Preclinical Stages Of Disease Research Articles

Impaired glymphatic function as a biomarker for subjective cognitive decline: An exploratory dual cohort study.

Subjective cognitive decline (SCD) has been recognized as a potential risk stage for progression to Alzheimer's disease (AD), while glymphatic dysfunction is considered an important characteristic of AD. We hypothesize that glymphatic dysfunction occurs during the SCD stage, aiming to discover potential biomarkers for SCD. Participants from two independent studies, Sino Longitudinal Study on Cognitive Decline (SILCODE, n=654) and the Alzheimer's Disease Neuroimaging Initiative (ADNI, n=650), representing different ethnicities and disease stages, were included to assess glymphatic function using diffusion tensor image analysis along the perivascular space (DTI-ALPS). Abnormal glymphatic function occurs during the SCD stage, with the ALPS index demonstrating excellent classification performance for SCD and normal controls (area under the receiver operating characteristic curve [AUC]SILCODE=0.816, AUCADNI=0.797). Lower ALPS index indicates higher risk of cognitive progression, which is negatively correlated with Subjective Cognitive Decline Questionnaire 9 scores and amyloid positron emission tomography burden. Our study suggests the ALPS index has the potential to serve as a biomarker for SCD. Glymphatic function characterized by the analysis along the perivascular space (ALPS) index becomes abnormal in subjective cognitive decline (SCD), the earliest symptomatic manifestation and preclinical stage of Alzheimer's disease (AD). The ALPS index demonstrates excellent classification performance for SCD and normal controls in the East Asian and Western cohorts. Participants with a lower ALPS index show a higher risk of clinical progression. The ALPS index is closely associated with serval cognitive scales and amyloid beta burden.

Subjective Cognitive Decline in Community-Dwelling Older Adults With Objectively Normal Cognition: Mediation by Depression and Instrumental Activities of Daily Living.

Subjective cognitive decline (SCD) refers to self-reported memory loss despite normal cognitive function and is considered a preclinical stage of Alzheimer's disease. This study aimed to examine the mediating effects of depression and Instrumental Activities of Daily Living (IADL) on the association between the scoring of Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) and Subjective Cognitive Decline Questionnaire (SCD-Q). A sample of 139 community-dwelling older adults aged 65-79 with normal cognitive function completed the SCD-Q, a comprehensive neuropsychological battery, and functional/psychiatric scales. We conducted 1) a correlation analysis between SCD-Q scores and other variables and 2) a path analysis to examine the mediating effects of depression and IADL on the relationship between CDR-SB and SCD-Q. CDR-SB was found to be indirectly associated with SCD-Q, with depressive symptoms mediating this relationship. However, no direct association was observed between SCD-Q and CDR-SB. Additionally, IADL was not associated with SCD-Q and did not mediate the relationship between CDR-SB and SCD-Q. The model fit was acceptable (minimum discrepancy function by degrees of freedom divided [CMIN/DF]=1.585, root mean square error of approximation [RMSEA]=0.065, comparative fit index [CFI]=0.955, Tucker-Lewis index [TLI]=0.939). Our results suggest that SCD-Q is influenced by depressive symptoms, but not by IADL. The role of depressive symptoms as a mediator between CDR-SB and SCD-Q indicates that psychological factors may contribute to the perception of SCD. Therefore, interventions targeting depression may mitigate the concerns associated with SCD and reduce feelings of worse performance compared to others of the same age group.

Cerebrospinal fluid biomarkers and cognitive trajectories in patients with Alzheimer’s disease and a history of traumatic brain injury

Traumatic brain injury (TBI) and Alzheimer’s disease (AD) have overlapping mechanisms but it remains unknown if pathophysiological characteristics and cognitive trajectories in AD patients are influenced by TBI history. Here, we studied AD patients (stage MCI or dementia) with TBI history (ADTBI+, n=110), or without (ADTBI-, n=110) and compared baseline CSF concentrations of amyloid beta 1–42 (Aβ42), phosphorylated tau181 (pTau181), total tau, neurofilament light chain (NfL), synaptosomal associated protein-25kDa (SNAP25), neurogranin (Ng), neuronal pentraxin-2 (NPTX2) and glutamate receptor-4 (GluR4), as well as differences in cognitive trajectories using linear mixed models. Explorative, analyses were repeated within stratified TBI groups by TBI characteristics (timing, severity, number). We found no differences in baseline CSF biomarker concentrations nor in cognitive trajectories between ADTBI+ and ADTBI- patients. TBI >5 years ago was associated with higher NPTX2 and a tendency for higher SNAP25 concentrations compared to TBI ≤ 5 years ago, suggesting that TBI may be associated with long-term synaptic dysfunction only when occurring before onset or in a pre-clinical disease stage of AD.

Amyloid and tau burden relate to longitudinal changes in the performance of complex everyday activities among cognitively unimpaired older adults: results from the performance-based Harvard Automated Phone Task.

Changes in everyday functioning constitute a clinically meaningful outcome, even in the early stages of Alzheimer's disease. Performance-based assessments of everyday functioning might help uncover these early changes. We aimed to investigate how changes over time in everyday functioning relate to tau and amyloid in cognitively unimpaired older adults. Seventy-six cognitively unimpaired participants (72 ± 6 years old, 61% female) completed multiple Harvard Automated Phone Task (APT) assessments over 2.0 ± 0.9 years. The Harvard APT consists of three tasks, performed through an automated phone system, in which participants refill a prescription (APT-Script), select a new primary care physician (APT-PCP), and transfer money to pay a bill (APT-Bank). Participants underwent Pittsburgh compound-B and flortaucipir positron emission tomography scans at baseline. We computed distribution volume ratios for a cortical amyloid aggregate and standardized uptake volume ratios for medial temporal and neocortical tau regions. In separate linear mixed models, baseline amyloid by time and tau by time interactions were used to predict longitudinal changes in performance on the Harvard APT tasks. Three-way amyloid by tau by time interactions were also investigated. Lastly, we examined associations between tau and change in Harvard APT scores in exploratory voxel-wise whole-brain analyses. All models were adjusted for age, sex, and education. Amyloid [unstandardized partial regression coefficient estimate (β) = -0.007, 95% confidence interval (95% CI) = (-0.013, -0.001)], and medial temporal tau [β = -0.013, 95% CI = (-0.022, -0.004)] were associated with change over time in years on APT-PCP only, i.e., higher baseline amyloid and higher baseline tau were associated with steeper rate of decline of APT-PCP. Voxel-wise analyses showed widespread associations between tau and change in APT-PCP scores over time. Even among cognitively unimpaired older adults, changes over time in the performance of cognitively complex everyday activities relate to cortical amyloid and widespread cerebral tau burden at baseline. These findings support the link between Alzheimer's disease pathology and function and highlight the importance of measuring everyday functioning in preclinical disease stages.

Difference between subjective and objective cognitive decline confirmed by power spectral density

ABSTRACT Introduction The study aims to use power spectrum changes in subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI), preclinical stages of Alzheimer's disease (AD), for future biomarker studies in early AD diagnosis. Methods We recruited 23 SCD and 32 aMCI subjects and conducted comparative analysis using relative power spectral density (PSD). Automated preprocessing and statistical analysis were performed using iSync Brain® (iMediSync Inc., Republic of Korea) (https://isyncbrain.com/). Results Theta band power in the temporal region was 14.826 ± 7.2394 for the SCD group and 20.003 ± 10.1768 for the aMCI group. In the parietal region, theta band power was 13.614 ± 7.5689 for SCD and 19.894 ± 11.1387 for aMCI. Beta1 band power in the frontal region was 6.639 ± 2.2904 for SCD and 5.465 ± 1.8907 for aMCI, and in the temporal region it was 7.359 ± 2.5619 for SCD and 5.921 ± 2.1605 for aMCI. Conclusion PSD analysis of resting-state EEG predicted SCD, a preclinical stage of AD. This cross-sectional study observed electrical-physiological characteristics of preclinical AD; however, follow-up studies are needed to evaluate predictive value for future cognitive decline.

Exploring the Genetic Landscape of Mild Behavioral Impairment as an Early Marker of Cognitive Decline: An Updated Review Focusing on Alzheimer's Disease.

The clinical features and pathophysiology of neuropsychiatric symptoms (NPSs) in dementia have been extensively studied. However, the genetic architecture and underlying neurobiological mechanisms of NPSs at preclinical stages of cognitive decline and Alzheimer's disease (AD) remain largely unknown. Mild behavioral impairment (MBI) represents an at-risk state for incident cognitive impairment and is defined by the emergence of persistent NPSs among non-demented individuals in later life. These NPSs include affective dysregulation, decreased motivation, impulse dyscontrol, abnormal perception and thought content, and social inappropriateness. Accumulating evidence has recently begun to shed more light on the genetic background of MBI, focusing on its potential association with genetic factors related to AD. The Apolipoprotein E (APOE) genotype and the MS4A locus have been associated with affective dysregulation, ZCWPW1 with social inappropriateness and psychosis, BIN1 and EPHA1 with psychosis, and NME8 with apathy. The association between MBI and polygenic risk scores (PRSs) in terms of AD dementia has been also explored. Potential implicated mechanisms include neuroinflammation, synaptic dysfunction, epigenetic modifications, oxidative stress responses, proteosomal impairment, and abnormal immune responses. In this review, we summarize and critically discuss the available evidence on the genetic background of MBI with an emphasis on AD, aiming to gain insights into the potential underlying neurobiological mechanisms, which till now remain largely unexplored. In addition, we propose future areas of research in this emerging field, with the aim to better understand the molecular pathophysiology of MBI and its genetic links with cognitive decline.

Naturalistic assessment of reaction time variability in older adults at risk for Alzheimer's disease.

Maintaining attention underlies many aspects of cognition and becomes compromised early in neurodegenerative diseases like Alzheimer's disease (AD). The consistency of maintaining attention can be measured with reaction time (RT) variability. Previous work has focused on measuring such fluctuations during in-clinic testing, but recent developments in remote, smartphone-based cognitive assessments can allow one to test if these fluctuations in attention are evident in naturalistic settings and if they are sensitive to traditional clinical and cognitive markers of AD. Three hundred and seventy older adults (aged 75.8 +/- 5.8 years) completed a week of remote daily testing on the Ambulatory Research in Cognition (ARC) smartphone platform and also completed clinical, genetic, and conventional in-clinic cognitive assessments. RT variability was assessed in a brief (20-40 seconds) processing speed task using two different measures of variability, the Coefficient of Variation (CoV) and the Root Mean Squared Successive Difference (RMSSD) of RTs on correct trials. Symptomatic participants showed greater variability compared to cognitively normal participants. When restricted to cognitively normal participants, APOE ε4 carriers exhibited greater variability than noncarriers. Both CoV and RMSSD showed significant, and similar, correlations with several in-clinic cognitive composites. Finally, both RT variability measures significantly mediated the relationship between APOE ε4 status and several in-clinic cognition composites. Attentional fluctuations over 20-40 seconds assessed in daily life, are sensitive to clinical status and genetic risk for AD. RT variability appears to be an important predictor of cognitive deficits during the preclinical disease stage.

ЭФФЕКТИВНОСТЬ ФИЗИОТЕРАПИИ У РАБОТНИКОВ РЕЧНОГО ТРАНСПОРТА, ИМЕЮЩИХ ДОКЛИНИЧЕСКИЕ СТАДИИ СЕРДЕЧНО-СОСУДИСТЫХ ЗАБОЛЕВАНИЙ, И ФАКТОРЫ РИСКА ИХ РАЗВИТИЯ

Aim. The primary objective of this study was to evaluate the effect of physical therapy on blood pressure, dyslipidemia, the level of somatic and mental health, and cardiovascular risk in river transport workers with preclinical stages of cardiovascular disease and risk factors for their development. Methods. Sixty-two employees of JSC "Tomsk Shipping Company" who were divided into 2 groups were studied. The first group consisted of riverboat workers with risk factors for cardiovascular disease, and the second group included workers with preclinical stages of cardiovascular disease and risk factors for their development. In the river transport crew, the correction of the main risk factors for cardiovascular disease was carried out following the DASH diet, moderate physical activity, application of physical factors, preventive talks, and biofeedback training. In preclinical forms of cardiovascular disease (AH of the 1st degree), complex hypotensive therapy was also applied. To study the effectiveness before and after physical therapy, BP was recorded, the level of somatic health and psychoemotional status was evaluated, the adaptation potential was calculated, the contents of total cholesterol and low density lipoprotein cholesterol, as well as absolute or relative cardiovascular risk were determined. Results. Therapeutic and prophylactic measures allow to increase adaptation and psychological capabilities of rivermen, to normalize blood pressure in all workers of the river transport crew under 40 years old, to reduce the degree of arterial hypertension in workers over 40 years old, to reach target values of total cholesterol and low density lipoprotein cholesterol in 18% of cases, to increase the level of somatic health in 1/3 of workers, and to reduce the level of cardiovascular risk in 38% of workers. Conclusion. The therapeutic and prophylactic measures carried out on the seafaring personnel had positive hypotensive, antispastic, antianginal, hemodynamic, lipid-correcting, and adaptogenic effects.

Reflexive and voluntary saccadic eye movements as biomarker of Huntington's Disease.

Subtle abnormalities in the preclinical stage of Huntington's Disease (HD) can be detected using saccadic eye movement assessment reflecting disease progression. This study was aimed to evaluate abnormalities in saccade parameters in asymptomatic carriers and symptomatic HD patients at various stages of HD. The study enrolled 104 participants, including 14 asymptomatic carriers of HTT mutations, 44 symptomatic HD patients, and 46 control subjects. HD severity was measured using the Unified Huntington's Disease Rating Scale Total Motor Score (UHDRS-TMS) and Total Functional Capacity Scale (TFC). The evaluation of rapid eye movements (reflexive saccades, anti-saccades, memory-guided saccades) was carried out using 'Saccadometer Research'. Measures of reflexive and volitional saccades did not differ between the asymptomatic carriers and controls. Significant latency prolongation and increased physiological variability of latency times, as well as higher error rates among HD patients, were found in all saccade tasks (p < 0.001) compared to the controls. Abnormalities in saccade parameters were more pronounced in the advanced stages of the disease. Latency of saccades and error rate of volitional saccades correlated with the UHDRS-TMS and TFC scores. The saccade parameters in asymptomatic HD carriers with a long time to disease development were similar to those in the control group. Saccade abnormalities appeared in symptomatic patients at the beginning of the disease, and correlated with HD severity.

Reduced overnight memory consolidation and associated alterations in sleep spindles and slow oscillations in early Alzheimer's disease

Spatial navigation critically underlies hippocampal-entorhinal circuit function that is early affected in Alzheimer's disease (AD). There is growing evidence that AD pathophysiology dynamically interacts with the sleep/wake cycle impairing hippocampal memory. To elucidate sleep-dependent consolidation in a cohort of symptomatic AD patients (n = 12, 71.25 ± 2.16 years), we tested hippocampal place learning by means of a virtual reality task and verbal memory by a word-pair association task before and after a night of sleep. Our results show an impaired overnight memory retention in AD compared with controls in the verbal task, together with a significant reduction of sleep spindle activity (i.e., lower amplitude of fast sleep spindles, p = 0.016) and increased duration of the slow oscillation (SO; p = 0.019). Higher spindle density, faster down-to-upstate transitions within SO, and the time delay between SO and nested spindles predicted better memory performance in healthy controls but not in AD patients. Our results show that mnemonic processing and memory consolidation in AD is slightly impaired as reflected by dysfunctional oscillatory dynamics and spindle-SO coupling during NonREM sleep. In this translational study based on experimental paradigms in animals and extending previous work in healthy aging and preclinical disease stages, our results in symptomatic AD further deepen the understanding of the memory decline within a bidirectional relationship of sleep and AD pathology.

Cross‐Sectional and Longitudinal Associations of Mild Behavioural Impairment‐Apathy and Alzheimer’s Disease‐Related Biomarkers

AbstractBackgroundApathy, characterized by decreased interest, initiative, and emotional reactivity, is amongst the most common neuropsychiatric symptoms in Alzheimer’s Disease (AD) dementia, but it can also manifest in prodromal, and even preclinical disease stages. Apathy in individuals who are cognitively normal and who have mild cognitive impairment (MCI), is associated with accelerated progression to AD, and apathy in AD has been associated with greater disability, lower quality of life, poorer health, greater caregiver distress and burden, as well as higher morbidity and mortality. The multitude of negative outcomes associated with apathy highlight the importance of research whose primary goal is to identify mild behavioural impairment(MBI)‐apathy in non‐dementia samples and combine this behavioural syndrome with well‐established AD‐biomarkers, such as beta‐amyloid (Aβ), phosphorylated tau (p‐tau), and total tau (t‐tau), to better predict AD dementia risk.MethodDementia‐free participants in the Alzheimer’s Disease Neuroimaging Initiative were stratified as MBI‐apathy and no neuropsychiatric symptoms (no‐NPS) based on Neuropsychiatric Inventory (NPI) and NPI‐Questionnaire (NPI‐Q) scores at two consecutive visits. Covariates of interest included age, sex, apolipoprotein ε4 carriership, years of education, Mini Mental State Examination scores, and the questionnaire NPS status was derived from. Linear regressions assessed the association of MBI‐apathy (predictor) with Aβ40, Aβ42, p‐tau181, t‐tau, Aβ40/Aβ42, p‐tau181/Aβ42, and t‐tau/Aβ42 (outcome variables). We also used linear mixed effect models for repeated measures to investigate change in our outcome variables across a two‐year period.ResultsOf the 253 participants (127 CN); 51 had MBI‐apathy. MBI‐apathy was found to be significantly associated with baseline p‐tau181/Aβ42 (p&lt;0.05) and t‐tau/Aβ42 (p&lt;0.05) ratios. MBI‐apathy was also found to be significantly associated with changes in Aβ42 (p = 0.001), Aβ40/Aβ42 (p&lt;0.01), p‐tau181/Aβ42 (p = 0.001), and t‐tau/Aβ42 (p = 0.001) levels and ratios over a two‐year period.ConclusionTo our knowledge, this is the first study examining the relationship between MBI‐apathy and AD‐related biomarkers. Results suggest that MBI‐apathy is significantly associated with several AD‐related biomarkers both cross‐sectionally and longitudinally. Combining the presence of persistent and emergent apathy with these biomarkers might serve as a prognostically useful approach for predicting AD dementia at a time when there is opportunity for intervention.

High prevalence of subjective cognitive decline in older Chinese adults: a systematic review and meta-analysis.

Subjective cognitive decline (SCD) is considered a preclinical stage of Alzheimer's disease. However, reliable prevalence estimates of SCD in the Chinese population are lacking, underscoring the importance of such metrics for policymakers to formulate appropriate healthcare strategies. To systematically evaluate SCD prevalence among older Chinese adults. PubMed, Web of Science, The Cochrane Library, Embase, CNKI, Wanfang, VIP, CBM, and Airiti Library databases were searched for studies on SCD in older Chinese individuals published before May 2023. Two investigators independently screened the literature, extracted the information, and assessed the bias risk of the included studies. A meta-analysis was then conducted using Stata 16.0 software via a random-effects model to analyze SCD prevalence in older Chinese adults. A total of 17 studies were included (n = 31,782). The SCD prevalence in older Chinese adults was 46.4% (95% CI, 40.6-52.2%). Further, subgroup analyzes indicated that SCD prevalence was 50.8% in men and 58.9% among women. Additionally, SCD prevalence in individuals aged 60-69, 70-79, and ≥ 80 years was 38.0, 45.2, and 60.3%, respectively. Furthermore, SCD prevalence in older adults with BMI <18.5, 18.5-24.0, and > 24.0 was 59.3, 54.0, and 52.9%, respectively. Geographically, SCD prevalence among older Chinese individuals was 41.3% in North China and 50.0% in South China. In terms of residence, SCD prevalence was 47.1% in urban residents and 50.0% among rural residents. As for retired individuals, SCD prevalence was 44.2% in non-manual workers and 49.2% among manual workers. In the case of education, individuals with an education level of "elementary school and below" had an SCD prevalence rate of 62.8%; "middle school, "52.4%; "high school, "55.0%; and "college and above, "51.3%. Finally, SCD prevalence was lower among married individuals with surviving spouses than in single adults who were divorced, widowed, or unmarried. Our systematic review and meta-analysis identified significant and widespread SCD prevalence in the older population in China. Therefore, our review findings highlight the urgent requirement for medical institutions and policymakers across all levels to prioritize and rapidly develop and implement comprehensive preventive and therapeutic strategies for SCD.Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023406950, identifier: CRD42023406950.

Development of a Cognitive Composite for Preclinical Alzheimer's Disease in Korean Older Adults.

As tracking subtle cognitive declines in the preclinical stage of Alzheimer's disease (AD) is difficult with traditional individual outcome measures, need for cognitive composite for preclinical AD is widely recognized. We aimed to develop culturally appropriate cognitive composite that sensitively identifies subtle cognitive decline of preclinical AD in Korean older adults. A total 225 cognitively normal elderly individuals from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease, were included. Tests of episodic memory, orientation, and executive function were carefully selected through review of previously established composites. Three candidate composites including Consortium to Establish a Registry for Alzheimer's Disease Word list recall (WLR), Logical memory (LM) II, and Mini-Mental status examination (MMSE) in common, and Letter fluency test (LF), category fluency test, or Stroop color and word test, were selected. Student t-tests demonstrated that only the composite composed of WLR, LM II, MMSE, and LF (Composite 1) showed a significant difference in score decline over two-year follow-up period between Aβ positive and negative group (p = 0.03). Linear mixed model analyses also showed that the Aβ x time interaction effect was significant only for Composite 1 (p = 0.025). Based on the results, Composite 1 was chosen as the final cognitive composite for preclinical Alzheimer's disease (CPAD). CPAD can be used to assess subtle cognitive decline of preclinical AD in clinical research settings, especially in Korean older adults. It also may be used for monitoring progression or treatment benefits in clinical practices.

COVID-19 Impacts the Mental Health and Speech Function in Spinocerebellar Ataxia Type 2: Evidences from a Follow-Up Study.

Limited evidence suggests that the SARS-CoV-2 infection can accelerate the progression of neurodegenerative diseases, but this has been not verified in the spinocerebellar ataxias (SCA). The objective of this study is to assess the impact of COVID-19 on the mental health and motor features of SCA2. A follow-up study was carried out in 170 Cuban SCA2 subjects and 87 community controls between 2020 and 2021. All subjects underwent a structured questionnaire to assess the risks of exposure to COVID-19, the confirmation of COVID-19 diagnosis, and the Hospital Anxiety and Depression Scale (HADS). Moreover, 36 subjects underwent the Scale for the Assessment and Rating of ataxia (SARA). The risk of exposure to SARS-CoV-2 and the frequency of COVID-19 were similar between the ataxia cohort and the community controls. Within the ataxia group, significantly increased HADS scores existed at the 2nd visit in both groups, but this increase was more evident for the infected group regarding the depression score. Moreover, a significant within-group increase of SARA score was observed in the infected group but not the non-infected group, which was mainly mediated by the significant increase of the speech item score in the infected group. Similar results were observed within the subgroup of preclinical carriers. Our study identified no selective vulnerability nor protection to COVID-19 in SCA2, but once infected, the patients experienced a deterioration of mental health and speech function, even at preclinical disease stage. These findings set rationales for tele-health approaches that minimize the detrimental effect of COVID-19 on SCA2 progression and identify SCA2 individuals as clinical model to elucidate the link between SARS-CoV-2 infection and neurodegeneration.

Hemoglobin A1c Serum Level Predicts 5-year Mortality in Patients with Cognitive Impairment

BackgroundSubjective cognitive decline (SCD) and mild cognitive impairment (MCI) may occur as preclinical stages of Alzheimer's disease (AD), ultimately leading to dementia. Glycated hemoglobin A1c (HbA1c) is a diagnostic marker for diabetes mellitus and indicates mortality risk.ObjectivesThis university-based, exploratory retrospective study examined the impact of HbA1c serum level on 5-year mortality among individuals with cognitive impairment.MethodsIncluded were 1076 subjects aged at least 50 years who visited the Memory Outpatient Clinic of the Medical University of Vienna due to memory problems. Participants were diagnosed with SCD, MCI, or AD subsequent to neurological examination, standard laboratory blood tests, and neuropsychological testing. Survival was compared between diagnostic subgroups and with respect to HbA1c categories using log-rank tests based on Kaplan–Meier functions. The Neuropsychological Test Battery Vienna (NTBV) was dimensionally reduced, and a principal component analysis (PCA) was performed to further analyze results. Corresponding factor scores, HbA1c values, and baseline characteristics were included in Cox proportional hazards models to assess 5-year mortality risk.ResultsDuring the observation period, 323 patients (30%) died at a mean age comparable between diagnostic subgroups (SCD 84.2 ± 10.1, MCI 81.2 ± 8.3, AD 82.2 ± 7.4 years). Individuals with normal serum HbA1c levels had significant advantages in survival within the MCI (12.9 ± .3 vs. 10.0 ± .8 years) and the AD subgroups (8.2 ± .4 vs. 5.5 ± .6 years), and metric HbA1c predicted 5-year mortality (HR 1.24).ConclusionThis study demonstrates an association between abnormal HbA1c serum levels and increased mortality.

DOPA decarboxylase is an emerging biomarker for Parkinsonian disorders including preclinical Lewy body disease.

The diagnosis of Parkinsonian disorders is currently based on clinical criteria, which have limited sensitivity until most dopaminergic neurons are lost. Here we show that cerebrospinal fluid levels of DOPA decarboxylase (DDC) (also known as aromatic L-amino acid decarboxylase) can accurately identify patients with Lewy body disease (LBD) (area under the curve (AUC) = 0.89; PFDR = 2.6 × 10-13) and are associated with worse cognitive performance (P < 0.05). We also found that DDC can detect preclinical LBD stages in clinically unimpaired individuals with a positive seed amplification α-synuclein assay (AUC = 0.81, P = 1.0 × 10-5) and that this biomarker could predict progression to clinical LBD over a 3-year period in preclinical cases (hazard ratio = 3.7 per s.d. change, confidence interval = 1.1-12.7). Moreover, DDC levels were also increased in atypical Parkinsonian disorders but not in non-Parkinsonian neurodegenerative disorders. These cerebrospinal fluid results were replicated in an independent cohort, where we also found that DDC levels in plasma could identify both LBD and atypical Parkinsonian disorders (AUC = 0.92, P = 1.3 × 10-14). Our results show that DDC might have a future role in clinical practice as a biomarker of dopaminergic dysfunction to detect Parkinsonian disorders even during the preclinical disease stages and predict their progression to clinical LBD.

Low thalamic activity during a digit-symbol substitution task is associated with symptoms of subjective cognitive decline.

Subjective cognitive decline (SCD) may represent the earliest preclinical stage of Alzheimer's Disease (AD) for some older adults. However, the underlying neurobiology of SCD is not completely understood. Since executive function may be affected earlier than memory function in the progression of AD, we aimed to characterize SCD symptoms in terms of fMRI brain activity during the computerized digit-symbol substitution task (DSST), an executive function task. We also explored associations of DSST task performance with brain activation, SCD severity, and amyloid-ß (Aß) load. We analyzed data from 63 cognitively normal older individuals (mean age 73.6 ± 7.2) with varying degree of SCD symptoms. Participants completed a computerized version of DSST in the MR scanner and a Pittsburgh Compound-B (PiB)-PET scan to measure global cerebral Aß load. A voxel-wise analysis revealed that greater SCD severity was associated with lower dorsomedial thalamus activation. While task performance was not associated with brain activation nor Aß load, slower reaction time was associated with greater SCD severity. The observed lower dorsomedial thalamus activation may reflect declining familiarity-based working memory and the trans-thalamic executive function pathway in SCD. SCD symptoms may reflect altered neural function and subtle decline of executive function, while Aß load may have an indirect impact on neural function and performance. Self-perceived cognitive decline may serve as a psychological/subjective marker reflecting subtle brain changes.

Motor-Cognitive Interventions May Effectively Improve Cognitive Function in Older Adults with Mild Cognitive Impairment: A Randomized Controlled Trial.

Mild cognitive impairment (MCI) is a syndrome that occurs in the preclinical stage of Alzheimer's disease. Early intervention can be effective in preventing Alzheimer's disease, but further research is needed on intervention methods. To identify interventions that are more suitable for Chinese characteristics and to investigate the effects of motor-cognitive intervention on the cognitive functions of older adults with MCI, we screened 103 community-dwelling older adults with MCI aged 65 years and older in Qingdao, Shandong, China; divided them into an intervention group and a control group; and administered a motor-cognitive intervention to the intervention group for 12 weeks. The study used the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) to assess the initial cognitive level of the MCI participants and detect the effects of the intervention. We found that the cognitive abilities of the intervention group were significantly improved at the end of the intervention, as well as at the end of the follow-up, compared with the control group. The results of the current study suggest that the motor-cognitive intervention we used may improve the cognition of older people with MCI in the Chinese community.

Plasma neurofilament light chain in relation to 10-year change in cognition and neuroimaging markers: a population-based study

Neurofilament light chain (NfL) is a promising biomarker for risk stratification and disease monitoring of dementia, but its utility in the preclinical disease stage remains uncertain. We determined the association of plasma NfL with (change in) neuroimaging markers and cognition in the population-based Rotterdam Study, using linear and logistic regression and mixed-effects models. Plasma NfL levels were measured using the Simoa NF-light™ assay in 4705 dementia-free participants (mean age 71.9 years, 57% women), who underwent cognitive assessment and brain MRI with repeated assessments over a 10-year follow-up period. Higher plasma NfL was associated with worse cognitive performance at baseline (g-factor: β = − 0.12 (− 0.15; − 0.09), p < 0.001), and accelerated cognitive decline during follow-up on the Stroop color naming task (β = 0.04 (0.02; 0.06), p < 0.001), with a smaller trend for decline in global cognition (g-factor β = − 0.02 (− 0.04; 0.00), p = 0.044). In the subset of 975 participants with brain MRI, higher NfL was associated with poorer baseline white matter integrity (e.g., global mean diffusivity: β = 0.12 (0.06; 0.19), p < 0.001), with similar trends for volume of white matter hyperintensities (β = 0.09 (0.02; 0.16), p = 0.011) and presence of lacunes (OR = 1.55 (1.13; 2.14), p = 0.007). Plasma NfL was not associated with volumes or thickness of the total gray matter, hippocampus, or Alzheimer signature regions. In conclusion, higher plasma NfL levels are associated with cognitive decline and larger burden of primarily white matter pathology in the general population.

Topological properties of individual gray matter morphological networks in identifying the preclinical stages of Alzheimer's disease: a preliminary study.

Subjective cognitive decline (SCD) and mild cognitive impairment (MCI) are preclinical stages of Alzheimer's disease (AD). Individual biomarkers are essential for evaluating altered neurological outcomes at both SCD and MCI stages for early diagnosis and intervention of AD. In this study, we aimed to investigate the relationships between topological properties of the individual brain morphological network and clinical cognitive performances among healthy controls (HCs) and patients with SCD or MCI. The topological measurements of individual morphological networks were analyzed using graph theory, and inter-group differences of standard graph topology were correlated and regressed to scores of clinical cognitive functions. Compared with HCs, the topology of the individual morphological networks in SCD and MCI patients was significantly altered. At the global level, altered topology was characterized by lower global efficiency, shorter characteristics path length, and normalized characteristics path length [all P<0.05, false discovery rate (FDR) corrected]. In addition, at the regional level, SCD and MCI patients exhibited abnormal degree centrality in the caudate nucleus and nodal efficiency in the caudate nucleus, right insula, lenticular nucleus, and putamen (all P<0.05, FDR corrected). The topological features of individual gray matter morphological networks may serve as biomarkers to improve disease prognosis and intervention in the early stages of AD, namely SCD and MCI. Moreover, these findings may further elucidate the relationships between brain morphological alterations and cognitive dysfunctions in SCD and MCI.