

Objectives/AimsFunctional Cognitive Disorder (FCD) describes distressing or disabling cognitive symptoms that can be positively identified as internally inconsistent with recognised brain or systemic disease processes. FCD is common amongst attendees to cognitive or memory clinics. We aimed to improve the clinical characterisation of such patients, and identify means to differentiate them from patients with early neurodegeneration.MethodsWe identified two samples of patients recruited from a specialist cognitive clinic, classified on the basis of consensus expert clinical opinion following relevant investigations: FCD, (n=21), and neurodegenerative Mild Cognitive Impairment ‘MCI’, (n=17). We also recruited healthy control participants (n=25). All participants completed a cognitive battery: Montreal Cognitive Assessment (MoCA), Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test part B (TMT-B); and the Minnesota Multiphasic Personality Inventory (MMPI-2RF). Analyses included regression models controlling for age and gender. Analysis of the personality data focused on specific hypotheses generated from previous work on functional disorders.ResultsAs expected, the FCD participants were younger than the MCI participants (mean age 58 vs 72), and were more likely to be occupationally active (35% vs 6%).As described previously in this sample*, subjective cognitive symptoms were equally elevated in FCD and MCI compared to controls. Both the FCD and MCI groups were impaired in comparison to controls on MoCA, TMT-B and the initial recall component of HVLT-R. However, FCD participants demonstrated a dip in scores from free recall to recognition on HVLT-R, which was not seen in MCI (pConclusionsCognitive symptoms, basic bedside cognitive testing, personality analysis, and mood symptoms are all similar across both early neurodegenerative and FCD groups, making them hard to disentangle clinically. We hope that by highlighting certain testing modalities that can illustrate internal inconsistency (such as delayed recall spared relative to recognition, as opposed to consistently poor delayed recall and recognition that is more typical of Alzheimer’s neurodegeneration), we can improve diagnosis and thereby management strategies. It is unclear why both mood and non-cognitive somatic symptoms are elevated in both FCD and MCI; this could reflect an epiphenomenon of distress surrounding the cognitive symptoms, despite diverse origins of the cognitive symptoms.ReferencePennington C, Ball HA, Swirski M. Functional cognitive disorder: diagnostic challenges and future directions.Diagnostics 2019; 9: 131.

A substantial body of research evidence is indicative of disproportionately slowed information processing speed in a wide range of multi-trial, computer-based, neuroimaging- and electroencephalography-based reaction time (RT) tests in Alzheimer's disease and mild cognitive impairment (MCI). However, in what is arguably a dichotomy between research evidence and clinical practice, RT associated with different brain functions is rarely assessed as part of their diagnosis. Indeed, often only the time taken to perform a single, specific task, commonly the Trail making test (TMT), is measured. In clinical practice therefore, there can be a failure to assess adequately the integrity of the rapid, serial information processing and response, necessary for efficient, appropriate, and safe interaction with the environment. We examined whether a typical research-based RT task could at least match the TMT in differentiating amnestic MCI (aMCI) from cognitively healthy aging at group level. As aMCI is a heterogeneous group, typically containing only a proportion of individuals for whom aMCI represents the early stages of dementia, we examined the ability of each test to provide intra-group performance variation. The results indicate that as well as significant slowing in performance of the operations involved in TMT part B (but not part A), individuals with aMCI also experience significant slowing in RT compared to controls. The results also suggest that research-typical RT tests may be superior to the TMT in differentiating between cognitively healthy aging and aMCI at group level and in revealing the performance variability one would expect from an etiologically heterogeneous disorder such as aMCI.

Both recognition of familiar objects and pattern separation, a process that orthogonalises overlapping events, are critical for effective memory. Evidence is emerging that human pattern separation requires dentate gyrus. Dentate gyrus is intimately connected to CA3 where, in animals, an autoassociative network enables recall of complete memories to underpin object/event recognition. Despite huge motivation to treat age-related human memory disorders, interaction between human CA3 and dentate subfields is difficult to investigate due to small size and proximity. We tested the hypothesis that human dentate gyrus is critical for pattern separation, whereas, CA3 underpins identical object recognition. Using 3 T MR hippocampal subfield volumetry combined with a behavioural pattern separation task, we demonstrate that dentate gyrus volume predicts accuracy and response time during behavioural pattern separation whereas CA3 predicts performance in object recognition memory. Critically, human dentate gyrus volume decreases with age whereas CA3 volume is age-independent. Further, decreased dentate gyrus volume, and no other subfield volume, mediates adverse effects of aging on memory. Thus, we demonstrate distinct roles for CA3 and dentate gyrus in human memory and uncover the variegated effects of human ageing across hippocampal regions. Accurate pinpointing of focal memory-related deficits will allow future targeted treatment for memory loss.

This research explored whether individuals diagnosed with probable Alzheimer's disease report stable attitudes. Two groups of participants (16 memory-impaired individuals with dementia and 16 matched controls without memory impairment) were presented with photos of various common objects and asked to indicate their attitude towards each object. Participants completed this task on two occasions, separated by 1 week. The results of the experiment revealed that memory-impaired individuals showed significant stability across time in their attitudes, although their level of attitude stability was less pronounced than that demonstrated by the matched controls. Theoretical and applied implications of the results are discussed.

Patients frequently present to the memory clinic with self-reported cognitive symptoms that cannot be attributed to structural, toxic, or metabolic causes, and are out of keeping with their performance on neuropsychological assessment. This can be considered to be Functional (psychosomatic) Cognitive Disorder, which results in significant patient distress and often has a major impact on social functioning and employment. We performed a retrospective analysis of the Bristol ReMemBr group cognitive clinic database to ascertain the prevalence of Functional Cognitive Disorder, review the patient characteristics, and develop new guidelines for diagnosis and management. 196 patients were screened of whom 23 were diagnosed with Functional Cognitive Disorder; the oldest patient with this diagnosis was aged 60 years at symptom onset. When considering only those presenting below the age of 60 years (total no. held on database = 69), a third were diagnosed with Functional Cognitive Disorder. On neuropsychological testing, 47% had an atypical (invalid) pattern of results, or failed tests of performance validity. Of those with valid neuropsychological results, 80% scored in the normal range. Depression and anxiety were common but did not appear to be the primary cause of cognitive symptoms. Particular characteristics seen were excessively low self-rating of memory ability, and discrepancies between perceived and actual cognitive performance. The rate of unemployment was high, often due to the cognitive symptomatology. This is an important disorder to address, being common in working adults, and carrying a risk of misdiagnosis as early neurodegeneration, with subsequent inappropriate treatment and inclusion in clinical trials.

Subjective memory complaints (SMC) are important and may, in certain individuals, herald the onset of neurodegenerative diseases such Alzheimer's disease. However, they are very common and in some individuals will result from mood disorders/personality factors or systemic illnesses. Research has been hampered by the wide variety of criteria and neuropsychological tests used to define this disorder. Different terminology has also hindered the ability to generate generalizable results. We evaluate how subjects with SMC are defined within different research settings (community, primary care, and memory clinic), their rates of progression to mild cognitive impairment and dementia, and how individuals within these contexts differ in terms of complaints, personal characteristics, and help-seeking behavior.

To err is human, and it is normal to make minor cognitive errors from time to time. Some people experience persistent subjective cognitive difficulties that cause distress and functional impairment, with no underlying structural, neurodegenerative, toxic or metabolic cause. This is considered a form of functional disorder. In this article, we review functional cognitive disorder and outline its core clinical features. Patients with this are typically of working age and have a source of psychological distress, such as chronic pain, work stress or family difficulties. Its distinction from incipient dementia is difficult and usually requires interval follow-up. Pointers towards possible dementia include abnormal neuroimaging or loss of insight. Many patients accept a functional cognitive disorder diagnosis and willingly engage with psychological therapies but there is no defined optimal treatment. Functional cognitive disorder is common but under-studied; future research priorities include the development of clear diagnostic criteria and robust trials of therapeutic strategies.

Neuropsychological assessment plays a prominent role in the diagnosis of Alzheimer's disease (AD) and other cognitive impairments. Increasingly, neuropsychological test results are also used to guide clinicians in the prescription of anti-dementia medication. There is evidence to suggest that the cognitive ability of an individual with AD may vary over the course of a day. If time of day can influence an individual's performance on cognitive tests, then it could potentially affect his or her diagnosis and eligibility for treatment. This study set out to explore the effect of time of day on Mini-Mental State Examination (MMSE) performance in individuals with AD and Age-Associated Cognitive Decline (AACD). No significant effect of time of day (TOD) on Folstein MMSE performance was found. However, some interesting results were highlighted and future research suggested. Overall, the study does not provide evidence that time of day needs to be considered when interpreting the result of a short cognitive screening test.

A concurrent speaking paradigm was used to assess the importance of subvocalization during the reading of lengthy natural prose passages. Experiment 1 showed that having subjects count aloud while reading interfered with their comprehension and recall of the text's details as well as its gist, but did not affect the durability of the memory trace. Experiment 2 replicated these findings and established the validity of using concurrent speaking as a technique to interfere with speech-specific processes during silent reading. By pitting concurrent speaking against a nonverbal concurrent task, Experiment 2 provided evidence that its detrimental effect on comprehension was due to a competition for speech-related resources rather than a general competition for cognitive resources. Interfering with speech recoding during silent reading led to an average decrement of 10–12% in comprehension performance. However, Experiment 2 also showed that there were substantial individual differences in the magnitude of the speech interference effect and that these differences were systematically related to subjective reports about the concurrent speaking manipulation.