%0 Journal Article %J J Alzheimers Dis %D 2021 %T The Right Temporal Variant of Frontotemporal Dementia Is Not Genetically Sporadic: A Case Series. %A Ulugut Erkoyun, Hulya %A van der Lee, Sven J %A Nijmeijer, Bas %A van Spaendonk, Rosalina %A Nelissen, Anne %A Scarioni, Marta %A Dijkstra, Anke %A Samancı, Bedia %A Gürvit, Hakan %A Yıldırım, Zerrin %A Tepgeç, Fatih %A Bilgic, Basar %A Barkhof, Frederik %A Rozemuller, Annemieke %A van der Flier, Wiesje M %A Scheltens, Philip %A Cohn-Hokke, Petra %A Pijnenburg, Yolande %K Aphasia, Primary Progressive %K DNA-Binding Proteins %K Female %K Frontotemporal Dementia %K Functional Laterality %K Genetic Testing %K Genetic Variation %K Gyrus Cinguli %K Humans %K Male %K Middle Aged %K Progranulins %K tau Proteins %X

BACKGROUND: Right temporal variant frontotemporal dementia (rtvFTD) has been generally considered as a right sided variant of semantic variant primary progressive aphasia (svPPA), which is a genetically sporadic disorder. Recently, we have shown that rtvFTD has a unique clinical syndrome compared to svPPA and behavioral variant frontotemporal dementia.

OBJECTIVE: We challenge the assumption that rtvFTD is a sporadic, non-familial variant of FTD by identifying potential autosomal dominant inheritance and related genes in rtvFTD.

METHODS: We collected all subjects with a diagnosis of FTD or primary progressive aphasia who had undergone genetic screening (n = 284) and subsequently who had a genetic variant (n = 48) with a diagnosis of rtvFTD (n = 6) in 2 specialized memory clinics.

RESULTS: Genetic variants in FTD related genes were found in 33% of genetically screened rtvFTD cases; including MAPT (n = 4), GRN (n = 1), and TARDBP (n = 1) genes, whereas only one svPPA case had a genetic variant in our combined cohorts. Additionally, 4 out of 6 rtvFTD subjects had a strong family history for dementia.

CONCLUSION: Our results demonstrate that rtvFTD, unlike svPPA, is not a pure sporadic, but a heterogeneous potential genetic variant of FTD, and screening for genetic causes for FTD should be performed in patients with rtvFTD.

%B J Alzheimers Dis %V 79 %P 1195-1201 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33427744?dopt=Abstract %R 10.3233/JAD-201191 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology. %A Shi, Liu %A Winchester, Laura M %A Liu, Benjamine Y %A Killick, Richard %A Ribe, Elena M %A Westwood, Sarah %A Baird, Alison L %A Buckley, Noel J %A Hong, Shengjun %A Dobricic, Valerija %A Kilpert, Fabian %A Franke, Andre %A Kiddle, Steven %A Sattlecker, Martina %A Dobson, Richard %A Cuadrado, Antonio %A Hye, Abdul %A Ashton, Nicholas J %A Morgan, Angharad R %A Bos, Isabelle %A Vos, Stephanie J B %A Ten Kate, Mara %A Scheltens, Philip %A Vandenberghe, Rik %A Gabel, Silvy %A Meersmans, Karen %A Engelborghs, Sebastiaan %A De Roeck, Ellen E %A Sleegers, Kristel %A Frisoni, Giovanni B %A Blin, Olivier %A Richardson, Jill C %A Bordet, Régis %A Molinuevo, José L %A Rami, Lorena %A Wallin, Anders %A Kettunen, Petronella %A Tsolaki, Magda %A Verhey, Frans %A Lleo, Alberto %A Alcolea, Daniel %A Popp, Julius %A Peyratout, Gwendoline %A Martínez-Lage, Pablo %A Tainta, Mikel %A Johannsen, Peter %A Teunissen, Charlotte E %A Freund-Levi, Yvonne %A Frölich, Lutz %A Legido-Quigley, Cristina %A Barkhof, Frederik %A Blennow, Kaj %A Rasmussen, Katrine Laura %A Nordestgaard, Børge Grønne %A Frikke-Schmidt, Ruth %A Nielsen, Sune Fallgaard %A Soininen, Hilkka %A Vellas, Bruno %A Kloszewska, Iwona %A Mecocci, Patrizia %A Zetterberg, Henrik %A Morgan, B Paul %A Streffer, Johannes %A Visser, Pieter Jelle %A Bertram, Lars %A Nevado-Holgado, Alejo J %A Lovestone, Simon %X

BACKGROUND: Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown.

OBJECTIVE: We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes.

METHODS: We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677).

RESULTS: We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts.

CONCLUSIONS: Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo.

%B J Alzheimers Dis %V 77 %P 1353-1368 %8 2020 Sep 29 %G eng %N 3 %R 10.3233/JAD-200208 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Gait Disturbances are Associated with Increased Cognitive Impairment and Cerebrospinal Fluid Tau Levels in a Memory Clinic Cohort. %A Muurling, Marijn %A Rhodius-Meester, Hanneke F M %A Pärkkä, Juha %A van Gils, Mark %A Frederiksen, Kristian S %A Bruun, Marie %A Hasselbalch, Steen G %A Soininen, Hilkka %A Herukka, Sanna-Kaisa %A Hallikainen, Merja %A Teunissen, Charlotte E %A Visser, Pieter Jelle %A Scheltens, Philip %A van der Flier, Wiesje M %A Mattila, Jussi %A Lötjönen, Jyrki %A de Boer, Casper %X

BACKGROUND: Gait analysis with accelerometers is a relatively inexpensive and easy to use method to potentially support clinical diagnoses of Alzheimer's disease and other dementias. It is not clear, however, which gait features are most informative and how these measures relate to Alzheimer's disease pathology.

OBJECTIVE: In this study, we tested if calculated features of gait 1) differ between cognitively normal subjects (CN), mild cognitive impairment (MCI) patients, and dementia patients, 2) are correlated with cerebrospinal fluid (CSF) biomarkers related to Alzheimer's disease, and 3) predict cognitive decline.

METHODS: Gait was measured using tri-axial accelerometers attached to the fifth lumbar vertebra (L5) in 58 CN, 58 MCI, and 26 dementia participants, while performing a walk and dual task. Ten gait features were calculated from the vertical L5 accelerations, following principal component analysis clustered in four domains, namely pace, rhythm, time variability, and length variability. Cognitive decline over time was measured using MMSE, and CSF biomarkers were available in a sub-group.

RESULTS: Linear mixed models showed that dementia patients had lower pace scores than MCI patients and CN subjects (p < 0.05). In addition, we found associations between the rhythm domain and CSF-tau, especially in the dual task. Gait was not associated with CSF Aβ42 levels and cognitive decline over time as measured with the MMSE.

CONCLUSION: These findings suggest that gait-particularly measures related to pace and rhythm-are altered in dementia and have a direct link with measures of neurodegeneration.

%B J Alzheimers Dis %V 76 %P 1061-1070 %8 2020 Aug 04 %G eng %N 3 %R 10.3233/JAD-200225 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Validation of Plasma Proteomic Biomarkers Relating to Brain Amyloid Burden in the EMIF-Alzheimer's Disease Multimodal Biomarker Discovery Cohort. %A Westwood, Sarah %A Baird, Alison L %A Anand, Sneha N %A Nevado-Holgado, Alejo J %A Kormilitzin, Andrey %A Shi, Liu %A Hye, Abdul %A Ashton, Nicholas J %A Morgan, Angharad R %A Bos, Isabelle %A Vos, Stephanie J B %A Baker, Susan %A Buckley, Noel J %A Ten Kate, Mara %A Scheltens, Philip %A Teunissen, Charlotte E %A Vandenberghe, Rik %A Gabel, Silvy %A Meersmans, Karen %A Engelborghs, Sebastiaan %A De Roeck, Ellen E %A Sleegers, Kristel %A Frisoni, Giovanni B %A Blin, Olivier %A Richardson, Jill C %A Bordet, Régis %A Molinuevo, José L %A Rami, Lorena %A Wallin, Anders %A Kettunen, Petronella %A Tsolaki, Magda %A Verhey, Frans %A Lleo, Alberto %A Sala, Isabel %A Popp, Julius %A Peyratout, Gwendoline %A Martínez-Lage, Pablo %A Tainta, Mikel %A Johannsen, Peter %A Freund-Levi, Yvonne %A Frölich, Lutz %A Dobricic, Valerija %A Legido-Quigley, Cristina %A Bertram, Lars %A Barkhof, Frederik %A Zetterberg, Henrik %A Morgan, B Paul %A Streffer, Johannes %A Visser, Pieter Jelle %A Lovestone, Simon %X

We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer's disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E ɛ4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure.

%B J Alzheimers Dis %V 74 %P 213-225 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31985466?dopt=Abstract %R 10.3233/JAD-190434 %0 Journal Article %J J Alzheimers Dis %D 2019 %T The Clinical Phenotype of Vascular Cognitive Impairment in Patients with Type 2 Diabetes Mellitus. %A Groeneveld, Onno N %A Moneti, Costanza %A Heinen, Rutger %A de Bresser, Jeroen %A Kuijf, Hugo J %A Exalto, Lieza G %A Boomsma, Jooske M F %A Kappelle, L Jaap %A Barkhof, Frederik %A Prins, Niels D %A Scheltens, Philip %A van der Flier, Wiesje M %A Biessels, Geert Jan %X

BACKGROUND: Type 2 diabetes mellitus (T2DM) increases the risk of vascular cognitive impairment (VCI). It is unknown which type of vascular lesions and co-morbid etiologies, in particular Alzheimer's disease pathology, are associated with T2DM in patients with VCI, and how this relates to cognition and prognosis.

OBJECTIVE: To compare brain MRI and cerebrospinal fluid (CSF) markers, cognition, and prognosis in patients with possible VCI with and without T2DM.

METHODS: We included 851 memory clinic patients with vascular brain injury on MRI (i.e., possible VCI) from a prospective cohort study (T2DM: n = 147, 68.4±7.9 years, 63% men; no T2DM: n = 704, 67.6±8.5 years, 52% men). At baseline, we assessed between-group differences in brain MRI abnormalities, CSF markers of Alzheimer's disease, and cognitive profile. After two years follow-up, we compared occurrence of cognitive decline, stroke, and death.

RESULTS: The distribution of clinical diagnoses did not differ between patients with and without T2DM. T2DM patients had more pronounced brain atrophy (total and white matter volume), and more lacunar infarcts, whereas microbleeds were less common (all p <  0.05). CSF amyloid-β levels were similar between the groups. T2DM patients performed worse on working memory (effect size: - 0.17, p = 0.03) than those without, whereas performance on other domains was similar. During follow-up, risk of further cognitive decline was not increased in T2DM.∥Conclusion: In patients with possible VCI, presence of T2DM is related to more pronounced brain atrophy and a higher burden of lacunar infarcts, but T2DM does not have a major impact on cognitive profile or prognosis.∥.

%B J Alzheimers Dis %V 68 %P 311-322 %8 2019 Mar 12 %G eng %N 1 %R 10.3233/JAD-180914 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Why Is Amyloid-β PET Requested After Performing Cerebrospinal Fluid Biomarkers? %A Reimand, Juhan %A Groot, Colin %A Teunissen, Charlotte E %A Windhorst, Albert D %A Boellaard, Ronald %A Barkhof, Frederik %A Nazarenko, Sergei %A van der Flier, Wiesje M %A van Berckel, Bart N M %A Scheltens, Philip %A Ossenkoppele, Rik %A Bouwman, Femke %X

BACKGROUND: Amyloid-β PET and cerebrospinal fluid (CSF) Aβ42 are considered interchangeable for clinical diagnosis of Alzheimer's disease.

OBJECTIVE: To explore the clinical reasoning for requesting additional amyloid-β PET after performing CSF biomarkers.

METHODS: We retrospectively identified 72 memory clinic patients who underwent amyloid-β PET after CSF biomarkers analysis for clinical diagnostic evaluation between 2011 and 2019. We performed patient chart reviews to identify factors which led to additional amyloid-β PET. Additionally, we assessed accordance with appropriate-use-criteria (AUC) for amyloid-β PET.

RESULTS: Mean patient age was 62.0 (SD = 8.1) and mean Mini-Mental State Exam score was 23.6 (SD = 3.8). CSF analysis conflicting with the clinical diagnosis was the most frequent reason for requesting an amyloid-β PET scan (n = 53, 74%), followed by incongruent MRI (n = 16, 22%), unusual clinical presentation (n = 11, 15%) and young age (n = 8, 11%). An amyloid-β PET scan was rarely (n = 5, 7%) requested in patients with a CSF Aβ+/tau+ status. Fifteen (47%) patients with a post-PET diagnosis of AD had a predominantly non-amnestic presentation. In n = 11 (15%) cases, the reason that the clinician requested amyloid-β was not covered by AUC. This happened most often (n = 7) when previous CSF analysis did not support current clinical diagnosis, which led to requesting amyloid-β PET.

CONCLUSION: In this single-center study, the main reason for requesting an amyloid-β PET scan after performing CSF biomarkers was the occurrence of a mismatch between the primary clinical diagnosis and CSF Aβ/tau results.

%B J Alzheimers Dis %V 73 %P 559-569 %8 2020 Jan 21 %G eng %N 2 %R 10.3233/JAD-190836 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Amsterdam Dementia Cohort: Performing Research to Optimize Care. %A van der Flier, Wiesje M %A Scheltens, Philip %X

The Alzheimer center of the VU University Medical Center opened in 2000 and was initiated to combine both patient care and research. Together, to date, all patients forming the Amsterdam Dementia Cohort number almost 6,000 individuals. In this cohort profile, we provide an overview of the results produced based on the Amsterdam Dementia Cohort. We describe the main results over the years in each of these research lines: 1) early diagnosis, 2) heterogeneity, and 3) vascular factors. Among the most important research efforts that have also impacted patients' lives and/or the research field, we count the development of novel, easy to use diagnostic measures such as visual rating scales for MRI and the Amsterdam IADL Questionnaire, insight in different subgroups of AD, and findings on incidence and clinical sequelae of microbleeds. Finally, we describe in the outlook how our research endeavors have improved the lives of our patients.

%B J Alzheimers Dis %V 62 %P 1091-1111 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562540?dopt=Abstract %R 10.3233/JAD-170850 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebral White Matter Lesions have Low Impact on Cognitive Function in a Large Elderly Memory Clinic Population. %A Claus, Jules J %A Coenen, Mirthe %A Staekenborg, Salka S %A Schuur, Jacqueline %A Tielkes, Caroline E M %A Koster, Pieter %A Scheltens, Philip %X

BACKGROUND: Evidence suggests that cerebral white matter lesions (WML) play a role in cognitive decline.

OBJECTIVE: 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.

METHODS: 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).

RESULTS: 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.

CONCLUSION: 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.

%B J Alzheimers Dis %8 2018 Apr 27 %G eng %R 10.3233/JAD-171111 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Plasma Amyloid-β (Aβ42) Correlates with Cerebrospinal Fluid Aβ42 in Alzheimer's Disease. %A Teunissen, Charlotte E %A Chiu, Ming-Jang %A Yang, Che-Chuan %A Yang, Shieh-Yueh %A Scheltens, Philip %A Zetterberg, Henrik %A Blennow, Kaj %X

The 42 amino acid form of amyloid-β (Aβ42) plays a key role in the pathogenesis of Alzheimer's disease (AD) and is a core biomarker for the diagnosis of AD. Numerous studies have shown that cerebrospinal fluid (CSF) Aβ42 concentrations are decreased in AD, when measured by enzyme-linked immunosorbent assay (ELISA) and other conventional immunoassays. While most studies report no change in plasma Aβ42, independent studies using the immunomagnetic reduction (IMR) technique report an increase in plasma Aβ42 levels in AD. To confirm the opposite changes of Aβ42 levels in CSF and plasma for AD, we assayed the levels of Aβ42 in plasma of subjects with known CSF Aβ42 levels. In total 43 controls and 63 AD patients were selected at two sites: the VU University Medical Center (n = 55) and Sahlgrenska University Hospital (n = 51). IMR and ELISA were applied to assay Aβ42 in plasma and CSF, respectively. We found a moderately negative correlation between plasma and CSF Aβ42 levels in AD patients (r = -0.352), and a weakly positive correlation in controls (r = 0.186). These findings further corroborate that there are opposite changes of Aβ42 levels in CSF and plasma in AD. The possible causes for the negative correlation are discussed by taken assay technologies, Aβ42 transport from brain to peripheral blood, and sample matrix into account.

%B J Alzheimers Dis %V 62 %P 1857-1863 %8 2018 Mar 27 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614646?dopt=Abstract %R 10.3233/JAD-170784 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Prominent Non-Memory Deficits in Alzheimer's Disease Are Associated with Faster Disease Progression. %A Scheltens, Nienke M E %A Tijms, Betty M %A Heymans, Martijn W %A Rabinovici, Gil D %A Cohn-Sheehy, Brendan I %A Miller, Bruce L %A Kramer, Joel H %A Wolfsgruber, Steffen %A Wagner, Michael %A Kornhuber, Johannes %A Peters, Oliver %A Scheltens, Philip %A van der Flier, Wiesje M %X

BACKGROUND: Alzheimer's disease (AD) is a heterogeneous disorder.

OBJECTIVE: To investigate whether cognitive AD subtypes are associated with different rates of disease progression.

METHODS: We included 1,066 probable AD patients from the Amsterdam Dementia Cohort (n = 290), Alzheimer's Disease Neuroimaging Initiative (n = 268), Dementia Competence Network (n = 226), and University of California, San Francisco (n = 282) with available follow-up data. Patients were previously clustered into two subtypes based on their neuropsychological test results: one with most prominent memory impairment (n = 663) and one with most prominent non-memory impairment (n = 403). We examined associations between cognitive subtype and disease progression, as measured with repeated Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale sum of boxes (CDR sob), using linear mixed models. Furthermore, we investigated mortality risk associated with subtypes using Cox proportional hazard analyses.

RESULTS: Patients were 71±9 years old; 541 (51%) were female. At baseline, pooled non-memory patients had worse MMSE scores (23.1±0.1) and slightly worse CDR sob (4.4±0.1) than memory patients (MMSE 24.0±0.1; p < 0.001; CDR sob 4.1±0.1; p < 0.001). During follow-up, pooled non-memory patients showed steeper annual decline in MMSE (-2.8±0.1) and steeper annual increase in CDR sob (1.8±0.1) than memory patients (MMSE - 1.9±0.1; pinteraction<0.001; CDR sob 1.3±0.1; pinteraction<0.001). Furthermore, the non-memory subtype was associated with an increased risk of mortality compared with the memory subtype at trend level (HR = 1.36, CI = 1.00-1.85, p = 0.05).

CONCLUSIONS: AD patients with most prominently non-memory impairment show faster disease progression and higher risk of mortality than patients with most prominently memory impairment.

%B J Alzheimers Dis %8 2018 Aug 03 %G eng %R 10.3233/JAD-171088 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Quantitative PET and Histology of Brain Biopsy Reveal Lack of Selective Pittsburgh Compound-B Binding to Intracerebral Amyloidoma. %A Groot, Colin %A Tolboom, Nelleke %A Ikonomovic, Milos D %A Lammertsma, Adriaan A %A Boon, Baayla D C %A Barkhof, Frederik %A Scheltens, Philip %A Klunk, William E %A Rozemuller, Annemieke J M %A Ossenkoppele, Rik %A van Berckel, Bart N M %X

This single case study examines selective Pittsburgh compound-B (PiB) binding to an intracerebral light-chain amyloidoma using a 90-minute dynamic [11C]PiB-PET scan and brain biopsy tissue. Parametric non-displaceable binding potential (BPND) images showed low specific binding in the amyloidoma (BPND = 0.23), while relative tracer delivery was adequate (R1 = 0.44). Histology of the tissue revealed strong coloring with Congo-red, thioflavin-S, and X-34, indicating presence of amyloid. However, immunological staining with 6F/3D revealed absence of amyloid-β and histofluorescence of 6-CN-PiB, a highly fluorescent derivative of PiB, was at background levels. Our results suggest that PiB does not detect the atypical amyloid pathology associated with an intracerebral light-chain amyloidoma. These findings are of interest to clinicians and researchers applying [11C]PiB-PET to detect atypical forms of amyloid pathology.

%B J Alzheimers Dis %8 2018 Jul 18 %G eng %R 10.3233/JAD-180316 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Single Subject Classification of Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia Using Anatomical, Diffusion Tensor, and Resting-State Functional Magnetic Resonance Imaging. %A Bouts, Mark J R J %A Möller, Christiane %A Hafkemeijer, Anne %A van Swieten, John C %A Dopper, Elise %A van der Flier, Wiesje M %A Vrenken, Hugo %A Wink, Alle Meije %A Pijnenburg, Yolande A L %A Scheltens, Philip %A Barkhof, Frederik %A Schouten, Tijn M %A de Vos, Frank %A Feis, Rogier A %A van der Grond, Jeroen %A de Rooij, Mark %A Rombouts, Serge A R B %X

BACKGROUND/OBJECTIVE: Overlapping clinical symptoms often complicate differential diagnosis between patients with Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Magnetic resonance imaging (MRI) reveals disease specific structural and functional differences that aid in differentiating AD from bvFTD patients. However, the benefit of combining structural and functional connectivity measures to-on a subject-basis-differentiate these dementia-types is not yet known.

METHODS: Anatomical, diffusion tensor (DTI), and resting-state functional MRI (rs-fMRI) of 30 patients with early stage AD, 23 with bvFTD, and 35 control subjects were collected and used to calculate measures of structural and functional tissue status. All measures were used separately or selectively combined as predictors for training an elastic net regression classifier. Each classifier's ability to accurately distinguish dementia-types was quantified by calculating the area under the receiver operating characteristic curves (AUC).

RESULTS: Highest AUC values for AD and bvFTD discrimination were obtained when mean diffusivity, full correlations between rs-fMRI-derived independent components, and fractional anisotropy (FA) were combined (0.811). Similarly, combining gray matter density (GMD), FA, and rs-fMRI correlations resulted in highest AUC of 0.922 for control and bvFTD classifications. This, however, was not observed for control and AD differentiations. Classifications with GMD (0.940) and a GMD and DTI combination (0.941) resulted in similar AUC values (p = 0.41).

CONCLUSION: Combining functional and structural connectivity measures improve dementia-type differentiations and may contribute to more accurate and substantiated differential diagnosis of AD and bvFTD patients. Imaging protocols for differential diagnosis may benefit from also including DTI and rs-fMRI.

%B J Alzheimers Dis %V 62 %P 1827-1839 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614652?dopt=Abstract %R 10.3233/JAD-170893 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Apolipoprotein A1 in Cerebrospinal Fluid and Plasma and Progression to Alzheimer's Disease in Non-Demented Elderly. %A Slot, Rosalinde E R %A Van Harten, Argonde C %A Kester, Maartje I %A Jongbloed, Wesley %A Bouwman, Femke H %A Teunissen, Charlotte E %A Scheltens, Philip %A Veerhuis, Robert %A van der Flier, Wiesje M %X

BACKGROUND: HDL-cholesterol transporter Apolipoprotein A1 (ApoA1) holds neuroprotective properties, such as inhibition of amyloid-β aggregation. Low plasma ApoA1 concentrations are associated with Alzheimer's disease (AD). Little is known about ApoA1 levels in the pre-dementia stages of AD.

OBJECTIVE: To investigate associations between cerebrospinal fluid (CSF) and plasma ApoA1 levels and clinical progression toward AD in non-demented elderly.

METHODS: From the Amsterdam Dementia Cohort, we included 429 non-demented elderly with subjective cognitive decline (SCD; n = 206, 61±9 years, Mini-Mental State Exam (MMSE) 28±2) and mild cognitive impairment (MCI; n = 223, 67±8 years, MMSE 27±2), with a mean follow-up of 2.5±1.6 years. We used Cox proportional hazard models to investigate relations between CSF and plasma ApoA1 concentrations and clinical progression, defined as progression to MCI or AD for SCD, and progression to AD for MCI. Analyses were adjusted for age, gender, MMSE, and plasma cholesterol levels. Analyses were stratified for diagnosis and APOEɛ4 carriership.

RESULTS: 117 patients (27%) showed clinical progression. One standard deviation increase of CSF ApoA1 was associated with a 30% increased risk of clinical progression (hazard ratio (HR) (95% CI)  = 1.3(1.0-1.6)). The effect appeared to be attributable to the APOEɛ4 carriers with SCD (HR 3.3(1.0-10.9)). Lower plasma ApoA1 levels were associated with an increased risk of clinical progression in APOEɛ4 carriers with SCD (HR 5.0(1.3-18.9)).

CONCLUSION: Higher CSF and lower plasma ApoA1 levels were associated with an increased risk of clinical progression in APOEɛ4 carriers with SCD; suggesting that ApoA1 may be involved in the earliest stages of AD.

%B J Alzheimers Dis %V 56 %P 687-697 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035918?dopt=Abstract %R 10.3233/JAD-151068 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Association Between Later Life Lifestyle Factors and Alzheimer's Disease Biomarkers in Non-Demented Individuals: A Longitudinal Descriptive Cohort Study. %A Reijs, Babette L R %A Vos, Stephanie J B %A Soininen, Hilkka %A Lötjönen, Jyrki %A Koikkalainen, Juha %A Pikkarainen, Maria %A Hall, Anette %A Vanninen, Ritva %A Liu, Yawu %A Herukka, Sanna-Kaisa %A Freund-Levi, Yvonne %A Frisoni, Giovanni B %A Frölich, Lutz %A Nobili, Flavio %A Rikkert, Marcel Olde %A Spiru, Luiza %A Tsolaki, Magda %A Wallin, Asa K %A Scheltens, Philip %A Verhey, Frans %A Visser, Pieter Jelle %X

BACKGROUND: Lifestyle factors have been associated with the risk of dementia, but the association with Alzheimer's disease (AD) remains unclear.

OBJECTIVE: To examine the association between later life lifestyle factors and AD biomarkers (i.e., amyloid-β 1-42 (Aβ42) and tau in cerebrospinal fluid (CSF), and hippocampal volume) in individuals with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). In addition, to examine the effect of later life lifestyle factors on developing AD-type dementia in individuals with MCI.

METHODS: We selected individuals with SCD (n = 111) and MCI (n = 353) from the DESCRIPA and Kuopio Longitudinal MCI studies. CSF Aβ42 and tau concentrations were assessed with ELISA assay and hippocampal volume with multi-atlas segmentation. Lifestyle was assessed by clinical interview at baseline for: social activity, physical activity, cognitive activity, smoking, alcohol consumption, and sleep. We performed logistic and Cox regression analyses adjusted for study site, age, gender, education, and diagnosis. Prediction for AD-type dementia was performed in individuals with MCI only.

RESULTS: Later life lifestyle factors were not associated with AD biomarkers or with conversion to AD-type dementia. AD biomarkers were strongly associated with conversion to AD-type dementia, but these relations were not modulated by lifestyle factors. Apolipoprotein E (APOE) genotype did not influence the results.

CONCLUSIONS: Later life lifestyle factors had no impact on key AD biomarkers in individuals with SCD and MCI or on conversion to AD-type dementia in MCI.

%B J Alzheimers Dis %V 60 %P 1387-1395 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036813?dopt=Abstract %R 10.3233/JAD-170039 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Current Approaches and Clinician Attitudes to the Use of Cerebrospinal Fluid Biomarkers in Diagnostic Evaluation of Dementia in Europe. %A Miller, Anne-Marie %A Balasa, Mircea %A Blennow, Kaj %A Gardiner, Mary %A Rutkowska, Aleksandra %A Scheltens, Philip %A Teunissen, Charlotte E %A Visser, Pieter Jelle %A Winblad, Bengt %A Waldemar, Gunhild %A Lawlor, Brian %X

BACKGROUND: BIOMARKAPD seeks to diminish the barriers associated with the clinical use of cerebrospinal fluid (CSF) biomarker analysis by reducing variation in CSF laboratory methodologies and generating consensus recommendations on their clinical interpretation and application for dementia diagnosis.

OBJECTIVE: To examine the disparity in practitioner attitudes and clinical practice relating to the use of CSF biomarkers for dementia diagnosis across Europe.

METHODS: Clinical dementia experts were surveyed on the prevalence of national consensus guidelines and analytical reimbursement across Europe, their biomarker platform preferences, lumbar puncture methodologies and application of reference values and cut-offs for CSF analysis.

RESULTS: 74% of respondents (total n = 51) use CSF biomarkers in clinical practice and 69% perform lumbar punctures on an outpatient basis. Most use CSF biomarkers to diagnose atypical (84%) and early-onset cases of cognitive impairment (71%) and for the differential diagnosis of other dementias (69%). 82% state they are sufficiently informed about CSF biomarkers yet 61% report a lack of national consensus guidelines on their use for dementia diagnosis. 48% of countries represented do not reimburse clinical CSF analysis costs. 43% report using normal reference ranges derived from publications.

CONCLUSION: Variations in attitude and practice relating to CSF biomarkers, widely recognised as barriers to their clinical acceptance, remain evident within and between countries across Europe, even in expert centres. These shortcomings must be addressed by developing consensus guidelines on CSF-related methodologies and their clinical application, to further their use for the diagnostic evaluation of dementia.

%B J Alzheimers Dis %V 60 %P 201-210 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28826189?dopt=Abstract %R 10.3233/JAD-170502 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Diagnostic and Prognostic Value of Neuropsychological Assessment in Memory Clinic Patients. %A Jansen, Willemijn J %A Handels, Ron L H %A Visser, Pieter Jelle %A Aalten, Pauline %A Bouwman, Femke %A Claassen, Jurgen %A van Domburg, Peter %A Hoff, Erik %A Hoogmoed, Jan %A Leentjens, Albert F G %A Rikkert, Marcel Olde %A Oleksik, Ania M %A Smid, Machiel %A Scheltens, Philip %A Wolfs, Claire %A Verhey, Frans %A Ramakers, Inez H G B %X

BACKGROUND: Neuropsychological testing has long been embedded in daily clinical practice at memory clinics but the added value of a complete neuropsychological assessment (NPA) to standard clinical evaluation is unknown.

OBJECTIVE: To evaluate the added diagnostic and prognostic value of NPA to clinical evaluation only in memory clinic patients.

METHODS: In 221 memory clinic patients of a prospective cohort study, clinical experts diagnosed clinical syndrome (subjective cognitive impairment (SCI), mild cognitive impairment (MCI), or dementia) and etiology (Alzheimer's disease (AD) or no AD), and provided a prognosis of disease course (decline or no decline) before and after results of NPA were made available. The reference standard was a panel consensus based on all clinical information at baseline and up to 2 follow-up assessments.

RESULTS: With NPA data available, clinicians changed their initial syndromal diagnosis in 22% of patients, and the etiological diagnosis as well as the prognosis in 15%. This led to an increase in correctly classified cases of 18% for syndromal diagnosis, 5% for etiological diagnosis, and 1% for prognosis. NPA data resulted in the largest improvement in patients initially classified as SCI (syndrome: 93.3% (n = 14) correctly reclassified, etiology: net reclassification improvement [NRI] = 0.61, prognosis: NRI = 0.13) or MCI (syndrome: 89.3% (n = 23) correctly reclassified, etiology: NRI = 0.17, prognosis: NRI = 0.14), while there was no improvement in patients with dementia (syndrome: 100% (n = 1) correctly reclassified, etiology: NRI = -0.05, prognosis: NRI = -0.06). Overall, inclusion of NPA in the diagnostic process increased confidence in all diagnoses with 6-7%.

CONCLUSION: Administration of a complete NPA after standard clinical evaluation has added value for diagnosing cognitive syndrome and its underlying etiology in patients regarded as non-demented based on the first clinical impression.

%B J Alzheimers Dis %V 55 %P 679-689 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716658?dopt=Abstract %R 10.3233/JAD-160126 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effect Size Analyses of Souvenaid in Patients with Alzheimer's Disease. %A Cummings, Jeffrey %A Scheltens, Philip %A McKeith, Ian %A Blesa, Rafael %A Harrison, John E %A Bertolucci, Paulo H F %A Rockwood, Kenneth %A Wilkinson, David %A Wijker, Wouter %A Bennett, David A %A Shah, Raj C %X

BACKGROUND: Souvenaid® (uridine monophosphate, docosahexaenoic acid, eicosapentaenoic acid, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium), was developed to support the formation and function of neuronal membranes.

OBJECTIVE: To determine effect sizes observed in clinical trials of Souvenaid and to calculate the number needed to treat to show benefit or harm.

METHODS: Data from all three reported randomized controlled trials of Souvenaid in Alzheimer's disease (AD) dementia (Souvenir I, Souvenir II, and S-Connect) and an open-label extension study were included in analyses of effect size for cognitive, functional, and behavioral outcomes. Effect size was determined by calculating Cohen's d statistic (or Cramér's V method for nominal data), number needed to treat and number needed to harm. Statistical calculations were performed for the intent-to-treat populations.

RESULTS: In patients with mild AD, effect sizes were 0.21 (95% confidence intervals: -0.06, 0.49) for the primary outcome in Souvenir II (neuropsychological test battery memory z-score) and 0.20 (0.10, 0.34) for the co-primary outcome of Souvenir I (Wechsler memory scale delayed recall). No effect was shown on cognition in patients with mild-to-moderate AD (S-Connect). The number needed to treat (6 and 21 for Souvenir I and II, respectively) and high number needed to harm values indicate a favorable harm:benefit ratio for Souvenaid versus control in patients with mild AD.

CONCLUSIONS: The favorable safety profile and impact on outcome measures converge to corroborate the putative mode of action and demonstrate that Souvenaid can achieve clinically detectable effects in patients with early AD.

%B J Alzheimers Dis %V 55 %P 1131-1139 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27767993?dopt=Abstract %R 10.3233/JAD-160745 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Improved Cerebrospinal Fluid-Based Discrimination between Alzheimer's Disease Patients and Controls after Correction for Ventricular Volumes. %A van Waalwijk van Doorn, Linda J C %A Gispert, Juan D %A Kuiperij, H Bea %A Claassen, Jurgen A H R %A Arighi, Andrea %A Baldeiras, Ines %A Blennow, Kaj %A Bozzali, Marco %A Castelo-Branco, Miguel %A Cavedo, Enrica %A Emek-Savaş, Derya D %A Eren, Erden %A Eusebi, Paolo %A Farotti, Lucia %A Fenoglio, Chiara %A Ormaechea, Juan Fortea %A Freund-Levi, Yvonne %A Frisoni, Giovanni B %A Galimberti, Daniela %A Genc, Sermin %A Greco, Viviana %A Hampel, Harald %A Herukka, Sanna-Kaisa %A Liu, Yawu %A Lladó, Albert %A Lleo, Alberto %A Nobili, Flavio M %A Oguz, Kader K %A Parnetti, Lucilla %A Pereira, João %A Picco, Agnese %A Pikkarainen, Maria %A de Oliveira, Catarina Resende %A Saka, Esen %A Salvadori, Nicola %A Sánchez-Valle, Raquel %A Santana, Isabel %A Scarpini, Elio %A Scheltens, Philip %A Soininen, Hilkka %A Tarducci, Roberto %A Teunissen, Charlotte %A Tsolaki, Magda %A Urbani, Andrea %A Vilaplana, Eduard %A Visser, Pieter Jelle %A Wallin, Asa K %A Yener, Görsev %A Molinuevo, José L %A Meulenbroek, Olga %A Verbeek, Marcel M %X

Cerebrospinal fluid (CSF) biomarkers may support the diagnosis of Alzheimer's disease (AD). We studied if the diagnostic power of AD CSF biomarker concentrations, i.e., Aβ42, total tau (t-tau), and phosphorylated tau (p-tau), is affected by differences in lateral ventricular volume (VV), using CSF biomarker data and magnetic resonance imaging (MRI) scans of 730 subjects, from 13 European Memory Clinics. We developed a Matlab-algorithm for standardized automated segmentation analysis of T1 weighted MRI scans in SPM8 for determining VV, and computed its ratio with total intracranial volume (TIV) as proxy for total CSF volume. The diagnostic power of CSF biomarkers (and their combination), either corrected for VV/TIV ratio or not, was determined by ROC analysis. CSF Aβ42 levels inversely correlated to VV/TIV in the whole study population (Aβ42: r = -0.28; p < 0.0001). For CSF t-tau and p-tau, this association only reached statistical significance in the combined MCI and AD group (t-tau: r = -0.15; p-tau: r = -0.13; both p < 0.01). Correction for differences in VV/TIV improved the differentiation of AD versus controls based on CSF Aβ42 alone (AUC: 0.75 versus 0.81) or in combination with t-tau (AUC: 0.81 versus 0.91). In conclusion, differences in VV may be an important confounder in interpreting CSF Aβ42 levels.

%B J Alzheimers Dis %V 56 %P 543-555 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059783?dopt=Abstract %R 10.3233/JAD-160668 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Longitudinal Study on Resting State Functional Connectivity in Behavioral Variant Frontotemporal Dementia and Alzheimer's Disease. %A Hafkemeijer, Anne %A Möller, Christiane %A Dopper, Elise G P %A Jiskoot, Lize C %A van den Berg-Huysmans, Annette A %A van Swieten, John C %A van der Flier, Wiesje M %A Vrenken, Hugo %A Pijnenburg, Yolande A L %A Barkhof, Frederik %A Scheltens, Philip %A van der Grond, Jeroen %A Rombouts, Serge A R B %X

BACKGROUND/OBJECTIVE: Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) are the most common types of early-onset dementia. We applied longitudinal resting state functional magnetic resonance imaging (fMRI) to delineate functional brain connections relevant for disease progression and diagnostic accuracy.

METHODS: We used two-center resting state fMRI data of 20 AD patients (65.1±8.0 years), 12 bvFTD patients (64.7±5.4 years), and 22 control subjects (63.8±5.0 years) at baseline and 1.8-year follow-up. We used whole-network and voxel-based network-to-region analyses to study group differences in functional connectivity at baseline and follow-up, and longitudinal changes in connectivity within and between groups.

RESULTS: At baseline, connectivity between paracingulate gyrus and executive control network, between cuneal cortex and medial visual network, and between paracingulate gyrus and salience network was higher in AD compared with controls. These differences were also present after 1.8 years. At follow-up, connectivity between angular gyrus and right frontoparietal network, and between paracingulate gyrus and default mode network was lower in bvFTD compared with controls, and lower compared with AD between anterior cingulate gyrus and executive control network, and between lateral occipital cortex and medial visual network. Over time, connectivity decreased in AD between precuneus and right frontoparietal network and in bvFTD between inferior frontal gyrus and left frontoparietal network. Longitudinal changes in connectivity between supramarginal gyrus and right frontoparietal network differ between both patient groups and controls.

CONCLUSION: We found disease-specific brain regions with longitudinal connectivity changes. This suggests the potential of longitudinal resting state fMRI to delineate regions relevant for disease progression and for diagnostic accuracy, although no group differences in longitudinal changes in the direct comparison of AD and bvFTD were found.

%B J Alzheimers Dis %V 55 %P 521-537 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662284?dopt=Abstract %R 10.3233/JAD-150695 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Pitfall of Behavioral Variant Frontotemporal Dementia Mimics Despite Multidisciplinary Application of the FTDC Criteria. %A Krudop, Welmoed A %A Dols, Annemieke %A Kerssens, Cora J %A Eikelenboom, Piet %A Prins, Niels D %A Möller, Christiane %A Schouws, Sigfried %A Rhebergen, Didi %A van Exel, Eric %A van der Flier, Wiesje M %A Sikkes, Sietske %A Scheltens, Philip %A Stek, Max L %A Pijnenburg, Yolande A L %X

BACKGROUND: The behavioral variant of frontotemporal dementia (bvFTD) has a broad differential diagnosis including other neurological and psychiatric disorders. Psychiatric misdiagnoses occur in up to 50% of bvFTD patients. Numbers on misdiagnosis of bvFTD in psychiatric disorders are lacking.

OBJECTIVE: The aim of our study was to investigate the frequency and characteristics of bvFTD misdiagnoses in psychiatric disorders and other neurologic disorders.

METHODS: Thirty-five patients with a (possible or probable) bvFTD diagnosis made by specialized memory clinic neurologists were included. Change in diagnosis after consulting a psychiatrist at baseline was recorded as well as change in diagnosis after two years of multidisciplinary neuropsychiatric follow-up. Differences in cognitive and behavioral profiles were investigated per diagnostic group after follow-up (bvFTD, psychiatry, other neurologic disorders). Clinical profiles are described in detail.

RESULTS: In 17 patients (48.5%), the bvFTD baseline diagnosis changed: Two at baseline after psychiatric consultation, and 15 after two years of multidisciplinary follow-up. Eleven (64.5%) of these 17 patients (31.5% of total) were reclassified with a psychiatric diagnosis. We found no differences for cognitive baseline profiles between patients with bvFTD versus psychiatric diagnoses.

CONCLUSION: In almost half of cases, the initial bvFTD diagnosis was changed after follow-up, most often into a psychiatric disorder. A multidisciplinary neuropsychiatric approach in the diagnostic process of bvFTD results in the identification of treatable disorders. Our findings illustrate a limited specificity of the [18F]FDG-PET-scan and the bvFTD criteria in a neuropsychiatric cohort, especially combined with certain clinical symptoms, like disinhibition, apathy, or loss of empathy.

%B J Alzheimers Dis %V 60 %P 959-975 %8 2017 %G eng %N 3 %R 10.3233/JAD-170608 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Rare Genetic Variant in SORL1 May Increase Penetrance of Alzheimer's Disease in a Family with Several Generations of APOE-ɛ4 Homozygosity. %A Louwersheimer, Eva %A Cohn-Hokke, Petra E %A Pijnenburg, Yolande A L %A Weiss, Marjan M %A Sistermans, Erik A %A Rozemuller, Annemieke J %A Hulsman, Marc %A van Swieten, John C %A van Duijn, Cock M %A Barkhof, Frederik %A Koene, Teddy %A Scheltens, Philip %A van der Flier, Wiesje M %A Holstege, Henne %X

BACKGROUND: The major genetic risk factor for late onset Alzheimer's disease (AD) is the APOE-ɛ4 allele. However, APOE-ɛ4 homozygosity is not fully penetrant, suggesting co-occurrence of additional genetic variants.

OBJECTIVE: To identify genetic factors that, next to APOE-ɛ4 homozygosity, contribute to the development of AD.

METHODS: We identified a family with nine AD patients spanning four generations, with an inheritance pattern suggestive of autosomal dominant AD, with no variants in PSEN1, PSEN2, or APP. We collected DNA from four affected and seven unaffected family members and performed exome sequencing on DNA from three affected and one unaffected family members.

RESULTS: All affected family members were homozygous for the APOE-ɛ4 allele. Statistical analysis revealed that AD onset in this family was significantly earlier than could be expected based on APOE genotype and gender. Next to APOE-ɛ4 homozygosity, we found that all four affected family members carried a rare variant in the VPS10 domain of the SORL1 gene, associated with AβPP processing and AD risk. Furthermore, three of four affected family members carried a rare variant in the TSHZ3 gene, also associated with AβPP processing. Affected family members presented between 61 and 74 years, with variable presence of microbleeds/cerebral amyloid angiopathy and electroencephalographic abnormalities.

CONCLUSION: We hypothesize that next to APOE-ɛ4 homozygosity, impaired SORL1 protein function, and possibly impaired TSHZ3 function, further disturbed Aβ processing. The convergence of these genetic factors over several generations might clarify the increased AD penetrance and the autosomal dominant-like inheritance pattern of AD as observed in this family.

%B J Alzheimers Dis %V 56 %P 63-74 %G eng %N 1 %R 10.3233/JAD-160091 %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 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Dementia and Rapid Mortality: Who is at Risk? %A Staekenborg, Salka S %A Pijnenburg, Yolande A L %A Lemstra, Afina W %A Scheltens, Philip %A Vd Flier, Wiesje M %X

BACKGROUND: Dementia is typically known for its insidious onset and slowly progressive course, but a subgroup deteriorates fast and dies within years or even months.

OBJECTIVE: The purpose of this study was to characterize dementia patients with a rapidly progressive course to death and evaluate their cause of death.

METHODS: We retrospectively included all patients from the Amsterdam Dementia Cohort who died within two years after diagnosis. We evaluated the characteristics of these rapid progressors and compared them to patients known to be alive two years after diagnosis ('non-rapid mortality').

RESULTS: We included 129 dementia patients (13% of our total cohort with known follow-up) with rapid mortality (age 72±10 y [29%  <65 y], 70[55%]M, MMSE 20±5). Mean(SD) survival was 12±7 months. Compared to non-rapid mortality patients (n = 892; age 68±9, 503(56%)M, MMSE 22±5), patients with rapid mortality were slightly older at time of diagnosis, had lower MMSE scores, more depressive symptoms and higher prevalence of a cardiovascular history (all p < 0.05). Alzheimer's disease (AD, 43%) was most frequent in patients with rapid mortality, but the occurrence was much lower compared to non-rapid mortality patients (71%), while all other dementia diagnoses, especially Creutzfeldt-Jakob disease (CJD), vascular dementia (VaD), and frontotemporal dementia (FTD), were more frequent (p < 0.001). There were no specific characteristics for AD patients with rapid versus non-rapid mortality, especially APOE genotypes and CSF-profiles were comparable (p > 0.70). Cause of death was highly variable without a clear relation to dementia diagnosis, with exception of dementia itself in CJD, intracerebral hematoma in VaD, and motor neuron disease in FTD.

CONCLUSIONS: Short survival is relatively common (∼13% in our cohort) and occurs in all different types of dementia, with overrepresentation of non-AD dementias like CJD, VaD, and FTD.

%B J Alzheimers Dis %V 53 %P 135-42 %8 2016 Apr 19 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104894?dopt=Abstract %R 10.3233/JAD-151063 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Diagnostic Accuracy of MRI and Additional [18F]FDG-PET for Behavioral Variant Frontotemporal Dementia in Patients with Late Onset Behavioral Changes. %A Vijverberg, Everard G B %A Wattjes, Mike P %A Dols, Annemiek %A Krudop, Welmoed A %A Möller, Christiane %A Peters, Anne %A Kerssens, Cora J %A Gossink, Flora %A Prins, Niels D %A Stek, Max L %A Scheltens, Philip %A van Berckel, Bart N M %A Barkhof, Frederik %A Pijnenburg, Yolande A L %X

BACKGROUND: Neuroimaging has a reasonable accuracy to differentiate behavioral variant frontotemporal dementia (bvFTD) from other neurodegenerative disorders, its value for the differentiation of bvFTD among subjects with acquired behavioral disturbances is unknown.

OBJECTIVE: To determine the diagnostic accuracy of MRI, additional [18F]FDG-PET, and their combination for bvFTD among subjects with late onset behavioral changes.

METHODS: Patients with late onset behavioral changes referred to a memory clinic or psychiatric services were included. At baseline, 111 patients had a brain MRI scan and 74 patients received an additional [18F]FDG-PET when the MRI was inconclusive. The consensus diagnosis after two-year-follow-up was used as the gold standard to calculate sensitivity and specificity for baseline neuroimaging.

RESULTS: 27 patients had probable/definite bvFTD and 84 patients had a non-bvFTD diagnosis (primary psychiatric diagnosis or other neurological disorders). MRI had a sensitivity of 70% (95% CI 52-85%) with a specificity of 93% (95% CI 86-97%). Additional [18F]FDG-PET had a sensitivity of 90% (95% CI 66-100%) with a specificity of 68% (95% CI 56-79%). The sensitivity of combined neuroimaging was 96% (95% CI 85-100%) with a specificity of 73% (95% CI 63-81%). In 66% of the genetic FTD cases, MRI lacked typical frontotemporal atrophy. 40% of cases with a false positive [18F]FDG-PET scan had a primary psychiatric diagnosis.

CONCLUSION: A good diagnostic accuracy was found for MRI and additional [18F]FDG-PET for bvFTD in patients with late onset behavioral changes. Caution with the interpretation of neuroimaging results should especially be taken in cases with a genetic background and in cases with a primary psychiatric differential diagnosis where [18F]FDG-PET is the only abnormal investigation.

%B J Alzheimers Dis %V 53 %P 1287-97 %8 2016 Jun 30 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27372646?dopt=Abstract %R 10.3233/JAD-160285 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Formal Psychiatric Disorders are not Overrepresented in Behavioral Variant Frontotemporal Dementia. %A Gossink, Flora T %A Dols, Annemieke %A Krudop, Welmoed A %A Sikkes, Sietske A %A Kerssens, Cora J %A Prins, Niels D %A Scheltens, Philip %A Stek, Max L %A Pijnenburg, Yolande A L %K Aged %K Cohort Studies %K Diagnostic and Statistical Manual of Mental Disorders %K Female %K Frontotemporal Dementia %K Humans %K Male %K Mental Disorders %K Middle Aged %K Neuropsychological Tests %K Psychiatric Status Rating Scales %X

While psychiatric misdiagnosis is well-known in behavioral variant frontotemporal dementia (bvFTD), a systematic evaluation of standardized criteria for psychiatric disorders in bvFTD is still missing. Our aim was to define frequency and character of DSM-IV psychiatric disorders among patients with probable and definite bvFTD compared to possible bvFTD, other neurodegenerative diseases, and psychiatric diagnoses, using MINI-International Neuropsychiatric Interview. We additionally compared psychiatric prodromes between these groups. Subjects were participants of the late-onset frontal lobe (LOF) study, a longitudinal multicenter study. In each patient, after baseline diagnostic procedure, a neurologist and geriatric psychiatrist made a joint clinical diagnosis. Independently, a structured diagnostic interview according to DSM-IV and ICD-10 criteria (MINI-Plus) was performed by a trained professional blinded to clinical diagnosis. Out of 91 patients, 23 with probable and definite bvFTD, 3 with possible bvFTD, 25 with a non bvFTD neurodegenerative disease, and 40 with a clinical psychiatric diagnosis were included. Overall frequency of formal current and past psychiatric disorders in probable and definite bvFTD (21.7% current, 8.7% past) did not differ from other neurodegenerative diseases (12.0% current, 16.0% past) or possible bvFTD (66.7% current, 66.7% past), but was less than in patients with a clinical psychiatric diagnosis (57.5% current, 62.5% past; p <  0.01). In probable and definite bvFTD unipolar mood disorders were most common. Formally diagnosed psychiatric disorders are not overrepresented in probable bvFTD, suggesting that psychiatric misdiagnosis in bvFTD can be reduced by strictly applying diagnostic criteria. In suspected bvFTD close collaboration between neurologists and psychiatrists will advance diagnostics and subsequent treatment.

%B J Alzheimers Dis %V 51 %P 1249-56 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967225?dopt=Abstract %R 10.3233/JAD-151198 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Heterogeneous Language Profiles in Patients with Primary Progressive Aphasia due to Alzheimer's Disease. %A Louwersheimer, Eva %A Keulen, M Antoinette %A Steenwijk, Martijn D %A Wattjes, Mike P %A Jiskoot, Lize C %A Vrenken, Hugo %A Teunissen, Charlotte E %A van Berckel, Bart N M %A van der Flier, Wiesje M %A Scheltens, Philip %A van Swieten, John C %A Pijnenburg, Yolande A L %K Aged %K Alzheimer Disease %K Aphasia, Primary Progressive %K Atrophy %K Biomarkers %K Brain %K Female %K Humans %K Language %K Language Tests %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Organ Size %K Positron-Emission Tomography %K Retrospective Studies %X

BACKGROUND: The logopenic variant of Primary Progressive Aphasia (lvPPA) is associated with underlying Alzheimer's disease (AD) pathology and characterized by impaired single word retrieval and repetition of phrases and sentences.

OBJECTIVE: We set out to study whether logopenic aphasia is indeed the prototypic language profile in PPA patients with biomarker evidence of underlying AD pathology and to correlate language profiles with cortical atrophy patterns on MRI.

METHODS: Inclusion criteria: (I) clinical diagnosis of PPA; (II) CSF profile and/or PiB-PET scan indicative for amyloid pathology; (III) availability of expert language evaluation. Based on language evaluation, patients were classified as lvPPA (fulfilling lvPPA core criteria), lvPPA extended (fulfilling core criteria plus other language disturbances), or PPA unclassifiable (not fulfilling lvPPA core criteria). Cortical atrophy patterns on MRI were visually rated and quantitative measurements of cortical thickness were performed using FreeSurfer.

RESULTS: We included 22 patients (age 67±7 years, 50% female, MMSE 21±6). 41% were classified as lvPPA, 36% as lvPPA extended with additional deficits in language comprehension and/or confrontation naming, and 23% as PPA unclassifiable. By both qualitative and quantitative measurements, patients with lvPPA showed mild global cortical atrophy on MRI, whereas patients with lvPPA extended showed more focal cortical atrophy, predominantly at the left tempo-parietal side. For PPA unclassifiable, qualitative measurements revealed a heterogeneous atrophy pattern.

CONCLUSION: Although most patients fulfilled the lvPPA criteria, we found that their language profiles were heterogeneous. The clinical and radiological spectrum of PPA due to underlying AD pathology is broader than pure lvPPA.

%B J Alzheimers Dis %V 51 %P 581-90 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890751?dopt=Abstract %R 10.3233/JAD-150812 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Integrating Biomarkers for Underlying Alzheimer's Disease in Mild Cognitive Impairment in Daily Practice: Comparison of a Clinical Decision Support System with Individual Biomarkers. %A Rhodius-Meester, Hanneke F M %A Koikkalainen, Juha %A Mattila, Jussi %A Teunissen, Charlotte E %A Barkhof, Frederik %A Lemstra, Afina W %A Scheltens, Philip %A Lötjönen, Jyrki %A van der Flier, Wiesje M %K Aged %K Aged, 80 and over %K Algorithms %K Alzheimer Disease %K Area Under Curve %K Biomarkers %K Cognitive Dysfunction %K Cohort Studies %K Decision Support Systems, Clinical %K Disease Progression %K Female %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Outcome Assessment (Health Care) %K Predictive Value of Tests %X

BACKGROUND: Recent criteria allow biomarkers to provide evidence of Alzheimer's disease (AD) pathophysiology. How they should be implemented in daily practice remains unclear, especially in mild cognitive impairment (MCI) patients.

OBJECTIVE: We evaluated how a clinical decision support system such as the PredictAD tool can aid clinicians to integrate biomarker evidence to support AD diagnosis.

METHODS: With available data on demographics, cerebrospinal fluid (CSF), and MRI, we trained the PredictAD tool on a reference population of 246 controls and 491 AD patients. We then applied the identified algorithm to 211 MCI patients. For comparison, we also classified patients based on individual biomarkers (MRI; CSF) and the NIA-AA criteria. Progression to dementia was used as outcome measure.

RESULTS: After a median follow up of 3 years, 72 (34%) MCI patients remained stable and 139 (66%) progressed to AD. The PredictAD tool assigned a likelihood of underlying AD to each patient (AUC 0.82). Excluding patients with missing data resulted in an AUC of 0.87. According to the NIA-AA criteria, half of the MCI patients had uninformative biomarkers, precluding an assignment of AD likelihood. A minority (41%) was assigned to high or low AD likelihood with good predictive value. The individual biomarkers showed best value for CSF total tau (AUC 0.86).

CONCLUSION: The ability of the PredictAD tool to identify AD pathophysiology was comparable to individual biomarkers. The PredictAD tool has the advantage that it assigns likelihood to all patients, regardless of missing or conflicting data, allowing clinicians to integrate biomarker data in daily practice.

%B J Alzheimers Dis %V 50 %P 261-70 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26577521?dopt=Abstract %R 10.3233/JAD-150548 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Low Prevalence of Mixed Dementia in a Cohort of 2,000 Elderly Patients in a Memory Clinic Setting. %A Claus, Jules J %A Staekenborg, Salka S %A Roorda, Jelmen J %A Stevens, Martijn %A Herderschee, Dirk %A van Maarschalkerweerd, Willy %A Schuurmans, Lilly %A Tielkes, Caroline E M %A Koster, Pieter %A Bavinck, Chris %A Scheltens, Philip %K Age Factors %K Aged %K Aged, 80 and over %K Analysis of Variance %K Cognitive Dysfunction %K Cohort Studies %K Dementia %K Female %K Humans %K Male %K Middle Aged %K Neuropsychological Tests %K Prevalence %K Regression Analysis %K Risk Factors %K Tomography Scanners, X-Ray Computed %X

BACKGROUND: It is generally assumed that with increasing age, pathology in clinically diagnosed Alzheimer's disease (AD) becomes more mixed, i.e., co-existence of amyloid plaques and cerebrovascular pathology.

OBJECTIVE: To test the hypothesis of increasing prevalence of mixed dementia in late-onset clinically diagnosed Alzheimer's disease (AD) in a single-center memory clinic population.

METHODS: Patients included had diagnoses of AD (n = 832), subjective cognitive impairment (SCI, n = 333), mild cognitive impairment (MCI, n = 492), vascular dementia (VaD, n = 57), other dementia (n = 53), or other diagnosis (n = 233). Prevalence of severe white matter lesions (WML) was defined as a score of 2 or higher on the Fazekas-scale on brain computed tomography to classify AD patients as having mixed dementia. We examined the effect of age on WML using multiple linear regression analysis, and AD patients were compared to SCI to determine the effect of disease on WML.

RESULTS: Prevalence of severe WML was 33.6% in AD patients (mixed dementia), 11.4% in SCI, 22.7% in MCI, 75.4% in VaD, 3.8% in other dementia, and 15.5% in other diagnosis. With increasing age there was a significant and similar increase of WML scores in SCI, MCI, AD, other dementia, and other diagnosis, indicating no effect modification by AD. The difference between AD patients and SCI averaged 0.16 on the WML score and difference in percentage severe WML between AD and SCI patients was 15% across all ages.

CONCLUSION: We found a low prevalence of mixed dementia. Furthermore, severe WML in AD was largely explained by age rather than effect of disease.

%B J Alzheimers Dis %V 50 %P 797-806 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757192?dopt=Abstract %R 10.3233/JAD-150796 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Protein Kinase Activity Decreases with Higher Braak Stages of Alzheimer's Disease Pathology. %A Rosenberger, Andrea F N %A Hilhorst, Riet %A Coart, Elisabeth %A García Barrado, Leandro %A Naji, Faris %A Rozemuller, Annemieke J M %A van der Flier, Wiesje M %A Scheltens, Philip %A Hoozemans, Jeroen J M %A van der Vies, Saskia M %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cohort Studies %K Female %K Hippocampus %K Humans %K Male %K Middle Aged %K Phosphorylation %K Protein Kinases %K Protein-Serine-Threonine Kinases %K Severity of Illness Index %X

Alzheimer's disease (AD) is characterized by a long pre-clinical phase (20-30 years), during which significant brain pathology manifests itself. Disease mechanisms associated with pathological hallmarks remain elusive. Most processes associated with AD pathogenesis, such as inflammation, synaptic dysfunction, and hyper-phosphorylation of tau are dependent on protein kinase activity. The objective of this study was to determine the involvement of protein kinases in AD pathogenesis. Protein kinase activity was determined in postmortem hippocampal brain tissue of 60 patients at various stages of AD and 40 non-demented controls (Braak stages 0-VI) using a peptide-based microarray platform. We observed an overall decrease of protein kinase activity that correlated with disease progression. The phosphorylation of 96.7% of the serine/threonine peptides and 37.5% of the tyrosine peptides on the microarray decreased significantly with increased Braak stage (p-value <0.01). Decreased activity was evident at pre-clinical stages of AD pathology (Braak I-II). Increased phosphorylation was not observed for any peptide. STRING analysis in combination with pathway analysis and identification of kinases responsible for peptide phosphorylation showed the interactions between well-known proteins in AD pathology, including the Ephrin-receptor A1 (EphA1), a risk gene for AD, and sarcoma tyrosine kinase (Src), which is involved in memory formation. Additionally, kinases that have not previously been associated with AD were identified, e.g., protein tyrosine kinase 6 (PTK6/BRK), feline sarcoma oncogene kinase (FES), and fyn-associated tyrosine kinase (FRK). The identified protein kinases are new biomarkers and potential drug targets for early (pre-clinical) intervention.

%B J Alzheimers Dis %V 49 %P 927-43 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519433?dopt=Abstract %R 10.3233/JAD-150429 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Subjective Memory Complaints in APOEɛ4 Carriers are Associated with High Amyloid-β Burden. %A Zwan, Marissa D %A Villemagne, Victor L %A Doré, Vincent %A Buckley, Rachel %A Bourgeat, Pierrick %A Veljanoski, Robyn %A Salvado, Olivier %A Williams, Rob %A Margison, Laura %A Rembach, Alan %A Macaulay, S Lance %A Martins, Ralph %A Ames, David %A van der Flier, Wiesje M %A Ellis, Kathryn A %A Scheltens, Philip %A Masters, Colin L %A Rowe, Christopher C %K Aged %K Aging %K Amyloid beta-Peptides %K Aniline Compounds %K Apolipoprotein E4 %K Benzothiazoles %K Brain %K Cognition Disorders %K Female %K Genotyping Techniques %K Heterozygote %K Humans %K Logistic Models %K Male %K Neuropsychological Tests %K Positron-Emission Tomography %K Radiopharmaceuticals %K Thiazoles %X

BACKGROUND: APOEɛ4 genotype and aging have been identified as risk factors for Alzheimer's disease (AD). In addition, subjective memory complaints (SMC) might be a first clinical expression of the effect of AD pathology on cognitive functioning.

OBJECTIVE: To assess whether APOEɛ4 genotype, age, SMC, and episodic memory are risk factors for high amyloid-β (Aβ) burden in cognitively normal elderly.

METHODS: 307 cognitively normal participants (72.7 ± 6.8 years, 53% female, 55% SMC) from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study underwent amyloid PET and APOE genotyping. Logistic regression analyses were performed to determine the association of APOEɛ4 genotype, age, SMC, and episodic memory with Aβ pathology.

RESULTS: Odds of high Aβ burden were greater at an older age (OR = 3.21; 95% CI = 1.68-6.14), when SMC were present (OR = 1.90; 95% CI = 1.03-3.48), and for APOEɛ4 carriers (OR = 7.49; 95% CI = 3.96-14.15), while episodic memory was not associated with odds of high Aβ burden. Stratified analyses showed that odds of SMC for high Aβ burden were increased in specifically APOEɛ4 carriers (OR = 4.58, 95% CI = 1.83-11.49) and younger participants (OR = 3.73, 95% CI = 1.39-10.01).

CONCLUSION: Aging, APOEɛ4 genotype, and SMC were associated with high Aβ burden. SMC were especially indicative of high Aβ burden in younger participants and in APOEɛ4 carriers. These findings suggest that selection based on the presence of SMC, APOEɛ4 genotype and age may help identify healthy elderly participants with high Aβ burden eligible for secondary prevention trials.

%B J Alzheimers Dis %V 49 %P 1115-22 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639956?dopt=Abstract %R 10.3233/JAD-150446 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Timely Diagnosis for Alzheimer's Disease: A Literature Review on Benefits and Challenges. %A Dubois, Bruno %A Padovani, Alessandro %A Scheltens, Philip %A Rossi, Andrea %A Dell'Agnello, Grazia %K Alzheimer Disease %K Databases, Bibliographic %K Humans %K Time Factors %X

BACKGROUND: Timely diagnosis of Alzheimer's disease (AD) refers to a diagnosis at the stage when patients come to the attention of clinicians because of concerns about changes in cognition, behavior, or functioning and can be still free of dementia and functionally independent.

OBJECTIVES: To comprehensively review existing scientific evidence on the benefits and potential challenges of making a timely diagnosis of AD.

METHODS: Relevant studies were identified by searching electronic databases (Medline, Embase) and bibliographies for studies published in English between 1 January 2000 and 2 June 2014 on the consequences of a timely diagnosis of AD.

RESULTS: Nine studies were identified that investigated the consequences of diagnosing AD at the initial stages; none were specifically focused on prodromal AD. A timely diagnosis potentially offers the opportunities of early intervention, implementation of coordinated care plans, better management of symptoms, patient safety, cost savings, and postponement of institutionalization. Barriers to making a timely diagnosis include stigma, suicide risk, lack of training, diagnostic uncertainty, shortage of specialized diagnostic services, and the reluctance of healthcare providers to make a diagnosis when no effective disease-modifying options are available.

CONCLUSIONS: Despite its potential benefits, few published studies have explored the advantages or risks of a timely diagnosis of AD. In light of the cultural shift toward diagnosis at the initial stage of the disease continuum, when the patient does not yet have dementia, more investigations are needed to evaluate the benefits and address the barriers that may impede making a timely AD diagnosis.

%B J Alzheimers Dis %V 49 %P 617-31 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484931?dopt=Abstract %R 10.3233/JAD-150692 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Correcting for the Absence of a Gold Standard Improves Diagnostic Accuracy of Biomarkers in Alzheimer's Disease. %A Coart, Els %A Barrado, Leandro García %A Duits, Flora H %A Scheltens, Philip %A van der Flier, Wiesje M %A Teunissen, Charlotte E %A van der Vies, Saskia M %A Burzykowski, Tomasz %X

BACKGROUND: Studies investigating the diagnostic accuracy of biomarkers for Alzheimer's disease (AD) are typically performed using the clinical diagnosis or amyloid-β positron emission tomography as the reference test. However, neither can be considered a gold standard or a perfect reference test for AD. Not accounting for errors in the reference test is known to cause bias in the diagnostic accuracy of biomarkers.

OBJECTIVE: To determine the diagnostic accuracy of AD biomarkers while taking the imperfectness of the reference test into account.

METHODS: To determine the diagnostic accuracy of AD biomarkers and taking the imperfectness of the reference test into account, we have developed a Bayesian method. This method establishes the biomarkers' true value in predicting the AD-pathology status by combining the reference test and the biomarker data with available information on the reliability of the reference test. The new methodology was applied to two clinical datasets to establish the joint accuracy of three cerebrospinal fluid biomarkers (amyloid-β1-42, Total tau, and P-tau181) by including the clinical diagnosis as imperfect reference test into the analysis.

RESULTS: The area under the receiver-operating-characteristics curve to discriminate between AD and controls, increases from 0.949 (with 95% credible interval [0.935,0.960]) to 0.990 ([0.985,0.995]) and from 0.870 ([0.817,0.912]) to 0.975 ([0.943,0.990]) for the cohorts, respectively.

CONCLUSIONS: Use of the Bayesian methodology enables an improved estimate of the exact diagnostic value of AD biomarkers and overcomes the lack of a gold standard for AD. Using the new method will increase the diagnostic confidence for early stages of AD.

%B J Alzheimers Dis %8 2015 Apr 13 %G eng %R 10.3233/JAD-142886 %0 Journal Article %J Lancet Neurol %D 2014 %T Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. %A Dubois, Bruno %A Feldman, Howard H %A Jacova, Claudia %A Hampel, Harald %A Molinuevo, José Luis %A Blennow, Kaj %A DeKosky, Steven T %A Gauthier, Serge %A Selkoe, Dennis %A Bateman, Randall %A Cappa, Stefano %A Crutch, Sebastian %A Engelborghs, Sebastiaan %A Frisoni, Giovanni B %A Fox, Nick C %A Galasko, Douglas %A Habert, Marie-Odile %A Jicha, Gregory A %A Nordberg, Agneta %A Pasquier, Florence %A Rabinovici, Gil %A Robert, Philippe %A Rowe, Christopher %A Salloway, Stephen %A Sarazin, Marie %A Epelbaum, Stéphane %A de Souza, Leonardo C %A Vellas, Bruno %A Visser, Pieter J %A Schneider, Lon %A Stern, Yaakov %A Scheltens, Philip %A Cummings, Jeffrey L %K Alzheimer Disease %K Biomarkers %K Humans %K International Cooperation %K Phenotype %K Practice Guidelines as Topic %K Societies, Medical %X

In the past 8 years, both the International Working Group (IWG) and the US National Institute on Aging-Alzheimer's Association have contributed criteria for the diagnosis of Alzheimer's disease (AD) that better define clinical phenotypes and integrate biomarkers into the diagnostic process, covering the full staging of the disease. This Position Paper considers the strengths and limitations of the IWG research diagnostic criteria and proposes advances to improve the diagnostic framework. On the basis of these refinements, the diagnosis of AD can be simplified, requiring the presence of an appropriate clinical AD phenotype (typical or atypical) and a pathophysiological biomarker consistent with the presence of Alzheimer's pathology. We propose that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease. This paper also elaborates on the specific diagnostic criteria for atypical forms of AD, for mixed AD, and for the preclinical states of AD.

%B Lancet Neurol %V 13 %P 614-29 %8 2014 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/24849862?dopt=Abstract %R 10.1016/S1474-4422(14)70090-0 %0 Journal Article %J Alzheimers Dement %D 2011 %T The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. %A McKhann, Guy M %A Knopman, David S %A Chertkow, Howard %A Hyman, Bradley T %A Jack, Clifford R %A Kawas, Claudia H %A Klunk, William E %A Koroshetz, Walter J %A Manly, Jennifer J %A Mayeux, Richard %A Mohs, Richard C %A Morris, John C %A Rossor, Martin N %A Scheltens, Philip %A Carrillo, Maria C %A Thies, Bill %A Weintraub, Sandra %A Phelps, Creighton H %K Alzheimer Disease %K Biomarkers %K Diagnosis, Differential %K Diagnostic Imaging %K Disease Progression %K Humans %K National Institute on Aging (U.S.) %K Practice Guidelines as Topic %K Societies, Medical %K United States %X

The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.

%B Alzheimers Dement %V 7 %P 263-9 %8 2011 May %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/21514250?dopt=Abstract %R 10.1016/j.jalz.2011.03.005