Stages Of Cognitive Impairment Research Articles

Recent advances in understanding Alzheimer's Disease: diagnosis and management strategies.

As the rates of Alzheimer's Disease (AD) increase in the world due to the aging of the population, research has made tremendous advances to target the two hallmark pathologies of AD: amyloid-β (Aβ) plaque deposition and neurofibrillary tangles of hyperphosphorylated tau. Here, we discuss recent advances in the clinical evaluation and management of AD, with a focus on new hypotheses related to the etiology of AD and new evidence related to AD-mimicking neurodegenerative diseases. Though recent clinical studies suggest anti-amyloid disease modifying agents may slow the progression of AD, there is currently no medication that stops it. Moreover, slowing the progression will result in more individuals in the mild cognitive impairment (MCI) and mild dementia stages of AD. Given this reality, we evaluate the development of non-pharmacological strategies to help sustain cognitive function and quality of life.

Clock Drawing Test: Types of Errors and Accuracy in Early Cognitive Screening.

Clock Drawing Test (CDT) is a commonly used screening tool for cognitive disorders, known for its ease of administration and scoring. Despite frequent use by clinicians, CDT is criticized for its poor predictive value in mild cases of impairment. To evaluate CDT as a screening tool for early stage of cognitive impairment in biomarker-verified Alzheimer's disease (AD) and depressive disorder (DD). We analyzed CDT of 172 patients with verified AD, 70 patients with DD, in whom neurodegenerative disorder was excluded using cerebrospinal fluid biomarkers, and 58 healthy older adults. CDT was scored using the semi-quantitative (Shulman) and itemized criteria (adapted from Mendez). Logistic regression showed that for both DD and AD patients with high Mini-Mental State Examination (MMSE) scores (27 and above) the significant predicting variable is uneven number spacing. As MMSE deteriorates (24-26 points), an additional error of setting clock hands is predictive of the disease. In the low MMSE condition, CDT showed an acceptable discrimination for AD (AUC itemized 0.740, Shulman 0.741) and DD (AUC itemized 0.827, Shulman 0.739) using both scoring methods. In the high MMSE condition, discrimination rates were acceptable using itemized scoring but poor using Shulman scoring for both AD (AUC itemized 0.707, Shulman 0.677) and DD (AUC itemized 0.755, Shulman 0.667) groups. Ideally, modern diagnostic process should take place before the cognitive performance drops beneath the healthy range. This makes CDT of little use when screening patients with very mild cognitive deficits.

The Paradox in Positive and Negative Aspects of Emotional Functioning Among Older Adults with Early Stages of Cognitive Impairment.

Introduction: Emotional functioning in older adults is influenced by normal aging and cognitive impairment, likely heterogeneous across positive versus negative aspects of emotional functioning. Little is known about positive emotional experiences at the early stages of cognitive impairment. Methods: We assessed different aspects of emotional functioning among 448 participants aged 65+ (Normal Control (NC) = 276, Mild Cognitive Impairment (MCI) = 103, and mild dementia of the Alzheimer type (mild DAT) = 69) and tested moderators. Results: Compared to NC, older adults with MCI and mild DAT have maintained many positive aspects of emotional functioning, despite higher levels of negative affect, sadness, and loneliness. Among the oldest-old, the mild DAT group experienced higher fear and lower self-efficacy. Discussion: Older adults at early stages of cognitive impairment can experience positive aspects of emotional functioning, such as positive affect, purpose, and life satisfaction, all of which are important buildable psychological resources for coping.

Quantitative analysis of balance function characteristics in older patients with mild to moderate cognitive impairment

BackgroundCognitive decline in older adults may affect balance function, but the relationship between the two is not fully understood, especially in the early stages of cognitive impairment. Mild to moderate cognitive impairment can be assessed with the Montreal Cognitive Assessment (MOCA). AimThis study quantitatively analyzed balance function in older adults with mild to moderate cognitive impairment using computerized dynamic posturography (CDP) testing. Methods248 older patients were divided into a cognitive impaired group (MOCA <26, n = 126) and a normal group (MOCA ≥26, n = 122) based on the Montreal Cognitive Assessment (MOCA) Beijing Version. Patients underwent CDP testing, which included the sensory organization test (SOT) and the limits of stability test (LOS). ResultsThe cognitive impaired group had significantly lower SOT composite and visual scores, as well as reaction time (RT), movement velocity (MVL), endpoint excursion (EPE), maximum excursion (MXE), and directional control (DCL) of the LOS test. Binary logistic regression analysis revealed that RT and MXE were independent factors significantly associated with MOCA, even after adjustment for age and sex. ConclusionsOlder patients with mild to moderate cognitive impairment may have reduced sensory integration and balance stability limits, mainly manifested as prolonged motor reaction time and shortened maximum movement distance.

Objective sleep was longitudinally associated with brain amyloid burden in mild cognitive impairment.

Understanding the longitudinal association of objective sleep and physical activity with brain amyloid burden and cortical glucose metabolism has critical clinical and public health implications for dementia prevention in later life. We enrolled 118 individuals aged ≥65 years with mild cognitive impairment, who were followed up on from August 2015 to September 2019. All participants continuously wore an accelerometer sensor for 7 consecutive days every 3 months and received annual 11 C-Pittsburgh compound-B and 18 F-fluorodeoxyglucose positron emission tomography (PET). Sleep and physical activity parameters were assessed using accelerometer sensor data andPET imaging was quantified using a standardized uptake-value ratio. Fifty-seven participants (48.3%) completed a lifestyle factor assessment and PET imaging over the 3-year period. A linear mixed-effects model was applied to examine the longitudinal association of sleep and physical activity parameters with PET imaging over the 3-year period, controlling for potential confounders. Sleep efficiency was inversely associated with amyloid uptake in the frontal lobe. Although sleep duration was positively associated with global amyloid uptake, particularly in the frontal lobe, their impact was extremely small. However, physical activity parameters were not significantly associated with the 11 C-Pittsburgh compound-B-uptake. Furthermore, sleep and physical activity parameters were not significantly associated with cortical glucose metabolism. Lower sleep efficiency could be an early symptom of greater brain amyloid burden at the mild cognitive impairment stage. Therefore, the assessment of sleep may be useful for identifying individuals at higher risk for brain amyloid burden. Future longer term observational studies are required to confirm these findings.

Voxel Extraction and Multiclass Classification of Identified Brain Regions across Various Stages of Alzheimer's Disease Using Machine Learning Approaches.

This study sought to investigate how different brain regions are affected by Alzheimer's disease (AD) at various phases of the disease, using independent component analysis (ICA). The study examines six regions in the mild cognitive impairment (MCI) stage, four in the early stage of Alzheimer's disease (AD), six in the moderate stage, and six in the severe stage. The precuneus, cuneus, middle frontal gyri, calcarine cortex, superior medial frontal gyri, and superior frontal gyri were the areas impacted at all phases. A general linear model (GLM) is used to extract the voxels of the previously mentioned regions. The resting fMRI data for 18 AD patients who had advanced from MCI to stage 3 of the disease were obtained from the ADNI public source database. The subjects include eight women and ten men. The voxel dataset is used to train and test ten machine learning algorithms to categorize the MCI, mild, moderate, and severe stages of Alzheimer's disease. The accuracy, recall, precision, and F1 score were used as conventional scoring measures to evaluate the classification outcomes. AdaBoost fared better than the other algorithms and obtained a phenomenal accuracy of 98.61%, precision of 99.00%, and recall and F1 scores of 98.00% each.

Abstract 105: Potential Effect Modifiers In The Relationship Between Late-life Systolic Blood Pressure And Alzheimer’s Neuropathology

Mixed evidence exists on the relationship between late-life blood pressure (BP) and Alzheimer’s disease (AD) pathology such as amyloid and tau deposition in the brain, possibly partly due to heterogeneous effects across population subgroups. Utilizing data from the National Alzheimer’s Coordinating Center longitudinal dataset, we investigated to what extent age (&lt;65 yrs, 65-74 yrs, &gt;74 yrs), APOE genotype, stroke history, and baseline cognitive status modified the association between systolic BP (SBP) at baseline and amyloid and tau neuropathology in 3165 older adults (mean [SD] age=74 [9.8] yrs, women 47.4% [1501 of 3165]). Amyloid pathology was assessed by Thal staging, diffuse plaque, neuritic plaque and tau pathology was assessed by Braak staging at brain autopsy. Effect modification was assessed by stratified analyses and interaction analyses in multinomial logistic regression with adjustment for age at first visit, sex, APOE genotype, education years and antihypertensive medications use. We observed that both APOE e4 carriership (interaction p-value = 0.03) and stroke history (interaction p-value = 0.03) statistically modified the association of SBP with amyloid pathology, whereas baseline cognitive status modified the association with both amyloid and tau pathology (interaction p-value &lt;0.001). The SBP-amyloid association appears to be pronounced in older age group (65-74 group: OR=1.19 [CI:1.05-1.35], &gt;74 group: OR=1.12 [CI:1.02-1.23]), APOE e4 carriers (OR=1.17[CI:1.02-1.34]), and those with stroke history (OR=1.69 [CI:1.20-2.38]) and participants with dementia at baseline (OR=1.16 [CI:1.05-1.27]), whereas SBP-tauopathy association was only found in APOE e4 carriers (OR=1.25[CI:1.05-1.48]), participants without stroke history (OR=1.12[CI:1.01-1.24]), and participants with normal cognitive function at baseline (OR=1.67[CI:1.24-2.24]). Our study suggests that the relationship between SBP and amyloid and tau pathology may vary across subgroups based on age, APOE genotype, cerebrovascular burden, and stage of cognitive impairment. The underlying mechanisms warrant further investigation to inform precision blood pressure control for the prevention of dementia.

A blunted TH17 cytokine signature in women with mild cognitive impairment: insights from inflammatory profiling of a community-based cohort of older adults.

People with dementia have an increase in brain inflammation, caused in part by innate and adaptive immune cells. However, it remains unknown whether dementia-associated diseases alter neuro-immune reflex arcs to impact the systemic immune system. We examined peripheral immune cells from a community-based cohort of older adults to test if systemic inflammatory cytokine signatures associated with early stages of cognitive impairment. Human peripheral blood mononuclear cells were cultured with monocyte or T-cell-targeted stimuli, and multiplex assays quantitated cytokines in the conditioned media. Following T-cell-targeted stimulation, cells from women with cognitive impairment produced lower amounts of TH17 cytokines compared with cells from cognitively healthy women, while myeloid-targeted stimuli elicited similar amounts of cytokines from cells of both groups. This TH17 signature correlated with the proportion of circulating CD4+ and CD8+ T cells and plasma glial fibrillary acidic protein and neurofilament light concentrations. These results suggest that decreases in TH17 cytokines could be an early systemic change in women at risk for developing dementia. Amelioration of TH17s cytokines in early cognitive impairment could, in part, explain the compromised ability of older adults to respond to vaccines or defend against infection.

Clinical and biochemical markers of neurodegenerative process in Alzheimer's disease

Recently, numerous studies have been devoted to describing the heterogeneity of Alzheimer's disease (AD). The aim of our work was to study the clinical, biochemical, and neuropsychological signs of AD depending on the form of the disease. The study involved 173 patients with AD, of whom 65 patients with early onset and 108 with late onset at the stage of moderate cognitive impairment. All study participants underwent the Montreal Cognitive Assessment Scale (MoCA test), the Free and Cued Selective Reminding Test with Immediate Recall (FCSRT-IR), and a lumbar puncture with the determination of the levels of Aβ42 and Aβ40 biomarkers in the cerebrospinal fluid by enzyme immunoassay. The mean age of the patients with early onset of AD was 65.1±0.3 years, and with late onset - 78.6±0.5 years. According to our data, it was found that the majority of the patients with late-onset AD had a longer education (p=0.000) and had coffee more often (p=0.000) than the study participants with early onset of AD. We did not reveal the effect of alcohol and smoking on the neurodegenerative process. The patients with early-onset AD scored lower on the MoCA test than those with late-onset AD (p=0.000). The results of free recall and cue index on the FCSRT-IR test in the patients with late AD were significantly lower than in the patients with early AD onset (p&lt;0.001). We found that the level of Aβ42 and the ratio of Aβ42/Aβ40 in the cerebrospinal fluid was significantly lower (p=0.000) in the patients with early AD onset. The results of our study prove the need for an integrated approach to diagnosing AD using clinical, neuropsychological,and biochemical research methods.

Age-, sex-, and pathology-related variability in brain structure and cognition

This work aimed to investigate potential pathways linking age and imaging measures to early age- and pathology-related changes in cognition. We used [18F]-Flutemetamol (amyloid) and [18F]-Flortaucipir (tau) positron emission tomography (PET), structural MRI, and neuropsychological assessment from 232 elderly individuals aged 50–89 years (46.1% women, 23% APOE-ε4 carrier, 23.3% MCI). Tau-PET was available for a subsample of 93 individuals. Structural equation models were used to evaluate cross-sectional pathways between age, amyloid and tau burden, grey matter thickness and volumes, white matter hyperintensity volume, lateral ventricle volume, and cognition. Our results show that age is associated with worse outcomes in most of the measures examined and had similar negative effects on episodic memory and executive functions. While increased lateral ventricle volume was consistently associated with executive function dysfunction, participants with mild cognitive impairment drove associations between structural measures and episodic memory. Both age and amyloid-PET could be associated with medial temporal lobe tau, depending on whether we used a continuous or a dichotomous amyloid variable. Tau burden in entorhinal cortex was related to worse episodic memory in individuals with increased amyloid burden (Centiloid >12) independently of medial temporal lobe atrophy. Testing models for sex differences revealed that amyloid burden was more strongly associated with regional atrophy in women compared with men. These associations were likely mediated by higher tau burden in women. These results indicate that influences of pathological pathways on cognition and sex-specific vulnerabilities are dissociable already in early stages of neuropathology and cognitive impairment.

Aducanumab: an uprising hope with vague horizons

Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Amyloid-beta (Aβ) deposition, is one of the processes involved in the pathophysiology of AD, has inspired interest in targeted therapies, including monoclonal antibodies. Aducanumab acts as a fully human IgG1 monoclonal antibody against Aβ by binding to amyloid plaques and was approved by the Food and Drug Administration (FDA) as the first disease-modifying drug for mild cognitive impairment and mild stages of AD. This accelerated approval, albeit the termination of the two phase III clinical trials of aducanumab due to results of futility analysis, has provoked controversy among the key opinion leaders in the field of cognitive neurology. Aducanumab poses significant financial constraints on patients and healthcare systems. Furthermore, the precise diagnosis of AD stages for appropriate aducanumab initiation remains a formidable challenge. The drug’s administration necessitates specialized infrastructure and medical equipment, and it may induce amyloid-related imaging abnormalities (ARIA), potentially resulting in cerebral edema or hemorrhage. These disadvantages might outweigh the potential benefits of the medication, especially considering the uncertainties regarding its efficacy. This commentary is intended to briefly evaluate the application of aducanumab in developing countries, considering the associated diagnostic challenges, clinical efficacy, cost, and potential adverse effects.

Relationships between quantitative retinal microvascular characteristics and cognitive function based on automated artificial intelligence measurements.

Introduction: The purpose of this study is to assess the relationship between retinal vascular characteristics and cognitive function using artificial intelligence techniques to obtain fully automated quantitative measurements of retinal vascular morphological parameters. Methods: A deep learning-based semantic segmentation network ResNet101-UNet was used to construct a vascular segmentation model for fully automated quantitative measurement of retinal vascular parameters on fundus photographs. Retinal photographs centered on the optic disc of 3107 participants (aged 50-93years) from the Beijing Eye Study 2011, a population-based cross-sectional study, were analyzed. The main parameters included the retinal vascular branching angle, vascular fractal dimension, vascular diameter, vascular tortuosity, and vascular density. Cognitive function was assessed using the Mini-Mental State Examination (MMSE). Results: The results showed that the mean MMSE score was 26.34 ± 3.64 (median: 27; range: 2-30). Among the participants, 414 (13.3%) were classified as having cognitive impairment (MMSE score < 24), 296 (9.5%) were classified as mild cognitive impairment (MMSE: 19-23), 98 (3.2%) were classified as moderate cognitive impairment (MMSE: 10-18), and 20 (0.6%) were classified as severe cognitive impairment (MMSE < 10). Compared with the normal cognitive function group, the retinal venular average diameter was significantly larger (p = 0.013), and the retinal vascular fractal dimension and vascular density were significantly smaller (both p < 0.001) in the mild cognitive impairment group. The retinal arteriole-to-venular ratio (p = 0.003) and vascular fractal dimension (p = 0.033) were significantly decreased in the severe cognitive impairment group compared to the mild cognitive impairment group. In the multivariate analysis, better cognition (i.e., higher MMSE score) was significantly associated with higher retinal vascular fractal dimension (b = 0.134, p = 0.043) and higher retinal vascular density (b = 0.152, p = 0.023) after adjustment for age, best corrected visual acuity (BCVA) (logMAR) and education level. Discussion: In conclusion, our findings derived from an artificial intelligence-based fully automated retinal vascular parameter measurement method showed that several retinal vascular morphological parameters were correlated with cognitive impairment. The decrease in retinal vascular fractal dimension and decreased vascular density may serve as candidate biomarkers for early identification of cognitive impairment. The observed reduction in the retinal arteriole-to-venular ratio occurs in the late stages of cognitive impairment.

Neuropsychiatric symptoms in mild cognitive impairment and Alzheimer’s disease: Relation with disease stage, sex, and daily function impairment

AbstractBackgroundTo reveal the relations between neuropsychiatric symptoms (NPS), stages of cognitive impairment, sex, and daily function impairment in patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD).Method1,154 patients with MCI and AD were enrolled from 2014 to 2021 from the Memory Clinic, The First Affiliated Hospital of Chongqing Medical University. Mini‐mental State Examination (MMSE) was used to assess the cognitive function, and Clinical dementia rating scale (CDR) was used to evaluate the disease severity of patients. NPS and function of patients’ daily life were evaluated by Neuropsychiatric Inventory (NPI) and activities of daily living (ADL) respectively.ResultPsychosis symptoms displayed the highest prevalence in MCI (43.3%) and mild AD stage (62.2%), while in moderate and severe AD, behavior symptoms showed its dominance (86.7% and 96.4%, respectively). Delusion, apathy, AMB and sleep disturbance were the discriminant symptoms across the spectrum of cognitive decline (all P &lt;0.05). Depression was more prominent in female (26.1% vs. 14.9% in MCI; 40.2% vs. 21.0% in AD, all P&lt; 0.05) while male patients presented higher prevalence in apathy (27.0% vs. 18.6% in MCI; 54.1% vs. 42.8% in AD, all P&lt; 0.05). Physical self‐maintenance was negatively impacted by apathy and sleep disturbance at mild AD stage, while instrumental activity of daily living was significantly influenced by aberrant motor behavior in MCI and mild AD (all P&lt; 0.05).ConclusionThe prevalence of NPS is correlated with sex, the stage of cognitive impairment and daily living function. Revealing their relations can allow he development of better prevention and treatment strategies for patients with cognitive impairment.

Dual tasking paradigm in clinical stages of early Alzheimer’s disease

AbstractBackgroundIn Alzheimer’s disease (AD) both motor and cognitive domains are impaired [1‐2]. However, these domains are usually assessed independently, even when performing dual‐task (DT) paradigms, the cognitive‐motor interaction (CMI) is not taken into account which may lead to misinterpretation of the patient’s global state. To date, there are no precise markers to neither detect subtle signs of pre‐clinical neurodegeneration nor accurately monitor disease progression.MethodWe have evaluated the motor and cognitive components of a DT paradigm concurrently (Figure 1). 50 participants, aged 60 to 80 years, were included in the study, distributed across four cohorts corresponding to progressive clinical stages of early AD [3]: 1) amyloid negative, cognitively healthy participants (control group), 2) amyloid positive pre‐symptomatic AD, 3) Mild Cognitive Impairment (MCI) due to AD and 4) mild AD. Two inertial measurement units (IMUs) (Physilog, GaitUp S.A.) were attached to each foot to measure gait parameters and a small microphone (Wireless GO, RØDE) was attached to the shirt to record counting. Both timing and gait features were extracted from raw data, however only conventional features, correct response rate (CRR) and gait speed, were considered for this abstract and were used to evaluate the CMI based on Plummer’s classification system [5]. Moreover two‐way ANOVA was carried out to evaluate the effect of cohort and cognitive load conditions on the CMI.ResultOur results show that there is a significant drop in performance at both the cognitive and motor tasks while performing DT and that this drop is more pronounced as we move toward stages of greater cognitive impairment and as we increase the cognitive load of the task (Figure 2). Moreover, CMI shows a cognitive‐priority trade‐off in all cohorts (better/similar counting while slower walking), but movement toward mutual interference effect (worst counting and slower walking) when increasing cognitive load and state of cognitive decline (Figure 3).ConclusionTo our knowledge, this is the first feasibility study assessing the CMI at preclinical and early clinical stages of AD. Our preliminary results suggest that the DT paradigm is a sensitive method to detect early signs of neurodegeneration and monitor AD progression.

Regional cerebral atrophy correlates with amyloid accumulation in preclinical Alzheimer’s disease

AbstractBackgroundThis study was aimed to evaluate the regional hierarchical brain atrophy among the preclinical to mild cognitive impairment (MCI) stages of Alzheimer’s disease associated with amyloid deposition using [18F]flutemetamol positron emission tomography and volumetric magnetic resonance imaging.MethodThis was a prospective, single‐cohort study of volunteers who were living independently in Itabashi‐ku (Tokyo, Japan). One hundred thirty‐six participants (female/male = 96/40, mean age/standard deviation = 79.2/4.0 years) were recruited. Two subjects, one with meningeal thickening and another with sequelae in the brain, and 17 visually amyloid‐negative MCI subjects who possibly had neurodegenerative disease other than Alzheimer’s disease were excluded from the further analysis. We applied voxel‐based regression slope analysis between composite voxel of interest values calculated with Cortex ID Suite (GE Healthcare) on [18F]flutemetamol positron emission tomography and volumetric magnetic resonance images in three groups: 70 amyloid‐negative cognitively normal (CN) participants, 29 amyloid‐positive cognitively normal (PreC) participants, and 18 amyloid‐positive MCI (MCI+) participants. Statistical Parametric Mapping 12 software was used for analysis.ResultEven in the cognitively normal stage, the PreC group showed a larger slope of atrophy in the basal forebrain and middle frontal gyri than the CN group. In the MCI+ group, the slopes were larger in the lateral and medial parietal lobes, uncus, and right lateral temporal areas.ConclusionThe speed of amyloid‐related atrophy in the basal forebrain and middle frontal gyri was quick even in the preclinical stage of Alzheimer’s disease. As no significant slope changes were observed among the three groups in the medial temporal area, except for the uncus, the well‐known medial temporal atrophy in early Alzheimer’s disease might not be related to the accumulation of amyloid.

Association of Telomere Length with Cognitive Impairment.

Telomere attrition is attributed to Alzheimer's disease (AD), major depressive disorder, stress levels, physical inactivity, short sleep duration, and reduced educational abilities. In this article, we tried to assess the association between the telomere length in peripheral blood leukocytes and level of cognitive impairment and its dependence on age and sex.Healthy subjects and patients with amnestic mild cognitive impairment (aMCI) and different AD stages were recruited in the study. All patients were assessed by the same standard diagnostic procedure, including neurological examination-Mini-Mental State Examination (MMSE). Blood samples from 66 subjects (18 men and 48 women, mean age 71.2 ± 0.56years) were collected for DNA extraction from peripheral mononuclear cells (PBMC). Relative telomere length (RTL) was measured by monochrome multiplex polymerase chain reaction.The data obtained in the study indicate that RTL in PBMCs has a statistically significant association with MMSE score (p < 0.02). Moreover, the sex-specific difference was observed for the association between telomere length and various parameters of MMSE. Also, it has been found that a decrease in RTL by one unit is associated with an increase in the odds to get AD at a ratio of 2.54 (95% CI, 1.25 to 5.17).The results obtained in this research are in coherence with other studies that telomere length may be a valuable biomarker of cognitive decline. However, the potential need for longitudinal studies of telomere length, in order to estimate the influence of hereditary and environmental factors, remains.

Amyloid accumulation in the medial temporal area starts in the mild cognitive impairment stage of Alzheimer’s disease in [18F]flutemetamol positron emission tomography

AbstractBackgroundThis study was aimed to evaluate the hierarchical accumulation of amyloid in the Alzheimer’s brain according to clinical stage using [18F]flutemetamol positron emission tomography.MethodThis was a prospective, single‐cohort study of volunteers who lived independently in Itabashi‐ku (Tokyo, Japan). One hundred thirty‐six participants (female/male = 96/40, mean age/standard deviation = 79.2/4.0 years) were recruited. Two subjects, one with meningeal thickening and another with sequelae in the brain, and 17 visually amyloid‐negative MCI subjects who possibly had neurodegenerative disease other than Alzheimer’s disease were excluded from the further analysis. We applied voxel‐based regression slope analysis using composite voxel of interest values calculated with Cortex ID Suite (GE Healthcare) and [18F]flutemetamol positron emission tomography images in three groups: 70 amyloid‐negative cognitively normal (CN) participants, 29 amyloid‐positive cognitively normal (PreC) participants, and 18 amyloid‐positive MCI (MCI+) participants. Statistical Parametric Mapping 12 software was used for analysis.ResultCompared with the CN group, the PreC group showed accelerated amyloid accumulation in a wide area, except for the medial temporal lobe, paracentral sulcus, and medial occipital lobe. In amyloid‐positive subjects, amyloid accumulation was quicker in the paracentral sulcus, occipital cortex, and left medial temporal lobe in the MCI+ group than in the PreC group. Additional voxel of interest analyses were applied to the statistically significant areas. In the right posterior cingulate area, there was no significant difference between the PreC and MCI+ groups; however, the PreC and MCI+ groups showed a significantly quicker amyloid accumulation than the CN group. In contrast, in the left medial temporal area, the increase of amyloid accumulation was greater only in the MCI+ group compared to the PreC and CN groups.ConclusionIn amyloid‐positive subjects, amyloid accumulation in the left medial temporal lobe did not increase in the preclinical stage. In the medial temporal and occipital lobes, which are relatively spared from amyloid accumulation, it is considered to start late in the MCI stage and not in the preclinical stage. Further study of volume and other biomarkers is requreid to evaluate the regional pathophysiological variability of AD.

Plasma neuregulin 1 as a synaptic biomarker in Alzheimer’s disease

AbstractBackgroundSynaptic dysfunction is an early core feature of Alzheimer’s disease (AD), closely associated with cognitive symptoms. Neuregulin 1 (NRG1) is a growth and differentiation factor with a key role in the development and maintenance of synaptic transmission. Previous reports have shown that changes in cerebrospinal fluid (CSF) NRG1 concentration are associated with cognitive status and biomarker evidence of AD pathology. Plasma biomarkers reflecting synaptic impairment would be of great clinical interest. Our oubjective was to measure plasma NRG1 concentration in AD patients in comparison with other neurodegenerative disorders and neurological controls (NC) and to study its association with cerebrospinal fluid (CSF) core AD and synaptic biomarkers.MethodThis retrospective study enrolled 127 participants including patients with AD at mild cognitive impairment stage (AD‐MCI, n = 27) and at dementia stage (n = 35), non‐AD dementia (n = 26, Aβ‐negative), non‐AD MCI (n = 19) and neurological controls (n = 20). Plasma and CSF NRG1, as well as CSF core AD biomarkers (Aβ 42/Aβ 40 ratio, phospho‐tau and total tau), were measured using ELISA. CSF synaptic markers were measured using ELISA for GAP‐43 and neurogranin and through immunoprecipitation mass spectrometry for SNAP‐25.ResultPlasma NRG1 concentration was higher in AD‐MCI and AD dementia patients compared with neurological controls (respectively P = 0.005 and P&lt;0.001). Plasma NRG1 differentiated AD MCI patients from neurological controls with an area under the curve of 88.3%, and AD dementia patients from NC with an area under the curve of 87.3%. Plasma NRG1 correlated with CSF NRG1 (β = 0.372, P = 0.0056, adjusted on age and sex). Plasma NRG1 was associated with AD CSF core biomarkers in the whole cohort and in Aβ‐positive patients (β = ‐0.197‐ 0.423). Plasma NRG1 correlated with CSF GAP‐43, neurogranin and SNAP‐25 (β = 0.278‐0.355). Plasma NRG1 concentration correlated inversely with MMSE in the whole cohort and in Aβ‐positive patients (all, β = ‐0.188, P = 0.038; Aβ+: β = ‐0.255, P = 0.038).ConclusionPlasma NRG1 concentration is increased in AD patients and correlates with CSF core AD and synaptic biomarkers, and cognitive status. Thus, plasma NRG1 is a promising non‐invasive biomarker to monitor synaptic impairment in AD.

CSF Synaptic Biomarkers in AT(N)-Based Subgroups of Lewy Body Disease.

Patients with Lewy body disease (LBD) often show a co-occurring Alzheimer disease (AD) pathology. CSF biomarkers allow the detection in vivo of AD-related pathologic hallmarks included in the amyloid-tau-neurodegeneration (AT(N)) classification system. Here, we aimed to investigate whether CSF biomarkers of synaptic and neuroaxonal damage are correlated with the presence of AD copathology in LBD and can be useful to differentiate patients with LBD with different AT(N) profiles. We retrospectively measured CSF levels of AD core biomarkers (Aβ42/40 ratio, phosphorylated tau protein, and total tau protein) and of synaptic (β-synuclein, α-synuclein, synaptosomal-associated protein 25 [SNAP-25], and neurogranin) and neuroaxonal proteins (neurofilament light chain [NfL]) in 28 cognitively unimpaired participants with nondegenerative neurologic conditions and 161 participants with a diagnosis of either LBD or AD (at both mild cognitive impairment, AD-MCI, and dementia stages, AD-dem). We compared CSF biomarker levels in clinical and AT(N)-based subgroups. CSF β-synuclein, α-synuclein, SNAP-25, neurogranin, and NfL levels did not differ between LBD (n = 101, age 67.2 ± 7.8 years, 27.7% females) and controls (age 64.8 ± 8.6 years, 39.3% females) and were increased in AD (AD-MCI: n = 30, AD-dem: n = 30, age 72.3 ± 6.0 years, 63.3% females) compared with both groups (p < 0.001 for all comparisons). In LBD, we found increased levels of synaptic and neuroaxonal degeneration biomarkers in patients with A+T+ (LBD/A+T+) than with A-T- profiles (LBD/A-T-) (p < 0.01 for all), and β-synuclein showed the highest discriminative accuracy between the 2 groups (area under the curve 0.938, 95% CI 0.884-0.991). CSF β-synuclein (p = 0.0021), α-synuclein (p = 0.0099), and SNAP-25 concentrations (p = 0.013) were also higher in LBD/A+T+ than in LBD/A+T- cases, which had synaptic biomarker levels within the normal range. CSF α-synuclein was significantly decreased only in patients with LBD with T- profiles compared with controls (p = 0.0448). Moreover, LBD/A+T+ and AD cases did not differ in any biomarker level. LBD/A+T+ and AD cases showed significantly increased CSF levels of synaptic and neuroaxonal biomarkers compared with LBD/A-T- and control subjects. Patients with LBD and AT(N)-based AD copathology showed, thus, a distinct signature of synaptic dysfunction from other LBD cases. This study provides Class II evidence that CSF levels of β-synuclein, α-synuclein, SNAP-25, neurogranin, and NfL are higher in patients with AD than in patients with LBD.

Electroencephalographic slowdowns during sleepare associated with cognitive impairment in patients who have obstructive sleep apneabut no dementia.

To research the relationship between quantitative electroencephalogram (qEEG) and impaired cognitive function patients who have obstructive sleep apnea (OSA)but no dementia. Subjects who complained of snoring between March 2020 and April 2021 in the Sleep Medicine Center of Weihai Municipal Hospital were included. All subjects underwent overnight in-laboratory polysomnography (PSG) and were assessed using a neuropsychological scale. Standard fast fourier transform (FFT) was usedto obtain the electroencephalogram (EEG) power spectral density curve, and tocalculate the delta, theta, alpha, and beta relative power and the ratio between slow and fast frequencies. Binary logistic regression was used to assess the risk factors for cognitive impairment in patients who had OSAbut no dementia. Correlation analysis was performed to determine the relationship between qEEG and cognitive impairment. A total of 175 participants without dementiawho met the inclusion criteria were included in this study. There were 137 patients withOSA, including 76 with mild cognitive impairment (OSA + MCI), 61 without mild cognitive impairment (OSA-MCI), and 38 participants without OSA (non-OSA). The relative theta power in the frontal lobe in stage 2 of non-rapid eye movement sleep (NREM 2) in OSA + MCI was higher than that in OSA-MCI (P = 0.038) and non-OSA (P = 0.018). Pearson correlation analysis showed that the relative theta power in the frontal lobe in NREM 2 was negatively correlated with Mini-Mental State Examination (MMSE) scores, Montreal Cognitive Assessment (MoCA) Beijing version scores, and MoCA subdomains scores (visual executive function, naming, attention, language, abstraction, delayed recall and orientation) outside language. In patients who had OSAbut no dementia, the EEG slower frequency power increased. The relative theta power in the frontal lobe in NREM 2 was associated with MCI of patients withOSA. These results suggest that the slowing of theta activity may be one of the neurophysiological changes in the early stage of cognitive impairment in patients withOSA.