Memory Clinic Population Research Articles

Low serum concentration of free triiodothyronine (FT3) is associated with increased risk of Alzheimer’s disease

BackgroundIn epidemiological studies, thyroid hormones (THs) have been associated with the risk of dementia. However, little is known of the relation between THs and risk of Alzheimer’s disease (AD) or vascular dementia (VaD) in a memory clinic population. MethodsIn a mono-center study, serum concentrations of thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) were assessed in 302 patients. All patients had subjective or objective mild cognitive impairment and none received treatment with THs. Cox proportional hazards regression analyses was used to determine whether THs at baseline were associated with the risk of conversion to all-cause dementia, AD or VaD. ResultsDuring the follow-up (mean 2.8 years), 82 (28%) of the patients progressed to dementia [AD, n = 55 (18%) and VaD, n = 17 (6%)]. Serum concentrations of TSH, FT4, and FT3 did not associate with all-cause dementia or VaD. Higher serum FT3 was associated with lower risk of conversion to AD [hazard ratio (HR) = 054; 95% confidence interval (CI): 0.32–0.92 per 1 pmol/L increase]. Furthermore, patients in the lowest serum FT3 quartile had a twofold increased risk of AD compared to those in the highest quartile (HR = 2.63; 95% CI: 1.06–6.47). These associations remained after adjustment for multiple covariates. ConclusionsIn a memory clinic population, there was an inverse, linear association between serum FT3 and risk of AD whereas THs did not associate with all-cause dementia or VaD. Further studies are needed to determine the underlying mechanisms as well as the clinical significance of these findings.

B - 75Verbal and Visuospatial Episodic Memory: Roles of Attention and Executive Function in a Memory Clinic Population

B - 75Verbal and Visuospatial Episodic Memory: Roles of Attention and Executive Function in a Memory Clinic Population

One Size Does Not Fit All: Comparative Diagnostic Accuracy of the Rowland Universal Dementia Assessment Scale and the Mini Mental State Examination in a Memory Clinic Population with Very Low Education

Background: Diagnosing dementia in elderly immigrants is often difficult due to language and cultural barriers, low education, and illiteracy. We compared the diagnostic accuracy of the Rowland Universal Dementia Assessment Scale (RUDAS) to that of the Mini Mental State Examination (MMSE). Methods: A total of 144 patients (42 with intact cognition, 44 with mild cognitive impairment [MCI], and 58 with dementia) were administered both instruments and were diagnosed by specialists blinded for MMSE and RUDAS results. Results: Areas under the curve for discriminating intact cognition from MCI and dementia were comparable for RUDAS (0.81; 95% confidence interval 0.74–0.88) and MMSE (0.75; 95% confidence interval 0.69–0.85). Education and literacy were not correlated with the RUDAS but had a medium-large correlation with the MMSE (rho = 0.39). Conclusions: The study provides additional evidence for the usefulness of the RUDAS in a highly illiterate, culturally diverse geriatric outpatient population.

Prevalence and association of syphilis reactivity in an Asian memory clinic population.

Data on the association between syphilis reactivity and dementia in memory clinic patients are scarce. We studied the prevalence of syphilis reactivity and investigated its association with dementia and markers of cerebrovascular disease (CeVD) and neurodegeneration. Data on age, gender, education, brain computed tomography scan findings and syphilis reactivity were obtained from patients who attended the National University Hospital memory clinics (February 2006-February 2016) and subjects from the community. Binary logistic regression models were used to investigate associations between syphilis reactivity and dementia, CeVD and neurodegeneration, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Of 1271 memory clinic patients eligible for the study, 57 (4.5%) were syphilis reactive, with the rate of syphilis reactivity higher in demented (44/745; 5.9%) compared to non-demented (13/526; 2.5%) patients ( p = 0.004) and non-demented community-based (21/872; 2.4%) subjects ( p < 0.001). Binary logistic regression showed a significant association between syphilis reactivity and dementia in memory clinic patients independent of demographic factors (odds ratio: 2.06; 95% CI: 1.02-4.17, p = 0.044). A significant association between syphilis reactivity and dementia was found in memory clinic patients. The mechanism of this association requires further research and may involve neuroinflammation.

Total MRI Small Vessel Disease Burden Correlates with Cognitive Performance, Cortical Atrophy, and Network Measures in a Memory Clinic Population.

Recent evidence suggests that combining individual imaging markers of cerebral small vessel disease (SVD) may more accurately reflect its overall burden and better correlate with clinical measures. We wished to establish the clinical relevance of the total SVD score in a memory clinic population by investigating the association with SVD score and cognitive performance, cortical atrophy, and structural network measures, after adjusting for amyloid-β burden. We included 243 patients with amnestic mild cognitive impairment (MCI), Alzheimer's disease dementia, subcortical vascular MCI, or subcortical vascular dementia. All underwent MR and [11C] PiB-PET scanning and had standardized cognitive testing. Multiple linear regression was used to evaluate the relationships between SVD score and cognition, cortical thickness, and structural network measures. Path analyses were performed to evaluate whether network disruption mediates the effects of SVD score on cortical thickness and cognition. Total SVD score was associated with the performance of frontal (β - 4.31, SE 2.09, p = 0.040) and visuospatial (β - 0.95, SE 0.44, p = 0.032) tasks, and with reduced cortical thickness in widespread brain regions. Total SVD score was negatively correlated with nodal efficiency, as well as changes in brain network organization, with evidence of reduced integration and increasing segregation. Path analyses showed that the associations between SVD score and frontal and visuospatial scores were partially mediated by decreases in their corresponding nodal efficiency and cortical thickness. Total SVD burden has clinical relevance in a memory clinic population and correlates with cognition, and cortical atrophy, as well as structural network disruption.

Cerebral White Matter Lesions have Low Impact on Cognitive Function in a Large Elderly Memory Clinic Population.

Evidence suggests that cerebral white matter lesions (WML) play a role in cognitive decline. To assess the impact of cerebral WML on cognitive function relative to absence or presence of medial temporal atrophy (MTA) in a large single-center memory clinic population. Patients included had subjective cognitive impairment (SCI, n = 333), mild cognitive impairment (MCI, n = 492) and Alzheimer's disease (AD, n = 832). The relationships between visually rated WML (Fazekas scale, 0-3) on brain Computed Tomography and CAMCOG memory and non-memory function were investigated with regression analysis adjusted for age, gender and education in combined patient groups. We assessed possible interaction versus addition effects of these relationships with visually rated MTA (Scheltens scale). The highly statistical significant relationship between WML and memory function was no longer significant when MTA was taken into account. However, the strong significant relationship between WML and non-memory function remained significant after adjustment for MTA, but the explained variance attributed to WML was only 1.3%. There was no interaction between WML and MTA on CAMCOG test scores. In addition, shown by a 2×2 factorial model by presence versus absence of WML and MTA, WML affected non-memory function only in the presence of MTA. Our data suggest that presence of WML is associated with lower non-memory cognitive function but this effect is conditional on the presence of pre-existing MTA. The very small explained variance suggests little impact of WML to the clinical profile of a memory clinic patient.

Detection of neurodevelopmental diversity in memory clinics—Validation of a self-report measure

BackgroundNeurodevelopmental learning and attentional disorders (NLAD) such as dyslexia, dyscalculia and attention deficit hyperactivity disorder (ADHD) affect at least 6% of the adult population or more. They are associated with atypical cognitive patterns in early and adult life. The cognitive patterns of affected individuals in late life have never been described. One main challenge is detecting individuals in clinical settings during which mild cognitive changes could be confounding the clinical presentation. This is a critical research gap because these conditions interact, across the life course, with an individual’s risk for dementia. Also, learning disabilities which present in childhood pose persistent cognitive differences in areas involving executive function, reading and math.Clinicians lack tools to detect undiagnosed neurodevelopmental in adults with memory disorders. The majority of patients presenting at memory clinics today come from a generation during which NLAD were not yet clinically recognized. In this study, we hypothesized that a self-report scale can detect NLAD in a memory clinic population. MethodsWe developed a self-report, retrospective childhood cognitive questionnaire including key attributes adapted from prior validated measures. 233 participants were included in the primary analysis. ResultsConfirmatory Factor Analysis resulted in a best-fit model with six labelled factors (Math, Language, Attention, Working Memory, Sequential Processing, and Executive Function) and 15 total question items. The model demonstrated unidimensionality, reliability, convergent validity, discriminant validity, and predictive validity. Using 1.5 standard deviations as the cut-off, subjects were categorized into: Normal (n = 169), Language (n = 10), Math (n = 12), Attention (n = 10) or Other/Mixed (n = 32). ConclusionA self-report measure can be a useful tool to elicit childhood cognitive susceptibilities in various domains that could represent NLAD among patients in a memory clinic setting, even in the presence of mild cognitive impairment.

Amyloid load but not regional glucose metabolism predicts conversion to Alzheimer's dementia in a memory clinic population.

The value of imaging regional glucose metabolism with [18F]FDG PET for the prediction of progression from mild cognitive impairment (MCI) to Alzheimer's dementia (AD) is controversial. The predictive value of imaging with [18F]FDG PET was therefore tested and compared with that of imaging beta-amyloid load with [11C]PIB PET in the same memory clinic population of MCI patients. Thirty-nine patients with MCI who had undergone [18F]FDG as well as [11C]PIB PET were identified from a single-centre clinical registry. [18F]FDG and [11C]PIB PET images were rated as positive or negative for the presence of regional hypometabolism typical of AD and beta-amyloid deposition, respectively. Raters were blinded to the clinical information. Patients were followed clinically for 2.7 ± 1.2years after PET. Cox proportional hazards models, adjusted for age and sex, were used to test the predictive value of [18F]FDG PET, [11C]PIB PET, and both in combination. [18F]FDG PET did not significantly predict conversion to AD (p > 0.1). By contrast, models including [11C]PIB PET only (p < 0.05) or both [18F]FDG and [11C]PIB PET (p < 0.05) significantly predicted conversion to AD. The hazard ratio for AD in patients with a positive [11C]PIB scan was 10.2 (95% confidence interval 1.3-78.1). The results were confirmed by analysis of semiquantitative measures using normalized [18F]FDG uptake and [11C]PIB standardized uptake value ratios in AD-typical regions as continuous predictors. In contrast to [11C]PIB PET, [18F]FDG PET did not predict conversion from MCI to AD in this clinical patient sample. Therefore, amyloid PET should be preferred for individual prediction and patient counselling in clinical practice.

Poster Number: EI 59 - Successful Aging in Place: Physician Predictions of Prognosis Do Dot Reliably Align with Patient Outcomes in a Memory Clinic Population

Poster Number: EI 59 - Successful Aging in Place: Physician Predictions of Prognosis Do Dot Reliably Align with Patient Outcomes in a Memory Clinic Population

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.

Association of Cerebrospinal Fluid (CSF) Insulin with Cognitive Performance and CSF Biomarkers of Alzheimer's Disease.

Background:Abnormal insulin signaling in the brain has been linked to Alzheimer’s disease (AD).Objective:To evaluate whether cerebrospinal fluid (CSF) insulin levels are associated with cognitive performance and CSF amyloid-β and Tau. Additionally, we explore whether any such association differs by sex or APOE ɛ4 genotype.Methods:From 258 individuals participating in the Parelsnoer Institute Neurodegenerative Diseases, a nationwide multicenter memory clinic population, we selected 138 individuals (mean age 66±9 years, 65.2% male) diagnosed with subjective cognitive impairment (n = 45), amnestic mild cognitive impairment (n = 44), or AD (n = 49), who completed a neuropsychological assessment, including tests of global cognition and memory performance, and who underwent lumbar puncture. We measured CSF levels of insulin, amyloid-β1-42, total (t-)Tau, and phosphorylated (p-)Tau.Results:CSF insulin levels did not differ between the diagnostic groups (p = 0.136). Across the whole study population, CSF insulin was unrelated to cognitive performance and CSF biomarkers of AD, after adjustment for age, sex, body mass index, diabetes status, and clinic site (all p≥0.131). Importantly, however, we observed effect modification by sex and APOE ɛ4 genotype. Specifically, among women, higher insulin levels in the CSF were associated with worse global cognition (standardized regression coefficient –0.483; p = 0.008) and higher p-Tau levels (0.353; p = 0.040). Among non-carriers of the APOE ɛ4 allele, higher CSF insulin was associated with higher t-Tau (0.287; p = 0.008) and p-Tau (0.246; p = 0.029).Conclusion:Our findings provide further evidence for a relationship between brain insulin signaling and AD pathology. It also highlights the need to consider sex and APOE ɛ4 genotype when assessing the role of insulin.

Low serum insulin-like growth factor-I (IGF-I) level is associated with increased risk of vascular dementia

BackgroundInsulin-like growth factor-I (IGF-I) is important for the adult brain, but little is known of the role of IGF-I in Alzheimeŕs disease (AD) or vascular dementia (VaD). MethodsA prospective study of 342 patients with subjective or objective mild cognitive impairment recruited at a single memory clinic. We determined whether serum IGF-I concentrations at baseline were associated with the risk of all-cause dementia, AD, or VaD. Patients developing mixed forms of AD and VaD were defined as suffering from VaD. The statistical analyses included Cox proportional hazards regression analysis. ResultsDuring the follow-up (mean 3.6 years), 95 (28%) of the patients developed all-cause dementia [AD, n=37 (11%) and VaD, n=42 (12%)]. Low as well as high serum IGF-I (quartile 1 or 4 vs. quartiles 2–3) did not associate with all-cause dementia [crude hazard ratio (HR) 1.30, 95% confidence interval (CI): 0.81–2.08 and crude HR 1.05, 95% CI: 0.63–1.75, respectively] or AD (crude HR 0.79, 95% CI: 0.35–1.79 and crude HR 0.94, 95% CI: 0.43–2.06, respectively]. In contrast, low serum IGF-I concentrations were associated with increased risk of VaD (quartile 1 vs. quartiles 2–3, crude HR 2.22, 95% CI: 1.13–4.36). The latter association remained significant also after adjustment for multiple covariates. ConclusionsIn a memory clinic population, low serum IGF-I was a risk marker for subsequent VaD whereas low IGF-I did not associate with the risk of AD. High serum IGF-I was not related to the risk of conversion to dementia.

MICROBLEEDS ARE ASSOCIATED WITH DEPRESSIVE SYMPTOMS IN ALZHEIMER’S DISEASE

The co-occurrence of cerebrovascular disease (CVD) and depression led to the ‘vascular depression hypothesis’. In particular white matter hyperintensities (WMH) have been found to be associated with depressive symptoms in population-based studies. We studied whether imaging markers of small vessel disease (SVD) were associated with depressive symptoms in a memory clinic population. We included 2136 patients from the Amsterdam Dementia Cohort: 810 subjective cognitive decline (SCD; 59±9yrs; 43%F; MMSE 28±1), 488 mild cognitive impairment (MCI; 66±7yrs; 36%F; MMSE 26±2) and 838 Alzheimer's disease (AD; 67±7yrs; 51%F; MMSE 20±4). Depressive symptoms were assessed using the 15-item Geriatric Depression Scale (GDS) and scored as absent (GDS<5) or present (GDS≥5). MRI was rated for presence of WMH (Fazekas, 0/1 vs. 2/3), lacunes (absent vs. present) and microbleeds (absent vs. present). We performed logistic regression analyses to investigate associations between WMH, lacunes and microbleeds (independent, in separate models) and depressive symptoms (dependent). All analyses were adjusted for age, gender and education (model 1) and additionally adjusted for MRI field strength, MMSE-score and vascular risk factors (model 2). We stratified for diagnosis. We observed depressive symptoms in 189 (23%) SCD-patients, 123 (25%) MCI-patients, and 143 (17%) AD-patients. Presence of SVD (WMH, lacunes and/or microbleeds) was found in 227 (28%) SCD-patients, 226 (46%) MCI-patients and 342 (40%) AD-patients. AD-patients with microbleeds were more likely to have depressive symptoms compared to AD-patients without microbleeds (odds ratio (OR)=1.75; 95%CI: 1.13–2.71, p<0.05). Microbleeds were not associated with depressive symptoms in SCD or MCI. AD-patients with WMH tended to show less often depressive symptoms compared to AD-patients without WMH (OR=0.64; 95%CI: 0.39–1.06, p=0.08). WMH were not associated with depressive symptoms in SCD and MCI (SCD: OR=1.46; 95%CI: 0.89–2.57;MCI: OR=0.91; 95%CI: 0.55–1.49, both p>0.05). We found no associations between lacunes and depressive symptoms in any group. We found that microbleeds are associated with depressive symptoms in AD. Contrary to our expectations, more severe WMH did not predispose for depressive symptoms in our memory clinic population. These findings suggest that depressive symptoms in AD may be related to underlying cerebral amyloid angiopathy.

THE RELATIONSHIP AMONG MEMORY PERFORMANCE AND HIPPOCAMPAL SUBREGION VOLUMES IN A MEMORY CLINIC POPULATION

Medial temporal lobe structures, including the hippocampus, are important for the formation and recollection of memories. Regions of the hippocampus have been found to be associated with specific aspects of memory. Specifically, the CA4 has been implicated in pattern separation, encoding, and recognition of visual information, while the presubiculum has been implicated in memory retrieval. The current study examined the relationship between these hippocampal subregions bilaterally and standard measures of verbal and nonverbal memory in order to evaluate whether these regions predict such memory performance. Participants were drawn from a clinical sample of older adults (mean age = 69.9) seen in a memory disorders clinic (n = 651). All participants underwent a brain MRI as well as a neuropsychological evaluation that included measures of verbal, the Hopkins Verbal Learning Test-Revised, and nonverbal, the Brief Visuospatial Memory Test-Revised, memory. Multivariate regressions were conducted in order to assess whether subregions of the hippocampus predict verbal and/or nonverbal memory, after accounting for the influence of age, gender, and total intracranial volume. Results indicated that age, total intracranial volume, left and right presubiculum and CA4 volumes were significant predictors of verbal and nonverbal memory encoding and retrieval (all p <.005). Gender was not a significant pedictor of memory performance. Results suggest that the volumes of bilateral presubiculum and CA4 are predictive of both verbal and nonverbal memory encoding and retrieval in a memory clinic population. Future research examining other hippocampal subregions and specific diagnostic categories will inform understanding of the contributions of these and other subfields to memory function.

INCIDENCE AND FACTORS ASSOCIATED WITH THE ONSET OF POST-DURAL PUNCTURE HEADACHE: EXPERIENCE FROM THE JAPANESE ADNI AND REVIEW OF LITERATURE

High diagnostic accuracy of cerebral spinal fluid (CSF) biomarkers, such as Aβ1–42, total tau and phosphorylated tau, has been shown for Alzheimer's disease (AD). As utility of these biomarkers is recognized, collection of CSF by lumbar puncture is increasingly performed in memory clinics. Post-dural puncture headache (PDPH) is the most common adverse event associated with lumbar puncture. We investigated incidence of PDPH in Japanese AD Neuroimaging Initiative (J-ADNI) cohorts, and reviewed literature regarding incidence of PDPH in memory clinic populations to determine factors associated with the onset of PDPH, such as age, cognitive status, history of headache, puncture position, needle type, needle size, collected CSF volume, and rest after LP. Of the 303 LP procedures in J-ADNI cohorts, PDPH occurred in 8 subjects (incidence 2.6%). Of these, two cases were hospitalized, but their symptoms relieved without blood patch treatment. Incidence of PDPH in 9 previous reports ranged from 0.9 to 20.3%. Review of literature revealed that older age (4 of 7 reports) and atraumatic needles (3 of 3 reports) reduced incidence of PDPH in memory clinic populations, whereas rest after LP had no effect (0 of 3 reports). The other factors were inconsistent among the studies. LP appears to be a relatively safe procedure for the differential diagnosis of dementia for the elderly in clinical research and memory clinic setting. Meanwhile, it is recommended to use atraumatic needles to reduce incidence of PDPH when performing LP for younger subjects.

MRI-visible perivascular space location is associated with Alzheimer's disease independently of amyloid burden

Perivascular spaces that are visible on magnetic resonance imaging (MRI) are a neuroimaging marker of cerebral small vessel disease. Their location may relate to the type of underlying small vessel pathology: those in the white matter centrum semi-ovale have been associated with cerebral amyloid angiopathy, while those in the basal ganglia have been associated with deep perforating artery arteriolosclerosis. As cerebral amyloid angiopathy is an almost invariable pathological finding in Alzheimer's disease, we hypothesized that MRI-visible perivascular spaces in the centrum semi-ovale would be associated with a clinical diagnosis of Alzheimer's disease, whereas those in the basal ganglia would be associated with subcortical vascular cognitive impairment. We also hypothesized that MRI-visible perivascular spaces in the centrum semi-ovale would be associated with brain amyloid burden, as detected by amyloid positron emission tomography using 11C-Pittsburgh B compound (PiB-PET). Two hundred and twenty-six patients (Alzheimer's disease n = 110; subcortical vascular cognitive impairment n = 116) with standardized MRI and PiB-PET imaging were included. MRI-visible perivascular spaces were rated using a validated 4-point visual rating scale, and then categorized by severity ('none/mild', 'moderate' or 'frequent/severe'). Univariable and multivariable regression analyses were performed. Those with Alzheimer's disease-related cognitive impairment were younger, more likely to have a positive PiB-PET scan and carry at least one apolipoprotein E ɛ4 allele; those with subcortical vascular cognitive impairment were more likely to have hypertension, diabetes mellitus, hyperlipidaemia, prior stroke, lacunes, deep microbleeds, and carry the apolipoprotein E ɛ3 allele. In adjusted analyses, the severity of MRI-visible perivascular spaces in the centrum semi-ovale was independently associated with clinically diagnosed Alzheimer's disease (frequent/severe grade odds ratio 6.26, 95% confidence interval 1.66-23.58; P = 0.017, compared with none/mild grade), whereas the severity of MRI-visible perivascular spaces in the basal ganglia was associated with clinically diagnosed subcortical vascular cognitive impairment and negatively predicted Alzheimer's disease (frequent/severe grade odds ratio 0.03, 95% confidence interval 0.00-0.44; P = 0.009, compared with none/mild grade). MRI-visible perivascular space severity in either location did not predict PiB-PET. These findings provide further evidence that the anatomical distribution of MRI-visible perivascular spaces may reflect the underlying cerebral small vessel disease. Using MRI-visible perivascular space location and severity together with other imaging markers may improve the diagnostic value of neuroimaging in memory clinic populations, in particular in differentiating between clinically diagnosed Alzheimer's and subcortical vascular cognitive impairment.

Unbiased estimates of cerebrospinal fluid \u03b2-amyloid 1\u201342 cutoffs in a large memory clinic population

BackgroundWe sought to define a cutoff for β-amyloid 1–42 in cerebrospinal fluid (CSF), a key marker for Alzheimer’s disease (AD), with data-driven Gaussian mixture modeling in a memory clinic population.MethodsWe performed a combined cross-sectional and prospective cohort study. We selected 2462 subjects with subjective cognitive decline, mild cognitive impairment, AD-type dementia, and dementia other than AD from the Amsterdam Dementia Cohort. We defined CSF β-amyloid 1–42 cutoffs by data-driven Gaussian mixture modeling in the total population and in subgroups based on clinical diagnosis, age, and apolipoprotein E (APOE) genotype. We investigated whether abnormal β-amyloid 1–42 as defined by the data-driven cutoff could better predict progression to AD-type dementia than abnormal β-amyloid 1–42 defined by a clinical diagnosis-based cutoff using Cox proportional hazards regression.ResultsIn the total group of patients, we found a cutoff for abnormal CSF β-amyloid 1–42 of 680 pg/ml (95% CI 660–705 pg/ml). Similar cutoffs were found within diagnostic and APOE genotype subgroups. The cutoff was higher in elderly subjects than in younger subjects. The data-driven cutoff was higher than our clinical diagnosis-based cutoff and had a better predictive accuracy for progression to AD-type dementia in nondemented subjects (HR 7.6 versus 5.2, p < 0.01).ConclusionsMixture modeling is a robust method to determine cutoffs for CSF β-amyloid 1–42. It might better capture biological changes that are related to AD than cutoffs based on clinical diagnosis.

Gait Speed and Grip Strength Reflect Cognitive Impairment and Are Modestly Related to Incident Cognitive Decline in Memory Clinic Patients With Subjective Cognitive Decline and Mild Cognitive Impairment: Findings From the 4C Study.

Prospective studies in the general population show that slow gait speed is associated with cognitive decline and clinical progression to dementia. However, longitudinal studies in memory clinic populations are mostly lacking. We aimed to study the association between gait speed and grip strength and cognitive functioning at baseline and cognitive decline over time in memory clinic patients with subjective cognitive decline and mild cognitive impairment. We included 309 patients (age 70 ± 9 years, 108 [35%] women, Mini-Mental State Examination 27 ± 3 points). Baseline gait speed was assessed over 15 feet, grip strength with a hydraulic hand dynamometer. Cognitive functioning was assessed annually with a comprehensive test battery during 3 years. Age- and gender-adjusted linear mixed models showed that slower gait speed was related to worse baseline attention, memory, information processing speed, and verbal fluency. Longitudinally, gait speed was related to decline in information processing speed and executive functioning. Weaker grip strength was related to worse baseline information processing speed and executive functioning but there were no longitudinal associations. Cox proportional hazards models revealed no significant associations with clinical progression. Our findings suggest that markers of physical performance are related to current cognitive status and modestly related to cognitive decline but are seemingly not useful as an early marker of incident clinical progression.

Practical use of visual medial temporal lobe atrophy cut-off scores in Alzheimer\u2019s disease: Validation in a large memory clinic population

ObjectiveTo provide age-specific medial temporal lobe atrophy (MTA) cut-off scores for routine clinical practice as marker for Alzheimer’s disease (AD).MethodsPatients with AD (n = 832, mean age 81.8 years) were compared with patients with subjective cognitive impairment (n = 333, mean age 71.8 years) in a large single-centre memory clinic. Mean of right and left MTA scores was determined with visual rating (Scheltens scale) using CT (0, no atrophy to 4, severe atrophy). Relationships between age and MTA scores were analysed with regression analysis. For various MTA cut-off scores, decade-specific sensitivity and specificity and area under the curve (AUC) values, computed with receiver operator characteristic curves, were determined.ResultsMTA strongly increased with age in both groups to a similar degree. Optimal MTA cut-off values for the age ranges <65, 65–74, 75–84 and ≥85 were: ≥1.0, ≥1.5, ≥ 2.0 and ≥2.0. Corresponding values of sensitivity and specificity were 83.3% and 86.4%; 73.7% and 84.6%; 73.7% and 76.2%; and 84.0% and 62.5%.ConclusionFrom this large unique memory clinic cohort we suggest decade-specific MTA cut-off scores for clinical use. After age 85 years, however, the practical usefulness of the MTA cut-off is limited.Key Points• We suggest decade-specific MTA cut-off scores for AD.• MTA cut-off after the age of 85 years has limited use.• CT is feasible and accurate for visual MTA rating.

White Matter Hyperintensities Potentiate Hippocampal Volume Reduction in Non-Demented Older Individuals with Abnormal Amyloid-β.

Cerebral small vessel disease (cSVD) and amyloid-β (Aβ) deposition often co-exist in (prodromal) dementia, and both types of pathology have been associated with neurodegeneration. We examined whether cSVD and Aβ have independent or interactive effects on hippocampal volume (HV) in a memory clinic population. We included 87 individuals with clinical diagnoses of Alzheimer's disease (AD) (n = 24), mild cognitive impairment (MCI) (n = 26), and subjective cognitive complaints (SCC) (n = 37). cSVD magnetic resonance imaging markers included white matter hyperintensity (WMH) volume, lacunar infarct presence, and microbleed presence. Aβ pathology was assessed as cerebrospinal fluid-derived Aβ1-42 levels and dichotomized into normal or abnormal, and HV was determined by manual volumetric measurements. A linear hierarchical regression approach was applied for the detection of additive or interaction effects between cSVD and Aβ on HV in the total participant group (n = 87) and in the non-demented group (including SCC and MCI individuals only, n = 63). The results revealed that abnormal Aβ and lacunar infarct presence were independently associated with lower HV in the non-demented individuals. Interestingly, Aβ and WMH pathology interacted in the non-demented individuals, such that WMH had a negative effect on HV in individuals with abnormal CSF Aβ42 levels, but not in individuals with normal CSF Aβ42 levels. These associations were not present when individuals with AD were included in the analyses. Our observations suggest that relatively early on in the disease process older individuals with abnormal Aβ levels are at an increased risk of accelerated disease progression when concomitant cSVD is present.