Acceptable performance of blood biomarker tests of amyloid pathology - recommendations from the Global CEO Initiative on Alzheimer's Disease.

Anti-amyloid treatments for early symptomatic Alzheimer disease have recently become clinically available in some countries, which has greatly increased the need for biomarker confirmation of amyloid pathology. Blood biomarker (BBM) tests for amyloid pathology are more acceptable, accessible and scalable than amyloid PET or cerebrospinal fluid (CSF) tests, but have highly variable levels of performance. The Global CEO Initiative on Alzheimer's Disease convened a BBM Workgroup to consider the minimum acceptable performance of BBM tests for clinical use. Amyloid PET status was identified as the reference standard. For use as a triaging test before subsequent confirmatory tests such as amyloid PET or CSF tests, the BBM Workgroup recommends that a BBM test has a sensitivity of ≥90% with a specificity of ≥85% in primary care and ≥75-85% in secondary care depending on the availability of follow-up testing. For use as a confirmatory test without follow-up tests, a BBM test should have performance equivalent to that of CSF tests - a sensitivity and specificity of ~90%. Importantly, the predictive values of all biomarker tests vary according to the pre-test probability of amyloid pathology and must be interpreted in the complete clinical context. Use of BBM tests that meet these performance standards could enable more people to receive an accurate and timely Alzheimer disease diagnosis and potentially benefit from new treatments.

Prognostic and Predictive Factors in Early Alzheimer's Disease: A Systematic Review.

Background: Alzheimer's disease (AD) causes progressive decline of cognition and function. There is a lack of systematic literature reviews on prognostic and predictive factors in its early clinical stages (eAD), i.e., mild cognitive impairment due to AD and mild AD dementia. Objective: To identify prognostic factors affecting eAD progression and predictive factors for treatment efficacy and safety of approved and/or under late-stage development disease-modifying treatments. Methods: Databases were searched (August 2022) for studies reporting prognostic factors associated with eAD progression and predictive factors for treatment response. The Quality in Prognostic Factor Studies tool or the Cochrane risk of bias tool were used to assess risk of bias. Two reviewers independently screened the records. A single reviewer performed data extraction and quality assessment. A second performed a 20% check. Content experts reviewed and interpreted the data collected. Results: Sixty-one studies were included. Self-reporting, diagnosis definition, and missing data led to high risk of bias. Population size ranged from 110 to 11,451. Analyses found data indicating that older age was and depression may be associated with progression. Greater baseline cognitive impairment was associated with progression. APOE4 may be a prognostic factor, a predictive factor for treatment efficacy and predicts an adverse response (ARIA). Elevated biomarkers (CSF/plasma p-tau, CSF t-tau, and plasma neurofilament light) were associated with disease progression. Conclusions: Age was the strongest risk factor for progression. Biomarkers were associated with progression, supporting their use in trial selection and aiding diagnosis. Baseline cognitive impairment was a prognostic factor. APOE4 predicted ARIA, aligning with emerging evidence and relevant to treatment initiation/monitoring.

Biomarkers in Alzheimer's disease: role in early and differential diagnosis and recognition of atypical variants.

BACKGROUND: Development of in vivo biomarkers has shifted the diagnosis of Alzheimer's disease (AD) from the later dementia stages of disease towards the earlier stages and has introduced the potential for pre-symptomatic diagnosis. The International Working Group recommends that AD diagnosis is restricted in the clinical setting to people with specific AD phenotypes and supportive biomarker findings. MAIN BODY: In this review, we discuss the phenotypic presentation and use of biomarkers for the early diagnosis of typical and atypical AD and describe how this can support clinical decision making, benefit patient communication, and improve the patient journey. Early diagnosis is essential to optimize the benefits of available and emerging treatments. As atypical presentations of AD often mimic other dementias, differential diagnosis can be challenging and can be facilitated using AD biomarkers. However, AD biomarkers alone are not sufficient to confidently diagnose AD or predict disease progression and should be supplementary to clinical assessment to help inform the diagnosis of AD. CONCLUSIONS: Use of AD biomarkers with incorporation of atypical AD phenotypes into diagnostic criteria will allow earlier diagnosis of patients with atypical clinical presentations that otherwise would have been misdiagnosed and treated inappropriately. Early diagnosis is essential to guide informed discussion, appropriate care and support, and individualized treatment. It is hoped that disease-modifying treatments will impact the underlying AD pathology; thus, determining the patient's AD phenotype will be a critical factor in guiding the therapeutic approach and the assessment of the effects of interventions.

Clinical application of CSF biomarkers for Alzheimer's disease: From rationale to ratios.

Biomarker testing is recommended for the accurate and timely diagnosis of Alzheimer's disease (AD). Using illustrative case narratives we consider how cerebrospinal fluid (CSF) biomarker tests may be used in different presentations of cognitive impairment to facilitate timely and differential diagnosis, improving diagnostic accuracy, providing prognostic information, and guiding personalized management in diverse scenarios. Evidence shows that (1) CSF ratios are superior to amyloid beta (Aß)1-42 alone; (2) concordance of CSF ratios to amyloid positron emission tomography (PET) is better than Aß1-42 alone; and (3) phosphorylated tau (p-tau)/Aß1-42 ratio is superior to p-tau alone. CSF biomarkers are recommended for the exclusion of AD as the underlying cause of cognitive impairment, diagnosis of AD at an early stage, differential diagnosis of AD in individuals presenting with other neuropsychiatric symptoms, accurate diagnosis of AD in an atypical presentation, and for clinical trial enrichment. Highlights:  Cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker testing may be underused outside specialist centers.CSF biomarkers improve diagnostic accuracy, guiding personalized management of AD.CSF ratios (amyloid beta [Aß]1-42/Aß1-40 and phosphorylated tau/Aß1-42) perform better than single markers.CSF ratios produce fewer false-negative and false-positive results than individual markers.CSF biomarkers should be included in diagnostic work-up of AD and mild cognitive impairment due to AD.

The Cambridge Semantic Memory Test Battery: detection of semantic deficits in semantic dementia and Alzheimer's disease.

The aims of this study were (a) to explore the utility of, and make more widely available, an updated and extended version of the Cambridge Semantic Memory test battery, and (b) to use this battery in conjunction with other tests to characterise the profile of several different forms of progressive cognitive impairment: semantic dementia (SD, n = 15), mild cognitive impairment (MCI, n = 7), established Alzheimer's disease (AD) (n = 8), all in comparison to normal controls (n = 45). The semantic battery is useful in a variety of ways for exploring the nature of semantic deficits; on its own, however, it does not provide sensitive differentiation between patients with AD and SD. An assessment including measures of episodic memory and visuospatial abilities as well as the semantic battery is recommended for good characterisation of the cognitive profiles associated with SD and AD.

Semantic knowledge in mild cognitive impairment and mild Alzheimer's disease.

The aim of this study was to investigate memory in patients with mild cognitive impairment (MCI) and mild Alzheimer's disease (AD). Ten patients with MCI, 11 with AD and a group of age and education matched healthy control participants were assessed on a comprehensive battery of semantic memory tests, including traditional semantic memory measures and a non-verbal test of knowledge of object use. The MCI group was impaired on tests of category fluency and all three conditions of an object knowledge test (matching to recipient, function and action), plus a difficult object-naming test. The mild AD group showed additional impairments on traditional measures of semantic memory, including naming high frequency items, comprehension and semantic association. Together these findings suggest that semantic memory impairments occur early in the course of AD, more specifically in patients with "amnesic" MCI, and provide further evidence that impaired category fluency reflects semantic breakdown.

Structure and deterioration of semantic memory: a neuropsychological and computational investigation.

Wernicke (1900, as cited in G. H. Eggert, 1977) suggested that semantic knowledge arises from the interaction of perceptual representations of objects and words. The authors present a parallel distributed processing implementation of this theory, in which semantic representations emerge from mechanisms that acquire the mappings between visual representations of objects and their verbal descriptions. To test the theory, they trained the model to associate names, verbal descriptions, and visual representations of objects. When its inputs and outputs are constructed to capture aspects of structure apparent in attribute-norming experiments, the model provides an intuitive account of semantic task performance. The authors then used the model to understand the structure of impaired performance in patients with selective and progressive impairments of conceptual knowledge. Data from 4 well-known semantic tasks revealed consistent patterns that find a ready explanation in the model. The relationship between the model and related theories of semantic representation is discussed.

A duck with four legs: Investigating the structure of conceptual knowledge using picture drawing in semantic dementia.

In Study 1, six patients with semantic dementia were asked to produce drawings of concrete concepts from dictation of their names. The drawings were characterised by a loss of distinctive features. In the artefact domain, this feature loss resulted in representations that were increasingly box-like. In the living domain, as well as distinctive features being lost, there was a tendency for patients to include incorrect features that resulted in more familiar and "prototypical" representations. A second study included two further conditions in the drawing assessment: immediate and delayed copying of line drawings of concrete concepts. Analysis of the drawings produced by three patients with semantic dementia confirmed that overall performance was significantly influenced by the task condition (immediate delayed) and severity of disease. The rate of intruding features, but not of omitted ones, was influenced by the domain of the item, with a greater proportion of intrusions in the living than in the nonliving domain. There was also a significant effect of feature distinctiveness on the proportions of these error types: Intruded features were most likely to come from the pool of properties that are shared across domain.

The influence of personal familiarity and context on object use in semantic dementia.

Several laboratory experiments assessing the ability of patients with semantic dementia to use familiar objects have revealed deficits corresponding directly to the patients' remaining conceptual knowledge for the same items. The same patients, however, were reported to demonstrate normal use of some objects relevant to their everyday lives. The study reported here was designed to explore this apparent discrepancy by examining the influence of personal familiarity with object exemplars, and of the contexts in which they are typically used. Two patients with severe semantic impairment were given single objects that they were still using at home on a regular basis and asked to demonstrate the use of each. Performance on these items was compared with use of perceptually similar and perceptually different exemplars of the same objects. All three sets were tested in the patients' own homes and also in the laboratory. Both patients were significantly more successful at using their own objects than the perceptually different exemplars, while an advantage for 'own' relative to similar exemplars characterized one of the two patients. Familiar home context had no impact on performance. The results suggest that repeated experience with personally familiar objects helps to maintain appropriate responses to them in the face of severely degraded conceptual knowledge.

Apraxia, mechanical problem solving and semantic knowledge: contributions to object usage in corticobasal degeneration.

To investigate the nature of the apraxia in corticobasal degeneration (CBD) five patients with CBD and five matched controls were compared on tests of: i) meaningless and symbolic gesture production, ii) a battery of semantic tasks based on 20 everyday items (involving naming and picture-picture matching according to semantic attributes, matching gestures-to-objects, object usage from name and with the real object) and iii) a novel tool test of mechanical problem solving. All five patients showed severe impairment in the production of meaningless and symbolic gestures from command, and by imitation, and were also impaired when using real objects. Deficits were not, however, restricted to action production: four were unable to match gestures to objects and all five showed impairment in the selection and usage of novel tools in the mechanical problem solving task. Surprising was the finding of an additional semantic knowledge breakdown in three cases, two of whom were markedly anomic. The apraxia in CBD is, therefore, multifactorial. There is profound breakdown in the organisation and co-ordination of motor programming. In addition, patients show central deficits in action knowledge and mechanical problem solving, which has been linked to parietal lobe pathology. General semantic memory may also be affected in CBD in some cases and this may then contribute to impaired object usage. This combination of more than one deficit relevant for object use may explain why CBD patients are far more disabled by their dyspraxia in everyday life than any other patient group.

When objects lose their meaning: what happens to their use?

The 8 patients involved in this study were impaired on tests assessing knowledge of objects and on the demonstration of their use. The patients' success in object use was significantly correlated with their knowledge about the objects, providing further evidence that conceptual knowledge plays a key role in object use. Having a recipient present improved performance in the moderately impaired patients, suggesting that a certain level of conceptual knowledge must remain for the additional information to be beneficial. Although overall accuracy in using the target objects was not related to our measures of affordance, the specific aspects of use afforded by the objects' structures were relatively impervious to semantic impairment, suggesting a role for affordance information when object-specific knowledge is disrupted. The patients' familiarity with the objects was an important predictor of performance. Finally, despite good performance on tests of mechanical problem solving, the patients showed very little evidence of employing these skills in their interactions with real objects.