Predicting cognitive scores from wearable-based digital physiological features using machine learning: data from a clinical trial in mild cognitive impairment.

BACKGROUND: Continuous assessment and remote monitoring of cognitive function in individuals with mild cognitive impairment (MCI) enables tracking therapeutic effects and modifying treatment to achieve better clinical outcomes. While standardized neuropsychological tests are inconvenient for this purpose, wearable sensor technology collecting physiological and behavioral data looks promising to provide proxy measures of cognitive function. The objective of this study was to evaluate the predictive ability of digital physiological features, based on sensor data from wrist-worn wearables, in determining neuropsychological test scores in individuals with MCI. METHODS: We used the dataset collected from a 10-week single-arm clinical trial in older adults (50-70 years old) diagnosed with amnestic MCI (N = 30) who received a digitally delivered multidomain therapeutic intervention. Cognitive performance was assessed before and after the intervention using the Neuropsychological Test Battery (NTB) from which composite scores were calculated (executive function, processing speed, immediate memory, delayed memory and global cognition). The Empatica E4, a wrist-wearable medical-grade device, was used to collect physiological data including blood volume pulse, electrodermal activity, and skin temperature. We processed sensors' data and extracted a range of physiological features. We used interpolated NTB scores for 10-day intervals to test predictability of scores over short periods and to leverage the maximum of wearable data available. In addition, we used individually centered data which represents deviations from personal baselines. Supervised machine learning was used to train models predicting NTB scores from digital physiological features and demographics. Performance was evaluated using "leave-one-subject-out" and "leave-one-interval-out" cross-validation. RESULTS: The final sample included 96 aggregated data intervals from 17 individuals. In total, 106 digital physiological features were extracted. We found that physiological features, especially measures of heart rate variability, correlated most strongly to the executive function compared to other cognitive composites. The model predicted the actual executive function scores with correlation r = 0.69 and intra-individual changes in executive function scores with r = 0.61. CONCLUSIONS: Our findings demonstrated that wearable-based physiological measures, primarily HRV, have potential to be used for the continuous assessments of cognitive function in individuals with MCI.

Capgras Syndrome in the Young: Schizophrenia or Alzheimer Disease?

This is a case report of an atypical presentation of early onset Alzheimer disease (EOAD) in a young patient with Capgras syndrome and cognitive impairment. The concurrent onset of psychiatric and cognitive symptoms prompted a detailed evaluation for a neurodegenerative disease. A 50-year-old male lawyer presented with low mood, apathy, delusions, and auditory hallucinations over 18 months. He considered his wife as an imposter and would require her text message to confirm her identity. He became more forgetful and had to give up his law practice. His neuropsychological assessment was impaired in all domains. Genetic testing revealed homozygosity for APOEe4 alleles. His magnetic resonance imaging showed predominant parietal and medial temporal atrophy, [18F]Fluorodeoxyglucose positron emission tomography showed frontal, parietal and posterior temporal hypometabolism and [18F]Flutemetamol positron emission tomography was positive for amyloid deposition, leading to the diagnosis of EOAD. This case highlights EOAD as a differential diagnosis in young patients who present with Capgras syndrome.

Interactions Between Acute Infarcts and Cerebrovascular Pathology Predict Poststroke Dementia.

BACKGROUND: Chronic cerebrovascular pathology accelerates the incidence of poststroke dementia (PSD). Whether the risk of PSD varies according to different types of chronic cerebrovascular pathology remains unclear. OBJECTIVES: We investigated whether PSD is associated with a unique pattern of interactions between chronic cerebrovascular pathologies and acute stroke lesions. MATERIALS AND METHOD: In this case-control study of acute mild stroke patients (n=185), cases included patients who developed PSD at a 6-month poststroke follow-up, and controls included patients who remained nondemented at 6 months, matched on prestroke cognitive status. Magnetic resonance imaging was performed at initial stroke presentation; neuropsychological assessments were performed 6 months after the stroke. RESULTS: White matter hyperintensities (WMH), chronic lacunes, microbleeds, and acute infarcts were not associated with PSD after controlling for demographics, cardiovascular risk, and global cortical atrophy. The risk of PSD was largest for patients with acute large subcortical infarcts (>15 mm) and concomitant periventricular WMH compared with patients with large subcortical infarcts and punctate/absent periventricular WMH [odds ratio (OR)=5.85, 95% confidence interval (CI)=1.85-40.04]. A moderate risk of PSD was observed for patients with acute multiple small infarcts (3 to 15 mm) and concomitant lacunes (OR=2.48, 95% CI=0.94-6.51) or concomitant lobar microbleeds (OR=2.20, 95% CI=0.89-5.41), compared with patients with acute multiple small infarcts and absent lacunes or microbleeds. Single small infarcts did not interact with cerebrovascular pathology to affect PSD. CONCLUSIONS: The risk of PSD varies depending on the presence of chronic cerebrovascular pathologies and type of acute infarcts. Clinical implications support a precision medicine approach for stratifying those at highest risk of PSD.

Suicidal ideation is common in autosomal dominant Alzheimer's disease at-risk persons.

OBJECTIVES: To study the frequency of suicidal ideation and its association with clinical and neurobiological correlates among cognitively intact autosomal dominant Alzheimer's disease (ADAD) at-risk individuals. METHODS/DESIGN: In a cross-sectional study of 183 ADAD at-risk individuals (91 mutation carriers and 92 noncarriers), we compared the frequency of suicidal ideation among carriers and noncarriers. Linear mixed-effects models with family-level random effects evaluated the relationships between geriatric depression scale (GDS), neuropsychiatric inventory-questionnaire (NPI-Q), and suicidal ideation scores among all ADAD at-risk individuals. An interaction term was added to the regression models to evaluate the interactions of suicidal ideation and mutation status on neuropsychiatric symptoms. RESULTS: Twenty-six (14.20%) ADAD at-risk individuals (13 [14.28%] carriers and 13 [14.13%] noncarriers) had suicidal ideation. The frequency of suicidal ideation did not differ between carriers and noncarriers. Suicidal ideation was associated with higher GDS among all ADAD at-risk individuals. When stratified into mutation carrier status, noncarriers with suicidal ideation had higher GDS than carriers. There was no statistically significant association between suicidal ideation and NPI-Q among ADAD at-risk individuals. Awareness of mutation status, neuropsychological performances, and cerebrospinal fluid AD biomarkers were not associated with suicidal ideation among carriers and noncarriers. CONCLUSIONS: Suicidal ideation is common among cognitively intact ADAD at-risk individuals. While ADAD at-risk individuals with suicidal ideation have greater depressive symptoms, noncarriers with suicidal ideation have higher GDS scores than carriers. Interestingly, awareness of the mutation status was not associated with suicidal ideation in our study. Early identification of suicidal thoughts can facilitate timely interventions to prevent suicidal behaviours. Keywords autosomal dominant Alzheimer's diseasedominantly inherited Alzheimer's networkneuropsychiatric symptomssuicidal ideation.

Construct validity of the Visual Cognitive Assessment Test (VCAT)-a cross-cultural language-neutral cognitive screening tool.

BACKGROUND: The Visual Cognitive Assessment Test (VCAT) is a language-neutral cognitive screening tool designed for use in culturally diverse populations without the need for translations or adaptations. While it has been established to be language-neutral, the VCAT's construct validity has not been investigated. METHODS: 471 participants were recruited, comprising 233 healthy comparisons, 117 mild cognitive impairment (MCI), and 121 mild Alzheimer's disease (AD) patients. VCAT and domain-specific neuropsychological tests were administered in the same sitting. Construct validity was assessed by analyzing domain-specific associations between the VCAT and well-established cognitive assessments. Reliability (internal consistency) was measured by Cronbach's alpha. Diagnostic ability (area under the curve) and recommended cutoffs were determined by receiver operating characteristic (ROC) analysis. RESULTS: The VCAT and its subdomains demonstrated good construct validity in terms of both convergent and divergent validity and good internal consistency (α = .74). ROC analysis found that the VCAT was on par with the Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) at distinguishing between healthy comparisons, MCI, and mild AD. Consistent with previous studies, VCAT scores were not affected by language of administration or ethnicity in our cohort. Findings suggest the following cutoffs: Dementia 0-19, MCI 20-24, Normal 25-30. CONCLUSION: This study established the construct validity of the VCAT, which is vital to ensure its subdomains effectively measure the cognitive processes they were designed to. The VCAT is capable of detecting early cognitive impairments and allows for meaningful cross-cultural comparisons, especially useful for international collaborations and clinical trials, and for clinical use in diverse multiethnic populations.

Mechanisms Linking White Matter Lesions, Tract Integrity, and Depression in Alzheimer Disease.

OBJECTIVE: Late-life depression involves the disconnection of white matter tracts that regulate mood. A pathogenic link between poor tract integrity and depressive symptoms is believed to be white matter lesions (WML), however the mechanisms linking tract integrity, WML, and depression remains unexplored. The authors sought to identify whether the association between reduced tract integrity and depressive symptoms is mediated by WML in patients with Alzheimer disease (AD), and whether individual characteristics moderate this effect. METHODS: This was a cross-sectional study in a tertiary memory clinic. A total of 91 patients with mild AD and 79 healthy elderly, comparable in depressive symptoms, white matter hyperintensities (WMH) volume, cardiovascular risk, age, and sex were chosen. Tract integrity was assessed using diffusion tensor imaging, WML were indexed as WMH, measured using fluid-attenuation inversion recovery imaging, and depressive symptoms were measured with the informant-based Geriatric Depression Scale. RESULTS: In patients with mild AD, reduced tract integrity in right hemispheric cortical-subcortical tracts and the genu of the corpus callosum was moderately associated with depressive symptoms. This association was fully mediated by WML. Moderation analysis indicated that old age strengthened the association between all tracts and depressive symptoms, as mediated by WML. In cognitively healthy elderly, neither tracts nor WML were related to depressive symptoms. CONCLUSION: Reduced tract integrity may be important but not sufficient for the manifestation of depressive symptoms in mild AD. Instead, WML may drive the pathogenic link between reduced tract integrity and depressive symptoms.

Dyslexic Characteristics of Chinese-Speaking Semantic Variant of Primary Progressive Aphasia.

Reading disorder is a recognized feature in primary progressive aphasia (PPA). Surface dyslexia, characterized by regularization errors, is typically seen in the English-speaking semantic variant of PPA (svPPA). However, dyslexic characteristics of other languages, particularly logographical languages such as Chinese, remain sparse in the literature. This study aims to characterize and describe the dyslexic pattern in this group of patients by comparing an English-speaking svPPA group with a Chinese-speaking svPPA group. The authors hypothesized that Chinese-speaking individuals with svPPA would likely commit fewer surface dyslexic errors. By accessing the database of Singapore's National Neuroscience Institute and the National Alzheimer's Coordinating Center of the United States, the authors identified three Chinese-speaking and 18 English-speaking patients with svPPA, respectively, for comparison. The results suggest that, instead of surface dyslexia, svPPA in Chinese-speaking individuals is characterized by a profound deep dyslexic error. Based on current evidence suggesting the role of the temporal pole as a semantic convergence center, the authors conclude that this region also mediates and converges lexical-semantic significance in logographical languages.

Modelling the Distribution of Cognitive Outcomes for Early-Stage Neurocognitive Disorders: A Model Comparison Approach.

Background: Cognitive assessments for patients with neurocognitive disorders are mostly measured by the Montreal Cognitive Assessment (MoCA) and Visual Cognitive Assessment Test (VCAT) as screening tools. These cognitive scores are usually left-skewed and the results of the association analysis might not be robust. This study aims to study the distribution of the cognitive outcomes and to discuss potential solutions. Materials and Methods: In this retrospective cohort study of individuals with subjective cognitive decline or mild cognitive impairment, the inverse-transformed cognitive outcomes are modelled using different statistical distributions. The robustness of the proposed models are checked under different scenarios: with intercept-only, models with covariates, and with and without bootstrapping. Results: The main results were based on the VCAT score and validated via the MoCA score. The findings suggested that the inverse transformation method improved the modelling the cognitive scores compared to the conventional methods using the original cognitive scores. The association of the baseline characteristics (age, gender, and years of education) and the cognitive outcomes were reported as estimates and 95% confidence intervals. Bootstrap methods improved the estimate precision and the bootstrapped standard errors of the estimates were more robust. Cognitive outcomes were widely analysed using linear regression models with the default normal distribution as a conventional method. We compared the results of our suggested models with the normal distribution under various scenarios. Goodness-of-fit measurements were compared between the proposed models and conventional methods. Conclusions: The findings support the use of the inverse transformation method to model the cognitive outcomes instead of the original cognitive scores for early-stage neurocognitive disorders where the cognitive outcomes are left-skewed.

Visual Cognitive Assessment Test: Utility of the brief cognitive battery for early screening of cognitive impairment in Chongqing, China.

OBJECTIVES: Early detection of cognitive impairment is essential for timely intervention. Currently, most widely used cognitive screening tests are influenced by language and cultural differences; therefore, there is a need for the development of a language-neutral, visual-based cognitive assessment tool. The Visual Cognitive Assessment Test (VCAT), a 30-point test that assesses memory, executive function, visuospatial function, attention, and language, has demonstrated its utility in a multilingual population. In this study, we evaluated the reliability, validity, and diagnostic performance of the VCAT for screening early cognitive impairment in Chongqing, China METHODS: A total of 134 individuals (49 healthy controls (HCs), 52 with mild cognitive impairment (MCI), and 33 with mild dementia) completed the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), VCAT, and domain-specific neuropsychological assessments. The diagnostic performances of MMSE, MoCA, and VCAT were evaluated using the area under the curve (AUC), sensitivity, and specificity. Construct validity of the VCAT was assessed with well-established domain-specific cognitive assessments. Reliability was measured using Cronbach's alpha. RESULTS: The VCAT and its subdomains demonstrated both good construct validity and internal consistency (α = 0.577). The performance of VCAT was comparable to that of MoCA and MMSE in differentiating mild dementia from nondemented groups (AUC: 0.940 vs. 0.902 and 0.977, respectively; p = .098 and .053) and in distinguishing cognitive impairment (CI) from HC (AUC: 0.929 vs. 0.899 and 0.891, respectively; p = .239 and .161), adjusted for education level. The optimal score range for VCAT in determining dementia, MCI, and HC was 0-14, 15-19, and 20-30, respectively. CONCLUSION: The VCAT proves to be a reliable screening test for early cognitive impairment within our cohort. Being both language and cultural neutral, the VCAT has the potential to be utilized among a wider population within China.

Mild Behavioral Impairment and Cerebrovascular Profiles Are Associated with Early Cognitive Impairment in a Community-Based Southeast Asian Cohort.

Background: Mild behavioral impairment (MBI) is one of the earliest observable changes when a person experiences cognitive decline and could be an early manifestation of underlying Alzheimer's disease neuropathology. Limited attention has been given to investigating the clinical applicability of behavioral biomarkers for detection of prodromal dementia. Objective: This study compared the prevalence of self-reported MBI and vascular risk factors in Southeast Asian adults to identify early indicators of cognitive impairment and dementia. Methods: This cohort study utilized baseline data from the Biomarkers and Cognition Study, Singapore (BIOCIS). 607 participants were recruited and classified into three groups: cognitively normal (CN), subjective cognitive decline (SCD), and mild cognitive impairment (MCI). Group comparisons of cognitive-behavioral, neuroimaging, and blood biomarkers data were applied using univariate analyses. Multivariate logistic regression analyses were conducted to investigate the association between cerebrovascular disease, vascular profiles, and cognitive impairment. Results: SCD had significantly higher depression scores and poorer quality of life (QOL) compared to CN. MCI had significantly higher depression scores; total MBI symptoms, MBI-interest, MBI-mood, and MBI-beliefs; poorer sleep quality; and poorer QOL compared to CN. Higher Staals scores, glucose levels, and systolic blood pressure were significantly associated with MCI classification. Fasting glucose levels were significantly correlated with depression, anxiety, MBI-social, and poorer sleep quality. Conclusions: The results reflect current research that behavioral changes are among the first symptoms noticeable to the person themselves as they begin to experience cognitive decline. Self-reported questionnaires may aid in early diagnoses of prodromal dementia. Behavioral changes and diabetes could be potential targets for preventative healthcare for dementia.

Predicting functional decline in aging and Alzheimer's disease with PET-based Braak staging.

The progression of PET-based Braak stages correlates with cognitive deterioration in aging and Alzheimer's disease. Here, we investigate the association between PET-based Braak stages and functional impairment and assess whether PET-based Braak staging predicts a longitudinal decline in the performance of activities of daily living. In this cohort study, we evaluated cognitively unimpaired individuals and individuals with mild cognitive impairment or Alzheimer's disease dementia. Participants underwent [18F]MK6240 tau-PET, were assigned a PET-based Braak stage at baseline and were followed for a mean (SD) of 1.97 (0.66) years. Functional performance was evaluated with the Functional Activities Questionnaire, Everyday Cognition and functional Clinical Dementia Rating sum of boxes. Multiple linear regressions assessed the association of PET-based Braak stages with baseline functionality and with the longitudinal rate of change in functional scores, adjusting for age, sex and amyloid-ß load. We employed voxel-based regression models to investigate the association between functionality and tau-PET signal and assessed the voxel overlap with Braak regions of interest. We included 291 individuals (181 cognitively unimpaired, 56 amyloid-ß+ mild cognitive impairment and 54 amyloid-ß+ Alzheimer's disease) aged 70.60 (7.48) years. At baseline, PET-based Braak stages III-IV (ß = 0.43, P = 0.03) and V-VI (ß = 1.20, P < 0.0001) showed associations with poorer Functional Activities Questionnaire scores. Similarly, stages III-IV (ß = 0.43, P = 0.02) and V-VI (ß = 1.15, P < 0.0001) were associated with worse Everyday Cognition scores. Only stages V-VI were associated with higher functional Clinical Dementia Rating sum of boxes (ß = 1.17, P < 0.0001) scores. Increased tau-PET signals in all Braak regions of interest were linked to worse performance in all tools. The voxelwise analysis showed widespread cortical associations between functional impairment and tau-PET and high voxel overlap with Braak regions of interest. Baseline PET-based Braak stages V-VI predicted significant longitudinal functional decline as assessed by the Functional Activities Questionnaire (ß = 1.69, P < 0.0001), the Everyday Cognition (ß = 1.05, P = 0.001) and the functional Clinical Dementia Rating sum of boxes (ß = 1.29, P < 0.0001). Our results suggest that functional impairment increases with the severity of tau accumulation. These findings also indicate that PET-based Braak staging is a good predictor of functional impairment in the Alzheimer's disease continuum. Finally, our study provides evidence for the clinical significance of the PET-based Braak staging framework.

Corrigendum: Topology of diffusion changes in corpus callosum in Alzheimer's disease: An exploratory case-control study.

[This corrects the article DOI: 10.3389/fneur.2022.1005406.].

Clinical characteristics of pathological confirmed prodromal dementia with Lewy bodies.

INTRODUCTION: Misdiagnosis rate of Dementia with Lewy Bodies (DLB) remains high despite being second most common cause of neurodegenerative dementia. To date, understanding of clinical profile of pathologically confirmed prodromal DLB remains limited. The main objective of this study was to describe and compare it with pathologically confirmed Alzheimer's disease (AD). METHODS: We accessed the National Alzheimer's Coordinating Center database from 2005 to December 2022 data freeze and included 111 and 501 prodromal DLB and AD patients respectively. First visit data was analyzed. RESULTS: Clinician-determined memory impairment is common in prodromal DLB (>70%) but associated with higher risk for AD diagnosis (OR 0.355, p = 0.0003). DLB had a higher proportion of non-amnestic mild cognitive impairment (MCI) diagnoses but statistically insignificance in differentiating the two. Inattention (OR 2.273, p = 0.0015), and neuropsychiatric features, such as visual hallucinations (OR 11.98, p < 0.0001), depressed mood (OR1.709, p = 0.0292), apathy (1.824, p = 0.0345), and night/REM sleep behaviors, are associated with DLB diagnosis. Hallucinations are infrequent (7-11%). Motor symptoms, particularly gait disorders (OR 4.570, p < 0.001), falls (OR3.939, p = 0.0003), tremors (OR2.237, p = 0.0154), slowness (OR3.573, p < 0.0001), and parkinsonism signs (OR2.443, p < 0.0001), are common. 32% showed no parkinsonism during initial presentation. Neuropsychological examination revealed less impaired memory and language but impaired executive function in DLB. CONCLUSION: In clinical practice, it is important to note that memory symptoms although being higher risk associated with AD diagnosis, are prominent in prodromal DLB. Psychosis is infrequent, and non-amnestic MCI is not necessarily associated with higher risk of DLB diagnosis. A careful clinical approach is key to improve the diagnosis of prodromal DLB.

APOE4 carrier status determines association between white matter disease and grey matter atrophy in early-stage dementia.

BACKGROUND: White matter hyperintensities, a neuroimaging marker of small-vessel cerebrovascular disease and apolipoprotein ε4 (APOE4) allele, are important dementia risk factors. However, APOE4 as a key effect modifier in the relationship between white matter hyperintensities and grey matter volume needs further exploration. METHODS: One hundred ninety-two early-stage dementia (including mild cognitive impairment and mild dementia) and 259 cognitively unimpaired participants from a neurocognitive research cohort with neuroimaging data, APOE genotyping, and neuropsychological assessments were studied. We investigated independent and interactive effects of white matter hyperintensities and APOE4 on whole-brain voxel-wise grey matter volume using voxel-based morphometry (uncorrected p < 0.001; minimum cluster size = 100 voxels). We further assessed interactive effects between APOE4 and white matter hyperintensities on global cognition, memory, and executive function in early-stage dementia and cognitively unimpaired participants. RESULTS: Independent of APOE4 status, higher white matter hyperintensity load was associated with greater grey matter atrophy across frontal, parietal, temporal, and occipital lobes in cognitively unimpaired and early-stage dementia subjects. However, interaction analyses and independent sample analyses revealed that APOE4 non-carriers demonstrated greater white matter hyperintensity-associated grey matter atrophy compared to APOE4 carriers in both cognitively unimpaired and early-stage dementia groups. Additional confirmatory analyses among APOE4 non-carriers demonstrated that white matter hyperintensities resulted in widespread grey matter loss. Analyses of cognitive function demonstrated that higher white matter hyperintensity load was associated with worse global (Mini-Mental State Examination, Montreal Cognitive Assessment) and executive function (Color Trails 2) in APOE4 non-carriers compared to APOE4 carriers in early-stage dementia but not cognitively unimpaired participants. CONCLUSIONS: The association between white matter hyperintensities and grey matter loss is more pronounced in APOE4 non-carriers than APOE4 carriers in the cognitively unimpaired and early-stage dementia stages. Furthermore, white matter hyperintensity presence results in poorer executive function in APOE4 non-carriers compared to APOE4 carriers. This finding may have significant impact on the design of clinical trials with disease modifying therapies.

C9orf72 expansions are the most common cause of genetic frontotemporal dementia in a Southeast Asian cohort.

OBJECTIVE: Frontotemporal dementia (FTD) encompasses a spectrum of neurodegenerative disorders, including behavioural variant FTD (bvFTD), semantic variant primary progressive aphasia (svPPA) and non-fluent variant PPA (nfvPPA). While a strong genetic component is implicated in FTD, genetic FTD in Asia is less frequently reported. We aimed to investigate the frequency of Southeast Asian FTD patients harbouring known genetic FTD variants. METHODS: A total of 60 FTD-spectrum patients (25 familial and 35 sporadic) from Singapore and the Philippines were included. All underwent next-generation sequencing and repeat-primed PCR for C9orf72 expansion testing. Neurofilament light chain (NfL) levels were measured in a subset of patients. RESULTS: Overall, 26.6% (16/60 cases) carried pathogenic or likely pathogenic variants in a FTD-related gene, including: MAPT Gln351Arg (n = 1); GRN Cys92Ter (n = 1), Ser301Ter (n = 2), c.462 + 1G > C (n = 1); C9orf72 expansion (35-70 repeats; n = 8); TREM2 Arg47Cys (n = 1); and OPTN frameshift insertion (n = 2). Genetic mutations accounted for 48% (12/25) of patients with familial FTD, and 11.4% (4/35) of patients with sporadic FTD. C9orf72 repeat expansions were the most common genetic mutation (13.3%, 8/60), followed by GRN (6.7%, 4/60) variants. Within mutation carriers, plasma NfL was highest in a C9orf72 expansion carrier, and CSF NfL was highest in a GRN splice variant carrier. INTERPRETATION: In our cohort, genetic mutations are present in one-quarter of FTD-spectrum cases, and up to half of those with family history. Our findings highlight the importance of wider implementation of genetic testing in FTD patients from Southeast Asia.

The Use of Tau PET to Stage Alzheimer Disease According to the Braak Staging Framework.

Amyloid-ß plaques and neurofibrillary tangles (NFTs) are the 2 histopathologic hallmarks of Alzheimer disease (AD). On the basis of the pattern of NFT distribution in the brain, Braak and Braak proposed a histopathologic staging system for AD. Braak staging provides a compelling framework for staging and monitoring of NFT progression in vivo using PET imaging. Because AD staging remains based on clinical features, there is an unmet need to translate neuropathologic staging to a biologic clinical staging system. Such a biomarker staging system might play a role in staging preclinical AD or in improving recruitment strategies for clinical trials. Here, we review the literature regarding AD staging with the Braak framework using tau PET imaging, here called PET-based Braak staging. Our aim is to summarize the efforts of implementing Braak staging using PET and assess correspondence with the Braak histopathologic descriptions and with AD biomarkers. Methods: We conducted a systematic literature search in May 2022 on PubMed and Scopus combining the terms "Alzheimer" AND "Braak" AND ("positron emission tomography" OR "PET"). Results: The database search returned 262 results, and after assessment for eligibility, 21 studies were selected. Overall, most studies indicate that PET-based Braak staging may be an efficient method to stage AD since it presents an adequate ability to discriminate between phases of the AD continuum and correlates with clinical, fluid, and imaging biomarkers of AD. However, the translation of the original Braak descriptions to tau PET was done taking into account the limitations of this imaging technique. This led to important interstudy variability in the anatomic definitions of Braak stage regions of interest. Conclusion: Refinements in this staging system are necessary to incorporate atypical variants and Braak-nonconformant cases. Further studies are needed to understand the possible applications of PET-based Braak staging to clinical practice and research. Furthermore, there is a need for standardization in the topographic definitions of Braak stage regions of interest to guarantee reproducibility and methodologic homogeneity across studies.

APOE4 and Confluent White Matter Hyperintensities Have a Synergistic Effect on Episodic Memory Impairment in Prodromal Dementia.

BACKGROUND: White matter hyperintensities (WMH) are a known risk factor for cognitive decline. While the ɛ4 allele of apolipoprotein E gene (APOE4) is another risk factor for cognitive decline, it remains unclear how APOE4 affects the relationship between WMH and cognitive decline, specifically in the prodromal stage of dementia. OBJECTIVE: To determine how APOE4 moderates the relationship between WMH and cognition in prodromal dementia. METHODS: Two-hundred-sixteen participants with prodromal dementia underwent magnetic resonance imaging (MRI), neuropsychological testing (global and domain wise), cardiovascular risk factor assessments, and APOE genotyping. Visual ratings for WMH as well as total and lobar WMH volumes were quantified. Moderation analysis was performed to determine the influence of APOE4 on the relationship between WMH and performance on global and domain-specific cognitive measures. The role of confluent and non-confluent WMH on cognition was additionally studied using logistic regression. RESULTS: APOE4 carriers (n = 49) had poorer memory and higher global WMH (10.01 mL versus 6.23 mL, p = 0.04), temporal WMH (1.17 mL versus 0.58 mL, p = 0.01), and occipital WMH (0.38mL versus 0.22 mL, p = 0.02) compared to APOE4 non-carriers (n = 167). Moderation analysis revealed that APOE4 positivity strengthened the relationship between higher global as well as lobar WMH burden and poorer episodic memory. Furthermore, APOE4 carriers with confluent WMH were 4.81 times more likely to have impaired episodic memory compared to non-confluent WMH and non-APOE carriers. CONCLUSION: The impact of WMH on memory may be strongest among APOE4 carriers. Clinicians targeting WMH would need to consider the APOE4 allele and WMH severity status to strategize cognitive interventions.

Correlation Between Plasma Oligomeric Amyloid-ß and Performance on the Language Neutral Visual Cognitive Assessment Test in a Southeast Asian Population.

Oligomeric amyloid-ß (OAß), an upstream driver of Alzheimer's disease (AD) neuropathology, correlates with poor cognitive performance and brain volume reduction. Its effect on cognitive performance measured by the language neutral Visual Cognitive Assessment Test (VCAT) remains to be evaluated. We studied the correlation of plasma OAß with VCAT scores and grey matter volume (GMV) in a Southeast Asian cohort with mild cognitive impairment. Higher plasma OAß significantly correlated with lower; cognitive scores (VCAT, Mini-Mental State Examination) and GMV/intracranial volume ratio. Such findings reveal the clinical utility of plasma OAß as a promising biomarker and support validation through longitudinal studies.