The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) was developed in the 1980s to assess the level of cognitive dysfunction in Alzheimer's disease. Advancements in the research field have shifted focus toward pre-dementia populations, and use of the ADAS-Cog has extended into these pre-dementia studies despite concerns about its ability to detect important changes at these milder stages of disease progression. If the ADAS-Cog cannot detect important changes, our understanding of pre-dementia disease progression may be compromised and trials may incorrectly conclude that a novel treatment approach is not beneficial. The purpose of this review was to assess the performance of the ADAS-Cog in pre-dementia populations, and to review all modifications that have been made to the ADAS-Cog to improve its measurement performance in dementia or pre-dementia populations. The contents of this review are based on bibliographic searches of electronic databases to locate all studies using the ADAS-Cog in pre-dementia samples or subsamples, and to locate all modified versions. Citations from relevant articles were also consulted. Overall, our results suggest the original ADAS-Cog is not an optimal outcome measure for pre-dementia studies; however, given the prominence of the ADAS-Cog, care must be taken when considering the use of alternative outcome measures. Thirty-one modified versions of the ADAS-Cog were found. Modification approaches that appear most beneficial include altering scoring methodology or adding tests of memory, executive function, and/or daily functioning. Although modifications improve the performance of the ADAS-Cog, this is at the cost of introducing heterogeneity that may limit between-study comparison.

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The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog): Modifications and Responsiveness in Pre-Dementia Populations. A Narrative Review.

The dominant hypothesis of Alzheimer’s disease (AD) aetiology, the neuropathological guidelines for diagnosing AD and the majority of high-profile therapeutic efforts, in both research and in clinical practice, have been built around one possible causal factor, amyloid-β (Aβ). However, the causal link between Aβ and AD remains unproven. Here, in the context of a detailed assessment of historical and contemporary studies, we raise critical questions regarding the role of Aβ in the definition, diagnosis and aetiology of AD. We illustrate that a holistic view of the available data does not support an unequivocal conclusion that Aβ has a central or unique role in AD. Instead, the data suggest alternative views of AD aetiology are potentially valid, at this time. We propose that an unbiased way forward for the field, beyond the current Aβ-centric approach, without excluding a role for Aβ, is required to come to an accurate understanding of AD dementia and, ultimately, an effective treatment.

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Questions concerning the role of amyloid-β in the definition, aetiology and diagnosis of Alzheimer’s disease

Atopic dermatitis (AD) is a common chronic inflammatory skin disease with a complex pathophysiology that underlies a wide spectrum of clinical phenotypes. AD remains challenging to treat owing to the limited response to available therapies. However, recent advances in understanding of disease mechanisms have led to the discovery of novel potential therapeutic targets and drug candidates. In addition to regulatory approval for the IL-4Ra inhibitor dupilumab, the anti-IL-13 inhibitor tralokinumab and the JAK1/2 inhibitor baricitinib in Europe, there are now more than 70 new compounds in development. This Review assesses the various strategies and novel agents currently being investigated for AD and highlights the potential for a precision medicine approach to enable prevention and more effective long-term control of this complex disease. Recent advances in understanding of the complex phenotype and mechanisms underlying atopic dermatitis (AD) have revealed multiple new potential targets for pharmacological intervention. Here, Bieber reviews therapeutic strategies and assesses the expanding pipeline for the therapy of AD, highlighting the potential for a precision medicine approach to the management of this complex disorder.

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Atopic dermatitis: an expanding therapeutic pipeline for a complex disease.

Therapeutics targeting the IL-23 and IL-17 pathway in psoriasis.

Prior research has found that cognitive benefits of physical exercise and brain health in older adults may be enhanced when mental exercise is interactive simultaneously, as in exergaming. It is unclear whether the cognitive benefit can be maximized by increasing the degree of mental challenge during exercise. This randomized clinical trial (RCT), the Aerobic and Cognitive Exercise Study (ACES) sought to replicate and extend prior findings of added cognitive benefit from exergaming to those with or at risk for mild cognitive impairment (MCI). ACES compares the effects of 6 months of an exer-tour (virtual reality bike rides) with the effects of a more effortful exer-score (pedaling through a videogame to score points). Fourteen community-dwelling older adults meeting screening criteria for MCI (sMCI) were adherent to their assigned exercise for 6 months. The primary outcome was executive function, while secondary outcomes included memory and everyday cognitive function. Exer-tour and exer-score yielded significant moderate effects on executive function (Stroop A/C; d's = 0.51 and 0.47); there was no significant interaction effect. However, after 3 months the exer-tour revealed a significant and moderate effect, while exer-score showed little impact, as did a game-only condition. Both exer-tour and exer-score conditions also resulted in significant improvements in verbal memory. Effects appear to generalize to self-reported everyday cognitive function. Pilot data, including salivary biomarkers and structural MRI, were gathered at baseline and 6 months; exercise dose was associated with increased BDNF as well as increased gray matter volume in the PFC and ACC. Improvement in memory was associated with an increase in the DLPFC. Improved executive function was associated with increased expression of exosomal miRNA-9. Interactive physical and cognitive exercise (both high and low mental challenge) yielded similarly significant cognitive benefit for adherent sMCI exercisers over 6 months. A larger RCT is needed to confirm these findings. Further innovation and clinical trial data are needed to develop accessible, yet engaging and effective interventions to combat cognitive decline for the growing MCI population. ClinicalTrials.gov ID: NCT02237560.

The Aerobic and Cognitive Exercise Study (ACES) for Community-Dwelling Older Adults With or At-Risk for Mild Cognitive Impairment (MCI): Neuropsychological, Neurobiological and Neuroimaging Outcomes of a Randomized Clinical Trial.

Interleukin-36 Blockade in Pustular Psoriasis Seven patients with pustular psoriasis, three with mutations in IL36RN, were treated with a monoclonal antibody against interleukin-36 receptor and had...

https://www.nejm.org/doi/pdf/10.1056/NEJMc1811317?listPDF=true

Inhibition of the Interleukin-36 Pathway for the Treatment of Generalized Pustular Psoriasis

Development of new treatments for Alzheimer’s disease (AD) has broadened into early interventions in individuals with modest cognitive impairment and a slow decline. The 11-item version of the Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS-Cog) was originally developed to measure cognition in patients with mild to moderate AD. Attempts to improve its properties for early AD by removing items prone to ceiling and/or by adding cognitive measures known to be impaired early have yielded a number of ADAS-Cog variants. Using Alzheimer’s Disease Neuroimaging Initiative data, we compared the performance of the 3-, 5-, 11- and 13-item ADAS-Cog variants in subjects with early AD. Given the interest in enrichment strategies, we also examined this aspect with a focus on cerebrospinal fluid (CSF) markers. Subjects with mild cognitive impairment (MCI) and mild AD with available ADAS-Cog 13 and CSF data were analysed. The decline over time was defined by change from baseline. Direct cross-comparison of the ADAS-Cog variants was performed using the signal-to-noise ratio (SNR), with higher values reflecting increased sensitivity to detect change over time. The decline over time on any of the ADAS-Cog variants was minimal in subjects with MCI. Approximately half of subjects with MCI fulfilled enrichment criteria for positive AD pathology. The impact of enrichment was detectable but subtle in MCI. The annual decline in mild AD was more pronounced but still modest. More than 90 % of subjects with mild AD had positive AD pathology. SNRs were low in MCI but greater in mild AD. The numerically largest SNRs were seen for the ADAS-Cog 5 in MCI and for both the 5- and 13-item ADAS-Cog variants in mild AD, although associated confidence intervals were large. The possible value of ADAS-Cog expansion or reduction is less than compelling, particularly in MCI. In mild AD, adding items known to be impaired at early stages seems to provide more benefit than removing items on which subjects score close to ceiling.

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Alzheimer's Disease Assessment Scale-Cognitive subscale variants in mild cognitive impairment and mild Alzheimer's disease: change over time and the effect of enrichment strategies.

Michael Shear

Papers

Inhibition of the Interleukin-36 Pathway for the Treatment of Generalized Pustular Psoriasis

Alzheimer's Disease Assessment Scale-Cognitive subscale variants in mild cognitive impairment and mild Alzheimer's disease: change over time and the effect of enrichment strategies.