Developing Topics.

Working memory in mild cognitive impairment and Alzheimer's disease: Contribution of forgetting and predictive value of complex span tasks.

AimMATRICS Consensus Cognitive Battery was developed by the National Institute of Mental Health to establish acceptance criteria for measuring cognitive changes in schizophrenia and can be used to assess cognitive functions in other psychiatric disorders. We used a Japanese version of MATRICS Consensus Cognitive Battery to explore the changes in multiple cognitive functions in patients with mild cognitive impairment and mild Alzheimer's disease.MethodsWe administered the Japanese version of MATRICS Consensus Cognitive Battery to 11 patients with mild cognitive impairment (MCI), 11 patients with Alzheimer's disease, and 27 healthy controls. All Japanese versions of MATRICS Consensus Cognitive Battery domain scores were converted to t‐scores using sample means and standard deviations and were compared for significant performance differences among healthy control, MCI, and mild Alzheimer's disease groups.ResultsCompared with healthy controls, patients with MCI and mild Alzheimer's disease demonstrated the same degree of impairment to processing speed, verbal learning, and visual learning. Reasoning and problem‐solving showed significant impairments only in mild Alzheimer's disease. Verbal and visual abilities in working memory showed different performances in the MCI and mild Alzheimer's disease groups, with the Alzheimer's disease group demonstrating significantly more deficits in these domains. No significant difference was found among the groups in attention/vigilance and social cognition.ConclusionsThe Japanese version of MATRICS Consensus Cognitive Battery can be used to elucidate the characteristics of cognitive dysfunction of normal aging, MCI, and mild dementia in clinical practice.

IC-P-068: Diffusion tensor imaging of normal appearing white matter in MCI and AD

In addition to episodic memory impairment, working memory may also be compromised in mild cognitive impairment (MCI) or Alzheimer's dementia (AD), but standard verbal and visuospatial span tasks do not always detect impairments.ObjectiveTo examine whether more complex verbal and visuospatial working memory tasks result in more reliable impairment detection.MethodsThe Digit Span (forward, backward and sequencing), Spatial Span (forward and backward) and Spatial Addition test from the Wechsler batteries were administered to MCI and AD patients and performance compared to healthy older adult controls.ResultsResults showed that both the MCI and AD patients had impaired performance on the Spatial Addition test. Both groups also had impaired performance on all three Digit Span conditions, but no differences were found between forward and backward conditions in any of the groups. The sequencing condition differed from the backward condition only in the AD group. Spatial Span performance was impaired in AD group patients but not in MCI patients.ConclusionWorking memory deficits are evident in MCI and AD even on standard neuropsychological tests. However, available tests may not detect subtle impairments, especially in MCI. Novel paradigms tapping the episodic buffer component of working memory may be useful in the assessment of working memory deficits, but such instruments are not yet available for clinical assessment.

The present study examined the degree to which alexithymia is greater in mild Alzheimer's disease (AD) and mild cognitive impairment (MCI) relative to healthy volunteers (healthy comparison [HC]), and investigated relationships between alexithymia and cognition. Eighty-five participants (MCI = 30, AD = 21, HC = 34) underwent a comprehensive neuropsychological examination and completed the 20-item Toronto Alexithymia Scale (TAS-20). Relative to HC, MCI and AD reported greater alexithymia total scores and higher scores on the TAS factor difficulty in identifying feelings (DIF). The remaining two factors, difficulty in describing feelings (DDF) and externally oriented thinking showed no significant group differences. In MCI, TAS-20 and DIF were negatively correlated with working and long-term verbal memory. In AD, TAS-20 was negatively correlated with general cognition, attention, memory, and visual spatial constructive and executive abilities. Also in AD, DIF was negatively correlated with general cognition, memory, and executive abilities. The correlation between DIF and long-term verbal memory in both MCI and AD suggests a potential common mechanism for alexithymia in these neurocognitive disorders. Declines in verbal memory may hinder a patient's ability to recall an association between a given sensation and the episodic experience of that sensation, thus leading to difficulty identifying feelings, as measured by the DIF factor of the TAS-20.

Patients affected by sporadic Alzheimer disease (AD) show a significant alteration of amyloid precursor protein (APP) forms in platelets when compared with patients with dementia but without AD and age-matched controls. To evaluate the ratio of platelet APP forms (APPr) in early-stage AD and mild cognitive impairment (MCI) and its potential as a biomarker for the early identification of AD. Community population-based sample of patients admitted to 4 AD centers for investigation of cognitive disturbances. Thirty-five patients with mild AD (mAD), 21 patients with very mild AD (vmAD), 30 subjects with MCI, and 25 age-matched controls were included. The APPr was evaluated by Western blot analysis in platelet homogenate. Compared with controls (mean +/- SD, 0.93 +/- 0.3), the mean APPr was decreased in patients with mAD (0.44 +/- 0.24; P<.001) and patients with vmAD (0.49 +/- 0.3; P<.001). Regarding the MCI group, a significant decrease in APPr was found compared with controls (0.62 +/- 0.33; P<.001). Fixing a cutoff score of 0.6, sensitivity was 88.6% (31/35) for patients with mAD and 85.7% (18/21) for patients with vmAD, whereas specificity was 88% (22/25) for controls. Among patients with MCI, 18 (60%) of 30 individuals displayed APPr values below the cutoff. Alteration of platelet APP forms is an early event in AD, and the measurement of APPr may be useful for the identification of preclinical AD in patients with MCI.

(Reprinted with permission from American Psychiatric Association, http://psychiatryonline.org/guidelines).

BackgroundScreening for clinical trials identifies persons with clinical symptoms of Mild Cognitive Impairment (MCI) or Alzheimer's disease (AD) but no amyloid on PET. We compared blood biomarkers and proteomics in these screen failures with cognitively normal, amyloid PET negative persons and with amyloid PET positive MCI or mild AD patients.MethodWe analyzed data from 296 persons with clinical symptoms of MCI or mild AD from the Bio‐Hermes study who were amyloid PET negative (MCI + AD AB‐); we compared them with 313 Bio‐Hermes participants who were cognitively normal and amyloid PET negative (CN AB‐) and with 258 amyloid PET positive persons with clinical MCI or mild AD (MCI + AD AB+). Measures included regional amyloid PET, plasma A‐beta40 and 42, total tau, p‐tau 181, p‐tau 217, NfL, GFAP, a panel of 69 cytokines (Fireplex) and 7596 proteins from the Somalogic panel.ResultRelative to the CN AB‐ group, the MCI + AD AB‐ group were older, more cognitvely and functionally impaired, had slightly less education and were more likely to be non‐white; the groups did not differ in gender or APOE4 rates. The groups did not differ on amyloid SUVR, p‐tau 217, t‐tau or GFAP. NfL was higher in MCI + AD AB‐ persons compared with CN AB‐ persons (Table 1 and 2). After using a False Discovery Rate adjustment there were no Somalogic proteins significantly different in MCI + AD AB‐ participants vs CN AB‐ participants. Several proteins were different in amyloid PET positive persons compared with amyloid PET negative parsons (Figure 1).ConclusionNfL data indicate very significant neurodegeneration in symptomatic but amyloid PET negative clinical trial screen failures. Biomarkers reflecting amyloid and tau were not different and the proteomics profile did not find specific abnormalities in amyloid negative, symptomatic persons.

Objective To investigate platelet α and β secretase activities and the amounts of platelet soluble fragment of APP (sAPPα) produced by α-secretase in patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Methods The neurological functions of 48 non-demented patients, 42 MCI and 40 AD patients were evaluated by neuropsychological examinations. The platelet α and β secretase activities and sAPPα production in each group were measured by fluorescence and Western blotting analysis respectively. Results The α secretase activities in non-demented, MCI and AD group were 100.0%±10.6%, 78.2%±9.4% and 61.8%±7.2% respectively. As compared with non-demented group, the α secretase activities in MCI and AD group were decreased (F=22.935, P=0.001). The α secretase activity in AD group was significantly lower than MCI group. The β secretase activities in non-demented, MCI and AD group were 100.0%±11.2%, 145.8%±12.7% and 189.8%±14.2% respectively. The β secretase activities in MCI and AD group were significantly higher than that in non-demented group (F=16.368, P=0.001). The β secretase activity in AD group was significantly decreased as compared with MCI group. The sAPPα amounts in MCI group and AD group were all decreased as compared with that in control group; the sAPPα amount in AD patients was significantly decreased as compared with that in MCI group. Conclusions The platelet α secretase activity and its production sAPPα in MCI and AD patients are decreased, while β secretase activity is increased, as compared with that in control group; the altered α and β secretase activities may participate in the pathogenesis of MCI and AD patients and may have diagnostic potential for them. Key words: Cognition disorders; Alzheimer disease; Amyloid precursor protein secretases

Apathy and Executive Dysfunction in Mild Cognitive Impairment and Alzheimer Disease

How far is arterial spin labeling MRI from a clinical reality? Insights from arterial spin labeling comparative studies in Alzheimer's disease and other neurological disorders.

Objective: This study compared emotional recognition in participants with mild cognitive impairment (MCI) and mild to moderate Alzheimer 's disease (AD) against caregivers' perceptions of these participants' emotional states, while exploring the influence of clinical variables. Methods: We included 141 participants (32 with MCI, 50 with mild AD, and 59 with moderate AD) and their primary caregivers. We employed tasks assessing emotional decoding, identification, and correspondence, along with objective evaluations. Results: Participants across all groups showed significant differences in cognition and functionality. However, emotional recognition abilities did not significantly differ between MCI and mild or moderate AD groups. Most cognitive and neuropsychiatric variables had no significant impact on emotion recognition or social functioning. No differences emerged in patients' self-evaluations of social and emotional functioning. Caregiver assessments revealed significant differences only between the MCI and moderate AD groups. Conclusion: Participants with MCI and AD displayed expected clinical progression while retaining some emotional recognition and social functioning capabilities.

Working memory (WM) is the active retention and processing of information over a few seconds and is considered an essential component of cognitive function. The reduced WM capacity is a common feature in many diseases, such as schizophrenia, attention deficit hyperactivity disorder (ADHD), mild cognitive impairment (MCI), and Alzheimer's disease (AD). The theta-gamma neural code is an essential component of memory representations in the multi-item WM. A large body of studies have examined the association between cross-frequency coupling (CFC) across the cerebral cortices and WM performance; electrophysiological data together with the behavioral results showed the associations between CFC and WM performance. The oscillatory entrainment (sensory, non-invasive electrical/magnetic, and invasive electrical) remains the key method to investigate the causal relationship between CFC and WM. The frequency-tuned non-invasive brain stimulation is a promising way to improve WM performance in healthy and non-healthy patients with cognitive impairment. The WM performance is sensitive to the phase and rhythm of externally applied stimulations. CFC-transcranial-alternating current stimulation (CFC-tACS) is a recent approach in neuroscience that could alter cognitive outcomes. The studies that investigated (1) the association between CFC and WM and (2) the brain stimulation protocols that enhanced WM through modulating CFC by the means of the non-invasive brain stimulation techniques have been included in this review. In principle, this review can guide the researchers to identify the most prominent form of CFC associated with WM processing (e.g., theta/gamma phase-amplitude coupling), and to define the previously published studies that manipulate endogenous CFC externally to improve WM. This in turn will pave the path for future studies aimed at investigating the CFC-tACS effect on WM. The CFC-tACS protocols need to be thoroughly studied before they can be considered as therapeutic tools in patients with WM deficits.

Neuropsychiatric symptoms (NPS), commonly concomitant with Alzheimer's disease (AD), substantially impair the quality of life and accelerate disease progression, yet reliable biomarkers for early identification of individuals at high NPS risk remain elusive. In this study, we leveraged the data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), incorporating longitudinal data from 509 participants diagnosed with mild cognitive impairment (MCI) or mild AD at baseline and followed up for 1 and 2 years. The dataset included cerebrospinal fluid (CSF) proteomic profiles comprising 6361 proteins, along with comprehensive data on NPS diagnosis, cognitive function, and AD pathology. LASSO regression and recursive feature elimination were applied to identify NPS-related CSF proteins, followed by random forest modeling to predict NPS risk at baseline, 1 year, and 2 years. Incorporating selected CSF proteins significantly improved NPS prediction compared to the reference model, with AUCs increasing from 0.64 to 0.76 at baseline, 0.63 to 0.80 at 1 year, and 0.63 to 0.81 at 2 years. Notably, Cyclin-Dependent Kinase-Like 2 (CDKL2), Nidogen 2 (NID2), and Lin-7 Homolog B (LIN7B) were consistently associated with NPS across all time points. Among them, CDKL2 and NID2 were significantly associated with AD biomarkers and cognitive scores, and their expression changes were independently validated in cerebrospinal fluid from a mouse model, highlighting their potential as stable predictive biomarkers. Our findings highlight CSF proteomic signatures that robustly predict NPS progression in individuals with MCI and mild AD, offering a framework for early risk stratification and precision intervention in NPS.

BackgroundGosuranemab is a humanized monoclonal antibody that is hypothesized to neutralize extracellular tau and prevent the trans‐neuronal propagation of tau pathology across the brain. The TANGO study is an ongoing randomized, placebo‐controlled, global Phase 2 study evaluating safety and clinical efficacy of gosuranemab in individuals diagnosed with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) or mild AD dementia. The TANGO study included two biomarker sub‐studies: cerebrospinal fluid (CSF) sub‐study and Tau positron emission tomography (PET) sub‐study; the baseline characteristics of the Tau PET sub‐study are described below.MethodTANGO enrolled 654 individuals aged 50‐80 years, diagnosed with MCI or mild AD, who were amyloid positive as assessed by amyloid PET or CSF testing. Approximately 350 patients enrolled in the longitudinal 18F‐MK‐6240 Tau PET sub‐study. Randomization was stratified by biomarker sub‐study participation among other factors. Baseline standardized uptake value ratio (SUVR) was measured in composite brain regions of interest (ROIs) corresponding to Braak I‐II, Braak III‐IV, and Braak V‐VI regions using superior‐eroded cerebellum as the reference region. Tau extent (percentage of supra‐threshold voxels within an ROI relative to reference region), an exploratory measure of the spatial extent of 18F‐MK‐6240 binding, was also investigated.ResultThe baseline demographics of the Tau PET sub‐study population were consistent with the overall TANGO study population including clinical stage (MCI vs. mild AD), age, gender, APOE4, and clinical scores. At baseline, average SUVR (±SD) was 1.92±0.6 in Braak I‐II, 1.90±0.7 in Braak III‐IV and 1.75±0.8 in Braak V‐VI composite ROIs. The Braak composite SUVRs were positively associated with disease stage (i.e. higher SUVR with increasing disease severity). Exploratory analyses of extent were supportive of the SUVR results.ConclusionAt study baseline, tau SUVR was highest in Braak I‐II, followed by Braak III‐IV, then Braak V‐VI. Cross‐sectionally, higher tau PET SUVR was associated with increasing disease severity and worse clinical scores, as expected. The TANGO Tau PET sub‐study will aid our understanding of gosuranemab’s effect on tau pathology and further inform on the value of tau PET in clinical trials.