Memory Clinic Cohort Research Articles

A stepwise approach towards diagnostic workup in dementia using online cognitive tools

AbstractBackgroundDementia affects more and more people worldwide. Unfortunately, only half of dementia cases are well recognized. This indicates a need for both efficient and tailored tools for diagnosis. To improve the number of correctly diagnosed patients while retaining cost‐effectiveness, we study a stepwise data‐driven approach for the diagnostic workup. By using the online cognitive test tool cCOG [1] as prescreener, we aim to select the right diagnostic workup for each patient.MethodsWe included 710 subjects from three memory clinic cohorts (PredictND, VPH‐DARE and Amsterdam dementia cohort) with different types of dementia and subjective cognitive decline (SCD). All patients performed a neuropsychological (NP) test battery (consisting of MMSE, RAVLT, TMT‐A and B and Animal Fluency) and had MRI of the brain. A subset of 214 subjects additionally performed cCOG. To verify results we imputed missing cCOG based on corresponding NP tests [1]. From MRI, multiple imaging biomarkers were defined [2]. We tested a stepwise diagnostic approach, starting with screening using cCOG, then if needed testing with NP test battery and MRI, using the Disease State Index (DSI) classifier [2]. At each step patients were selected for the next step based on DSI model’s confidence (Figure 1).ResultsThe stepwise approach was as accurate as performing all tests in every patient (Table 1), but it reduced the number of tests done especially in SCD patients considerably, with NP in only 57% and MRI in 38% (Table 2). This was also reflected in reduced cost per patient in typical memory clinic population (from estimated 510 € to 238‐243 €). For dementia patients the reduction in number of tests and costs was smaller.ConclusionThis study suggest that using a stepwise approach, applying online cognitive tests as prescreening at home, can reduce the number of patient visits to clinic and costs. The results were as accurate as with the standard traditional work‐up. Online cognitive testing is therefore a promising tool to funnel the patient flow to memory clinics, also in times of social distancing.

The association between diabetes and Alzheimer’s disease pathophysiology

AbstractBackgroundDiabetes is common in persons with dementia and associated with cognitive decline. However, the relation between diabetes and AD pathophysiology is still unclear. Our aim is to assess the association of diabetes diagnosis and blood glucose regulation with CSF AD biomarkers across the AD clinical spectrum, and the potential moderating effects of vascular factors in this relationship.MethodAs part of the PRIME project, we included individuals from five European memory clinic cohorts with normal cognition (NC, n=419) mild cognitive impairment (MCI, n=363) and dementia (n=151). Inclusion criteria were availability of diabetes diagnosis, fasting blood glucose or HbA1c levels and cerebrospinal fluid (CSF) biomarkers amyloid‐beta42, p‐tau and t‐tau. Center‐specific cut‐offs were used to define biomarker positivity. We performed logistic and linear regression models adjusted for age, education years, gender, cohort, to assess the relation between diabetes and AD biomarkers, as well as the potential influence of hypertension, hypercholesterolemia and BMI on this relationship.ResultWe included 933 participants in our analysis with an average age of 66.1 years (Table 1). Diabetes was associated with lower odds of being amyloid positive in the total group and in individuals with NC and dementia (Table 2). Diabetes was associated with a lower risk for p‐tau and t‐tau positivity in the total group and in the MCI subgroup. Similar trends were found with HbA1c and blood glucose as predictors. A higher BMI was associated with less t‐tau pathology in persons with diabetes only. Presence of hypertension and hypercholesterolemia did not influence the association between diabetes and AD biomarkers. Additionally, post‐hoc analyses with diagnostic group stratified for amyloid positivity were performed. These analyses indicated that amyloid‐negative demented individuals more often had diabetes than amyloid‐negative NC and MCI individuals (Figure 1). Relative to amyloid‐negative NC, amyloid‐negative demented individuals had higher HbA1c and glucose levels (Figure 2). Amyloid‐positive demented individuals had higher HbA1c levels than amyloid‐positive NC and MCI patients.ConclusionDiabetes and impaired glucose regulation are associated with non‐AD dementia but not with AD‐related cognitive impairments. Surprisingly, amyloid positive individuals with normal cognition less often had diabetes.

Association of deep‐learning–derived brain computed tomography measures with cognition and blood‐based biomarkers of neurodegenerative diseases

AbstractBackgroundExisting imaging biomarkers for neurodegenerative diseases such as magnetic resonance imaging (MRI) and positron emission tomography are costly or have limited accessibility. Computed tomography (CT) and novel blood tests have greater potential as screening modalities for suspected neurodegenerative diseases and to potentially exclude other treatable causes of neurodegeneration.ObjectiveTo evaluate the association of volumetric brain measures, derived using a novel CT‐based deep‐learning algorithm with cognition and blood levels of neurodegeneration markers.MethodWe previously developed deep‐learning‐based models using 734 datasets (722 cognitively normals (CN)) from Gothenburg H70 Birth Cohort to segment head CTs by learning from MRI‐derived labels. We used these models to segment, without further training, 204 novel CT datasets (73 Alzheimer's disease (AD), 49 mild cognitive impairment (MCI), 20 vascular dementia (VAD), 40 vascular cognitive impairment (VCI), 22 CN) recruited from the Singaporean Memory Clinic cohort (mean age= 74.0±8.2 years, 50.5% female), without MRI intervention. We tested associations between six CT‐derived volumetric measures (grey matter (GM), white matter (WM), GM/CSF, GM/ventricular CSF (VCSF), brain volume (BV)/CSF, BV/VCSF) with diagnosis, plasma biomarkers, and cognition. The plasma biomarkers were measured using a Simoa platform (Quanterix, Bilerica, MA,USA).ResultThe novel CT segmentations correlated significantly with their corresponding MRI‐segmentations. Lower CT‐derived tissue volumes correlated with higher plasma neurofilament (NFL) concentrations in the H70 cohort. In the MCC NUH cohort, lower CT‐derived volumes correlated with lower MMSE scores and higher plasma NFL. CT‐derived volumes yielded high diagnostic accuracy for AD vs CN (AUC ROC 0.87). Mean CT‐based volumetric measures were lower in AD and VAD compared with CN. Kruskal‐Wallis tests showed a statistically significant difference in CT‐based volumetric measures predominantly for GM/CSF and BV/CSF across all diagnostic groups, notably between AD vs CN and CN vs early stages of dementia.ConclusionDeep‐learning‐derived CT‐based volumetric measures correlate with relevant other imaging, cognitive and biochemical markers of neurodegenerative diseases. This supports the potential application of CT‐derived volumetric measures in aiding diagnostics and early detection of dementia. Further explorations of the association between CT‐based measures with visual assessments and other clinical and imaging biomarkers will be undertaken.

The role of the hippocampus in mediating cognitive impairment in cerebral amyloid angiopathy

AbstractBackgroundThe interplay between cerebrovascular and Alzheimer’s pathology has an important role in the development of cognitive impairment1. Vascular risk factors and neuroimaging markers of cerebral small vessel disease (CSVD), have well been characterized in patients with Alzheimer’s disease (AD) in the past years2,3. Conversely, few studies asked how hippocampal neurodegeneration, a benchmark of AD, relates to cognition in CSVD patients4.MethodWe set out to investigate the relation between hippocampal neurodegeneration and cognition in a memory clinic cohort of 101 (75.8 ± 6.7 y, 58 F) patients with possible and probable cerebral amyloid angiopathy (CAA), a common CSVD form with defined diagnostic criteria. Linear regression models were used to assess the associations between the volume of hippocampal subfields and cognitive measures. Neuroimaging markers of CSVD were subsequently included in the analyses, to evaluate how they mediate the relation between cognition and hippocampal neurodegeneration.ResultWe found a significant positive association between CA1 volume and cognitive domains (memory: b=0.14, p=0.008; processing speed: b=0.15, p=0.03; language: b=0.14, p=0.03; executive function: b=0.20, p=0.01). CA1 volume was significantly related to memory and executive function, even when accounting for neuroimaging markers of CSVD. Furthermore, presence of cortical superficial siderosis and peak width of skeletonized mean diffusivity (PSMD), a measure of white matter (WM) integrity, were negatively associated with hippocampal and subfields’ volumes.ConclusionThese results suggest that neurodegeneration of CA1 is related to cognitive impairment in CAA patients, and may further support established links between vascular pathology and loss of CA1 integrity and/or overlap of AD pathology in these patients5‐7. Moreover, further studies exploring the relationship between WM and hippocampal integrity may be warranted.

Sex‐related differences in cognition with statin usage in a geriatric memory clinic cohort

AbstractBackgroundRecently, there has been debate for the suitability of statins for geriatric populations and patients with dementia as there is evidence suggesting improved quality of life following discontinuation of therapy in these groups, as well as conflicting evidence surrounding its potential to both prevent and potentiate downstream cognitive deficits. Despite large scale studies being conducted in the past regarding statins and cognition, there is a paucity of literature investigating its interaction with sex, as well as possible associations with other variables such as subjective complaints, neuropsychiatric symptoms, and function.MethodsAnalysis was done on patients assessed at a Memory Disorders Clinic at St. Michael’s Hospital between 2012 and 2017, comprising a population of 348 patients divided into groups taking daily atorvastatin (N = 45), rosuvastatin (N = 40), and controls (N = 263) (Table 1). Data form the Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Behavioural Neurology Assessment‐Revised (BNA‐R), Neuropsychological Impairment Scale (NIS), The Older Americans Resources and Services (OARS) Activities of Daily Living (ADL) Scale and Neuropsychiatric Inventory Questionnaire (NPI‐Q) were analyzed.ResultsTwo‐way ANOVA demonstrated a significant interaction between sex, cognitive performance, and statin use in which female statin users scored significantly lower on multiple subdomains of the BNA‐R (p < 0.05) (Table 2). Patients taking atorvastatin additionally scored lower on CERAD delayed recall, delayed recognition, and in the cumulative recognition domain than other groups (p < 0.05). Atorvastatin and rosuvastatin were additionally associated with higher frequency of dysphoria and disinhibition, respectively (p < 0.05). No significant results were found in other measures investigated.ConclusionsIn addition to minor associations between atorvastatin usage and lower memory performance, findings from this investigation suggest a possible interaction between sex, cognition and statin use that has not been well documented in literature. Though these findings were not reflected in other measures such as subjective complaint or function, further research may be warranted to provide insight into the relationship between sex, statin usage and neurological effects.

Dementia in Southeast Asia: influence of onset-type, education, and cerebrovascular disease

BackgroundSoutheast Asia represents 10% of the global population, yet little is known about regional clinical characteristics of dementia and risk factors for dementia progression. This study aims to describe the clinico-demographic profiles of dementia in Southeast Asia and investigate the association of onset-type, education, and cerebrovascular disease (CVD) on dementia progression in a real-world clinic setting.MethodsIn this longitudinal study, participants were consecutive series of 1606 patients with dementia from 2010 to 2019 from a tertiary memory clinic from Singapore. The frequency of dementia subtypes stratified into young-onset (YOD; <65 years age-at-onset) and late-onset dementia (LOD; ≥65 years age-at-onset) was studied. Association of onset-type (YOD or LOD), years of lifespan education, and CVD on the trajectory of cognition was evaluated using linear mixed models. The time to significant cognitive decline was investigated using Kaplan-Meier analysis.ResultsDementia of the Alzheimer’s type (DAT) was the most common diagnosis (59.8%), followed by vascular dementia (14.9%) and frontotemporal dementia (11.1%). YOD patients accounted for 28.5% of all dementia patients. Patients with higher lifespan education had a steeper decline in global cognition (p<0.001), with this finding being more pronounced in YOD (p=0.0006). Older patients with a moderate-to-severe burden of CVD demonstrated a trend for a faster decline in global cognition compared to those with a mild burden.ConclusionsThere is a high frequency of YOD with DAT being most common in our Southeast Asian memory clinic cohort. YOD patients with higher lifespan education and LOD patients with moderate-to-severe CVD experience a steep decline in cognition.

Caregiver Burden in a Culturally Diverse Memory Clinic Population: The Caregiver Strain Index-Expanded

Introduction: Although qualitative studies have highlighted substantial barriers to dementia diagnosis and care in culturally diverse populations in Europe, quantitative studies examining the level of caregiver burden in these populations have been lacking thus far and are urgently needed. Methods: We compared the caregiver burden levels on the Caregiver Strain Index (CSI)-Expanded of 63 culturally diverse patient-caregiver dyads from a multicultural memory clinic with 30 native Dutch patient-caregiver dyads and examined the association between caregiver burden and determinants of burden. Results: Informal caregivers in the multicultural memory clinic cohort experienced a high level of caregiver burden (mean CSI-score multicultural cohort: 6.1 [SD: 3.3]; mean CSI-score native Dutch cohort: 4.8 [SD: 3.2]). Burden was significantly associated with impairment on proxy-rated and objective measures of cognitive functioning, such as the Informant Questionnaire on Cognitive Decline and the Rowland Universal Dementia Assessment Scale, and with instrumental activities of daily living. Burden was the highest in spousal caregivers. The positive subscale of the CSI-Expanded provided limited additional information. Conclusion: Caregivers of culturally diverse patients experience a high level of caregiver burden, in particular at more advanced disease stages. This study highlights the need to screen culturally diverse caregivers in European memory clinics on caregiver burden to identify those in need of caregiver support.

The Impact of Amyloid PET Disclosure on Quality of Life in Patients With Young Onset Dementia.

The impact of amyloid positron emission tomography (PET) imaging on patient health outcomes for individuals with dementia is unknown. In the present study, we explored the association between diagnostic outcome and clinician's level of certainty with quality of life (QoL) after [18F]flutemetamol PET results were disclosed in young onset dementia patients in a memory clinic cohort. In 154 patients suspected of dementia, QoL was measured before and after [18F]flutemetamol PET results were disclosed. Multiple regression analyses were conducted with (changed) general and disease-specific QoL measures as dependent factors [QoL-Alzheimer disease (AD) and EQ-5D Dutch tariff] and etiological diagnosis and clinician's certainty as independent factors. (Change in) diagnosis of AD was associated to QOL in 2 of the 4 analyses (utility-based QoL β=0.15, P=0.010; disease-specific QoL β=2.0, P=0.037). Diagnostic certainty was associated to QOL in 1 of the 4 analyses (generic QoL β=0.002, P=0.028). The diverse results in this explorative analysis do not reflect a univocal association between diagnosis, certainty, and QoL. Nevertheless, this result could be interpreted as a possible potential for advanced diagnostic technologies for AD, which requires confirmation in future research.

Temporal Ordering of Inflammatory Analytes sTNFR2 and sTREM2 in Relation to Alzheimer's Disease Biomarkers and Clinical Outcomes.

Inflammatory changes are among the key markers of Alzheimer's disease (AD) related pathological changes. Pro-inflammatory analytes have been related to cognitive decline while others have been related to attenuating neuronal death. Among them, changes in cerebrospinal fluid (CSF) levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and soluble tumor necrosis factor receptor 2 (sTNFR2) have been described as impacting favorable clinical outcomes in AD. We therefore evaluate the effect of CSF sTREM2 and sTNFR2 when taken together on AD biomarkers and longitudinal clinical decline to understand their relative role on impacting AD clinical biomarkers and subsequent clinical outcomes. This longitudinal observational cohort study included 168 amyloid-positive (A+) and p-tau-positive (T+) participants with mild cognitive impairment (MCI) or AD dementia from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with 109 of them having concomitant CSF sTREM2 and sTNFR2 data and 48 A+ T+ participants with MCI from a tertiary memory clinic cohort. An exploratory analysis was performed using data from 86 cognitively normal (CN) participants from ADNI with 72 of them having concomitant CSF AD biomarkers and CSF sTREM2 and sTNFR2 data. General linear models were used to evaluate the effect of sTREM2 and sTNFR2 levels on baseline CSF Aβ42, t-tau, and p-tau, and a linear mixed-effects model was used to assess longitudinal cognitive change after controlling for well-known covariates. Among ADNI A+ T+ MCI and AD dementia participants, CSF sTNFR2 had a stronger association, than CSF sTREM2, with CSF t-tau and p-tau. This was replicated among A+ T+ MCI participants from the memory clinic cohort. On the contrary, among A+ T+ CN participants, CSF sTREM2 explained significant variance in CSF t-tau and p-tau, while CSF sTNFR2 did not. When the effects of CSF sTNFR2 and t-tau on longitudinal cognitive change were taken into account, higher CSF sTREM2 predicted slower cognitive decline in A+ T+ AD dementia participants and faster decline in A+ T+ CN participants. Our results show that given the dynamic changes in sTREM2 and sTNFR2, the clinical impact of these distinct inflammation related biomarkers in tracking AD temporal progression across disease stages are likely to differ.

Mild Behavioral Impairment Is Associated With Atrophy of Entorhinal Cortex and Hippocampus in a Memory Clinic Cohort.

ObjectivesMild behavioral impairment (MBI) is a syndrome describing late-onset persistent neuropsychiatric symptoms (NPS) in non-demented older adults. Few studies to date have investigated the associations of MBI with structural brain changes. Our aim was to explore structural correlates of NPS in a non-demented memory clinic sample using the Mild Behavioral Impairment Checklist (MBI-C) that has been developed to measure MBI.MethodsOne hundred sixteen non-demented older adults from the Czech Brain Aging Study with subjective cognitive concerns were classified as subjective cognitive decline (n = 37) or mild cognitive impairment (n = 79). Participants underwent neurological and neuropsychological examinations and brain magnetic resonance imaging (MRI) (1.5 T). The Czech version of the MBI-C was administered to participants’ informants. Five a priori selected brain regions were measured, namely, thicknesses of the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), and entorhinal cortex (ERC) and volume of the hippocampus (HV), and correlated with MBI-C total and domain scores.ResultsEntorhinal cortex was associated with MBI-C total score (rS = −0.368, p < 0.001) and with impulse dyscontrol score (rS = −0.284, p = 0.002). HV was associated with decreased motivation (rS = −0.248, p = 0.008) and impulse dyscontrol score (rS = −0.240, p = 0.011).ConclusionNeuropsychiatric symptoms, particularly in the MBI impulse dyscontrol and motivation domains, are associated with medial temporal lobe atrophy in a clinical cohort of non-demented older adults. This study supports earlier involvement of temporal rather than frontal regions in NPS manifestation. Since these regions are typically affected early in the course of Alzheimer’s disease (AD), the MBI-C may potentially help further identify individuals at-risk of developing AD dementia.

Saliva Neurofilament Light Chain Is Not a Diagnostic Biomarker for Neurodegeneration in a Mixed Memory Clinic Population.

Neurodegeneration and axonal injury result in an increasing release of neurofilament light chain (NfL) into bodily fluids, including cerebrospinal fluid (CSF) and blood. Numerous studies have shown that NfL levels in CSF and blood are increased in neurodegenerative disorders and monitor neurodegeneration. Saliva is an easily accessible biofluid that could be utilized as a biofluid measurement of Alzheimer’s disease (AD) biomarkers. In this study, for the first time, salivary NfL was measured and compared to plasma NfL in a consecutive cohort of patients referred to cognitive assessments. In two mixed memory clinic cohorts, saliva samples were taken from 152 patients, AD (n = 49), mild cognitive impairment (MCI) (n = 47), non-AD (n = 56), and also 17 healthy controls. In addition, 135 also had a matching plasma sample. All saliva and plasma samples were analyzed for NfL, and the association between saliva and plasma NfL and CSF levels of total tau (t-tau), phosphorylated tau (p-tau), and beta amyloid 1–42 (Aβ42) were investigated. In total, 162/169 had quantifiable levels of salivary NfL by single molecule array (Simoa). No statistically significant differences were found in salivary NfL concentration across the diagnostic groups, but as expected, significant increases were found for plasma NfL in dementia cases (P < 0.0001). There was no association between saliva and plasma NfL levels. Furthermore, saliva NfL did not correlate with CSF Aβ42, p-tau, or tau concentrations. In conclusion, NfL is detectable in saliva but does not reflect neurodegeneration in the brain.

Long-term neurobehavioral correlates of brain cortical microinfarcts in a memory clinic cohort in Singapore.

Cortical cerebral microinfarcts are a small vessel disease biomarker underlying cognitive impairment and dementia. However, it is unknown whether cortical cerebral microinfarcts are associated with neuropsychiatric disturbances, and whether its effects are independent of conventional small vessel disease markers. We investigated the associations of cortical cerebral microinfarcts burden with incidence and progression of neuropsychiatric subsyndromes in a memory clinic cohort of elderly in Singapore. In this prospective cohort, 496 subjects underwent detailed neuropsychological and clinical assessments, 3T brain MRI, and Neuropsychiatric Inventory assessment at baseline and two years later. Cortical cerebral microinfarcts and other small vessel disease markers, including white matter hyperintensities, lacunes, and microbleeds, were graded according to established criteria. Neuropsychiatric symptoms (NPS) were clustered into subsyndromes of hyperactivity, psychosis, affective, and apathy following prior findings. Functional decline was determined using the clinical dementia rating (CDR) scale. The presence of multiple cortical cerebral microinfarcts (≥2) was associated with higher total NPS scores (β = 4.19, 95% CI = 2.81-5.58, p < 0.001), particularly hyperactivity (β = 2.01, 95% CI = 1.30-2.71, p < 0.01) and apathy (β = 1.42, 95% CI = 0.65-2.18, p < 0.01) at baseline. Between baseline and year-2, multiple cortical cerebral microinfarcts were associated with accelerated progression in total NPS scores (β = 0.29, 95% CI = 0.06-0.53, p = 0.015), driven by hyperactivity (β = 0.45, 95% CI = 0.17-0.72, p < 0.01). Subjects with multiple cortical cerebral microinfarcts also had a faster functional decline, as measured with the CDR-sum-of-boxes scores, when accompanied with progression (β = 0.31, 95% CI = 0.11-0.51, p < 0.01) or hyperactivity in total NPS (β = 0.34, 95% CI = 0.13-0.56, p < 0.01). Cortical cerebral microinfarcts are associated with incidence and progression of geriatric neurobehavioral disturbances, independent of conventional small vessel disease markers. The impact of incident cortical cerebral microinfarcts on neurocognitive and neuropsychiatric trajectories warrants further investigations.

Cerebrospinal Fluid C18 Ceramide Associates with Markers of Alzheimer's Disease and Inflammation at the Pre- and Early Stages of Dementia.

Background:Understanding how dysregulation in lipid metabolism relates to the severity of Alzheimer‘s disease (AD) pathology might be critical in developing effective treatments.Objective:To identify lipid species in cerebrospinal fluid (CSF) associated with signature AD pathology and to explore their relationships with measures reflecting AD-related processes (neurodegeneration, inflammation, deficits in verbal episodic memory) among subjects at the pre- and early symptomatic stages of dementia.Methods: A total of 60 subjects that had been referred to an Icelandic memory clinic cohort were classified as having CSF AD (n = 34) or non-AD (n = 26) pathology profiles. Untargeted CSF lipidomic analysis was performed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) for the detection of mass-to-charge ratio (m/z) features. CSF proteins reflecting neurodegeneration (neurofilament light [NFL]) and inflammation (chitinase-3-like protein 1 [YKL-40], S100 calcium-binding protein B [S100B], glial fibrillary acidic protein [GFAP]) were also measured. Rey Auditory Verbal Learning (RAVLT) and Story tests were used for the assessment of verbal episodic memory.Results: Eight out of 1008 features were identified as best distinguishing between the CSF profile groups. Of those, only the annotation of the m/z feature assigned to lipid species C18 ceramide was confirmed with a high confidence. Multiple regression analyses, adjusted for age, gender, and education, demonstrated significant associations of CSF core AD markers (Aβ42: st.β= –0.36, p = 0.007; T-tau: st.β= 0.41, p = 0.005) and inflammatory marker S100B (st.β= 0.51, p = 0.001) with C18 ceramide levels.Conclusion: Higher levels of C18 ceramide associated with increased AD pathology and inflammation, suggesting its potential value as a therapeutic target.

The effect of intracranial stenosis on cognitive decline in a memory clinic cohort

Intracranial stenosis (ICS) is a risk factor for cognitive impairment and dementia in cross-sectional studies. However, data examining the effect of ICS on cognitive decline is limited. We investigated the effect of ICS on cognition over a period of three years in a memory-clinic cohort. Patients were recruited from the National University Hospital in Singapore. Data was collected using a standardised questionnaire, physical examination and 3T MRI at baseline. ICS was defined as arterial narrowing that exceeded 50% of the luminal diameter in any intracranial vessel. Cognition was measured at baseline and annually for 3 years using the mini-mental state examination, Montreal cognitive assessment, and a detailed neuropsychological test battery. The association between ICS and cognitive decline was analysed using generalized estimating equations. 364 patients were included in the analysis. The mean (±SD) age was 71.9 (±8.0) years and 164 (45.1%) patients were male. A total of 66 (18.1%) patients had ICS. ICS was associated with worse executive function (β:-0.37; [95%CI:-0.68;-0.05]; p=0.022) and modified the effect of follow-up time on memory (p=0.005) and visuomotor speed (p=0.047). These results remained significant after controlling for demographics, overall diagnosis, cardiovascular risk factors, and MRI markers of cerebrovascular disease. ICS was independently associated with worse executive function across all time points, and cognitive decline in memory and visuomotor speed over three-years of follow-up. This suggests that ICS may be a useful indicator of vascular brain damage leading to cognitive decline, and may warrant consideration of anti-atherosclerotic treatment in clinical trials.

Neural cell-surface and intracellular autoantibodies in patients with cognitive impairment from a memory clinic cohort

Autoantibody-associated cognitive impairment is an expanding field in geriatric psychiatry. We aim to assess the association between the presence of specific neural autoantibodies and cognitive performance in a memory clinic cohort. 154 patients with cognitive impairment were included between 2019 and 2020 presenting initially in a memory clinic. We evaluated their patient files retrospectively applying epidemiologic parameters, psychopathology, neuropsychology, intracellular and membrane-surface autoantibodies in serum and cerebrospinal fluid (CSF) and markers of neurodegeneration in CSF. In 26 of 154 patients, we searched for neural autoantibodies due to indicators for autoimmunity. In 15/26 (58%) of patients we detected serum and/or CSF autoantibodies. We identified autoantibodies against intracellular or cell-surface antigens in 7 of all 26 (27%) patients with cognitive dysfunction, although we cannot exclude patients with potential specific autoantibodies lacking autoimmune indicators. There were no significant differences between psychopathological and neuropsychological profiles in groups of patients with cognitive impairment comprising patients with autoantibodies (ABS + COG), no autoantibodies (ABS − COG), and Alzheimer’s disease (ADCOG). Concerning our CSF parameters, we detected intrathecal IgG synthesis in 14% of ABS + COG and in 13% of ABS − COG patients, whereas no intrathecal IgG synthesis was found in ADCOG patients. Furthermore, CSF Aß42 was significantly diminished in the ADCOG compared to the ABS + COG group (p < 0.05). In addition, the Aß42/40 ratio was lower in ADCOG patients than in the ABS + COG or ABS − COG group (p < 0.05). Our findings reveal the underestimated occurrence and autoantibodies’ potential role in patients presenting cognitive impairment. Furthermore, the patients with possible Alzheimer’s disease might be differentiated from autoantibody-positive patients via a reduced Aß42 and Aß42/40 ratio in the CSF. The antibody-type varies between patients to a relevant degree, thus demonstrating the need for more research to identify subgroup-specific phenotypes. These pilot study results open an avenue for improving diagnosis and treatment in a memory clinic.

Abstract P59: Peak Width of Skeletonized Mean Diffusivity Outperforms Other Diffusion Tensor Imaging Metrics as Biomarker for Cognition in Memory-Clinic Subjects With Cerebral Amyloid Angiopathy

Introduction: Peak width of skeletonized mean diffusivity (PSMD) is a novel fully automated diffusion tensor imaging (DTI) marker that has been consistently associated with cognition in cerebral small vessel disease (SVD) cohorts, including cerebral amyloid angiopathy (CAA). We hypothesized that PSMD would be more strongly associated with cognitive performance compared to other conventional DTI metrics in our CAA sample. Methods: We recruited non-demented subjects with probable-CAA from a single-center memory-clinic cohort. We analyzed structural MRIs to compute a validated CAA burden score (0-6 points scale, based on the following MRI features: lobar microbleeds, superficial siderosis, perivascular spaces in centrum semiovale, and white matter hyperintensities). PSMD was obtained using a freely available script ( www.psmd-marker.com ). We used the same skeleton-mask to compute: mean of skeletonized mean diffusivity (mean MD) and mean of skeletonized fractional anisotropy (mean FA). We used linear regression analyses to explore relationships with CAA burden score and cognitive composite scores (processing speed, executive function, memory, and language - z-scores adjusted for age, sex and education level). Results: We included 43 subjects (mean age 74.4 ± 5.9 years; 48.8% female; PSMD median [IQR]: 4.05 [3.58 - 4.80] x 10 -4 mm 2 /s). In linear regression models adjusting for age, DTI metrics were significantly associated with CAA burden score (mean FA: β = -0.563, Adj. R 2 : 0.27; p &lt; 0.001; mean MD: β = 0.581; Adj. R 2 : 0.32; p &lt; 0.001; PSMD: β = 0.364, Adj. R 2 : 0.12; p = 0.018). PSMD was significantly associated with cognitive performance, specifically in the domains of executive function ( β = -0.568; Adj. R 2 : 0.25; p &lt; 0.001) and processing speed ( β = -0.447; Adj. R 2 : 0.19; p = 0.004). Other DTI metrics were not significantly associated with cognitive scores. Conclusion: In this CAA sample, all DTI metrics were associated with CAA burden scores, however, only PSMD was significantly associated with cognition, in domains that are commonly affected in vascular cognitive impairment. Our results warrant confirmation in larger samples, but support PSMD as biomarker for cognition in CAA, outperforming other conventional DTI metrics.

Plasma osteopontin as a biomarker of Alzheimer\u2019s disease and vascular cognitive impairment

Cerebrovascular disease (CeVD) and neurodegenerative dementia such as Alzheimer’s disease (AD) are frequently associated comorbidities in the elderly, sharing common risk factors and pathophysiological mechanisms including neuroinflammation. Osteopontin (OPN) is an inflammatory marker found upregulated in vascular diseases as well as in AD. However, its involvement in vascular dementia (VaD) and pre-dementia stages, namely cognitive impairment no dementia (CIND), both of which fall under the spectrum of vascular cognitive impairment (VCI), has yet to be examined. Its correlations with inflammatory cytokines in cognitive impairment also await investigation. 80 subjects with no cognitive impairment (NCI), 160 with CIND and 144 with dementia were included in a cross-sectional study on a Singapore-based memory clinic cohort. All subjects underwent comprehensive clinical, neuropsychological and brain neuroimaging assessments, together with clinical diagnoses based on established criteria. Blood samples were collected and OPN as well as inflammatory cytokines interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF) were measured using immunoassays. Multivariate regression analyses showed significant associations between increased OPN and VCI groups, namely CIND with CeVD, AD with CeVD and VaD. Interestingly, higher OPN was also significantly associated with AD even in the absence of CeVD. We further showed that increased OPN significantly associated with neuroimaging markers of CeVD and neurodegeneration, including cortical infarcts, lacunes, white matter hyperintensities and brain atrophy. OPN also correlated with elevated levels of IL-6, IL-8 and TNF. Our findings suggest that OPN may play a role in both VCI and neurodegenerative dementias. Further longitudinal analyses are needed to assess the prognostic utility of OPN in disease prediction and monitoring.

Neuropsychiatric symptoms and comorbidity: Associations with dementia progression rate in a memory clinic cohort.

Neuropsychiatric symptoms (NPS) are associated with dementia severity and progression rate. NPS clusters have different neurobiological underpinnings; therefore, their effect on dementia progression may differ. Furthermore, little is known about whether individual comorbidities affect progression rate. We investigated the effect of NPS clusters and individual comorbidities on dementia progression. A memory clinic cohort with all-cause dementia (N=442) was followed for up to 3 years from diagnosis. Previously, we found trajectory groups of dementia progression in this cohort: one with slow progression and two with rapid progression. In the present study, using principal component analysis, three symptom clusters of NPS were identified on the Neuropsychiatric Inventory Questionnaire (NPI-Q): agitation, affective and psychosis symptom clusters. Data regarding comorbidity were collected by linkage to the Norwegian Patient Registry. Multinomial logistic regression was applied to explore the association between NPS clusters and comorbidity with trajectory-group membership. Adjusted for demographics, dementia aetiology, comorbidity and cognition, we found that, at the time of dementia diagnosis, for every point within the psychosis symptom cluster of the NPI-Q, the risk of rapid progression increased by 53%; for every point within the affective symptom cluster, the risk of rapid progression increased by 29%. A previous diagnosis of mental and behavioural disorders (excluding dementia) decreased the risk of rapid dementia progression by 65%. Psychosis and affective symptom clusters at the time of diagnosis were associated with rapid progression of dementia. Previous diagnoses of mental and behavioural disorders (excluding dementia) were associated with slow progression.

Head-to-head comparison of amplified plasmonic exosome Aβ42 platform and single-molecule array immunoassay in a memory clinic cohort.

Various blood biomarkers reflecting brain amyloid-β (Aβ) load have recently been proposed with promising results. However, to date, no comparative study amongst blood biomarkers has been reported. Our objective was to examine the diagnostic performance and cost effectiveness of three blood biomarkers on the same cohort. Using the same cohort (n=68), the performances of the single-molecule array (Simoa) Aβ40, Aβ42, Aβ42/Aβ40 and the amplified plasmonic exosome (APEX) Aβ42 blood biomarkers were compared using amyloid positron emission tomography (PET) as the reference standard. The extent to which these blood tests can reduce the recruitment cost of clinical trials was also determined by identifying amyloid positive (Aβ+) participants. Compared to Simoa biomarkers, APEX-Aβ42 showed significantly higher correlations with amyloid PET retention values and excellent diagnostic performance (sensitivity 100%, specificity 93.3%, area under the curve 0.995). When utilized for clinical trial recruitment, our simulation showed that pre-screening with blood biomarkers followed by a confirmatory amyloid PET imaging would roughly half the cost (56.8% reduction for APEX-Aβ42 and 48.6% for Simoa-Aβ42/Aβ40) compared to the situation where only PET imaging is used. Moreover, with 100% sensitivity, APEX-Aβ42 pre-screening does not increase the required number of initial participants. With its high diagnostic performance, APEX is an ideal candidate for Aβ+ subject identification, monitoring and primary care screening, and could efficiently enrich clinical trials with Aβ+ participants whilst halving recruitment costs.

Frailty, MRI, and FDG-PET Measures in an Australian Memory Clinic Cohort

Given that the global population is aging, the number of age-related syndromes, such as frailty, is expected to rise in conjunction. Frailty is characterized by the loss of homeostatic reserve, rendering the individual vulnerable to poor health outcomes. Many biological mechanisms have been proposed to contribute to frailty. However, few studies have assessed the associations between frailty and brain diseases or neuroimaging biomarkers.Aims: The aims of this study were to measure the prevalence of frailty in a memory clinic and to examine associations between frailty and brain changes found on magnetic resonance imaging (MRI) and 18-F deoxyglucose (FDG) positron emission tomography (PET) in memory clinic attendees.Methods: A 54-items Frailty Index was retrospectively assessed for all clinic attendees from 2014. Frailty was defined as FI > 0.25. MR images were analyzed for stroke, cerebral small vessel disease [CSVD, including cerebral microbleeds (CMBs), cortical superficial siderosis (CSS), and white matter hyperintensity (WMH)], and neurodegenerative changes [MRI: mesial temporal atrophy (MTA), FDG-PET: regional hypometabolism], blind to clinical findings.Results: There were 209 clinic attendees in 2014, of whom 121 had MRI performed. The prevalence of frailty (using FI) in the memory clinic in 2014 was 38.3% overall (patients without MRI: 43.2%, patients with MRI 34.7%, p = 0.25). Frailty was associated with presence of deep WMH, increased severity of periventricular WMH, and presence of CSS, but not neurodegeneration markers (MTA atrophy/FDG-PET hypometabolism).Conclusion: The findings support the idea that previously reported associations between frailty and imaging evidence of CSVD in other cohorts are also relevant to the Australian clinic setting. Given that a large proportion of memory clinic attendees are frail, there may be opportunities for interventions to reduce preventable adverse health outcomes, such as falls and fractures, and reduce the prevalence and impact of frailty in this cohort.