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.

OBJECTIVE: Reproductive hormones might impact disease course in cognitive decline. We examined the association between male and female endogenous reproductive hormones and subjective cognitive decline (SCD) score.
METHODS: A cross-sectional study design was used with baseline data from the Pingyin cohort study, involving 1943 participants aged 45-70 years. Oestrogen (E2), testosterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH) were measured in females and E2 and testosterone were measured in males. We categorised hormones into three levels of low, intermediate and high level. The 9-item subjective cognitive decline questionnaire (SCD-Q9) scores were collected to assess the symptoms of SCD. Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% confidence interval (CI) between categorised hormone levels and SCD status. Multivariable linear regression models were also used.
RESULTS: Overall, 1943 participants were involved and 1285 (66.1%) were female. The mean age at baseline was 59.1 (standard deviation 7.1) years. Women with high testosterone levels had a higher probability of having SCD compared with those with low testosterone levels (OR 1.43, 95% CI 1.01-2.05). Men with a high level of testosterone (0.59, 0.35-0.98) and high testosterone/E2 ratio (0.55, 0.33-0.90) were related to decreased chances of having SCD. Each one-unit increase of testosterone was linked to reduced SCD score in males [(β: -.029, 95% CI (-0.052, -0.007)].
CONCLUSIONS: There was sex-specific relationship between hormone levels and SCD abnormal. Those with higher testosterone levels in females may increase likelihood of experiencing SCD. Males with higher testosterone levels and higher testosterone/E2 ratio may be associated with reduced likelihood of SCD. The roles of endogenous reproductive hormone levels and their dynamic changes in cognitive function need further investigation.

BACKGROUND: The research criteria for subjective cognitive decline (SCD) exclude mild cognitive impairment (MCI), but do not stipulate the use of specific MCI criteria. This study compared different approaches to defining (i.e., excluding) MCI during the ascertainment of SCD, focusing on the impact on dementia incidence rates in SCD.
METHODS: This cohort study utilized routine healthcare data collected in the Essex Memory Clinic from 1999 to 2023. Two different operationalizations of the SCD criteria were used to categorize the cohort into two SCD patient samples. One sample was based on local clinical practice - MCI was excluded according to the Winblad criteria (this sample was termed SCDWinblad). The other sample was created via the retrospective application of the Jak/Bondi criteria for the exclusion of MCI (termed SCDJak/Bondi). Only patients aged ≥ 55 years at baseline with ≥ 12 months follow-up were considered for inclusion. The initial clinical/demographic characteristics of the samples were compared. Rates of incident dementia were calculated for each sample, and unadjusted and Mantel-Haenszel-adjusted incidence rate ratios were calculated to compare dementia incidence between the SCD samples.
RESULTS: The Essex Memory Clinic database included 2,233 patients in total. The SCD and study eligibility criteria were used to select SCDWinblad (n = 86) and SCDJak/Bondi (n = 185) samples from the database. Median follow-up (3 years) did not differ between the two samples. The SCDJak/Bondi sample was significantly older than the SCDWinblad at first assessment (median age: 74 versus 70 years) and had poorer scores on tests of global cognition, immediate and delayed verbal recall, and category fluency. Following adjustment for age, the dementia incidence rate ratio [95% confidence interval] was 3.7 [1.5 to 9.3], indicating a significantly greater rate of progression to dementia in SCDJak/Bondi.
CONCLUSIONS: This study highlights that the approach used to ascertain SCD has important implications for both SCD phenotypes and prognosis. This underscores the importance of how MCI is operationalized within SCD studies. More broadly, the findings add to a growing body of work indicating that objective cognition should not be overlooked in SCD, and offer a potential explanation for the heterogeneity across the SCD prognostic literature.

UNASSIGNED: Depressive symptoms are associated with Alzheimer\'s disease (AD), but their neurobiological and neuropsychological correlates remain poorly understood. We investigate if depressive symptoms are associated with amyloid (Aβ) pathology and cognition in predementia AD.
UNASSIGNED: We included subjective cognitive decline (SCD, n = 160) and mild cognitive impairment (MCI, n = 192) from the dementia disease initiation cohort. Depressive symptoms were assessed using the Geriatric Depression Scale (GDS-15). Aβ pathology was determined using cerebrospinal fluid (CSF) Aβ42/40 ratio. Associations between depressive symptoms and cognition were assessed with logistic regression.
UNASSIGNED: Only the Aβ negative MCI group (MCI-Aβ-) was associated with depressive symptoms (odds ratio [OR] = 2.65, p = 0.005). Depressive symptoms were associated with worse memory in MCI-Aβ- (OR = 0.94, p = 0.039), but with better performance in MCI-Aβ+ (OR = 1.103, p = 0.001).
UNASSIGNED: Our results suggest that depressive symptoms in MCI are neither associated with Aβ pathology, nor AD-associated memory impairment. However, memory impairment in non-AD MCI may relate to depressive symptoms.

BACKGROUND: Non-pharmacological interventions have a myriad of available intervention options and contain multiple components. Whether specific components of non-pharmacological interventions or combinations are superior to others remains unclear. The main aim of this study is to compare the effects of different combinations of non-pharmacological interventions and their specific components on health-related outcomes in adults with subjective cognitive decline.
METHODS: PubMed, Embase, Cochrane, CINAHL, PsycINFO, CENTRAL, Web of Science, and China\'s two largest databases, CNKI and Wanfang, were searched from inception to 22nd, January 2023. Randomized controlled trials using non-pharmacological interventions and reporting health outcomes in adults with subjective cognitive decline were included. Two independent reviewers screened studies, extracted data, and assessed risk of bias. Component network meta-analysis was conducted employing an additive component model for network meta-analysis. This study followed the PRISMA reporting guideline and the PRISMA checklist is presented in Additional file 2.
RESULTS: A total of 39 trials with 2959 patients were included (range of mean ages, 58.79-77.41 years). Resistance exercise might be the optimal intervention for reducing memory complaints in adults with subjective cognitive decline; the surface under the cumulative ranking p score was 0.888, followed by balance exercise (p = 0.859), aerobic exercise (p = 0.832), and cognitive interventions (p = 0.618). Music therapy, cognitive training, transcranial direct current stimulation, mindfulness therapy, and balance exercises might be the most effective intervention components for improving global cognitive function (iSMD, 0.83; 95% CI, 0.36 to 1.29), language (iSMD, 0.31; 95% CI, 0.24 to 0.38), ability to perform activities of daily living (iSMD, 0.55; 95% CI, 0.21 to 0.89), physical health (iSMD, 3.29; 95% CI, 2.57 to 4.00), and anxiety relief (iSMD, 0.71; 95% CI, 0.26 to 1.16), respectively.
CONCLUSIONS: The form of physical activity performed appears to be more beneficial than cognitive interventions in reducing subjective memory complaints for adults with subjective cognitive decline, and this difference was reflected in resistance, aerobic, and balance exercises. Randomized clinical trials with high-quality and large-scale are warranted to validate the findings.
BACKGROUND: PROSPERO registry number. CRD42022355363.

OBJECTIVE: There have been concerns that the COVID-19 pandemic and the measures used to contain it impacted the cognitive health of older adults. We therefore examined the prevalence of subjective cognitive decline, and its associated risk factors and health consequencs, among dementia-free older adults 2 years into the pandemic in Switzerland.
METHODS: Population-based cohort study.
METHODS: Prevalence of SCD was estimated using the cognitive complaint questionnaire administered to adults aged ≥65 years in June-September 2022 (Specchio-COVID19 cohort, N = 1414), and compared to prepandemic values from 2014 to 2018 (CoLaus|PsyCoLaus cohort, N = 1181). Associated risk factors and health consequences were assessed using logistic and/or linear regression.
RESULTS: Prevalence of SCD in 2022 (18.9% [95% CI, 16.2-21.9]) was comparable to prepandemic levels in 2014-2018 (19.5% [17.2-22.1]). Risk factors included established risks for dementia-namely health issues, health behaviours, and depressive symptoms. Self-reported post-COVID, perceived worsening of mental health since the start of the pandemic, less frequent social club attendance, and increased loneliness were also risk factors for SCD. In turn, SCD was associated with poorer objective cognitive performance, difficulty performing instrumental activities of daily living, greater risk of falls, and lower well-being at one-year follow-up.
CONCLUSIONS: While the overall prevalence of SCD in 2022 was comparable to prepandemic levels, we identified several pandemic-related risk factors for SCD, including perceived worsening of mental health and increased isolation since the start of the pandemic. These findings highlight the importance of mental health promotion strategies in reducing cognitive complaints and preventing cognitive decline.

OBJECTIVE: Accurate identification of individuals with subjective cognitive decline (SCD) is crucial for early intervention and prevention of neurodegenerative diseases. Fractal dimensionality (FD) has emerged as a robust and replicable measure, surpassing traditional geometric metrics, in characterizing the intricate fractal geometrical properties of brain structure. Nevertheless, the effectiveness of FD in identifying individuals with SCD remains largely unclear. A 3D regional FD method can be suggested to characterize and quantify the spatial complexity of the precise gray matter, providing insights into cognitive aging and aiding in the automated identification of individuals with SCD.
METHODS: This study introduces a novel integer ratio based 3D box-counting fractal analysis (IRBCFA) to quantify regional fractal dimensions (FDs) in structural magnetic resonance imaging (MRI) data. The innovative method overcomes limitations of conventional box-counting techniques by accommodating arbitrary box sizes, thereby enhancing the precision of FD estimation in small, yet neurologically significant, brain regions.
RESULTS: The application of IRBCFA to two publicly available datasets, OASIS-3 and ADNI, consisting of 520 and 180 subjects, respectively. The method identified discriminative regions of interest (ROIs) predominantly within the limbic system, fronto-parietal region, occipito-temporal region, and basal ganglia-thalamus region. These ROIs exhibited significant correlations with cognitive functions, including executive functioning, memory, social cognition, and sensory perception, suggesting their potential as neuroimaging markers for SCD. The identification model trained on these ROIs demonstrated exceptional performance achieving over 93 % accuracy on the discovery dataset and exceeding 87 % on the independent testing dataset. Furthermore, an exchange experiment between datasets revealed a substantial overlap in discriminative ROIs, highlighting the robustness of our method across diverse populations.
CONCLUSIONS: Our findings indicate that IRBCFA can serve as a valuable tool for quantifying the spatial complexity of gray matter, providing insights into cognitive aging and aiding in the automated identification of individuals with SCD. The demonstrated generalizability and robustness of this method position it as a promising tool for neurodegenerative disease research and offer potential for clinical applications.

Several studies have reported subtle differences in cognition between individuals with subjective cognitive decline (SCD) compared to those with normal cognition. This study aimed to (i) identify these differences using discrepancy scores (e.g., categorial-phonemic verbal fluency performance) derived from neuropsychological tests in three cognitive domains (memory: Wechsler\'s Word List and Digits; executive functions: Stroop and verbal fluency; and language: BNT and ECCO_Senior) and (ii) determine which discrepancy scores are significant for classification. Seventy-five older adults were included: 32 who were labeled SCD+ (age 71.50 ± 5.29), meeting Jessen et al.\'s criteria, and 43 in the normal cognition group (SCD-; age 69.81 ± 4.62). Both groups completed a protocol including screening and the specified neuropsychological tests. No differences were found between the groups in their age, education, episodic memory, global cognitive state, or mood. Significant differences between the groups were observed regarding the discrepancy scores derived from BNT (naming) and ECCO_Senior (sentence comprehension). These scores accurately classified participants (71.6%), with ECCO_Senior having a primary role. ROC curves indicated a poor-to-fair model quality or diagnostic accuracy (AUC_BNT = 0.690; AUC_ECCO = 0.722). In conclusion, discrepancy scores in the language domain are important for distinguishing between individuals with SCD and normal cognition, complementing previous findings in this domain. However, given their relatively poor diagnostic accuracy, they should be used with caution as part of a more detailed neuro-psychological assessment.

UNASSIGNED: Recent research has highlighted the insula as a critical hub in human brain networks and the most susceptible region to subjective cognitive decline (SCD). However, the changes in functional connectivity of insular subregions in SCD patients remain poorly understood. The present study aims to clarify the altered functional connectivity patterns within insular subregions in individuals with SCD using resting-state functional magnetic resonance imaging (rs-fMRI).
UNASSIGNED: In this study, we collected rs-fMRI data from 30 patients with SCD and 28 healthy controls (HCs). By defining three subregions of the insula, we mapped whole-brain resting-state functional connectivity (RSFC). We identified several distinct RSFC patterns of the insular subregions. Specifically, for positive connectivity, three cognitive-related RSFC patterns were identified within the insula, suggesting anterior-to-posterior functional subdivisions: (1) a dorsal anterior zone of the insula that shows RSFC with the executive control network (ECN); (2) a ventral anterior zone of the insula that shows functional connectivity with the salience network (SN); and (3) a posterior zone along the insula that shows functional connectivity with the sensorimotor network (SMN).
UNASSIGNED: Compared to the controls, patients with SCD exhibited increased positive RSFC to the sub-region of the insula, demonstrating compensatory plasticity. Furthermore, these abnormal insular subregion RSFCs are closely correlated with cognitive performance in the SCD patients.
UNASSIGNED: Our findings suggest that different insular subregions exhibit distinct patterns of RSFC with various functional networks, which are affected differently in patients with SCD.

UNASSIGNED: The NIA-AA Research Framework on Alzheimer\'s disease (AD) proposes a transitional stage (stage 2) characterized by subtle cognitive decline, subjective cognitive decline (SCD) and mild neurobehavioral symptoms (NPS).
UNASSIGNED: To identify participant clusters based on stage 2 features and assess their association with amyloid positivity in cognitively unimpaired individuals.
UNASSIGNED: We included baseline data of N = 338 cognitively unimpaired participants from the DELCODE cohort with data on cerebrospinal fluid biomarkers for AD. Classification into the AD continuum (i.e., amyloid positivity, A+) was based on Aβ42/40 status. Neuropsychological test data were used to assess subtle objective cognitive dysfunction (OBJ), the subjective cognitive decline interview (SCD-I) was used to detect SCD, and the Neuropsychiatric Inventory Questionnaire (NPI-Q) was used to assess NPS. A two-step cluster analysis was carried out and differences in AD biomarkers between clusters were analyzed.
UNASSIGNED: We identified three distinct participant clusters based on presented symptoms. The highest rate of A+ participants (47.6%) was found in a cluster characterized by both OBJ and SCD. A cluster of participants that presented with SCD and NPS (A+:26.6%) and a cluster of participants with overall few symptoms (A+:19.7%) showed amyloid positivity in a range that was not higher than the expected A+ rate for the age group. Across the full sample, participants with a combination of SCD and OBJ in the memory domain showed a lower Aβ42/ptau181 ratio compared to those with neither SCD nor OBJ.
UNASSIGNED: The cluster characterized by participants with OBJ and concomitant SCD was enriched for amyloid pathology.