Subjective Cognitive Decline Patients Research Articles

SUBJECTIVE COGNITIVE DECLINE VERSUS SUBTLE DEFICITS AS INDICATORS OF PRECLINICAL AD: RESULTS FROM THE MULTICENTER OBSERVATIONAL STUDY ON PREDEMENTIA ALZHEIMER’S DISEASE (DELCODE) STUDY

In preclinical AD, subtle neuropsychological deficits occur in groups without mild cognitive impairment (MCI), although the detection of a subtle decline in individual cases may be difficult. Subjective cognitive decline (SCD) has been emphasized as being one of the first symptomatic manifestations of preclinical AD, possibly even preceding subtle deficits because compensation of slight impairments is still possible. Subjective and subtle cognitive decline are both mentioned in the NIA-AA-criteria-2018 as indicators for the Alzheimer's continuum in cognitively normals, but their overlap and their possibly complementary contribution in this regard is unclear. By applying an operational definition for subtle cognitive decline in SCD patients, we aim to clarify the degree of overlap of these definitions and their association with CSF-AD biomarkers. We analyzed 240 memory-clinic patients with a worrisome subjective cognitive decline (SCD) and 209 controls (CON) without SCD. Both groups performed within the normal range on a comprehensive test battery (>-1.5SD). Presence of subtle deficits was defined by mild neuropsychological or functional impairments (Table1). Prevalence of subtle impairment was calculated in SCD and CON to gauge the extent of overlap. With logistic regression, we analyzed whether subjective decline (SCD vs. CON) would predict CSF-AD markers, controlling for age. We repeated this analysis after excluding all subjects with subtle deficits. Most CON and SCD participants had no subtle cognitive impairments and groups didn't differ significantly in this regard (Table1). Subjective decline was associated with amyloid load (SCD>CON; p<.05) in cases with and without subtle impairment. Subtle impairment was associated with amyloid in CON and SCD (Figure1). SCD were 2.979 more likely Aβ42-positive compared to CON, even if excluding all subjects with subtle decline from analysis (Exp(B)=2.762).

Awareness of Olfactory Dysfunction in Subjective Cognitive Decline, Mild Cognitive Decline, and Alzheimer\u2019s Disease

IntroductionHyposmia and metacognitive errors are related to aging, depression, male gender, and cognitive decline. The current study investigated the awareness of olfactory dysfunction in subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer’s disease (AD), as well as the influence of additional factors.MethodsA sample of 641 patients, including controls, SCD, non-amnestic MCI (naMCI), amnestic MCI (aMCI), and AD patients, was assessed with the Sniffin’ Sticks odor identification test (OIT) and the subjective olfactory capability (SOC) scale, in addition to measures of depressive symptoms, verbal memory, and executive functioning. Olfactory awareness groups were formed by means of the cutoffs of the OIT and the SOC.ResultsModerate and small, although significant, correlations between the OIT and the SOC were found among the study groups, with a significant discrimination of measured olfactory function via subjective assessment existing among controls but not among patients with AD. Of all AD patients, 34% overrated their sense of smell while 21% correctly identified themselves as being hyposmic, as opposed to corresponding 6% and 1% of healthy elderly. Overraters and correct hyposmic participants showed higher age and worse verbal memory and executive functions.ConclusionsReduced odor identification might underlie the same pathological changes within the brain as cognitive impairment and could serve as an additional marker for the development of AD.ImplicationsAlthough people with AD are aware of hyposmia to some extent, the majority is affected by overestimation of the ability to smell, making the combination of subjective ratings and measures of olfactory function an interesting topic for further research.

Amyloid-β Load Is Related to Worries, but Not to Severity of Cognitive Complaints in Individuals With Subjective Cognitive Decline: The SCIENCe Project

Objective: Subjective cognitive decline (SCD) is associated with an increased risk of Alzheimer’s Disease (AD). Early disease processes, such as amyloid-β aggregation measured with quantitative PET, may help to explain the phenotype of SCD. The aim of this study was to investigate whether quantitative amyloid-β load is associated with both self- and informant-reported cognitive complaints and memory deficit awareness in individuals with SCD.Methods: We included 106 SCD patients (mean ± SD age: 64 ± 8, 45%F) with 90 min dynamic [18F]florbetapir PET scans. We used the following questionnaires to assess SCD severity: cognitive change index (CCI, self and informant reports; 2 × 20 items), subjective cognitive functioning (SCF, four items), and five questions “Do you have complaints?” (yes/no) for memory, attention, organization and language), and “Does this worry you? (yes/no).” The Rivermead Behavioral Memory Test (RBMT)-Stories (immediate and delayed recall) was used to assess objective episodic memory. To investigate the level of self-awareness, we calculated a memory deficit awareness index (Z-transformed (inverted self-reported CCI minus episodic memory); higher index, heightened self-awareness) and a self-proxy index (Z-transformed self- minus informant-reported CCI). Mean cortical [18F]florbetapir binding potential (BPND) was derived from the PET data. Logistic and linear regression analyses, adjusted for age, sex, education, and depressive symptoms, were used to investigate associations between BPND and measures of SCD.Results: Higher mean cortical [18F]florbetapir BPND was associated with SCD-related worries (odds ratio = 1.76 [95%CI = 1.07 ± 2.90]), but not with other SCD questionnaires (informant and self-report CCI or SCF, total scores or individual items, all p > 0.05). In addition, higher mean cortical [18F]florbetapir BPND was associated with a higher memory deficit awareness index (Beta = 0.55), with an interaction between BPND and education (p = 0.002). There were no associations between [18F]florbetapir BPND and self-proxy index (Beta = 0.11).Conclusion: Amyloid-β deposition was associated with SCD-related worries and heightened memory deficit awareness (i.e., hypernosognosia), but not with severity of cognitive complaints. Our findings indicate that worries about self-perceived decline may reflect an early symptom of amyloid-β related pathology rather than subjective cognitive functioning.

Subregional volume reduction of the cholinergic forebrain in subjective cognitive decline (SCD).

Subjective cognitive decline (SCD) patients are considered as a risk population for preclinical Alzheimer's Disease (AD). Supporting this idea, previous studies in SCD populations report subtle alterations in various cognitive and neuroimaging biomarkers that are typically affected during AD progression. To extend these observations, the present study examined whether SCD patients show atrophy of cholinergic basal forebrain nuclei (chBFN), analogous with recent findings in prodromal and clinical AD patients. We assessed volume reductions of the chBFN in 24 SCD subjects compared to 49 matched controls on 3D-T1-weighted MR images based on a postmortem derived atlas. Furthermore, we assessed whether chBFN atrophy was linked with cognitive, structural and metabolic biomarker alterations we previously reported in this SCD cohort: Using correlation analyses we tested for associations between the volumes of the chBFN with the hippocampal gray matter volume, and posterior medial glucose consumption, and the trajectory of verbal memory performance. The SCD cases showed a significant total volume reduction of the chBFN, with largest effect sizes in the Ch1/2 and Ch4p subdivisions of the chBFN. The latter was associated with a reduced glucose metabolism in the precuneus for the SCD group only. These data show an early involvement of the cholinergic basal forebrain nuclei in SCD predominantly in Ch1/2 and Ch4p which supports the conceptual link between SCD and preclinical AD.

Identification of odors, faces, cities and naming of objects in patients with subjective cognitive decline, mild cognitive impairment and Alzheimer´s disease: a longitudinal study.

Six hundred fifty patients (median age 68, 58% females) including controls, SCD (subjective cognitive decline), non-amnestic MCI (naMCI), amnestic MCI (aMCI), and AD patients were tested for olfactory dysfunction by means of odor identification testing and semantic memory. Of those 650 patients, 120 participants with SCD, naMCI, or aMCI at baseline underwent a follow-up examination after two years on average. Of these 120 patients, 12% had developed AD at follow-up (converters), while 88% did not develop AD at follow-up (non-converters). Analysis showed a significant difference only for initial olfactory identification between converters and non-converters. Sensitivity of impairment of olfactory identification for AD prediction was low at 46.2%, although specificity was high at 81.9%. Semantic memory impairment at baseline was not significantly related to AD conversion, although, when naming objects, significant differences were found between AD patients and all other groups and between naMCI and aMCI patients compared to controls and SCD patients. Objective olfactory assessments are promising instruments for predicting the conversion to AD among MCI patients. However, due to their low sensitivity and high specificity, a combination with other neuropsychological tests might lead to an improved predictive accuracy. Further longitudinal studies with more participants are required to investigate the usefulness of semantic memory tests in this case.

Development, Application, and Results from a Precision-medicine Platform that Personalizes Multi-modal Treatment Plans for Mild Alzheimer's Disease and At-risk Individuals.

Introduction: Alzheimer’s Disease (AD) is a progressive neurodegenerative condition in which individuals exhibit memory loss, dementia, and impaired metabolism. Nearly all previous sin-gle-treatment studies to treat AD have failed, likely because it is a complex disease with multiple un-derlying drivers contributing to risk, onset, and progression. Here, we explored the efficacy of a mul-ti-therapy approach based on the disease risk factor status specific to individuals with AD diagnosis or concern.Methods: Novel software from uMETHOD Health was designed to execute a precision-medicine-based approach to de¬velop personalized treatment recommendations with the goal of slowing or re-versing biologic drivers of AD. AD-associated inputs encompassed genomic data, bio-specimen measurements, imaging data (such as MRIs or PET scans), medical histories, medications, allergies, co-morbidities, relevant lifestyle factors, and results of neuropsychological testing. Algorithms were then employed to prioritize physiologic and lifestyle states with the highest probability of contributing to disease status, and these priorities were incorporated into a personalized care plan, which was de-livered to physicians and supported by health coaches to increase adherence. The sample included 40 subjects with Subjective Cognitive Decline patients (SCD), and Mild Cognitive Impairment Patients (MCI).Results: Software analysis was completed for 40 individuals. They remained on their treatment plan for an average of 8.4 months, equal to 2.8 iterations of care plans. 80% of individuals overall showed improved memory function scores or held steady, as meas¬ured by standardized cognitive evaluations. Cognitive assessments showed significant improvement in the SCD group (Composite P value .002, Executive P value .01), and the CNS-VS Executive domain showed significant results in the com-bined group as well (P value .01). There was also biomarker improvement over time observed from the blood panels. 8 out of 12 selected biomarkers showed slight, though statistically non-significant, improvement overall for symptomatic individuals, and 6 out of 12 for the overall population. Only one biomarker, homocysteine, showed significant improvement, though (P values .03, .04, .002).Conclusions: Our analysis of these individuals lead to several interesting observations to¬gether sug-gesting that AD risk factors comprise a network of interlocking feedback loops that may be modifia-ble. Our findings indicate previously unidentified connectivity between AD risk factors, suggesting that treatment regimens should be tailored to the individual and multi-modal to simultaneously return sev¬eral risk factors to a normative state. If successfully performed, the possibility to slow progression of AD and possibly reverse aspects of cognitive decline may become achievable.

P73. A new cognitive diagnostic marker to distinguish between Subjective Cognitive Decline, mild cognitive impairment and healthy adults?

Patients with Subjective Cognitive Decline (SCD) have an increased risk of Alzheimer’s diseases (AD) pathology while their performance in usual cognitive tests is normal. The goal of the present study was to assess whether another cognitive test, late verbal recall, can distinguish between SCD, mild cognitive impairment (MCI) and no cognitive impairment (healthy controls, HC). We used a late recall method which has so far only been applied in epilepsy patients ( Witt et al., 2012 ). After being screened with the CERAD test battery ( Morris et al., 1989 , Mirra et al., 1991 ) patients from our memory clinic were called 24 h later and asked whether they still remembered words of the list they had to learn the day before. We also carried out the sleep quality (PSQI) and the smell function (Sniffin Sticks test) and compared the performance in SCD to a healthy control group and patients with mild cognitive impairment. Smell values and word recall differentiated between MCI and HC/SCD. HC and SCD did not show a significant difference in smell functions and late word recall. Sleep quality only differed between HC and MCI. Smell and late recall performance were correlated with each other and can predict the MMST score. Sleep quality did not explain additional variance in a regression model. Raw values of late recall showed highest sensitivity and specificity compared to sleep and smell. These findings reveal that the smell test and the late recall test were able to distinguish between SCD and MCI, but not between SCD and healthy controls. The regression model proves that our late recall method is a better predictor for cognitive impairment in MCI and SCD than smell or sleep. Our next goal is to define a marker that distinguishes between SCD patients who stay healthy and those who will develop objective cognitive decline. The question will be whether individual differences in SCDs performance (late recall, smell, sleep) can predict the probability for developing AD.

IMPACT OF SUBJECTIVE COGNITIVE COMPLAINTS ON INSTRUMENTAL ACTIVITIES OF DAILY LIVING IN PATIENTS WITH SUBJECTIVE COGNITIVE DECLINE AND AMNESTIC MILD COGNITIVE IMPAIRMENT: DATA FROM THE CZECH BRAIN AGING STUDY

Patients with subjective cognitive decline (SCD) are defined as having newly developed subjective cognitive complaints despite normal performance on standard neuropsychological tests. Some of SCD patients may represent subjects with preclinical Alzheimer's disease. The aim was to analyze their subjectively perceived difficulties with cognitive functioning and with instrumental activities of daily living (IADL) and to compare it to patients with amnestic mild cognitive impairment (aMCI) and cognitively healthy volunteers (HV). In total, 215 non-demented older adults seeking medical help for subjective cognitive complaints were recruited in the Czech Brain Aging Study (CBAS). They underwent a comprehensive neuropsychological examination and were further classified as having aMCI (n=132, mean MMSE=27.2) or SCD (n=83, mean MMSE=29.3). In addition, 25 age and education matched cognitively healthy volunteers without significant subjective cognitive complaints (HV, mean MMSE=29.7) for which they would ever seek for medical help were recruited. All subjects completed a newly developed Motol hospital questionnaire evaluating: 1) the presence/absence of subjective cognitive impairment in various cognitive domains (CD- i.e. memory, attention etc.), 2) the degree of subjectively perceived change in specific cognitive abilities (CA- i.e. remembering names, finding things, word finding difficulties etc.),3) the degree of self-perceived change in demanding IADL (i.e. car driving, using internet banking, using PC etc.). Both SCD and aMCI groups reported more than twice more difficulties in CD and CA than HV (ps<.01) but they did not differ from each other. The SCD group did not differ from HV in subjective worsening of demanding IADL and both groups reported twice less difficulties in IADL than aMCI (ps< .05). The amount of subjective cognitive complaints in SCD patients is similar to that reported by aMCI patients but unlike them it does not seem to have a significant impact on subjective worsening of demanding IADL.

Multimodal Neuroimaging in Alzheimer's Disease: Early Diagnosis, Physiopathological Mechanisms, and Impact of Lifestyle.

Over the last ten years, we have conducted research in Alzheimer’s disease (AD) using multimodal neuroimaging techniques to improve diagnosis, further our understanding of the pathological mechanisms underlying the disease, and support the development of innovative non-pharmacological preventive strategies. Our works emphasized the interest of hippocampal subfield volumetry in early diagnosis and the need for further development in this field including optimization, standardization, and automatization of the techniques. Also, we conducted several studies in cognitively intact at-risk elderly (e.g., subjective cognitive decline patients and APOE4 carriers) to better identify biomarkers associated with increased risk of developing AD. Regarding the physiopathological mechanisms, specific multimodal neuroimaging techniques allowed us to highlight the relevance of diaschisis, the mismatch between neurodegeneration and local Aβ deposition and the regional variation in the mechanisms underlying structural or functional alterations. Further works integrating other biomarkers known to play a role in the physiopathology of AD (tau, TDP-43, inflammation, etc.) in a longitudinal design would be useful to get a comprehensive understanding of their relative role, sequence, and causal relationships. Our works also highlighted the relevance of functional connectivity in further understanding the specificity of cognitive deficits in AD and how connectivity differentially influences the propagation of the different AD biomarkers. Finally, we conducted several studies on the links between lifestyle factors and neuroimaging biomarkers to unravel mechanisms of reserve. Further efforts are needed to better understand which lifestyle factor, or combination of factors, impact on AD pathology, and when, to help translating our knowledge to training programs that might prevent or delay brain and cognitive changes leading to AD dementia.

Rich club disturbances of the human connectome from subjective cognitive decline to Alzheimer's disease.

Alzheimer's disease (AD) has a preclinical phase that can last for decades prior to clinical dementia onset. Subjective cognitive decline (SCD) is regarded as the last preclinical AD stage prior to the development of amnestic mild cognitive decline (aMCI) and AD dementia (d-AD). The analysis of brain structural networks based on diffusion tensor imaging (DTI) has identified the so-called 'rich club', a set of cortical regions highly connected to each other, with other regions referred to as peripheral. It has been reported that rich club architecture is affected by regional atrophy and connectivity, which are reduced in patients with aMCI and d-AD.Methods: We recruited 62 normal controls, 47 SCD patients, 60 aMCI patients and 55 d-AD patients and collected DTI data to analyze rich-club organization.Results: We demonstrated that rich club organization was disrupted, with reduced structural connectivity among rich club nodes, in aMCI and d-AD patients but remained stable in SCD patients. In addition, SCD, aMCI and d-AD patients showed similar patterns of disrupted peripheral regions and reduced connectivity involving these regions, suggesting that peripheral regions might contribute to cognitive decline and that disruptions here could be regarded as an early marker of SCD. This organization could provide the fundamental structural architecture for complex cognitive functions and explain the low prevalence of cognitive problems in SCD patients.Conclusions: These findings reveal a disrupted pattern of the AD connectome that starts in peripheral regions and then hierarchically propagates to rich club regions, when patients show clinical symptoms. This pattern provides evidence that disruptions in rich club organization are a key factor in the progression of AD that can dynamically reflect the progression of AD, thus representing a potential biomarker for early diagnosis.

Wishes and preferences for an online lifestyle program for brain health—A mixed methods study

IntroductionIndividuals with subjective cognitive decline (SCD) are at increased risk of Alzheimer's disease and could benefit from a prevention strategy targeting lifestyle factors. Making a program available through the Internet gives a widespread reach at low cost, but suboptimal adherence is a major threat to effectiveness. As a first step in developing an online lifestyle program (OLP), we aimed to identify factors that are barriers and/or facilitators for the use of an OLP in individuals with SCD in three European countries. MethodsAs part of the Euro-SCD project, SCD subjects were recruited at memory clinics in the Netherlands, Germany, and Spain. We combined quantitative and qualitative methods, using a mixed methods approach. We conducted an online 18-item survey on the preferences of SCD patients for an OLP (N = 238). In addition, we held semi-structured interviews (N = 22) to gain in-depth understanding of factors acting as a facilitator and/or barrier for intended use of an OLP. Audio recordings were transcribed verbatim. Content analysis was performed. ResultsOne hundred seventy-six individuals completed the survey (response rate 74%). Almost all participants regularly use the Internet (97%). Participants reported trustworthiness (93%), user-friendliness (91%), and up-to-date information (88%) as main facilitators, whereas having contact with other users (26%), needing an account (21%), and assignments (16%) were reported as barriers. Barriers differed slightly between countries, but facilitators were largely similar. In-depth interviews revealed that both program characteristics (e.g., trustworthiness, user-friendliness, and personalization) and personal factors (e.g., expectancy to receive negative feedback) are likely to influence the intended use of an OLP. DiscussionInvolving users provided in-depth understanding of factors associated with the intended use of an OLP for brain health. Both program characteristics and personal factors are likely to influence the use of an OLP. Based on this input from the end-users, we will develop an OLP for individuals with SCD.

Microbleeds are associated with depressive symptoms in Alzheimer's disease

IntroductionCo-occurrence of cerebrovascular disease and depression led to the “vascular depression hypothesis”. White matter hyperintensities (WMHs) have been associated with depressive symptoms in population-based studies. We studied the association between small vessel disease and depressive symptoms in a memory clinic population. MethodsWe included >2000 patients with subjective cognitive decline (SCD), mild cognitive impairment, and Alzheimer's disease (AD). Magnetic resonance imaging was rated for WMHs, lacunes, and microbleeds. Depressive symptoms were assessed using the Geriatric Depression Scale. We performed logistic regression analysis. ResultsDepressive symptoms were present in AD: 17%; mild cognitive impairment: 25%; and SCD: 23%. SCD patients with WMHs showed higher propensity of depressive symptoms than AD patients with WMHs. AD patients with microbleeds were more likely to have depressive symptoms compared with AD patients without microbleeds (odds ratio = 1.70; 95% confidence interval: 1.08–2.68). DiscussionMicrobleeds are associated with depressive symptoms in AD, supporting a potential role of cerebral amyloid angiopathy in the occurrence of depressive symptoms in AD.

Regional patterns of gray matter volume, hypometabolism, and beta-amyloid in groups at risk of Alzheimer's disease

Alzheimer's disease (AD) is characterized by the presence of β-amyloid (Aβ) deposition and neurodegeneration. To seek for signs of such pathologies, we compared regional biomarker degrees and patterns of Aβ deposition, glucose hypometabolism, and gray matter volume (GMV) reduction in 3 groups at risk of AD. In elderly carriers of the apolipoprotein E ε4 (APOE4, n = 17), patients with subjective cognitive decline (n = 16), and patients with mild cognitive impairment (n = 30), head-to-head intermodality comparisons were performed on cross-sectional structural magnetic resonance images as well as 18F-fluorodeoxyglucose and 18F-florbetapir positron emission tomography scans. In mild cognitive impairment patients, 3 distinct biomarker patterns were recovered, similarly seen in AD patients: (1) in medial temporal regions, local GMV reduction exceeded hypometabolism, (2) in temporoparietal regions, hypometabolism predominated over GMV reduction, and (3) in frontal regions, Aβ deposition exceeded GMV reduction and hypometabolism. In subjective cognitive decline patients, only pattern 1 was detected, while APOE4 carriers demonstrated only pattern 3. Our findings highlight that regional AD-like biomarker patterns may vary across different at-risk populations, potentially reflecting differential mediators of these risks.

Atrophy of the Posterior Subiculum Is Associated with Memory Impairment, Tau- and Aβ Pathology in Non-demented Individuals

Alzheimer’s disease (AD) is associated with atrophy of the cornu ammonis (CA) 1 and the subiculum subfield of the hippocampus (HC), and with deficits in episodic memory and spatial orientation. These deficits are mainly associated with the functionality of the posterior HC. We therefore hypothesized that key AD pathologies, i.e., β-amyloid and tau pathology would be particularly associated with the volume of the posterior subiculum in non-demented individuals. In our study we included 302 cognitively normal elderly participants (CN), 183 patients with subjective cognitive decline (SCD) and 171 patients with amnestic mild cognitive impairment (MCI), all of whom underwent 3T magnetic resonance images (MRI). The subicular subfield was segmented using Freesurfer 5.3 and divided into 10 volumetric segments moving from the most posterior (segment 1) to the most anterior part along the axis of the hippocampal head and body (segment 10). Cerebrospinal fluid (CSF) Aβ42 and phosphorylated tau (P-tau) were quantified using ELISA and were used as biomarkers for β-amyloid and tau pathology, respectively. In the total sample, tau-pathology and Aβ-pathology and (measured by elevated P-tau and low Aβ42 levels in CSF) and mild memory dysfunction were mostly associated with the volume changes of the posterior subiculum. Both SCD and MCI patients with elevated P-tau or low Aβ42 levels displayed predominantly posterior subicular atrophy in comparisons to control subjects with normal CSF biomarker levels. Finally, there was no main effect of Aβ42 or P-tau when comparing SCD with abnormal P-tau or Aβ42 with SCD with normal levels of these CSF-biomarkers. However, in the left subiculum there was a significant interaction revealing atrophy in the left posterior but not the anterior subiculum in participants with low Aβ42 levels. The same pattern was observed on the contralateral side in participants with elevated P-tau levels. In conclusion, AD pathologies and mild memory dysfunction are mainly associated with atrophy of the posterior parts of the subicular subfields of the HC in non-demented individuals. In light of these findings we suggest that segmentation of the HC subfields may benefit from considering the volume of the different anterior-posterior subsections of each subfield.

Thinner cortex in patients with subjective cognitive decline is associated with steeper decline of memory

We aimed to investigate associations between regional cortical thickness and rate of decline over time in 4 cognitive domains in patients with subjective cognitive decline (SCD). We included 233 SCD patients with the total number of 654 neuropsychological assessments (median = 3, range = 2–8) and available baseline magnetic resonance imaging from the Amsterdam Dementia Cohort (125 males, age: 63 ± 9, Mini–Mental State Examination score: 28 ± 2). We assessed longitudinal cognitive functioning at baseline and follow-up in 4 cognitive domains (composite Z-scores): memory, attention, executive function, and language. Thickness (millimeter) was estimated using FreeSurfer for frontal, temporal, parietal, cingulate, and occipital cortices. We used linear mixed models to estimate effects of cortical thickness on cognitive performance (dependent variables). There were no associations between cortical thickness and baseline cognition, but a faster subsequent rate of memory loss was associated with thinner cortex of the frontal [β (SE) = 0.20 (0.07)], temporal [β (SE) = 0.18 (0.07)], and occipital [β (SE) = 0.22 (0.09)] cortices (all p < 0.05FDR). These findings illustrate that early cortical changes, particularly in the temporal cortex, herald incipient cognitive decline related to neurodegenerative diseases, most prominently Alzheimer's disease.

Prevalence of mild behavioral impairment in mild cognitive impairment and subjective cognitive decline, and its association with caregiver burden.

Mild behavioral impairment (MBI) describes later life acquired, sustained neuropsychiatric symptoms (NPS) in cognitively normal individuals or those with mild cognitive impairment (MCI), as an at-risk state for incident cognitive decline and dementia. We developed an operational definition of MBI and tested whether the presence of MBI was related to caregiver burden in patients with subjective cognitive decline (SCD) or MCI assessed at a memory clinic. MBI was assessed in 282 consecutive memory clinic patients with SCD (n = 119) or MCI (n = 163) in accordance with the International Society to Advance Alzheimer's Research and Treatment - Alzheimer's Association (ISTAART-AA) research diagnostic criteria. We operationalized a definition of MBI using the Neuropsychiatric Inventory Questionnaire (NPI-Q). Caregiver burden was assessed using the Zarit caregiver burden scale. Generalized linear regression was used to model the effect of MBI domains on caregiver burden. While MBI was more prevalent in MCI (85.3%) than in SCD (76.5%), this difference was not statistically significant (p = 0.06). Prevalence estimates across MBI domains were affective dysregulation (77.8%); impulse control (64.4%); decreased motivation (51.7%); social inappropriateness (27.8%); and abnormal perception or thought content (8.7%). Affective dysregulation (p = 0.03) and decreased motivation (p=0.01) were more prevalent in MCI than SCD patients. Caregiver burden was 3.35 times higher when MBI was present after controlling for age, education, sex, and MCI (p < 0.0001). MBI was common in memory clinic patients without dementia and was associated with greater caregiver burden. These data show that MBI is a common and clinically relevant syndrome.

Tau plasma levels in subjective cognitive decline: Results from the DELCODE study

Previous studies have demonstrated increased tau plasma levels in patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI) due to AD. Much less is known whether increased tau plasma levels can already be detected in the pre-MCI stage of subjective cognitive decline (SCD). In the present study we measured tau plasma levels in 111 SCD patients and 134 age- and gender-matched cognitively healthy controls participating in the DZNE (German Center for Neurodegenerative Diseases) longitudinal study on cognition and dementia (DELCODE). Tau plasma levels were measured using ultra-sensitive, single-molecule array (Simoa) technology. We found no significant different tau plasma levels in SCD (3.4 pg/ml) compared with healthy controls (3.6 pg/ml) after controlling for age, gender, and education (p = 0.137). In addition, tau plasma levels did not correlate with Aβ42 (r = 0.073; p = 0.634), tau (r = −0.179; p = 0.240), and p-tau181 (r = −0.208; p = 0.171) cerebrospinal fluid (CSF) levels in a subgroup of 45 SCD patients with available CSF. In conclusion, plasma tau is not increased in SCD patients. In addition, the lack of correlation between tau in plasma and CSF in the examined cohort suggests that tau levels are affected by different factors in both biofluids.

Functional Disintegration of the Default Mode Network in Prodromal Alzheimer's Disease.

Neurodegenerative brain changes can affect the functional connectivity strength between nodes of the default-mode network (DMN), which may underlie changes in cognitive performance. It remains unclear how the functional connectivity strength of DMN nodes differs from healthy to pathological aging and whether these changes are cognitively relevant. We used resting-state functional magnetic resonance imaging to investigate the functional connectivity strength across five DMN nodes in 25 healthy controls (HC), 28 subjective cognitive decline (SCD) participants, and 25 prodromal Alzheimer's disease (AD) patients. After identifying the ventral medial prefrontal cortex (vmPFC), posterior cingulate cortex (PCC), retrosplenial cortex (RSC), inferior parietal lobule, and the hippocampus we investigated the functional strength between DMN nodes using temporal network modeling. Functional coupling of the vmPFC and PCC in prodromal AD patients was disrupted. This vmPFC-PCC coupling correlated positively with memory performance in prodromal AD. Furthermore, the hippocampus de-coupled from posterior DMN nodes in SCD and prodromal AD patients. There was no coupling between the hippocampus and the anterior DMN. Additional mediation analyses indicated that the RSC enables communication between the hippocampus and DMN regions in HC but none of the other two groups. These results suggest an anterior-posterior disconnection and a hippocampal de-coupling from posterior DMN nodes with disease progression. Hippocampal de-coupling already occurring in SCD may provide valuable information for the development of a functional biomarker.

ATYPICAL VERBAL MEMORY RECOGNITION PATTERN IN PATIENTS WITH SUBJECTIVE COGNITIVE DECLINE

Subjective cognitive decline (SCD) is concerns about cognitive decline without any objective evidence of cognitive impairment. Patients with SCD showed normal neuropsychological performances. Thus, cued recall, recognition is typically superior to free recall. However, sometimes we faced with the opposite results that recognition is worse than free recall. Hence, we investigated whether the atypical recognition patterns are associated with other potential cognitive dysfunction or clinical features. We hypothesized that atypical recognition pattern would be associated with poor frontal/executive function or higher depression scores. SCD was clinically diagnosed by an experienced neurologist when patients visiting a memory clinic due to subjective memory decline did not have objective cognitive deficit in evaluation. We performed a retrospective review of patients with SCD in memory clinic of Seoul St. Mary's Hospital between July 2015 and September 2016. According to the results of Seoul verbal learning Test (SVLT), we divided SCD patients into the typical and atypical recognition pattern groups. We compared baseline characteristics, APOE genotyping, vascular risk factors, and neuropsychological test results. Total 223 SCD patients who underwent neuropsychological test were included. 105(47.1%) patients were classified as typical recognition pattern and the other 118(52.9%) patients were atypical pattern group. Demographic features, MMSE, CDR-SOB, vascular risk factors, APOE4 carrier frequency, and geriatric depression scales were not significantly different between two groups. Atypical recognition pattern group showed poorer performance in digit span backward (DSB) test. (P=0.009) In verbal memory test, patients with atypical recognition pattern showed better immediate and delayed recall performances. (P=0.006, P<0.001, respectively). Especially, among SCD patients with better verbal memory delayed recall (>50%ile), patients with atypical recognition pattern still showed significantly lower scores in DSB. However, in SCD patients with SVLT results below the 50%ile. There was no statistically significant difference between the typical and atypical recognition group. Our result revealed that SCD patients with atypical recognition pattern showed significantly poor working memory task. It means that this recognition pattern can be related to frontal dysfunction. However, we cannot find any significant difference in vascular risk factors or clinical variables. Future studies for the longitudinal follow up will be needed for the clinical significance of atypical recognition pattern in SCD.

GREY MATTER CONNECTIVITY IS RELATED TO A STEEPER LOSS OF MEMORY AND LANGUAGE FUNCTIONING OVER TIME IN PATIENTS WITH SUBJECTIVE COGNITIVE DECLINE

Grey matter connectivity is related to cognitive functioning, and disrupted in early stages of Alzheimer's disease (AD). We aimed to investigate the association between single-subject grey matter connectivity and changes in cognitive functioning over time in patients with subjective cognitive decline (SCD). We included 235 patients with SCD, with baseline 3D-T1 MRI and repeated neuropsychological testing (on average 3±1 years) from the Amsterdam Dementia Cohort (54% male, age: 63±9, MMSE: 28±2). We assessed baseline and annual change in cognitive functioning of four domains: memory, attention, executive function and language (n=654 neuropsychological investigations). Single-subject grey matter networks were extracted from T1-weighted structural MRI and the following parameters were computed at whole brain level and in 90 anatomical AAL areas: degree, connectivity density, path length, clustering, betweenness centrality, lambda and gamma. Effects of grey matter baseline connectivity measures (predictors) on changes in annual cognitive performance (dependent variables) were assessed with linear mixed models. Analyses were adjusted for age, sex, education, scanner and total intracranial volume. At baseline, there were no associations between structural connectivity and cognitive functioning. Lower lambda values were associated with a steeper decline in memory (β=0.09, SE=0.02; p<.05). Lower values of network size (β=0.11, SE=0.05), degree (β=0.10, SE=0.05) and betweenness centrality (β=0.13, SE=0.05) were associated with a steeper decline in language (all p<0.05). Additional adjustment for hippocampal volumes did not change these results. Regional analyses showed that lower path length values were associated with faster memory decline specifically in the bilateral parahippocampal gyri and the superior and middle temporal poles. Associations between lower betweenness centrality and faster language decline were specific for the bilateral orbitofrontal, medial frontal, middle temporal, inferior parietal, and right insula and parahippocampal gyrus (all p<0.05). SCD patients with lower values of grey matter network parameters showed faster decline in memory and language. Lower values of lambda are indicative of a loss of connectivity and a more random network organisation, which is often observed in AD-dementia patients. These findings suggest that less efficient grey matter network organisation may precede objective cognitive impairment and the clinical manifestation of AD.