Challenges in a Biological Definition of Alzheimer Disease.

It has been suggested that the diagnostic landscape of Alzheimer disease (AD) is undergoing a profound transformation, marked by a shift toward a biomarker-based approach, as proposed by the Revised Criteria for Diagnosis and Staging of Alzheimer's Disease. These criteria advocate for diagnosing AD solely on biomarkers, without requiring clinical symptoms. This article explores the drivers behind this transition, primarily influenced by the Food and Drug Administration's approval of amyloid-lowering treatments. We evaluate the proposed criteria, which allow for an AD diagnosis based on amyloid "A" or phosphorylated tau "T1" positivity through surrogate amyloid PET imaging, CSF, or plasma biomarkers, and consider the arguments for and against their use. The merits of the new criteria include a clearer definition of AD, which is currently used interchangeably to refer to both the presence of neuropathology and the clinical syndrome. We argue that a purely biological definition risks a category error and emphasize the need for longitudinal data to establish the lifetime risk of dementia in amyloid-positive and tau-positive individuals. We also caution against limiting the scope of biomarker-based AD diagnosis to amyloid and tau alone. In conclusion, we recommend that the criteria remain within the research domain for the present while advocating for the considered adoption of plasma biomarkers in clinical practice.

Dementia diagnosis rates and the impact of ethnicity, rurality and deprivation.

OBJECTIVES: NHS England publishes monthly national and regional estimated dementia diagnosis rates (DDR) to assess the healthcare system's effectiveness in identifying dementia cases. Previous research indicates that sociodemographic factors, such as ethnic minority status, socioeconomic deprivation, and rurality, influence both healthcare quality and dementia risk. This study aimed to examine the association between these sociodemographic factors and DDR, and to estimate an ethnicity-adjusted DDR using available ethnic group data. METHOD: We analysed NHS Digital Primary Care Dementia Data electronic health records for July 2023. We used a linear regression model to determine the association between DDR and ethnicity, deprivation, and rurality factors using local authority region level data. We also adjusted the DDR at the level of sub-integrated care boards based on previously published odds ratios of dementia diagnosis by ethnic group. RESULTS: Regression modelling revealed that areas with higher proportions of minority ethnic groups and greater rurality had lower DDRs. Conversely, higher levels of deprivation were linked to higher DDRs. After adjusting for different odds ratios for dementia in minority ethnic groups, the national DDR decreased by 1%, with regional diagnosis rates dropping by up to 5.4%. CONCLUSION: Higher regional proportional ethnic minority population and greater rurality were associated with a lower DDR which might reflect poorer access to diagnostic services. Higher deprivation levels were associated with a higher DDR which might reflect higher rates of dementia in more deprived populations. We discuss measures to improve the accuracy and utility of the DDR, with a specific focus on ethnicity.

The promise of molecular science in brain health. What breakthroughs are anticipated in the next 20 years?

Brain health means optimal physiological brain function across the normal life-course. It encompasses not only healthy brain aging but also brain diseases, their diagnosis and treatment. In all these areas, molecular science has advanced our understanding. This multi-disciplinary review combines viewpoints from laboratory science, clinical medicine and the bioscience industry. First, we review the advances that molecular science has brought to brain health in the past twenty years. These include therapeutic antibodies for CNS diseases (multiple sclerosis, Alzheimer disease) and the dramatic introduction of RNA-targeted therapeutics. Second, we highlight areas where greater molecular understanding is needed. Salient examples are the relation of brain structure to cognitive symptoms, and molecular biomarkers for diagnosis, target discovery and testing of interventions. Finally, we speculate on aspects of molecular science that are likely to advance brain health in the next twenty years. These include: cell senescence and chronobiology; gene editing (notably, CRISPR) and RNA targeting (RNA interference, miRNA manipulation); brain-immune interactions; novel drug targets (AQP4, HIF1, Toll-like receptors); and novel chemistry to make new drugs (molecular machines, quantum molecular modelling and "click" chemistry). Early testing of the relationships between molecular pathways and clinical manifestations will drive much-needed breakthroughs in neurology and psychiatry.

Perspectives on the diagnosis and management of functional cognitive disorder: An international Delphi study.

BACKGROUND: Current proposed criteria for functional cognitive disorder (FCD) have not been externally validated. We sought to analyse the current perspectives of cognitive specialists in the diagnosis and management of FCD in comparison with neurodegenerative conditions. METHODS: International experts in cognitive disorders were invited to assess seven illustrative clinical vignettes containing history and bedside characteristics alone. Participants assigned a probable diagnosis and selected the appropriate investigation and treatment. Qualitative, quantitative and inter-rater agreement analyses were undertaken. RESULTS: Eighteen diagnostic terminologies were assigned by 45 cognitive experts from 12 countries with a median of 13 years of experience, across the seven scenarios. Accurate discrimination between FCD and neurodegeneration was observed, independently of background and years of experience: 100% of the neurodegenerative vignettes were correctly classified and 75%-88% of the FCD diagnoses were attributed to non-neurodegenerative causes. There was <50% agreement in the terminology used for FCD, in comparison with 87%-92% agreement for neurodegenerative syndromes. Blood tests and neuropsychological evaluation were the leading diagnostic modalities for FCD. Diagnostic communication, psychotherapy and psychiatry referral were the main suggested management strategies in FCD. CONCLUSIONS: Our study demonstrates the feasibility of distinguishing between FCD and neurodegeneration based on relevant patient characteristics and history details. These characteristics need further validation and operationalisation. Heterogeneous labelling and framing pose clinical and research challenges reflecting a lack of agreement in the field. Careful consideration of FCD diagnosis is advised, particularly in the presence of comorbidities. This study informs future research on diagnostic tools and evidence-based interventions.

Estimating demand for potential disease-modifying therapies for Alzheimer's disease in the UK.

BACKGROUND: Phase three trials of the monoclonal antibodies lecanemab and donanemab, which target brain amyloid, have reported statistically significant differences in clinical end-points in early Alzheimer's disease. These drugs are already in use in some countries and are going through the regulatory approval process for use in the UK. Concerns have been raised about the ability of healthcare systems, including those in the UK, to deliver these treatments, considering the resources required for their administration and monitoring. AIMS: To estimate the scale of real-world demand for monoclonal antibodies for Alzheimer's disease in the UK. METHOD: We used anonymised patient record databases from two National Health Service trusts for the year 2019 to collect clinical, demographic, cognitive and neuroimaging data for these cohorts. Eligibility for treatment was assessed using the inclusion criteria from the clinical trials of donanemab and lecanemab, with consideration given to diagnosis, cognitive performance, cerebrovascular disease and willingness to receive treatment. RESULTS: We examined the records of 82 386 people referred to services covering around 2.2 million people. After applying the trial criteria, we estimate that a maximum of 906 people per year would start treatment with monoclonal antibodies in the two services, equating to 30 200 people if extrapolated nationally. CONCLUSIONS: Monoclonal antibody treatments for Alzheimer's disease are likely to present a significant challenge for healthcare services to deliver in terms of the neuroimaging and treatment delivery. The data provided here allows health services to understand the potential demand and plan accordingly.

Mild cognitive impairment: not much harm; not much help.

Mild cognitive impairment (MCI) represents a liminal state between full cognitive health and dementia. The diagnosis is applied unevenly and cannot be accurately prognosticated, even with the use of biomarkers, and there is no established intervention to reduce risk of progression to dementia. Owing to the limited benefit and potential for iatrogenic harm associated with an MCI diagnosis, a better understanding of its psychosocial consequences is needed. In the linked paper, Munawar and colleagues provide cautious optimism; their patients were generally unharmed by an MCI diagnosis. However, the majority of patients and families either did not recall or did not fully understand the implications for future dementia risk. Only 20% made lifestyle changes, and the number receiving hearing aids was very low. These data demonstrate the poor return on using the clinic as the setting for improving 'brain health'. Initiatives to prevent dementia are more effectively and equitably applied at population level.

Testing the cognitive effects of tadalafil. Neuropsychological secondary outcomes from the PASTIS trial.

Cerebral small vessel disease (SVD) is a major cause of cognitive impairment in older people. As secondary endpoints in a phase-2 randomised clinical trial, we tested the effects of single administration of a widely-used PDE5 inhibitor, tadalafil, on cognitive performance in older people with SVD. In a double-blinded, placebo-controlled, cross-over trial, participants received tadalafil (20 mg) and placebo on two visits ≥ 7 days apart (randomised to order of treatment). The Montreal Cognitive Assessment (MOCA) was administered at baseline, alongside a measure to estimate optimal intellectual ability (Test of Premorbid Function). Then, before and after treatment, a battery of neuropsychological tests was administered, assessing aspects of attention, information processing speed, working memory and executive function. Sixty-five participants were recruited and 55 completed the protocol (N = 55, age: 66.8 (8.6) years, range 52-87; 15/40 female/male). Median MOCA score was 26 (IQR: 23, 27], range 15-30). No significant treatment effects were seen in any of the neuropsychological tests. There was a trend towards improved performance on Digit Span Forward (treatment effect 0.37, C.I. 0.01, 0.72; P = 0.0521). We did not identify significant treatment effects of single-administration tadalafil on neuropsychological performance in older people with SVD. The trend observed on Digit Span Forward may help to inform future studies. Clinical trial registration: http://www.clinicaltrials.gov. Unique identifier: NCT00123456, https://eudract.ema.europa.eu. Unique identifier: 2015-001,235-20NCT00123456.

PDE5 inhibitor drugs for use in dementia.

Alzheimer's disease and related dementias (ADRD) remain a major health-care challenge with few licensed medications. Repurposing existing drugs may afford prevention and treatment. Phosphodiesterase-5 (PDE5) is widely expressed in vascular myocytes, neurons, and glia. Potent, selective, Food and Drug Administration-approved PDE5 inhibitors are already in clinical use (sildenafil, vardenafil, tadalafil) as vasodilators in erectile dysfunction and pulmonary arterial hypertension. Animal data indicate cognitive benefits of PDE5 inhibitors. In humans, real-world patient data suggest that sildenafil and vardenafil are associated with reduced dementia risk. While a recent clinical trial of acute tadalafil on cerebral blood flow was neutral, there may be chronic actions of PDE5 inhibition on cerebrovascular or synaptic function. We provide a perspective on the potential utility of PDE5 inhibitors for ADRD. We conclude that further prospective clinical trials with PDE5 inhibitors are warranted. The choice of drug will depend on brain penetration, tolerability in older people, half-life, and off-target effects. HIGHLIGHTS: Potent phosphodiesterase-5 (PDE5) inhibitors are in clinical use as vasodilators.In animals PDE5 inhibitors enhance synaptic function and cognitive ability.In humans the PDE5 inhibitor sildenafil is associated with reduced risk of Alzheimer's disease.Licensed PDE5 inhibitors have potential for repurposing in dementia.Prospective clinical trials of PDE5 inhibitors are warranted.

Has COVID-19 affected dementia diagnosis rates in England?

BACKGROUND: The COVID-19 pandemic impacted on the provision of care and routine activity of all National Health Service (NHS) services. While General Practitioner referrals to memory services in England have returned to pre-pandemic levels, the estimated dementia diagnosis rate (DDR) fell by 5.4% between March 2020 and February 2023. METHODS: In this paper we explore whether this reduction is accurate or is an artefact of the way the NHS collects data. RESULTS: We explore the processes that may have affected national dementia diagnosis rates during and following the COVID-19 pandemic. CONCLUSIONS: We discuss what action could be taken to improve the DDR in the future.

Functional cognitive disorder affects reaction time, subjective mental effort and global metacognition.

We previously hypothesized that functional cognitive disorder is characterized by heightened subjective mental effort, exhausted attentional reserve and metacognitive failure. To test this hypothesis, we administered a Stroop colour-word task in which attentional demand was varied by task difficulty (congruent versus incongruent cues) and the presence of a secondary auditory stimulus (passive or active listening to an oddball-type paradigm). We measured subjective mental effort, objective performance (reaction times and accuracy), metacognition and EEG-based biomarkers of mental workload. We tested 19 functional cognitive disorder patients and 23 healthy controls. Patients reported higher levels of depression, anxiety, fatigue, pain, sleep disruption, dissociation and obsessiveness. They rated their memory as significantly poorer than healthy controls; however, accuracy did not differ between groups in any condition. In contrast to healthy controls, patients rated their performance as poorer on the congruent Stroop task with background noise compared to silent conditions. Functional cognitive disorder was consistently associated with slower reaction times but this was not exacerbated by increased attentional demand. Patients but not healthy controls reported greater mental workload in noisy conditions but EEG biomarkers were similar between groups, regardless of task difficulty. Functional cognitive disorder has significant syndromic overlap with mood disorders and chronic fatigue and pain. It is associated with global metacognitive failure whereas local (task-specific) metacognition is only selectively impaired. Patients were slower than healthy controls, which might contribute to the 'brain fog' reported in this condition. Although subjective mental effort was increased in noisy conditions, we found no evidence of attentional exhaustion in functional cognitive disorder. Our results indicate that functional cognitive disorder is a multisystem condition affecting reaction time, subjective mental effort and global metacognition.

What does aducanumab treatment of Alzheimer's disease mean for research on vascular cognitive disorders?

•Controversial registration of aducanumab for Alzheimer's Disease•Aducanumab is the subject of post-licensing observational studies aiming to follow the effects of the drug•Given the high prevalence of cerebrovascular pathology it is important that these studies do not ignore vascular cognitive disorders•The studies may give detailed phenotyping data that may lead to knowledge of targets for treatments of patients with vascular cognitive disorders.

The PASTIS trial: Testing tadalafil for possible use in vascular cognitive impairment.

INTRODUCTION: There are few randomized clinical trials in vascular cognitive impairment (VCI). This trial tested the hypothesis that the PDE5 inhibitor tadalafil, a widely used vasodilator, increases cerebral blood flow (CBF) in older people with symptomatic small vessel disease, the main cause of VCI. METHODS: In a double-blind, placebo-controlled, cross-over trial, participants received tadalafil (20 mg) and placebo on two visits ≥7 days apart (randomized to order of treatment). The primary endpoint, change in subcortical CBF, was measured by arterial spin labelling. RESULTS: Tadalafil increased CBF non-significantly in all subcortical areas (N = 55, age: 66.8 (8.6) years) with greatest treatment effect within white matter hyperintensities (+9.8%, P = .0960). There were incidental treatment effects on systolic and diastolic blood pressure (-7.8, -4.9 mmHg; P < .001). No serious adverse events were observed. DISCUSSION: This trial did not identify a significant treatment effect of single-administration tadalafil on subcortical CBF. To detect treatment effects may require different dosing regimens.

Test-retest reliability of arterial spin labelling for cerebral blood flow in older adults with small vessel disease.

Cerebral small vessel disease (SVD) is common in older people and is associated with lacunar stroke, white matter hyperintensities (WMH) and vascular cognitive impairment. Cerebral blood flow (CBF) is reduced in SVD, particularly within white matter.Here we quantified test-retest reliability in CBF measurements using pseudo-continuous arterial spin labelling (pCASL) in older adults with clinical and radiological evidence of SVD (N=54, mean (SD): 66.9 (8.7) years, 15 females/39 males). We generated whole-brain CBF maps on two visits at least 7 days apart (mean (SD): 20 (19), range 7-117 days).Test-retest reliability for CBF was high in all tissue types, with intra-class correlation coefficient [95%CI]: 0.758 [0.616, 0.852] for whole brain, 0.842 [0.743, 0.905] for total grey matter, 0.771 [0.636, 0.861] for deep grey matter (caudate-putamen and thalamus), 0.872 [0.790, 0.923] for normal-appearing white matter (NAWM) and 0.780 [0.650, 0.866] for WMH (all p<0.001). ANCOVA models indicated significant decline in CBF in total grey matter, deep grey matter and NAWM with increasing age and diastolic blood pressure (all p<0.001). CBF was lower in males relative to females (p=0.013 for total grey matter, p=0.004 for NAWM).We conclude that pCASL has high test-retest reliability as a quantitative measure of CBF in older adults with SVD. These findings support the use of pCASL in routine clinical imaging and as a clinical trial endpoint.All data come from the PASTIS trial, prospectively registered at: https://eudract.ema.europa.eu (2015-001235-20, registered 13/05/2015), http://www.clinicaltrials.gov (NCT02450253, registered 21/05/2015).

Vasculocentric Axonal NfH in Small Vessel Disease.

Cerebral small vessel disease (SVD) causes lacunar stroke and vascular cognitive impairment in older people. The pathogenic pathways from vessel pathology to parenchymal damage in SVD are unknown. Neurofilaments are axonal structural proteins. Neurofilament-light (NfL) is an emerging biomarker for neurological disease. Here, we examined the high molecular weight form neurofilament-heavy (NfH) and quantified a characteristic pattern of peri-arterial (vasculocentric) NfH labeling. Subcortical frontal and parietal white matter from young adult controls, aged controls, and older people with SVD or severe Alzheimer disease (n = 52) was immunohistochemically labeled for hyperphosphorylated NfH (pNfH). The extent of pNfH immunolabeling and the degree of vasculocentric axonal pNfH were quantified. Axonal pNfH immunolabeling was sparse in young adults but a common finding in older persons (controls, SVD, or AD). Axonal pNfH was often markedly concentrated around small penetrating arteries. This vasculocentric feature was more common in older people with SVD than in those with severe AD (p = 0.004). We conclude that axonal pNfH is a feature of subcortical white matter in aged brains. Vasculocentric axonal pNfH is a novel parenchymal lesion that is co-located with SVD arteriopathy and could be a consequence of vessel pathology.

Differences in care between younger and older patients in the 2019 English national memory service audit.

AIMS AND METHOD: This paper analyses how practice varied between patients aged <65 and ≥65 years in the 2019 UK national memory service audit. RESULTS: Data on 3959 patients were analysed. Those aged <65 (7% of the sample) were less likely than those aged ≥65 to be diagnosed with dementia (23 v. 67%) and more likely to receive a functional, psychiatric or no diagnosis. Younger patients were more likely to have magnetic resonance imaging; use of dementia biomarkers was low in both groups. Frontotemporal dementia and functional cognitive disorder were diagnosed infrequently. Use of dementia navigators/advisors and carer psychoeducation was similar between groups; younger patients were less likely to be offered but more likely to accept cognitive stimulation therapy. CLINICAL IMPLICATIONS: Memory services seeing younger people need expertise in functional cognitive disorder, alongside clinical skills and technologies to diagnose rarer forms of dementia. Further work is needed to understand why cognitive stimulation therapy is less frequently offered to younger people.

Mild cognitive impairment: the Manchester consensus.

Given considerable variation in diagnostic and therapeutic practice, there is a need for national guidance on the use of neuroimaging, fluid biomarkers, cognitive testing, follow-up and diagnostic terminology in mild cognitive impairment (MCI). MCI is a heterogenous clinical syndrome reflecting a change in cognitive function and deficits on neuropsychological testing but relatively intact activities of daily living. MCI is a risk state for further cognitive and functional decline with 5-15% of people developing dementia per year. However, ~50% remain stable at 5 years and in a minority, symptoms resolve over time. There is considerable debate about whether MCI is a useful clinical diagnosis, or whether the use of the term prevents proper inquiry (by history, examination and investigations) into underlying causes of cognitive symptoms, which can include prodromal neurodegenerative disease, other physical or psychiatric illness, or combinations thereof. Cognitive testing, neuroimaging and fluid biomarkers can improve the sensitivity and specificity of aetiological diagnosis, with growing evidence that these may also help guide prognosis. Diagnostic criteria allow for a diagnosis of Alzheimer's disease to be made where MCI is accompanied by appropriate biomarker changes, but in practice, such biomarkers are not available in routine clinical practice in the UK. This would change if disease-modifying therapies became available and required a definitive diagnosis but would present major challenges to the National Health Service and similar health systems. Significantly increased investment would be required in training, infrastructure and provision of fluid biomarkers and neuroimaging. Statistical techniques combining markers may provide greater sensitivity and specificity than any single disease marker but their practical usefulness will depend on large-scale studies to ensure ecological validity and that multiple measures, e.g. both cognitive tests and biomarkers, are widely available for clinical use. To perform such large studies, we must increase research participation amongst those with MCI.