%0 Journal Article %J J Alzheimers Dis %D 2018 %T Alzheimer's Disease Biomarkers Have Distinct Associations with Specific Hippocampal Subfield Volumes. %A Müller-Ehrenberg, Lisa %A Riphagen, Joost M %A Verhey, Frans R J %A Sack, Alexander T %A Jacobs, Heidi I L %X

Measures of amyloid-β (Aβ) and phosphorylated tau (p-tau) concentrations in cerebrospinal fluid are extensively used for diagnostic and research purposes in Alzheimer's disease (AD) as correlates of cortical thinning and cognitive outcomes. The present study investigated the relationship of Aβ and p-tau with hippocampal subfield volumes Cornu Ammonis (CA) 1-4, dentate gyrus (DG), and subiculum. Subfields were segmented from T1-weighted images from the ADNI-population using FreeSurfer v6. Linear and polynomial regression models revealed distinct associations of Aβ and p-tau with subfield volumes. Aβ had a quadratic relationship with all hippocampal subfield volumes and the inflection point was higher than the validated cut-off for Aβ. For p-tau the relationships were linear, except for CA3, in which it was quadratic. For the CA1 and CA3, these quadratic relationships with Aβ were only observed when p-tau was low. Amyloid and p-tau contributed equally to the explained variance in CA4 and DG volume. Subicular volume was best explained by Aβ alone. These biomarker relationships with hippocampal subfield volumes seem to mirror the hippocampal-specific topography of Aβ and tau reported in neuropathological staging models. In addition, using continuous values of Aβ reveals positive patterns with imaging markers for individuals around the positivity threshold that would be masked when using dichotomized biomarker groups, which can be important for early detection and accurate inclusion of potential participants at risk for AD in clinical trials.

%B J Alzheimers Dis %V 66 %P 811-823 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320590?dopt=Abstract %R 10.3233/JAD-180676 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Association of Cerebrospinal Fluid (CSF) Insulin with Cognitive Performance and CSF Biomarkers of Alzheimer's Disease. %A Geijselaers, Stefan L C %A Aalten, Pauline %A Ramakers, Inez H G B %A De Deyn, Peter Paul %A Heijboer, Annemieke C %A Koek, Huiberdina L %A OldeRikkert, Marcel G M %A Papma, Janne M %A Reesink, Fransje E %A Smits, Lieke L %A Stehouwer, Coen D A %A Teunissen, Charlotte E %A Verhey, Frans R J %A van der Flier, Wiesje M %A Biessels, Geert Jan %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoprotein E4 %K Brain %K Cognition Disorders %K Female %K Humans %K Insulin %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Peptide Fragments %K Signal Transduction %K tau Proteins %X

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.

%B J Alzheimers Dis %V 61 %P 309-320 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154275?dopt=Abstract %R 10.3233/JAD-170522 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Impact of Untimely Access to Formal Care on Costs and Quality of Life in Community Dwelling People with Dementia. %A Janssen, Niels %A Handels, Ron L %A Sköldunger, Anders %A Woods, Bob %A Jelley, Hannah %A Edwards, Rhiannon Tudor %A Orrell, Martin %A Selbæk, Geir %A Røsvik, Janne %A Gonçalves-Pereira, Manuel %A Marques, Maria J %A Zanetti, Orazio %A Portolani, Elisa %A Irving, Kate %A Hopper, Louise %A Meyer, Gabriele %A Bieber, Anja %A Stephan, Astrid %A Kerpershoek, Liselot %A Wolfs, Claire A G %A de Vugt, Marjolein E %A Verhey, Frans R J %A Wimo, Anders %X

BACKGROUND: Access to formal care is not always timely and a better understanding on the impact of untimely access is needed.

OBJECTIVE: To examine, from a societal perspective, the impact of untimely access to formal care in terms of total costs and quality of life over one year in community dwelling people with dementia.

METHODS: Within the Actifcare study, needs, resource use, and quality of life were observed for one year in a cohort of 451 community dwelling people with dementia in 8 European countries. Untimely access to care was operationalized as having at least one unmet need for care identified by the Camberwell Assessment of Need for the Elderly (CANE) instrument. Two regression models were built for both total costs and quality of life measured by the EQ-5D-5L, one using sum of unmet needs and one using a predefined selection of need items.

RESULTS: Unmet needs were not associated with higher total costs but they were associated with a lower quality of life of people with dementia. Of all CANE items, only an unmet need for "company" was significantly related to lower total costs.

CONCLUSION: Total costs did not seem to differ between participants with unmet and met needs. Only few associations between specific unmet needs and costs and quality of life were found. Furthermore, quality of life of people with dementia decreases when multiple unmet needs are experienced, indicating that assessing and meeting needs is important to improve quality of life.

%B J Alzheimers Dis %V 66 %P 1165-1174 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30400096?dopt=Abstract %R 10.3233/JAD-180531 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Progression of Dementia and Cognitive Decline in a Dutch 2-Year Cohort Study of People with Young-Onset Dementia. %A Gerritsen, Adrie A J %A Bakker, Christian %A Verhey, Frans R J %A Bor, Hans %A Pijnenburg, Yolande A L %A de Vugt, Marjolein E %A Koopmans, Raymond T C M %X

BACKGROUND: The progression of dementia in people with young-onset dementia (YOD) is relatively unknown.

OBJECTIVE: To investigate the progression of dementia and cognitive decline in the three most common subtypes in YOD and to explore which factors are associated with this course.

METHODS: The course of dementia was examined in 198 people with YOD. The primary outcomes were cognitive function, as assessed by the Mini-Mental State Examination (MMSE) and dementia severity, as assessed by the Global Deterioration Scale (GDS). Mixed-model analyses were used to explore factors associated with the course of dementia of the diagnostic sub-types.

RESULTS: The mean overall two-year progression of dementia severity was 0.9 GDS points, this was a statistically significant change (p = 0.012) and was not significant different for the three dementia subtypes. The mean overall two-year decline in cognitive function was 1.6 points on the MMSE. The differences in cognitive decline were statistically significant (p = 0.046) among the three diagnosis groups, AD participants showed the greatest decline, of 2.3 points. In addition to lower education (p = 0.010), higher scores on the Neuropsychiatric Inventory (NPI) sub-syndromes psychosis (p < 0.001) and hyperactivity (p = 0.002) were associated with higher rates of cognitive decline. In contrast, higher scores on the NPI affect cluster were associated with lower levels of cognitive decline (p < 0.001).

CONCLUSION: Different YOD subtypes show different rates of decline in cognitive functioning, and this decline seems less progressive compared to those observed in studies in late-onset AD. Further research is needed to evaluate whether managing neuropsychiatric symptoms can positively influence the decline of cognitive function.

%B J Alzheimers Dis %V 63 %P 343-351 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614650?dopt=Abstract %R 10.3233/JAD-170859 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cost-Utility of Using Alzheimer's Disease Biomarkers in Cerebrospinal Fluid to Predict Progression from Mild Cognitive Impairment to Dementia. %A Handels, Ron L H %A Wimo, Anders %A Dodel, Richard %A Kramberger, Milica G %A Visser, Pieter Jelle %A Molinuevo, José Luis %A Verhey, Frans R J %A Winblad, Bengt %X

BACKGROUND: Diagnostic research criteria for Alzheimer's disease support the use of biomarkers in the cerebrospinal fluid (CSF) to improve the accuracy of the prognosis regarding progression to dementia for people with mild cognitive impairment (MCI).

OBJECTIVE: The aim of this study was to estimate the potential incremental cost-effectiveness ratio of adding CSF biomarker testing to the standard diagnostic workup to determine the prognosis for patients with MCI.

METHODS: In an early technology assessment, a mathematical simulation model was built, using available evidence on added prognostic value as well as expert opinion to estimate the incremental costs and quality-adjusted life years (QALYs) of 20,000 virtual MCI patients with (intervention strategy) and without (control strategy) relying on CSF, from a health-care sector perspective and with a 5-year time horizon.

RESULTS: Adding the CSF test improved the accuracy of prognosis by 11%. This resulted in an average QALY gain of 0.046 and € 432 additional costs per patient, representing an incremental cost-effectiveness ratio of € 9,416.

CONCLUSION: The results show the potential of CSF biomarkers in current practice from a health-economics perspective. This result was, however, marked by a high degree of uncertainty, and empirical research is required into the impact of a prognosis on worrying, false-positive/negative prognosis, and stigmatization.

%B J Alzheimers Dis %V 60 %P 1477-1487 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29081416?dopt=Abstract %R 10.3233/JAD-170324 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Modifiable Risk Factors for Prevention of Dementia in Midlife, Late Life and the Oldest-Old: Validation of the LIBRA Index. %A Vos, Stephanie J B %A van Boxtel, Martin P J %A Schiepers, Olga J G %A Deckers, Kay %A de Vugt, Marjolein %A Carrière, Isabelle %A Dartigues, Jean-François %A Pérès, Karine %A Artero, Sylvaine %A Ritchie, Karen %A Galluzzo, Lucia %A Scafato, Emanuele %A Frisoni, Giovanni B %A Huisman, Martijn %A Comijs, Hannie C %A Sacuiu, Simona F %A Skoog, Ingmar %A Irving, Kate %A O'Donnell, Catherine A %A Verhey, Frans R J %A Visser, Pieter Jelle %A Köhler, Sebastian %X

BACKGROUND: Recently, the LIfestyle for BRAin health (LIBRA) index was developed to assess an individual's prevention potential for dementia.

OBJECTIVE: We investigated the predictive validity of the LIBRA index for incident dementia in midlife, late life, and the oldest-old.

METHODS: 9,387 non-demented individuals were recruited from the European population-based DESCRIPA study. An individual's LIBRA index was calculated solely based on modifiable risk factors: depression, diabetes, physical activity, hypertension, obesity, smoking, hypercholesterolemia, coronary heart disease, and mild/moderate alcohol use. Cox regression was used to test the predictive validity of LIBRA for dementia at follow-up (mean 7.2 y, range 1-16).

RESULTS: In midlife (55-69 y, n = 3,256) and late life (70-79 y, n = 4,320), the risk for dementia increased with higher LIBRA scores. Individuals in the intermediate- and high-risk groups had a higher risk of dementia than those in the low-risk group. In the oldest-old (80-97 y, n = 1,811), higher LIBRA scores did not increase the risk for dementia.

CONCLUSION: LIBRA might be a useful tool to identify individuals for primary prevention interventions of dementia in midlife, and maybe in late life, but not in the oldest-old.

%B J Alzheimers Dis %V 58 %P 537-547 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453475?dopt=Abstract %R 10.3233/JAD-161208 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory Clinic Patients in a Prospective Cohort. %A Handels, Ron L H %A Joore, Manuela A %A Vos, Stephanie J B %A Aalten, Pauline %A Ramakers, Inez H G B %A Rikkert, Marcel Olde %A Scheltens, Philip %A Jansen, Willemijn J %A Visser, Pieter-Jelle %A van Berckel, Bart M N %A van Domburg, Peter %A Smid, Machiel %A Hoff, Erik %A Hoogmoed, Jan %A Bouwman, Femke %A Claassen, Jurgen %A Leentjens, Albert F G %A Wolfs, Claire A G %A Severens, Johan L %A Verhey, Frans R J %X

BACKGROUND: Limited information is available on short-term prognosis of Alzheimer's disease (AD) biomarkers in cerebrospinal fluid (CSF) in addition to routine diagnostic workup.

OBJECTIVE: This study aims to investigate the added prognostic value of AD CSF biomarkers.

METHODS: In a prospective cohort study, clinical experts predicted cognitive and functional symptoms in 114 memory clinic patients by assessing comprehensive routine diagnostic test information (patient history, and physical, neurological, psychiatric, neuropsychological, and MRI examinations), without and with CSF biomarkers. The reference standard was the 'observed clinically relevant decline' using baseline and 1- and 2-year follow-up information.

RESULTS: Decline over a 2-year period was observed in 51% of all participants (3% in SMC, 48% in MCI, 90% in mild dementia). In the total sample, the accuracy of predicted decline did not differ significantly between routine assessment without (79% correctly predicted) and with (74% correctly predicted) CSF biomarkers. Subgroup analyses revealed 25 (83%) correct predictions in SMC, 30 (68%) in MCI, and 35 (88%) in dementia without the use of CSF; and 21 (70%), 27 (61%), and 36 (90%), respectively, with the use of CSF in addition to the routine assessment.

CONCLUSION: AD CSF biomarkers did not increase accuracy of 2-year prognosis of cognitive and functional decline when added to routine diagnostic workup. This suggests that the standard diagnostic workup without CSF biomarkers allows fairly accurate predictions for the short-term course of symptoms. Routine AD biomarkers in CSF have limited prognostic value over 2 years in persons with a suspected cognitive disorder.

%B J Alzheimers Dis %V 52 %P 875-85 %8 2016 Mar 31 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031483?dopt=Abstract %R 10.3233/JAD-151120