Subjective Cognitive Decline Individuals Research Articles

Brain structure, amyloid, and behavioral features for predicting clinical progression in subjective cognitive decline.

As a potential preclinical stage of Alzheimer's dementia, subjective cognitive decline (SCD) reveals a higher risk of future cognitive decline and conversion to dementia. However, it has not been clear whether SCD status increases the clinical progression of older adults in the context of amyloid deposition, cerebrovascular disease (CeVD), and psychiatric symptoms. We identified 99 normal controls (NC), 15 SCD individuals who developed mild cognitive impairment in the next 2 years (P-SCD), and 54 SCD individuals who did not (S-SCD) from ADNI database with both baseline and 2-year follow-up data. Total white matter hyperintensity (WMH), WMH in deep (DWMH) and periventricular (PWMH) regions, and voxel-wise grey matter volumes were compared among groups. Furthermore, using structural equation modelling method, we constructed path models to explore SCD-related brain changes longitudinally and to determine whether baseline SCD status, age, and depressive symptoms affect participants' clinical outcomes. Both SCD groups showed higher baseline amyloid PET SUVR, baseline PWMH volumes, and larger increase of PWMH volumes over time than NC. In contrast, only P-SCD had higher baseline DWMH volumes and larger increase of DWMH volumes over time than NC. No longitudinal differences in grey matter volume and amyloid was observed among NC, S-SCD, and P-SCD. Our path models demonstrated that SCD status contributed to future WMH progression. Further, baseline SCD status increases the risk of future cognitive decline, mediated by PWMH; baseline depressive symptoms directly contribute to clinical outcomes. In conclusion, both S-SCD and P-SCD exhibited more severe CeVD than NC. The CeVD burden increase was more pronounced in P-SCD. In contrast with the direct association of depressive symptoms with dementia severity progression, the effects of SCD status on future cognitive decline may manifest via CeVD pathologies. Our work highlights the importance of multi-modal longitudinal designs in understanding the SCD trajectory heterogeneity, paving the way for stratification and early intervention in the preclinical stage. PRACTITIONER POINTS: Both S-SCD and P-SCD exhibited more severe CeVD at baseline and a larger increase of CeVD burden compared to NC, while the burden was more pronounced in P-SCD. Baseline SCD status increases the risk of future PWMH and DWMH volume accumulation, mediated by baseline PWMH and DWMH volumes, respectively. Baseline SCD status increases the risk of future cognitive decline, mediated by baseline PWMH, while baseline depression status directly contributes to clinical outcome.

White matter alterations and their associations with biomarkers and behavior in subjective cognitive decline individuals: a fixel-based analysis.

Subjective cognitive decline (SCD) is an early stage of dementia linked to Alzheimer's disease pathology. White matter changes were found in SCD using diffusion tensor imaging, but there are known limitations in voxel-wise tensor-based methods. Fixel-based analysis (FBA) can help understand changes in white matter fibers and how they relate to neurodegenerative proteins and multidomain behavior data in individuals with SCD. Healthy adults with normal cognition were recruited in the Northeastern Taiwan Community Medicine Research Cohort in 2018-2022 and divided into SCD and normal control (NC). Participants underwent evaluations to assess cognitive abilities, mental states,physical activity levels, and susceptibility to fatigue. Neurodegenerative proteins were measured usingan immunomagnetic reduction technique. Multi-shell diffusion MRI data were collected and analyzed using whole-brain FBA, comparing results between groups and correlating them with multidomain assessments. The final enrollment included 33 SCD and 46 NC participants, with no significant differences in age, sex, or education between the groups. SCD had a greater fiber-bundle cross-section than NC (pFWE < 0.05) at bilateral frontal superior longitudinal fasciculus II (SLFII). These white matter changes correlate negatively with plasma Aβ42 level (r = -0.38, p = 0.01) and positively with the AD8 score for subjective cognitive complaints (r = 0.42, p = 0.004) and the Hamilton Anxiety Rating Scale score for the degree of anxiety (Ham-A, r = 0.35, p = 0.019). The dimensional analysis of FBA metrics and blood biomarkers found positive correlations of plasma neurofilament light chain with fiber density at the splenium of corpus callosum (pFWE < 0.05) and with fiber-bundle cross-section at the right thalamus (pFWE < 0.05). Further examination of how SCD grouping interacts between the correlations of FBA metrics and multidomain assessments showed interactions between the fiber density at the corpus callosum with letter-number sequencing cognitive score (pFWE < 0.01) and with fatigue to leisure activities (pFWE < 0.05). Based on FBA, our investigation suggests white matter structural alterations in SCD. The enlargement of SLFII's fiber cross-section is linked to plasma Aβ42 and neuropsychiatric symptoms, which suggests potential early axonal dystrophy associated with Alzheimer's pathology in SCD. The splenium of the corpus callosum is also a critical region of axonal degeneration and cognitive alteration for SCD.

The taxonomy of subjective cognitive decline: proposal and first clinical evidence from the Geneva memory clinic cohort.

Subjective Cognitive Decline (SCD) is characterized by subjective cognitive concerns without objective cognitive impairment and is considered a risk factor for cognitive decline and dementia. However, most SCD patients will not develop neurodegenerative disorders, yet they may suffer from minor psychiatric, neurological, or somatic comorbidities. The aim of the present study is to provide a taxonomy of the heterogeneous SCD entity by isolating homogenous SCD subgroups with specific clinical features and cognitive trajectoriesand to conduct a preliminary validation using data from a memory clinic sample. Participants were fifty-five SCD individuals consecutively recruited at the Geneva Memory Center. Based on clinical reports, they were classified into three clinically pre-defined subgroups: (i) those with psychological or psychiatric comorbidities (Psy), (ii) those with somatic comorbidities (SomCom), (iii) and those with no apparent cause (NAC). Baseline demographics, clinical, cognitive, and biomarker differences among the SCD subgroups were assessed. Longitudinal cognitive changes (average 3 years follow-up) were modeled using a linear mixed model. Out of the 55 SCD cases, 16 were SomCom, 18 Psy, and 21 NAC. 47% were female, mean age was 71 years. We observed higher frequency of APOE ε4 carriers in NAC (53%) compared to SomCom (14%) and Psy (0%, P=0.023) and lower level of plasma Aβ42 in NAC (6.8±1.0) compared to SomCom (8.4±1.1; P=0.031). SomCom subjects were older (74 years) than Psy (67 years, P=0.011), and had greater medial temporal lobe atrophy (1.0±1.0) than Psy (0.2±0.6) and NAC (0.4±0.5, P=0.005). SomCom have worse episodic memory performances (14.5±3.5) than Psy (15.8±0.4) and NAC (15.8±0.7, P=0.032). We observed a slightly steeper, yet not statistically significant, cognitive decline in NAC (β=-0.48) compared to Psy (β=-0.28) and SomCom (β=-0.24). NAC feature higher proportion of APOE ε4 carriers, lower plasma Aβ42 and a trend towards steeper cognitive decline than SomCom and Psy. Taken together, these findings suggest that NAC are at higher risk of cognitive decline due to AD. The proposed clinical taxonomy might be implemented in clinical practice to identify SCD at higher risk. However, such taxonomy should be tested on an independent cohort with larger sample size.

Pathophysiology characterization of Alzheimer's disease in South China's aging population: for the Greater-Bay-Area Healthy Aging Brain Study (GHABS).

The Guangdong-Hong Kong-Macao Greater-Bay-Area of South China has an 86million population and faces a significant challenge of Alzheimer's disease (AD). However, the characteristics and prevalence of AD in this area are still unclear due to the rarely available community-based neuroimaging AD cohort. Following the standard protocols of the Alzheimer's Disease Neuroimaging Initiative, the Greater-Bay-Area Healthy Aging Brain Study (GHABS) was initiated in 2021. GHABS participants completed clinical assessments, plasma biomarkers, genotyping, magnetic resonance imaging (MRI), β-amyloid (Aβ) positron emission tomography (PET) imaging, and tau PET imaging. The GHABS cohort focuses on pathophysiology characterization and early AD detection in the Guangdong-Hong Kong-Macao Greater Bay Area. In this study, we analyzed plasma Aβ42/Aβ40 (A), p-Tau181 (T), neurofilament light, and GFAP by Simoa in 470 Chinese older adults, and 301, 195, and 70 had MRI, Aβ PET, and tau PET, respectively. Plasma biomarkers, Aβ PET, tau PET, hippocampal volume, and temporal-metaROI cortical thickness were compared between normal control (NC), subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia groups, controlling for age, sex, and APOE-ε4. The prevalence of plasma A/T profiles and Aβ PET positivity were also determined in different diagnostic groups. The aims, study design, data collection, and potential applications of GHABS are summarized. SCD individuals had significantly higher plasma p-Tau181 and plasma GFAP than the NC individuals. MCI and dementia patients showed more abnormal changes in all the plasma and neuroimaging biomarkers than NC and SCD individuals. The frequencies of plasma A+/T+ (NC; 5.9%, SCD: 8.2%, MCI: 25.3%, dementia: 64.9%) and Aβ PET positivity (NC: 25.6%, SCD: 22.5%, MCI: 47.7%, dementia: 89.3%) were reported. The GHABS cohort may provide helpful guidance toward designing standard AD community cohorts in South China. This study, for the first time, reported the pathophysiology characterization of plasma biomarkers, Aβ PET, tau PET, hippocampal atrophy, and AD-signature cortical thinning, as well as the prevalence of Aβ PET positivity in the Guangdong-Hong Kong-Macao Greater Bay Area of China. These findings provide novel insights into understanding the characteristics of abnormal AD pathological changes in South China's older population.

Cognitive and Hippocampal Changes in Older Adults With Subjective Cognitive Decline After Acupuncture Intervention

ObjectiveConverging evidence indicates that subjective cognitive decline (SCD) could be an early indicator of dementia. The hippocampus is the earliest affected region during the progression of cognitive impairment. However, little is known about whether and how acupuncture change the hippocampal structure and function of SCD individuals. MethodsHere, we used multi-modal MRI to reveal the mechanism of acupuncture in treating SCD. Seventy-two older participants were randomized into acupuncture or sham acupuncture group and treated for 12 weeks. ResultsAt the end of the intervention, compared to sham acupuncture, participants with acupuncture treatment showed improvement in composite Z score from multi-domain neuropsychological tests, as well as increased hippocampal volume and functional connectivity. Moreover, the greater white matter integrity of the fornix, which is the major output tract of the hippocampus, was shown in the acupuncture group. ConclusionThese findings suggest that acupuncture may improve the cognitive function of SCD individuals, and increase hippocampal volume on the regional level and enhance the structural and functional connectivity of hippocampus on the connective level.

Preclinical Brain Network Abnormalities in Patients with Subjective Cognitive Decline.

Alzheimer's disease (AD) is the most common form of dementia worldwide. Currently there are no disease modifying treatments available. Detecting subjects with increased risk to develop dementia is essential for future clinical trials. Subjective cognitive decline (SCD) is a condition defining individuals who perceive a decrease in their own cognitive functioning in the absence of any detectable deficit on neuropsychological testing. SCD individuals show AD-related biomarkers abnormalities in cerebrospinal fluid. The aim of the present study was to assess brain functional connectivity (FC) changes in SCD individuals. 23 SCD and 33 healthy subjects (HS) underwent an extensive neuropsychological assessment and 3T-MRI scanning including a T1-w volume and resting-state fMRI (RS-fMRI) to assess brain atrophy and brain FC. No between-group differences in grey matter volumes were detected. SCD subjects compared to HS showed both increased and decreased FC in the executive and parietal networks. Associations between cognitive measures, mainly assessing working memory, and FC within brain networks were found both in SCD and HS separately. SCD individuals showed FC abnormalities in networks involving fronto-parietal areas that may account for their lower visuo-spatial working memory performances. Dysfunctions in executive-frontal networks may be responsible for the cognitive decline subjectively experienced by SCD individuals despite the normal scores observed by formal neuropsychological assessment. The present study contributes to consider SCD individuals in an early AD stage with an increased risk of developing the disease in the long term.

Cortical Amyloid Burden Relates to Basal Forebrain Volume in Subjective Cognitive Decline.

Atrophy of cholinergic basal forebrain (BF) nuclei is a frequent finding in magnetic resonance imaging (MRI) volumetry studies that examined patients with prodromal or clinical Alzheimer's disease (AD), but less clear for individuals in earlier stages of the clinical AD continuum. To examine BF volume reductions in subjective cognitive decline (SCD) participants with AD pathologic changes. The present study compared MRI-based BF volume measurements in age- and sex-matched samples of N = 24 amyloid-positive and N = 24 amyloid-negative SCD individuals, based on binary visual ratings of Florbetaben positron emission tomography (PET) measurements. Additionally, we assessed associations of BF volume with cortical amyloid burden, based on semiquantitative Centiloid (CL) analyses. Group differences approached significance for BF total volume (p = 0.061) and the Ch4 subregion (p = 0.059) only, showing the expected relative volume reductions for the amyloid-positive subgroup. There were also significant inverse correlations between BF volumes and CL values, which again were most robust for BF total volume and the Ch4 subregion. The results are consistent with the hypothesis that amyloid-positive SCD individuals, which are considered to represent a transitional stage on the clinical AD continuum, already show incipient alterations of BF integrity. The negative association with a continuous measure of cortical amyloid burden also suggests that this may reflect an incremental process. Yet, further research is needed to evaluate whether BF changes already emerge at "grey zone" levels of amyloid accumulation, before amyloidosis is reliably detected by PET visual readings.

Different Trajectories of Apathy and Depression Among Subjective Cognitive Impairment Individuals with or without Conversion to Dementia: Results from the Memento Cohort in France.

Apathy and depression are two early behavioral symptoms in Alzheimer's disease (AD) and related disorders that often occur prior to the onset of cognitive decline and memory disturbances. Both have been associated with an increased risk of conversion to dementia, with a distinct neuropathology. The assessment of the trajectories of apathy and depression and their independent impact on dementia conversion. Apathy and Depression were measured using the Neuropsychiatric Inventory for caregiver (NPI) and clinician (NPI-C), among the nondemented individuals reporting subjective cognitive decline (SCD) at baseline. They were followed up over a 60-month period. Some converted to dementia, according to the methodology carried out by the French Memento Cohort. Among individuals with SCD (n = 2,323), the levels of apathy and depression were low and did not evolve significantly over the 60-month period, despite a trend in apathy increasing as of month 24. Regarding SCD individuals who converted to dementia within the 60-month period (n = 27), the prevalence of depression remained globally steady, while the levels of apathy increased over time. Apathy and depression have different trajectories among individuals with SCD and apathy alone is more likely-compared to depression-to be associated with conversion to dementia.

Hippocampal Volume and Episodic Associative Memory Identify Memory Risk in Subjective Cognitive Decline Individuals in the CIMA-Q Cohort, Regardless of Cognitive Reserve Level and APOE4 Status.

Subjective cognitive decline (SCD) was proposed to identify older adults who complain about their memory but perform within a normal range on standard neuropsychological tests. Persons with SCD are at increased risk of dementia meaning that some SCD individuals experience subthreshold memory decline due to an underlying progression of Alzheimer's disease (AD). Our main goal was to determine whether hippocampal volume and APOE4, which represent typical AD markers, predict inter-individual differences in memory performance among SCD individuals and can be used to identify a meaningful clinical subgroup. Neuropsychological assessment, structural MRI, and genetic testing for APOE4 were administered to one hundred and twenty-five older adults over the age of 65 from the CIMAQ cohort: 66 SCD, 29 individuals with mild cognitive impairment (MCI), and 30 cognitively intact controls (CTRLS). Multiple regression models were first used to identify which factor (hippocampal volume, APOE4 allele, or cognitive reserve) best predicted inter-individual differences in a Face-name association memory task within the SCD group. Hippocampal volume was found to be the only and best predictor of memory performance. We then compared the demographic, clinical and cognitive characteristics of two SCD subgroups, one with small hippocampal volume (SCD/SH) and another with normal hippocampal volume (SCD/NH), with MCI and CTRLS. SCD/SH were comparable to MCI on neuropsychological tasks evaluating memory (i.e., test of delayed word recall), whereas SCD/NH were comparable to CTRLS. Thus, using hippocampal volume allows identification of an SCD subgroup with a cognitive profile consistent with a higher risk of conversion to AD.

Heterogeneity in subjective cognitive decline in the Sino Longitudinal Study on Cognitive Decline(SILCODE): Empirically derived subtypes, structural and functional verification.

We evaluated whether Subjective Cognitive Decline (SCD) subtypes could be empirically derived within the Sino Longitudinal Study on Cognitive Decline (SILCODE) SCD cohort and examined associated neuroimaging markers, biomarkers, and clinical outcomes. A cluster analysis was performed on eight neuropsychological test scores from 124 SCD SILCODE participants and 57 normal control (NC) subjects. Structural and functional neuroimaging indices were used to evaluate the SCD subgroups. Four subtypes emerged: (1) dysexecutive/mixed SCD (n = 23), (2) neuropsychiatric SCD (n = 24), (3) amnestic SCD (n = 22), and (4) cluster-derived normal (n = 55) who exhibited normal performance in neuropsychological tests. Compared with the NC group, each subgroup showed distinct patterns in gray matter (GM) volume and the amplitude of low-frequency fluctuations (ALFF). Lower fractional anisotropy (FA) values were only found in the neuropsychiatric SCD group relative to NC. The identification of empirically derived SCD subtypes demonstrates the presence of heterogeneity in SCD neuropsychological profiles. The cluster-derived normal group may represent the majority of SCD individuals who do not show progressive cognitive decline; the dysexecutive/mixed SCD and amnestic SCD might represent high-risk groups with progressing cognitive decline; and finally, the neuropsychiatric SCD may represent a new topic in SCD research.

The neurodegeneration of the cholinergic pathways in subtypes of subjective cognitive decline

AbstractBackgroundNeurodegeneration of cholinergic pathways may be present in individuals with subjective cognitive decline (SCD). However, variability between SCD individuals in the integrity of cholinergic pathways needs to be elucidated. Our objective was to determine characteristics of neurodegeneration of cholinergic pathways in different SCD subtypes (i.e. amnestic vs. non‐amnestic).MethodIndividuals with amnestic SCD (n = 47), non‐amnestic SCD (n = 38), and healthy controls without cognitive complaints (HC; n = 20) from the GENIC database were included (all: &gt;60 years old; 58% females). White matter integrity was estimated by mean diffusivity (MD) on diffusion tensor imaging (DTI) for cingulum and external cholinergic pathways. Both pathways were previously modelled using tractography on DTI. Memory performance was measured based on Visual reproduction WMS‐III and TAVEC (the Spanish version of the California Verbal Learning Test, CVLT). ANOVA and bivariate Pearson correlation were used for the statistical analysis.ResultAmnestic and non‐amnestic SCD groups were comparable to HC in the integrity of cholinergic WM pathways. Bivariate Pearson correlation analyses showed different patterns of association between the cholinergic pathways and cognition within each group. In amnestic‐SCD, worse WM integrity in both cholinergic pathways was associated with poorer immediate recall of visual information (external capsule: rxy = ‐0.42; p&lt;0.05; cingulum: rxy = ‐0.34; p&lt;0.05). In non‐amnestic‐SCD, worse WM integrity in both cholinergic pathways was associated with poorer delayed recall of verbal information (external capsule: rxy = ‐0.54; p&lt;0.05; cingulum: rxy = ‐0.42; p&lt;0.05); and worse WM integrity in the external capsule pathway was associated with poorer performance in immediate and delayed recall of visual information (rxy = ‐0.37; p&lt;0.05 and rxy = ‐0.46; p&lt;0.05). In HC, none of the cognitive outcomes was associated with the integrity of the cholinergic pathways.ConclusionThe cholinergic pathways were mainly associated with immediate recall in the amnestic SCD (i.e. acquisition of new information); whereas in non‐amnestic SCD the integrity of cholinergic pathways was associated with several subcomponents of memory performance (i.e. acquisition and recall of new information). Thus, SCD subtypes show unique patterns of associations between poorer integrity of the cholinergic system and memory performance.

Association between Neuropsychological Performance and CSF Profile in Subjective Cognitive Decline: Towards the Diagnosis of Preclinical AD

BackgroundIn the perspective of novel treatments with disease-modifying drugs, a timely diagnosis of Alzheimer’s’ disease (AD) at preclinical phase represents a major issue. To this purpose, in clinical setting, there is the need to detect the earliest cognitive symptoms not yet fulfilling Mild Cognitive Impairment criteria, in order to proceed to biomarker assessment for diagnostic definition. In terms of cognitive performance, Subjective Cognitive Decline (SCD) is still a controversial entity, due to the difficulty of reliably measuring subtle deficits.ObjectiveTo evaluate the possibility to predict the presence of AD-like CSF pattern in SCD individuals, according to their neuropsychological performance assessed by means of both traditional and computerized measures.DesignRetrospective study.SettingClinical setting (Centre for Memory Disturbances, Section of Neurology, University Hospital of Perugia, Italy).Participants74 consecutive SCD subjects who underwent an in-depth (paper-pencil and computerized) neuropsychological assessment and CSF analysis for AD biomarkers (Aβ42/Aβ40 ratio, phospho-tau, total tau).MeasurementsNeuropsychological assessment was composed of traditional tests assessing five cognitive domains (verbal memory, attention, executive functions, language, visuo-spatial abilities) and computerized tasks from CAmbridge Neuropsychological Test Automated Battery (CANTAB) (Pattern Recognition Memory, Paired Associates Learning and Spatial Working Memory). According to their performance at traditional tests, SCD individuals were categorized into cognitively normal (CN) and subtle impaired (SI); with respect to CANTAB, they were defined as CANTAB− in presence of normal performance, and CANTAB+ in presence of at least one pathological score. The subgroup with completely normal performance was defined as CN/CANTAB−, and the subgroup with impairment in both measures as SI/CANTAB+. Differences in prevalence of A/T/N profile according to cognitive profiles were assessed by Fisher’s exact text for count data.ResultsNone of CN/CANTAB− subjects showed A+/T+ status. SI/CANTAB+ subjects showed a significantly high prevalence of A+/T+ profile (14/35, 40%, p=0.03 vs CN/CANTAB−).ConclusionThe neuropsychological profile may be of help in identifying SCD subjects requiring biomarker assessment. If confirmed in larger cohorts, the combination of traditional and computerized tests (namely, CANTAB) might represent a feasible strategy in clinical setting for carrying out biomarker assessment in individuals before the MCI stage. Detection of AD in these subjects would give them the highest chances to halt disease progression by means of disease modifying treatments.

Characteristics of Subjective Cognitive Decline Associated with Alzheimer's Disease Amyloid Pathology: Findings from The CABLE Study.

Subjective cognitive decline (SCD) is considered as a preclinical hallmark of Alzheimer's disease (AD). However, the characteristics of SCD associated with amyloid pathology remain unclear. We aimed to explore the associations between SCD characteristics with amyloid pathology. Using logistic regression analyses, we analyzed the associations between cerebrospinal fluid (CSF) amyloid pathology with AD risk factors, SCD-specific characteristics (onset of SCD within the last five years, age at onset ≥60 years, feelings of worse performance, informant confirmation of complaints, worries, other domains of cognition complaints), as well as subthreshold depressive and anxiety symptoms among individuals with SCD. A total of 535 SCD individuals with available CSF Aβ42 information from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study (mean age of 63.5 years, range 40 to 88 years; 47.10% female) were enrolled. The characteristics of informant confirmation of complaints (OR, 95% CI = 2.00, 1.19-3.36), subthreshold depressive symptoms (OR, 95% CI = 2.31, 1.05-5.09), and subthreshold anxiety symptoms (OR, 95% CI = 2.22, 1.09-4.51) were found to be significantly associated with pathological amyloid in multivariate analyses when adjusting for age, sex, education, and APOE ɛ4. Besides, age and females were observed risks for amyloid pathology in subscale analyses. Nonetheless, we did not find any associations of other SCD-specific characteristics with amyloid pathology in this study. Our study suggested that informant confirmed complaints and subthreshold psychiatric symptoms might be critical for discriminating AD-related SCD from non-AD related SCD.

Brain morphometric and metabolic changes in Subjective Cognitive Decline individuals

AbstractBackgroundSubjective cognitive decline (SCD) is defined as a memory complaint in individuals without an objective measure of cognitive impairment. In this study, we investigated the morphometric and metabolic brain changes in individuals presenting with SCD.MethodAge and sex matched structural MRI and [18F]FDG PET images from SCD and CU (n = 101, per group) were extracted from the ADNI database. We built general linear models corrected for multiple comparisons with 10,000 Monte‐Carlo simulations to verify differences in cortical thickness between groups, using age as a covariate (Freesurfer’s v7.1.1). Metabolic analysis was performed using voxel‐wise general linear models comparing the SUVR of the FDG signal, correcting for age and APOE4 allele carrying status, using the MINC toolkit and the R statistical program.ResultSCD and CU groups presented similar age, sex, years of education, CSF AD‐related protein levels (amyloid beta 1‐42, p‐tau and tau), and Clinical Dementia Rating – Sum of Boxes score (Table 1). Compared to CU individuals, SCD subjects showed increased cortical thickness in the right hemisphere rostral middle frontal gyrus (Figure 1), while glucose metabolism was increased in the right medial temporal lobe, including the hippocampus, and right occipital cortex (Figure 2).ConclusionIndividuals with SCD present cortical hypertrophy in the rostral middle frontal gyrus and glucose hypermetabolism in the medial temporal lobe and occipital cortex, all in the right hemisphere. Previous studies suggest that these areas play a role in personality and humor, and may be altering self‐perception of cognitive decline. At the biological level, given the high concentration of astrocytes in these areas, such changes may suggest a scenario of astrocyte reactivity. More specifically, astrocyte hypertrophy may account for increased cortical thickness and glucose uptake. In summary, we provide neuroimaging evidence of structural and functional changes in individuals with SCD, suggesting early astrocyte reactivity.

Cholinergic white matter pathways along the Alzheimer's disease continuum.

Previous studies have shown that the cholinergic nucleus basalis of Meynert and its white matter projections are affected in Alzheimer's disease dementia and mild cognitive impairment. However, it is still unknown whether these alterations can be found in individuals with subjective cognitive decline, and whether they are more pronounced than changes found in conventional brain volumetric measurements. To address these questions, we investigated microstructural alterations of two major cholinergic pathways in individuals along the Alzheimer's disease continuum using an in vivo model of the human cholinergic system based on neuroimaging. We included 402 participants (52 Alzheimer's disease, 66 mild cognitive impairment, 172 subjective cognitive decline and 112 healthy controls) from the Deutsches Zentrum für Neurodegenerative Erkrankungen Longitudinal Cognitive Impairment and Dementia Study. We modelled the cholinergic white matter pathways with an enhanced diffusion neuroimaging pipeline that included probabilistic fibre-tracking methods and prior anatomical knowledge. The integrity of the cholinergic white matter pathways was compared between stages of the Alzheimer's disease continuum, in the whole cohort and in a CSF amyloid-beta stratified subsample. The discriminative power of the integrity of the pathways was compared to the conventional volumetric measures of hippocampus and nucleus basalis of Meynert, using a receiver operating characteristics analysis. A multivariate model was used to investigate the role of these pathways in relation to cognitive performance. We found that the integrity of the cholinergic white matter pathways was significantly reduced in all stages of the Alzheimer's disease continuum, including individuals with subjective cognitive decline. The differences involved posterior cholinergic white matter in the subjective cognitive decline stage and extended to anterior frontal white matter in mild cognitive impairment and Alzheimer's disease dementia stages. Both cholinergic pathways and conventional volumetric measures showed higher predictive power in the more advanced stages of the disease, i.e. mild cognitive impairment and Alzheimer's disease dementia. In contrast, the integrity of cholinergic pathways was more informative in distinguishing subjective cognitive decline from healthy controls, as compared with the volumetric measures. The multivariate model revealed a moderate contribution of the cholinergic white matter pathways but not of volumetric measures towards memory tests in the subjective cognitive decline and mild cognitive impairment stages. In conclusion, we demonstrated that cholinergic white matter pathways are altered already in subjective cognitive decline individuals, preceding the more widespread alterations found in mild cognitive impairment and Alzheimer's disease. The integrity of the cholinergic pathways identified the early stages of Alzheimer's disease better than conventional volumetric measures such as hippocampal volume or volume of cholinergic nucleus basalis of Meynert.

The Effect of Hearing Loss on Cognitive Function in Subjective Cognitive Decline

Introduction: Subjective cognitive decline (SCD) is a self-reported cognitive decline without objective cognitive impairment. The relationship between audiometric hearing loss (HL) and cognitive function has not been reported in SCD. The purpose of this study was to investigate whether HL affects cognition-related indexes in SCD individuals. Methods: This is a cross-sectional study that used the baseline data of a multicenter cohort study that monitors clinical progression from SCD to dementia. Individuals aged ≥60 years who reported cognitive decline but had no objective cognitive impairment on comprehensive neuropsychological tests were recruited. Participants were grouped into the normal-hearing (NH) and bilateral HL groups. The demographics, clinical characteristics, dementia biomarkers, global cognition, questionnaire scores, neuropsychological test scores, and segmental brain volumes from MRI were compared between the groups. Results: Of a total of 120 participants, one hundred and two had NH (n = 57) or bilateral HL (n = 45). There were no group differences in the demographic and clinical data except the age. The biomarkers, global cognition, and questionnaire scores were not different between the groups. The HL group performed worse (the z-score of −0.06) in the Stroop Color Word Test than the NH group (0.27) (p = 0.025). Brain volumetric analysis revealed that the HL group had reduced gray matter volumes in four brain subregions: left temporal pole, left caudal middle frontal gyrus, left hippocampus, and right isthmus of the cingulate gyrus. Conclusion: In SCD, HL exerted an adverse effect on cognitive function, primarily frontal executive function tested in the Stroop task. HL was also related to gray matter volume reductions in brain subregions, although causality needs further investigation. This study may provide evidence for a potential link between hearing and cognition in SCD, an emerging clinical entity.

Altered pattern analysis and identification of subjective cognitive decline based on morphological brain network.

Subjective cognitive decline (SCD) is considered the first stage of Alzheimer’s disease (AD). Accurate diagnosis and the exploration of the pathological mechanism of SCD are extremely valuable for targeted AD prevention. However, there is little knowledge of the specific altered morphological network patterns in SCD individuals. In this present study, 36 SCD cases and 34 paired-matched normal controls (NCs) were recruited. The Jensen-Shannon distance-based similarity (JSS) method was implemented to construct and derive the attributes of multiple brain connectomes (i.e., morphological brain connections and global and nodal graph metrics) of individual morphological brain networks. A t-test was used to discriminate between the selected nodal graph metrics, while the leave-one-out cross-validation (LOOCV) was used to obtain consensus connections. Comparisons were performed to explore the altered patterns of connectome features. Further, the multiple kernel support vector machine (MK-SVM) was used for combining brain connectomes and differentiating SCD from NCs. We showed that the consensus connections and nodal graph metrics with the most discriminative ability were mostly found in the frontal, limbic, and parietal lobes, corresponding to the default mode network (DMN) and frontoparietal task control (FTC) network. Altered pattern analysis demonstrated that SCD cases had a tendency for modularity and local efficiency enhancement. Additionally, using the MK-SVM to combine the features of multiple brain connectomes was associated with optimal classification performance [area under the curve (AUC): 0.9510, sensitivity: 97.22%, specificity: 85.29%, and accuracy: 91.43%]. Therefore, our study highlighted the combination of multiple connectome attributes based on morphological brain networks and offered a valuable method for distinguishing SCD individuals from NCs. Moreover, the altered patterns of multidimensional connectome attributes provided a promising insight into the neuroimaging mechanism and early intervention in SCD subjects.

Discrimination of subjective cognitive decline from healthy control based on glucose-oxygen metabolism network coupling features and machine learning.

Our previous studies have proved that preclinical Alzheimer's disease (AD) which including subjective cognitive decline (SCD) stage, can be distinguished from normal control (NC) by glucose-oxygen metabolism coupling at the voxel level, but whether the coupling at the network level worked has not been studied. Therefore, this study aimed to explore the coupling relationship between brain glucose metabolic connectivity network and oxygen functional connectivity network, and whether its feasibility as a biomarker to discriminate SCD from healthy control (HC). Resting-state functional magnetic resonance imaging (rs-fMRI) and glucose positron emission tomography (PET) based on hybrid PET/MRI scans were used to investigate metabolism-oxygen metabolism coupling in 56 SCD individuals and 54 HCs. Network coupling features were selected by logistic regression-recursive feature elimination (LR-RFE), and then a linear support vector machine (SVM) was used to distinguish SCD and HC by using 5-fold cross-validation. The classification average accuracy of network coupling had reached 76.36% with a standard deviation of 9.85% (with a sensitivity of 77.82%±15.13% and a specificity of 75.30%±15.15%). After receiver operating characteristic (ROC) analysis, the average area under curve (AUC) of network coupling was 0.788 (95% confidence interval [Formula: see text]). This study provided a new perspective for exploring network coupling. The proposed classification method highlighted the potential clinical application by combing glucose-oxygen metabolism coupling and machine learning in identifying SCD.

Aberrant topological organization and age-related differences in the human connectome in subjective cognitive decline byusing regional morphology from magnetic resonance imaging.

Subjective cognitive decline (SCD) is characterized by self-experienced deficits in cognitive capacity with normal performance in objective cognitive tests. Previous structural covariance studies showed specific insights into understanding the structural alterations of the brain in neurodegenerative diseases. Moreover, in subjects with neurodegenerative diseases, accelerated brain degeneration with aging was shown. However, the age-related variations in coordinated topological patterns of morphological networks in individuals with SCD remain poorly understood. In this study, 77 individual morphological networks were constructed, including 42 normal controls (NCs) and 35 SCD individuals, from structural magnetic resonance imaging (sMRI). A stepwise linear regression model and partial correlation analysis were constructed to evaluate the differences in age-related alterations of the network properties in individuals with SCD compared with NCs. Compared with NC, the properties of integration and segregation in individuals with SCD were lower, and the aberrant metrics were negatively correlated with age in SCD. The rich-club connections persevered, but the paralimbic system connections were disrupted in individuals with SCD compared with NCs. In addition, age-related differences in nodal global efficiency are distributed mainly in prefrontal cortex regions. In conclusion, the age-related disruption of topological organizations in individuals with SCD may indicate that the degeneration of brain efficiency with aging was accelerated in individuals with SCD.

Subtle Cognitive Deficits Are Associated with Amyloid-β Positivity, but Not Severity of Self-Reported Decline: Results from the CoSCo Study

Introduction: Subjective cognitive decline (SCD) can be considered as the preclinical manifestation of Alzheimer’s disease (AD). The National Institute on Aging and the Alzheimer’s Association criteria for preclinical AD proposed that subtle cognitive changes appear along with AD biomarkers in the late stage of preclinical AD. The objective of this study was to explore whether subtle cognitive impairment (SCI) in individuals with SCD is associated with brain amyloid-β (Aβ) status and SCD severity. Methods: One hundred twenty individuals with SCD (mean age: 70.87 ± 6.10 years) were included in this study. SCI was defined as performance ≤ −1.0 SD on at least two neuropsychological tests. Participants underwent an amyloid positron emission tomography, which was assessed visually and quantitatively using standardized uptake value ratio (SUVR). The severity of SCD was assessed using two self-reported questionnaires: the SCD questionnaire based on the SCD-plus features and the Korean-Everyday Cognition (K-ECog) scale. Results: SCD individuals with SCI (n = 25) had more Aβ positivity than the SCD only group (n = 95) (44% vs. 15.79%; p = 0.002). In addition, the SCI group had a higher global SUVR than the SCD only group (p = 0.048). For self-reported questionnaires, there were no differences in SCD questionnaire total scores and K-ECog global and cognitive domain-specific scores between two groups. Conclusions: In SCD individuals, SCI was associated with higher Aβ positivity, but not with the severity of self-reported cognitive decline, compared to the SCD only group. These results suggest that the recognition of objectively defined subtle cognitive deficits may contribute to the early identification of AD in SCD.