%0 Journal Article %J J Alzheimers Dis %D 2021 %T Association of Malnutrition with Functional and Cognitive Trajectories in People Living with Dementia: A Five-Year Follow-Up Study. %A Borda, Miguel Germán %A Ayala Copete, Ana María %A Tovar-Rios, Diego Alejandro %A Jaramillo-Jimenez, Alberto %A Giil, Lasse Melvær %A Soennesyn, Hogne %A Gómez-Arteaga, Camilo %A Venegas-Sanabria, Luis Carlos %A Kristiansen, Ida %A Chavarro-Carvajal, Diego Andrés %A Caicedo, Sandra %A Cano-Gutierrez, Carlos Alberto %A Vik-Mo, Audun %A Aarsland, Dag %X

BACKGROUND: In dementia, functional status depends on multiple factors in addition to cognition. Nutritional status is a potentially modifiable factor related to homeostasis and proper functioning of body systems and may contribute to cognitive and functional decline.

OBJECTIVE: This paper aims to analyze the association of malnutrition with the course of cognitive and functional decline in people living with dementia.

METHODS: This is an analysis of a longitudinal cohort study, the Dementia Study of Western Norway. Data of 202 patients diagnosed with mild dementia were analyzed; Alzheimer's disease (AD) (n = 103), Lewy body dementia (LBD) (n = 74), and other dementias (OD) (n = 25). Cognition was assessed with the Mini-Mental State Examination and functional decline through the activities of daily living included in the Rapid Disability Rating Scale. The Global Leadership Initiative on Malnutrition Index was used to determine nutritional status. Associations of nutritional status with cognitive and functional decline were evaluated through adjusted linear mixed models.

RESULTS: At baseline, the prevalence of general malnutrition was 28.7%; 17.32% were classified as moderate malnutrition and 11.38% as severe malnutrition (there were no significant differences between AD and LBD). Malnutrition at diagnosis and over follow-up was a significant predictor of functional-decline, but not of cognitive decline.

CONCLUSION: According to our results malnutrition was associated with faster functional loss but, not cognitive decline in older adults with dementia. A more comprehensive dementia approach including nutritional assessments could improve prognosis.

%B J Alzheimers Dis %V 79 %P 1713-1722 %8 2021 Feb 16 %G eng %N 4 %R 10.3233/JAD-200961 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Plasma Neurofilament Light Chain Predicts Cognitive Progression in Prodromal and Clinical Dementia with Lewy Bodies. %A Pilotto, Andrea %A Imarisio, Alberto %A Carrarini, Claudia %A Russo, Mirella %A Masciocchi, Stefano %A Gipponi, Stefano %A Cottini, Elisabetta %A Aarsland, Dag %A Zetterberg, Henrik %A Ashton, Nicholas J %A Hye, Abdul %A Bonanni, Laura %A Padovani, Alessandro %X

Plasma neurofilament light chain (NfL) is a marker of neuronal damage in different neurological disorders and might predict disease progression in dementia with Lewy bodies (DLB). The study enrolled 45 controls and 44 DLB patients (including 17 prodromal cases) who underwent an extensive assessment at baseline and at 2 years follow-up. At baseline, plasma NfL levels were higher in both probable DLB and prodromal cases compared to controls. Plasma NfL emerged as the best predictor of cognitive decline compared to age, sex, and baseline severity variables. The study supports the role of plasma NfL as a useful prognostic biomarker from the early stages of DLB.

%B J Alzheimers Dis %V 82 %P 913-919 %8 2021 Aug 03 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34151807?dopt=Abstract %R 10.3233/JAD-210342 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Exploration of Plasma Lipids in Mild Cognitive Impairment due to Alzheimer's Disease. %A Bergland, Anne Katrine %A Proitsi, Petroula %A Kirsebom, Bjørn-Eivind %A Soennesyn, Hogne %A Hye, Abdul %A Larsen, Alf Inge %A Xu, Jin %A Legido-Quigley, Cristina %A Rajendran, Lawrence %A Fladby, Tormod %A Aarsland, Dag %X

BACKGROUND: Lipids have important structural roles in cell membranes and changes to these membrane lipids may influence β- and γ-secretase activities and thus contribute to Alzheimer's disease (AD) pathology.

OBJECTIVE: To explore baseline plasma lipid profiling in participants with mild cognitive impairment (MCI) with and without AD pathology.

METHODS: We analyzed 261 plasma lipid profiles using reversed phase chromatography mass spectrometry in cerebrospinal fluid amyloid positive (Aβ+) or negative (Aβ-) participants with MCI as compared to controls. Additionally, we analyzed the potential associations of plasma lipid profiles with performance on neuropsychological tests at baseline and after two years.

RESULTS: Sphingomyelin (SM) concentrations, particularly, SM(d43:2), were lower in MCI Aβ+ individuals compared to controls. Further, SM(d43:2) was also nominally reduced in MCI Aβ+ individuals compared to MCI Aβ-. No plasma lipids were associated with performance on neuropsychological tests at baseline or between the two time points after correction for multiple testing.

CONCLUSION: Reduced plasma concentrations of SM were associated with AD.

%B J Alzheimers Dis %V 77 %P 1117-1127 %8 2020 Sep 29 %G eng %N 3 %R 10.3233/JAD-200441 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Abnormalities of Resting State Cortical EEG Rhythms in Subjects with Mild Cognitive Impairment Due to Alzheimer's and Lewy Body Diseases. %A Babiloni, Claudio %A Del Percio, Claudio %A Lizio, Roberta %A Noce, Giuseppe %A Lopez, Susanna %A Soricelli, Andrea %A Ferri, Raffaele %A Pascarelli, Maria Teresa %A Catania, Valentina %A Nobili, Flavio %A Arnaldi, Dario %A Famá, Francesco %A Aarsland, Dag %A Orzi, Francesco %A Buttinelli, Carla %A Giubilei, Franco %A Onofrj, Marco %A Stocchi, Fabrizio %A Vacca, Laura %A Stirpe, Paola %A Fuhr, Peter %A Gschwandtner, Ute %A Ransmayr, Gerhard %A Garn, Heinrich %A Fraioli, Lucia %A Pievani, Michela %A Frisoni, Giovanni B %A D'Antonio, Fabrizia %A de Lena, Carlo %A Güntekin, Bahar %A Hanoğlu, Lutfu %A Başar, Erol %A Yener, Görsev %A Emek-Savaş, Derya Durusu %A Triggiani, Antonio Ivano %A Franciotti, Raffaella %A Taylor, John Paul %A De Pandis, Maria Francesca %A Bonanni, Laura %X

The present study tested the hypothesis that cortical sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms reveal different abnormalities in cortical neural synchronization in groups of patients with mild cognitive impairment due to Alzheimer's disease (ADMCI) and dementia with Lewy bodies (DLBMCI) as compared to cognitively normal elderly (Nold) subjects. Clinical and rsEEG data in 30 ADMCI, 23 DLBMCI, and 30 Nold subjects were available in an international archive. Age, gender, and education were carefully matched in the three groups. The Mini-Mental State Evaluation (MMSE) score was matched between the ADMCI and DLBMCI groups. Individual alpha frequency peak (IAF) was used to determine the delta, theta, alpha1, alpha2, and alpha3 frequency band ranges. Fixed beta1, beta2, and gamma bands were also considered. eLORETA estimated the rsEEG cortical sources. Receiver operating characteristic curve (ROCC) classified these sources across individuals. Compared to Nold, IAF showed marked slowing in DLBMCI and moderate in ADMCI. Furthermore, the posterior alpha 2 and alpha 3 source activities were more abnormal in the ADMCI than the DLBMCI group, while widespread delta source activities were more abnormal in the DLBMCI than the ADMCI group. The posterior delta and alpha sources correlated with the MMSE score and correctly classified the Nold and MCI individuals (area under the ROCC >0.85). In conclusion, the ADMCI and DLBMCI patients showed different features of cortical neural synchronization at delta and alpha frequencies underpinning brain arousal and vigilance in the quiet wakefulness. Future prospective cross-validation studies will have to test the clinical validity of these rsEEG markers.

%B J Alzheimers Dis %V 62 %P 247-268 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439335?dopt=Abstract %R 10.3233/JAD-170703 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Antibodies to Multiple Receptors are Associated with Neuropsychiatric Symptoms and Mortality in Alzheimer's Disease: A Longitudinal Study. %A Giil, Lasse M %A Aarsland, Dag %A Hellton, Kristoffer %A Lund, Anders %A Heidecke, Harald %A Schulze-Forster, Kai %A Riemekasten, Gabriela %A Vik-Mo, Audun Osland %A Kristoffersen, Einar K %A Vedeler, Christian A %A Nordrehaug, Jan Erik %X

BACKGROUND: Endogenous antibodies to signaling molecules and receptors (Abs) are associated with Alzheimer's disease (AD).

OBJECTIVES: To investigate the association of 33 Abs to dopaminergic, serotoninergic, muscarinic, adrenergic, vascular, and immune receptors with cognitive, neuropsychiatric, and mortality outcomes.

METHODS: Ninety-one patients with mild AD were followed annually for 5 years with the Mini-Mental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI; composite outcomes: "psychosis" (item 1 + 2), "mood" (item 4 + 5 + 7), and "agitation" (item 3 + 8 + 9)). Abs were quantified in sera obtained at baseline by ELISA and reduced to principal components (PCs). Associations between Abs and outcomes were assessed by a mixed model (MMSE decline), zero-inflated fixed effects count models (composite NPI scores), and Cox regression (mortality). The resulting p-values were adjusted for multiple testing according to a false discovery rate of 0.05 (Benjamini-Hochberg).

RESULTS: The measured levels of the 33 Abs formed four PCs. PC1 (dopaminergic and serotonergic Abs) was associated with increased mortality (Hazard ratio 2.57, p < 0.001), PC2 (serotonergic, immune, and vascular Abs) with decreased agitation symptoms (β - 0.19, p < 0.001), and PC3 (cholinergic receptor Abs) with increased mood symptoms (β 0.04, p = 0.002), over time. There were no associations between Abs and MMSE decline.

CONCLUSION: The associations between Abs, mortality, and neuropsychiatric symptoms reported in this cohort are intriguing. They cannot, however, be generalized. Validation in independent sample sets is required.

%B J Alzheimers Dis %V 64 %P 761-774 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914018?dopt=Abstract %R 10.3233/JAD-170882 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Abnormalities of Cortical Neural Synchronization Mechanisms in Subjects with Mild Cognitive Impairment due to Alzheimer's and Parkinson's Diseases: An EEG Study. %A Babiloni, Claudio %A Del Percio, Claudio %A Lizio, Roberta %A Noce, Giuseppe %A Cordone, Susanna %A Lopez, Susanna %A Soricelli, Andrea %A Ferri, Raffaele %A Pascarelli, Maria Teresa %A Nobili, Flavio %A Arnaldi, Dario %A Famá, Francesco %A Aarsland, Dag %A Orzi, Francesco %A Buttinelli, Carla %A Giubilei, Franco %A Onofrj, Marco %A Stocchi, Fabrizio %A Stirpe, Paola %A Fuhr, Peter %A Gschwandtner, Ute %A Ransmayr, Gerhard %A Caravias, Georg %A Garn, Heinrich %A Sorpresi, Fabiola %A Pievani, Michela %A D'Antonio, Fabrizia %A de Lena, Carlo %A Güntekin, Bahar %A Hanoğlu, Lutfu %A Başar, Erol %A Yener, Görsev %A Emek-Savaş, Derya Durusu %A Triggiani, Antonio Ivano %A Franciotti, Raffaella %A Frisoni, Giovanni B %A Bonanni, Laura %A De Pandis, Maria Francesca %X

The aim of this retrospective and exploratory study was that the cortical sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms might reveal different abnormalities in cortical neural synchronization in groups of patients with mild cognitive impairment due to Alzheimer's disease (ADMCI) and Parkinson's disease (PDMCI) as compared to healthy subjects. Clinical and rsEEG data of 75 ADMCI, 75 PDMCI, and 75 cognitively normal elderly (Nold) subjects were available in an international archive. Age, gender, and education were carefully matched in the three groups. The Mini-Mental State Evaluation (MMSE) was matched between the ADMCI and PDMCI groups. Individual alpha frequency peak (IAF) was used to determine the delta, theta, alpha1, alpha2, and alpha3 frequency band ranges. Fixed beta1, beta2, and gamma bands were also considered. eLORETA estimated the rsEEG cortical sources. Receiver operating characteristic curve (ROC) classified these sources across individuals. Results showed that compared to the Nold group, the posterior alpha2 and alpha3 source activities were more abnormal in the ADMCI than the PDMCI group, while the parietal delta source activities were more abnormal in the PDMCI than the ADMCI group. The parietal delta and alpha sources correlated with MMSE score and correctly classified the Nold and diseased individuals (area under the ROC = 0.77-0.79). In conclusion, the PDMCI and ADMCI patients showed different features of cortical neural synchronization at delta and alpha frequencies underpinning brain arousal and vigilance in the quiet wakefulness. Future prospective cross-validation studies will have to test these rsEEG markers for clinical applications and drug discovery.

%B J Alzheimers Dis %V 59 %P 339-358 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28621693?dopt=Abstract %R 10.3233/JAD-160883 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Accuracy of Clinical Diagnosis of Dementia with Lewy Bodies versus Neuropathology. %A Skogseth, Ragnhild %A Hortobágyi, Tibor %A Soennesyn, Hogne %A Chwiszczuk, Luiza %A Ffytche, Dominic %A Rongve, Arvid %A Ballard, Clive %A Aarsland, Dag %X

BACKGROUND: The first consensus criteria for dementia with Lewy bodies (DLB) published in 1996 were revised in 2005, partly because the original clinical criteria had suboptimal sensitivity. Few studies have assessed the accuracy of the 2005 criteria applied prospectively in newly diagnosed patients who have been followed longitudinally.

OBJECTIVE: To explore the correlation between clinical and pathological diagnoses in patients with DLB and Parkinson's disease with dementia (PDD).

METHODS: From a prospective referral cohort study with enriched recruitment of patients with DLB and PDD, we included the first 56 patients coming to autopsy. Patients had mild dementia at inclusion and were followed annually until death with standardized clinical assessments. Pathological assessment was performed blind to clinical information according to standardized protocols and consensus criteria for DLB.

RESULTS: 20 patients received a pathological diagnosis of Lewy body disease; the corresponding clinical diagnoses were probable DLB (n = 11), PDD (n = 5), probable (n = 2) or possible (n = 2) Alzheimer's disease (AD). Of 14 patients with a clinical diagnosis of probable DLB, 11 had DLB/PDD and 3 had AD at pathology. One patient with clinically possible DLB fulfilled criteria for pathological AD. Sensitivity, specificity, positive predictive value, and negative predictive values for probable DLB were 73%, 93%, 79%, and 90%.

CONCLUSION: Our findings suggest that the international clinical consensus criteria for DLB perform reasonably well. However, false positive and false negative diagnoses still occur, indicating that the criteria need to be improved, that biomarkers may be needed, and that neuropathological feedback is vital to improve accuracy.

%B J Alzheimers Dis %V 59 %P 1139-1152 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28731443?dopt=Abstract %R 10.3233/JAD-170274 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Antibodies to Signaling Molecules and Receptors in Alzheimer's Disease are Associated with Psychomotor Slowing, Depression, and Poor Visuospatial Function. %A Giil, Lasse M %A Vedeler, Christian A %A Kristoffersen, Einar K %A Nordrehaug, Jan Erik %A Heidecke, Harald %A Dechend, Ralf %A Schulze-Forster, Kai %A Muller, Dominik N %A von Goetze, Victoria S %A Cabral-Marques, Otavio %A Riemekasten, Gabriela %A Vogelsang, Petra %A Nygaard, Staale %A Lund, Anders %A Aarsland, Dag %X

BACKGROUND: Alzheimer's disease (AD) is associated with several antibodies as well as signaling molecules and receptors. These may be detrimental in the presence of a disrupted blood-brain barrier (BBB).

OBJECTIVE: To investigate whether the levels of antibodies toward 33 signaling molecules involved in neurotransmitter, vascular, and immune functions were associated with AD and, within the AD group; cognitive function and mood.

METHODS: Antibodies in sera from patients with mild AD [(n = 91) defined as a Mini-Mental State Examination ≥ 20 or a Clinical Dementia Rating Scale≤1] and healthy controls (n = 102) were measured with enzyme-linked immunosorbent assays. Levels in AD and controls were compared by Mann-Whitney test. In the AD group, associations between antibodies and psychometric test scores were analyzed by robust regression. The false discovery threshold was set to 0.05.

RESULTS: Antibodies to serotonin receptors [5-HT2AR (effect size (r) = 0.21, p = 0.004), 5-HT2CR (r = 0.25, p = 0.0005) and 5-HT7R (r = 0.21, p = 0.003)], vascular endothelial growth factor receptor 1 [VEGFR1 (r = 0.29, p < 0.001)] and immune-receptors (Stabilin-1 (r = 0.23, p = 0.001) and C5aR1 (r = 0.21, p = 0.004) were higher in AD. Psychomotor speed was associated with D1R-abs (β 0.49, p < 0.001), depression with ETAR-abs (β 0.31, p < 0.001), and visuospatial function with 5-HT1AR-abs (β 0.27, p = 0.004) despite similar antibody levels compared to controls.

CONCLUSIONS: Antibody levels to VEGFR1, serotonergic receptors, and receptors in the immune system were increased in AD. Antibodies at similar levels as in controls were associated cognitive dysfunction and depression in AD.

%B J Alzheimers Dis %V 59 %P 929-939 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28697567?dopt=Abstract %R 10.3233/JAD-170245 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Detecting At-Risk Alzheimer's Disease Cases. %A Fladby, Tormod %A Pålhaugen, Lene %A Selnes, Per %A Waterloo, Knut %A Bråthen, Geir %A Hessen, Erik %A Almdahl, Ina Selseth %A Arntzen, Kjell-Arne %A Auning, Eirik %A Eliassen, Carl Fredrik %A Espenes, Ragna %A Grambaite, Ramune %A Grøntvedt, Gøril Rolfseng %A Johansen, Krisztina Kunszt %A Johnsen, Stein Harald %A Kalheim, Lisa Flem %A Kirsebom, Bjørn-Eivind %A Müller, Kai Ivar %A Nakling, Arne Exner %A Rongve, Arvid %A Sando, Sigrid Botne %A Siafarikas, Nikias %A Stav, Ane Løvli %A Tecelao, Sandra %A Timon, Santiago %A Bekkelund, Svein Ivar %A Aarsland, Dag %X

While APOEɛ4 is the major genetic risk factor for Alzheimer's disease (AD), amyloid dysmetabolism is an initial or early event predicting clinical disease and is an important focus for secondary intervention trials. To improve identification of cases with increased AD risk, we evaluated recruitment procedures using pathological CSF concentrations of Aβ42 (pAβ) and APOEɛ4 as risk markers in a multi-center study in Norway. In total, 490 subjects aged 40-80 y were included after response to advertisements and media coverage or memory clinics referrals. Controls (n = 164) were classified as normal controls without first-degree relatives with dementia (NC), normal controls with first-degree relatives with dementia (NCFD), or controls scoring below norms on cognitive screening. Patients (n = 301) were classified as subjective cognitive decline or mild cognitive impairment. Subjects underwent a clinical and cognitive examination and MRI according to standardized protocols. Core biomarkers in CSF from 411 and APOE genotype from 445 subjects were obtained. Cases (both self-referrals (n = 180) and memory clinics referrals (n = 87)) had increased fractions of pAβ and APOEɛ4 frequency compared to NC. Also, NCFD had higher APOEɛ4 frequencies without increased fraction of pAβ compared to NC, and cases recruited from memory clinics had higher fractions of pAβ and APOEɛ4 frequency than self-referred. This study shows that memory clinic referrals are pAβ enriched, whereas self-referred and NCFD cases more frequently are pAβ negative but at risk (APOEɛ4 positive), suitable for primary intervention.

%B J Alzheimers Dis %V 60 %P 97-105 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28826181?dopt=Abstract %R 10.3233/JAD-170231 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effect of Vascular Risk Factors on the Progression of Mild Alzheimer's Disease and Lewy Body Dementia. %A Bergland, Anne Katrine %A Dalen, Ingvild %A Larsen, Alf Inge %A Aarsland, Dag %A Soennesyn, Hogne %X

BACKGROUND: Vascular risk factors (VRF) are associated with an increased risk of neurodegenerative disease.

OBJECTIVE: To examine the association between VRF and cognitive decline in patients with Alzheimer's disease (AD) and Lewy body dementia (LBD).

METHODS: We included consecutive referrals with mild AD or LBD to dementia clinics in western Norway from 2005 to 2013. The Mini-Mental Status Exam (MMSE) and Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) were administered at baseline and then annually for up to five years. The VRF include diabetes mellitus, hypertension, hypercholesterolemia, overweight and smoking. Generalized Estimating Equations (GEE) were used to examine the potential association between VRF scores and the change in MMSE and CDR-SB scores, adjusting for age, sex, and the apolipoprotein ɛ4 allele (APOE4).

RESULTS: A total of 200 patients were included (113 AD, 87 LBD) (mean age 76 years, mean baseline MMSE 24.0, mean follow-up time 3.5 years). Smoking was the only VRF significantly associated with a more rapid cognitive decline, however only in the AD group. Being overweight at baseline was associated with a slower cognitive decline. Moreover, hypertension at baseline predicted a slower decline in MMSE scores. In the LBD group diabetes mellitus was found to be associated with a slower increase in CDR-SB scores.

CONCLUSION: With the exception of smoking, VRF at time of dementia diagnosis were not associated with a more rapid cognitive decline.

%B J Alzheimers Dis %V 56 %P 575-584 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28035932?dopt=Abstract %R 10.3233/JAD-160847 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effects of Risperidone and Galantamine Treatment on Alzheimer's Disease Biomarker Levels in Cerebrospinal Fluid. %A Bloniecki, Victor %A Aarsland, Dag %A Blennow, Kaj %A Cummings, Jeffrey %A Falahati, Farshad %A Winblad, Bengt %A Freund-Levi, Yvonne %X

BACKGROUND: Treatment for neuropsychiatric symptoms (NPS) in dementia is insufficient. Antipsychotics and acetylcholinesterase inhibitors are used generating symptomatic improvements in behavior and cognition, but few studies have investigated their effect on Alzheimer's disease (AD) biomarkers in cerebrospinal fluid (CSF).

OBJECTIVE: This is a secondary analysis based on an earlier clinical trial comparing the treatment effects on NPS. The aim of this study was to examine whether treatment with risperidone and galantamine affect levels of the biomarkers T-Tau, P-Tau, Aβ1-42, and Aβ42/40-ratio in CSF. The secondary aim was to test if baseline levels of these biomarkers are associated with the clinical course of NPS.

METHODS: 83 patients (mean + SD 77.9.6±7.7 years) with dementia and NPS were randomized to galantamine (n = 44) or risperidone (n = 39) treatment. CSF samples were collected at baseline and after 12 weeks.

RESULTS: Changes in levels of biomarkers between the two treatment groups did not differ significantly. Low baseline levels of Aβ1 - 42 was significantly associated with reduction of irritability at follow up. Low baseline levels of Aβ1-42, Aβ42/40, and P-Tau were significant correlates of reduction in appetite and eating disorders. CSF Aβ1-42 levels in patients treated with risperidone were significantly decreased at follow up, showing an 8% (40 pg/mL) reduction as compared with baseline (p = 0.03).

CONCLUSIONS: Our results suggest that risperidone may affect the CSF profile of AD biomarkers indicating more amyloid pathology. Treatment with galantamine did not affect the CSF biomarkers in any direction. The AD CSF biomarkers displayed correlations with specific NPS suggesting potential research questions to be pursued.

%B J Alzheimers Dis %V 57 %P 387-393 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269767?dopt=Abstract %R 10.3233/JAD-160758 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Increased Transforming Growth Factor β2 in the Neocortex of Alzheimer's Disease and Dementia with Lewy Bodies is Correlated with Disease Severity and Soluble Aβ42 Load. %A Chong, Joyce R %A Chai, Yuek Ling %A Lee, Jasinda H %A Howlett, David %A Attems, Johannes %A Ballard, Clive G %A Aarsland, Dag %A Francis, Paul T %A Chen, Christopher P %A Lai, Mitchell K P %X

BACKGROUND: Of the three transforming growth factor (TGF)-β isoforms known, TGFβ1 deficits have been widely reported in Alzheimer's disease (AD) and studied as a potential therapeutic target. In contrast, the status of TGFβ2, which has been shown to mediate amyloid-β (Aβ)-mediated neuronal death, are unclear both in AD and in Lewy body dementias (LBD) with differential neuritic plaque and neurofibrillary tangle burden.

OBJECTIVE: To measure neocortical TGFβ2 levels and their correlations with neuropathological and clinical markers of disease severity in a well-characterized cohort of AD as well as two clinical subtypes of LBD, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), known to manifest relatively high and low Aβ plaque burden, respectively.

METHODS: Postmortem samples from temporal cortex (BA21) were measured for TGFβ2 using a Luminex-based platform, and correlated with scores for neuritic plaques, neurofibrillary tangles, α-synuclein pathology, dementia severity (as measured by annual decline of Mini-Mental State Examination scores) as well as soluble and total fractions of brain Aβ42.

RESULTS: TGFβ2 was significantly increased in AD and DLB, but not in PDD. TGFβ2 also correlated with scores for neurofibrillary tangles, Lewy bodies (within the LBD group), dementia severity, and soluble Aβ42 concentration, but not with neuritic plaque scores, total Aβ42, or monomeric α-synuclein immunoreactivity.

CONCLUSIONS: TGFβ2 is increased in the temporal cortex of AD and DLB, and its correlations with neuropathological and clinical markers of disease severity as well as with soluble Aβ42 load suggest a potential pathogenic role in mediating the neurotoxicity of non-fibrillar Aβ. Our study also indicates the potential utility of targeting TGFβ2 in pharmacotherapeutic approaches to AD and DLB.

%B J Alzheimers Dis %V 56 %P 157-166 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911312?dopt=Abstract %R 10.3233/JAD-160781 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Long-Term Cognitive Decline in Dementia with Lewy Bodies in a Large Multicenter, International Cohort. %A Kramberger, Milica G %A Auestad, Bjørn %A Garcia-Ptacek, Sara %A Abdelnour, Carla %A Olmo, Josep Garre %A Walker, Zuzana %A Lemstra, Afina W %A Londos, Elisabet %A Blanc, Frédéric %A Bonanni, Laura %A McKeith, Ian %A Winblad, Bengt %A de Jong, Frank Jan %A Nobili, Flavio %A Stefanova, Elka %A Petrova, Maria %A Falup-Pecurariu, Cristian %A Rektorova, Irena %A Bostantjopoulou, Sevasti %A Biundo, Roberta %A Weintraub, Daniel %A Aarsland, Dag %K Aged %K Aged, 80 and over %K Analysis of Variance %K Cognition Disorders %K Cohort Studies %K Female %K Humans %K International Cooperation %K Lewy Body Disease %K Male %K Mental Status Schedule %K Middle Aged %X

BACKGROUND/OBJECTIVE: The aim of this study was to describe the rate and clinical predictors of cognitive decline in dementia with Lewy bodies (DLB), and compare the findings with Alzheimer's disease (AD) and Parkinson's disease dementia (PDD) patients.

METHODS: Longitudinal scores for the Mini-Mental State Examination (MMSE) in 1,290 patients (835 DLB, 198 PDD, and 257 AD) were available from 18 centers with up to three years longitudinal data. Linear mixed effects analyses with appropriate covariates were used to model MMSE decline over time. Several subgroup analyses were performed, defined by anti-dementia medication use, baseline MMSE score, and DLB core features.

RESULTS: The mean annual decline in MMSE score was 2.1 points in DLB, compared to 1.6 in AD (p = 0.07 compared to DLB) and 1.8 in PDD (p = 0.19). Rates of decline were significantly higher in DLB compared to AD and PDD when baseline MMSE score was included as a covariate, and when only those DLB patients with an abnormal dopamine transporter SPECT scan were included. Decline was not predicted by sex, baseline MMSE score, or presence of specific DLB core features.

CONCLUSIONS: The average annual decline in MMSE score in DLB is approximately two points. Although in the overall analyses there were no differences in the rate of decline between the three neurodegenerative disorders, there were indications of a more rapid decline in DLB than in AD and PDD. Further studies are needed to understand the predictors and mechanisms of cognitive decline in DLB.

%B J Alzheimers Dis %V 57 %P 787-795 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304294?dopt=Abstract %R 10.3233/JAD-161109 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Reduction of RPT6/S8 (a Proteasome Component) and Proteasome Activity in the Cortex is associated with Cognitive Impairment in Lewy Body Dementia. %A Alghamdi, Amani %A Vallortigara, Julie %A Howlett, David R %A Broadstock, Martin %A Hortobágyi, Tibor %A Ballard, Clive %A Thomas, Alan J %A O'Brien, John T %A Aarsland, Dag %A Attems, Johannes %A Francis, Paul T %A Whitfield, David R %X

Lewy body dementia is the second most common neurodegenerative dementia and is pathologically characterized by α-synuclein positive cytoplasmic inclusions, with varying amounts of amyloid-β (Aβ) and hyperphosphorylated tau (tau) aggregates in addition to synaptic loss. A dysfunctional ubiquitin proteasome system (UPS), the major proteolytic pathway responsible for the clearance of short lived proteins, may be a mediating factor of disease progression and of the development of α-synuclein aggregates. In the present study, protein expression of a key component of the UPS, the RPT6 subunit of the 19S regulatory complex was determined. Furthermore, the main proteolytic-like (chymotrypsin- and PGPH-) activities have also been analyzed. The middle frontal (Brodmann, BA9), inferior parietal (BA40), and anterior cingulate (BA24) gyrus' cortex were selected as regions of interest from Parkinson's disease dementia (PDD, n = 31), dementia with Lewy bodies (DLB, n = 44), Alzheimer's disease (AD, n = 16), and control (n = 24) brains. Clinical and pathological data available included the MMSE score. DLB, PDD, and AD were characterized by significant reductions of RPT6 (one-way ANOVA, p < 0.001; Bonferroni post hoc test) in prefrontal cortex and parietal cortex compared with controls. Strong associations were observed between RPT6 levels in prefrontal, parietal cortex, and anterior cingulate gyrus and cognitive impairment (p = 0.001, p = 0.001, and p = 0.008, respectively). These findings highlight the involvement of the UPS in Lewy body dementia and indicate that targeting the UPS may have the potential to slow down or reduce the progression of cognitive impairment in DLB and PDD.

%B J Alzheimers Dis %V 57 %P 373-386 %G eng %N 2 %R 10.3233/JAD-160946 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Screening for Alzheimer's Disease: Cognitive Impairment in Self-Referred and Memory Clinic-Referred Patients. %A Kirsebom, Bjørn-Eivind %A Espenes, Ragna %A Waterloo, Knut %A Hessen, Erik %A Johnsen, Stein Harald %A Bråthen, Geir %A Aarsland, Dag %A Fladby, Tormod %X

BACKGROUND: Cognitive assessment is essential in tracking disease progression in AD. Presently, cohorts including preclinical at-risk participants are recruited by different means, which may bias cognitive and clinical features. We compared recruitment strategies to levels of cognitive functioning.

OBJECTIVE: We investigate recruitment source biases in self-referred and memory clinic-referred patient cohorts to reveal potential differences in cognitive performance and demographics among at-risk participants.

METHODS: We included 431 participants 40-80 years old. Participants were classified as controls (n = 132) or symptom group (n = 299). The symptom group comprised of subjective cognitive decline (SCD, n = 163) and mild cognitive impairment (MCI, n = 136). We compared cognitive performance and demographics in memory clinic-referrals (n = 86) to self-referred participants responding to advertisements and news bulletins (n = 179). Participants recruited by other means were excluded from analysis (n = 34).

RESULTS: At symptom group level, we found significant reductions in cognitive performance in memory clinic-referrals compared to self-referrals. However, here reductions were only found within the MCI group. We found no differences in cognitive performance due to recruitment within the SCD group. The MCI group was significantly impaired compared to controls on all measures. Significant reductions in learning, and executive functions were also found for the SCD group.

CONCLUSION: Regardless of recruitment method, both the SCD and MCI groups showed reductions in cognitive performance compared to controls. We found differences in cognitive impairment for memory clinic-referrals compared to self-referrals only within the MCI group, SCD-cases being equally affected irrespective of referral type.

%B J Alzheimers Dis %V 60 %P 1621-1631 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984581?dopt=Abstract %R 10.3233/JAD-170385 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association of Butyrylcholinesterase-K Allele and Apolipoprotein E ɛ4 Allele with Cognitive Decline in Dementia with Lewy Bodies and Alzheimer's Disease. %A Vijayaraghavan, Swetha %A Darreh-Shori, Taher %A Rongve, Arvid %A Berge, Guro %A Sando, Sigrid B %A White, Linda R %A Auestad, Bjørn H %A Witoelar, Aree %A Andreassen, Ole A %A Ulstein, Ingun D %A Aarsland, Dag %K Aged %K Aged, 80 and over %K Alleles %K Alzheimer Disease %K Apolipoprotein E4 %K Butyrylcholinesterase %K Cognition %K Disease Progression %K Female %K Gene Frequency %K Genotype %K Humans %K Lewy Body Disease %K Male %K Neuropsychological Tests %X

BACKGROUND: A common polymorphism of the butyrylcholinesterase gene, the K-variant (BCHE-K) is associated with reduced butyrylcholinesterase (BuChE) activity. Insufficient studies exist regarding the frequency and role of BCHE-K in dementias.

OBJECTIVE: To determine the association of BCHE-K and APOEɛ4 with diagnosis and rate of cognitive decline in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) patients.

METHODS: Genomic DNA from 368 subjects (108 AD, 174 DLB, and 86 controls) from two routine clinical cohort studies in Norway; DemVest and TrønderBrain, were genotyped for BCHE-K and APOEɛ4. The mild dementia DemVest subjects received annual Mini-Mental State Examination assessments for five years.

RESULTS: BCHE-K frequency was lower in DLB (33.9% ; p <  0.01) than in control subjects (51.2%), and was numerically lower in AD as well (38.9% ; p = 0.11). More rapid cognitive decline was associated with the APOEɛ4 genotype, but not with the BCHE-K genotype. In an exploratory analysis of patients who completed all five follow-up visits, there was greater cognitive decline in BCHE-K carriers in the presence of the APOEɛ4 allele than in the absence of these polymorphisms.

CONCLUSION: BCHE-K is associated with a reduced risk for AD and DLB whereas APOEɛ4 is associated with more rapid cognitive decline. The greater cognitive decline in individuals with both APOEɛ4 and BCHE-K alleles require prospective confirmation in well-controlled trials.

%B J Alzheimers Dis %V 50 %P 567-76 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757188?dopt=Abstract %R 10.3233/JAD-150750 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association of Platelet Serotonin Levels in Alzheimer's Disease with Clinical and Cerebrospinal Fluid Markers. %A Tajeddinn, Walid %A Fereshtehnejad, Seyed-Mohammad %A Seed Ahmed, Mohammed %A Yoshitake, Takashi %A Kehr, Jan %A Shahnaz, Tasmin %A Milovanovic, Micha %A Behbahani, Homira %A Höglund, Kina %A Winblad, Bengt %A Cedazo-Minguez, Angel %A Jelic, Vesna %A Järemo, Petter %A Aarsland, Dag %X

INTRODUCTION: Serotonin (5-HT) is involved in the pathology of Alzheimer's disease (AD).

OBJECTIVE: We aimed to measure 5-HT level in platelets in AD and explore its association with cerebrospinal fluid (CSF), AD biomarkers (amyloid-β 1-42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau)), and clinical symptoms.

METHODS: 15 patients with AD and 20 patients with subjective cognitive impairment (SCI) were included. 5-HT metabolites were measured, in a specific fraction, using high performance liquid chromatography with electrochemical detection (HPLC-ECD).

RESULTS: Significantly lower 5-HT concentrations were observed in AD patients compared to SCI patients both after normalization against total protein (p = 0.008) or platelet count (p = 0.019). SCI patients with lower 5-HT level have higher AD CSF biomarkers, total tau (p = 0.026) and tau/Aβ42 ratio (p = 0.001), compared to those with high 5-HT levels.

CONCLUSION: AD patients have reduced platelet 5-HT levels. In SCI, lower 5-HT content was associated with a higher AD-CSF biomarker burden.

%B J Alzheimers Dis %V 53 %P 621-30 %8 2016 May 04 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163811?dopt=Abstract %R 10.3233/JAD-160022 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebrospinal Fluid Alzheimer's Disease Biomarkers Across the Spectrum of Lewy Body Diseases: Results from a Large Multicenter Cohort. %A van Steenoven, Inger %A Aarsland, Dag %A Weintraub, Daniel %A Londos, Elisabet %A Blanc, Frédéric %A van der Flier, Wiesje M %A Teunissen, Charlotte E %A Mollenhauer, Brit %A Fladby, Tormod %A Kramberger, Milica G %A Bonanni, Laura %A Lemstra, Afina W %X

BACKGROUND: Concomitant Alzheimer's disease (AD) pathology is observed in Lewy body diseases (LBD), but the clinical impact is unknown. Only a few biomarker studies in LBD exist and have included small cohorts from single centers.

OBJECTIVE: We aimed to evaluate the prevalence of abnormal cerebrospinal fluid (CSF) AD biomarkers across the spectrum of LBD in a large multicenter cohort and to assess whether an AD biomarker profile was associated with demographic and clinical differences in dementia with Lewy bodies (DLB).

METHODS: We included 375 DLB patients, 164 Parkinson's disease (PD) patients without dementia, and 55 PD patients with dementia (PDD) from 10 centers. CSF amyloid-beta42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) values were dichotomized as abnormal or normal according to locally available cut-off values. A CSF AD profile was defined as abnormal Aβ42 combined with abnormal t-tau and/or p-tau.

RESULTS: A substantial proportion of DLB patients had abnormal values for CSF Aβ42, t-tau, and p-tau, while abnormal values were uncommon in PD without dementia. Patients with PDD had values in between. A CSF AD profile was observed in 25% of DLB patients, compared with only 9% of PDD and 3% of PD without dementia. Within DLB, patients with a CSF AD profile were older, more often female, performed worse on the Mini-Mental State Examination, and had shorter disease duration compared with patients with normal CSF.

CONCLUSION: A CSF AD profile is more common in DLB compared with PDD and PD, and is associated with more severe cognitive impairment in DLB.

%B J Alzheimers Dis %V 54 %P 287-95 %8 2016 Aug 18 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567832?dopt=Abstract %R 10.3233/JAD-160322 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Decreased Levels of VAMP2 and Monomeric Alpha-Synuclein Correlate with Duration of Dementia. %A Vallortigara, Julie %A Whitfield, David %A Quelch, William %A Alghamdi, Amani %A Howlett, David %A Hortobágyi, Tibor %A Johnson, Mary %A Attems, Johannes %A O'Brien, John T %A Thomas, Alan %A Ballard, Clive G %A Aarsland, Dag %A Francis, Paul T %K Aged %K Aged, 80 and over %K alpha-Synuclein %K Amyloid beta-Peptides %K Analysis of Variance %K Cognition Disorders %K Dementia %K Female %K Humans %K Male %K Mental Status Schedule %K Neuropsychological Tests %K Regression Analysis %K Synaptophysin %K tau Proteins %K Vesicle-Associated Membrane Protein 2 %X

Alpha-synuclein (α-syn) aggregations are the key pathological hallmark of dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), but are also frequently present in Alzheimer's disease (AD). Much remains unknown about the role of α-syn in the synapse and the wider role of synaptic dysfunction in these dementias. Changes in concentrations of key 'SNAP (Soluble N-ethylmaleimide Sensitive Factor Attachment Protein) Receptor' (SNARE) proteins as a consequence of alterations in the aggregation state of α-syn may contribute to synaptic dysfunction in patients with DLB, PDD, and AD and result in impaired cognition. We have studied a large cohort (n = 130) of autopsy confirmed DLB, PDD, AD, and control brains. Using semi-quantitative western blotting, we have demonstrated significant changes across the diagnostic groups of DLB, PDD, and AD in the SNARE and vesicle proteins syntaxin, Munc18, VAMP2, and monomeric α-syn in the prefrontal cortex, with a significant reduction of Munc18 in AD patients (p <  0.001). This correlated to the final MMSE score before death (p = 0.016). We also identified a significant negative correlation between the duration of dementia and the levels of the binding partners VAMP2 (p = 0.0004) and monomeric α-syn (p = 0.0002). Our findings may indicate that an upregulation of SNARE complex related proteins occurs in the early stages of disease as an attempt at compensating for failing synapses, prior to widespread deposition of pathological α-syn.

%B J Alzheimers Dis %V 50 %P 101-10 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639969?dopt=Abstract %R 10.3233/JAD-150707 %0 Journal Article %J J Alzheimers Dis %D 2016 %T EEG Markers of Dementia with Lewy Bodies: A Multicenter Cohort Study. %A Bonanni, Laura %A Franciotti, Raffaella %A Nobili, Flavio %A Kramberger, Milica G %A Taylor, John-Paul %A Garcia-Ptacek, Sara %A Falasca, N Walter %A Famá, Francesco %A Cromarty, Ruth %A Onofrj, Marco %A Aarsland, Dag %X

Quantitative EEG (QEEG) has demonstrated good discriminative capacity for dementia with Lewy bodies (DLB) diagnosis as compared to Alzheimer's disease (AD) with a predictive value of 100% in a single cohort study. EEG in DLB was characterized by a dominant frequency (DF) in pre-alpha (5.5-7.5 Hz), theta, or delta bands and DF variability (DFV) >1.2 Hz, frequency prevalence (FP) pre-alpha in >40% and FP alpha in <32% of the epochs. To validate the aforementioned QEEG findings in independent cohorts of clinically diagnosed DLB versus AD patients, we analyzed EEG traces of 79 DLB and 133 AD patients (MMSE >20) collected from four European Centers. EEG traces from 19 scalp derivations were acquired as at least 10 min continuous signals and epoched in off-setting as series of 2-second-long epochs, subsequently processed by Fast Fourier Transform (frequency resolution 0.5 Hz). DLB patients showed EEG specific abnormalities in posterior derivations characterized by DF <8 Hz FP pre-alpha >50%, FP alpha <25%. DFV was >0.5 Hz. AD patients displayed stable alpha DF, DFV <0.5 Hz, FP pre-alpha <30%, and FP alpha >55%. DLB and AD differed for DF (p < 10-6), DFV (p < 0.05), FP pre-alpha (p < 10-12) and FP alpha (p < 10-12). Discriminant analysis detected specific cut-offs for every EEG mathematical descriptor; DF = 8, DFV = 2.2 Hz, FP pre-alpha=33%, FP alpha = 41% for posterior derivations. If at least one of the cut-off values was met, the percentage of DLB and AD patients correctly classified was 90% and 64%, respectively. The findings in this multicenter study support the validity of QEEG analysis as a tool for diagnosis in DLB patients.

%B J Alzheimers Dis %V 54 %P 1649-1657 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589528?dopt=Abstract %R 10.3233/JAD-160435 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Neurocognitive Deficits Distinguishing Mild Dementia with Lewy Bodies from Mild Alzheimer's Disease are Associated with Parkinsonism. %A Brønnick, Kolbørn %A Breitve, Monica H %A Rongve, Arvid %A Aarsland, Dag %X

BACKGROUND: The cognitive profile of mild dementia with Lewy bodies (DLB) versus mild Alzheimer's disease (AD) has not been extensively studied, and the relation of cognitive deficits to the core diagnostic criteria for DLB (fluctuations, visual hallucinations, and parkinsonism) remains poorly understood.

OBJECTIVE: To compare the cognitive profile in patients with mild DLB to patients with mild AD and investigate the relation between cognitive deficits distinguishing DLB from AD and the core diagnostic features in DLB.

METHODS: Patients with mild dementia were recruited from the southwestern part of Norway and patients diagnosed with probable AD (n = 113) or probable DLB (n = 77) were included. The DLB core diagnostic symptoms were assessed using standardized clinical measures, and standardized neurocognitive tests assessing attention, language, memory, and visuospatial functions were administered. Univariate and multivariate comparisons of cognitive tests were performed, and tests distinguishing between AD and DLB were subjected to correlational analyses with the core diagnostic symptoms.

RESULTS: DLB patients performed worse than AD patients on test of visuoconstruction, but not visual perception and on all tests involving attention and executive functions, except verbal fluency. The multivariate model distinguished between DLB and AD with a sensitivity of 74% and a specificity of 82%. Tests where DLB performed worse than AD were highly correlated with degree of parkinsonism, but not with cognitive fluctuations or visual hallucinations.

CONCLUSIONS: The cognitive profile in mild DLB can be useful in distinguishing AD from DLB. The strong relation between relative deficits in DLB and parkinsonism warrants further studies.

%B J Alzheimers Dis %V 53 %P 1277-85 %8 2016 Jun 30 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27372647?dopt=Abstract %R 10.3233/JAD-160294 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Pharmacological Modulations of the Serotonergic System in a Cell-Model of Familial Alzheimer's Disease. %A Tajeddinn, Walid %A Persson, Torbjörn %A Calvo-Garrido, Javier %A Seed Ahmed, Mohammed %A Maioli, Silvia %A Vijayaraghavan, Swetha %A Kazokoglu, Mehmet Selim %A Parrado-Fernández, Cristina %A Yoshitake, Takashi %A Kehr, Jan %A Francis, Paul %A Winblad, Bengt %A Höglund, Kina %A Cedazo-Minguez, Angel %A Aarsland, Dag %X

Serotonin (5-HT) plays a central role in the integrity of different brain functions. The 5-HT homeostasis is regulated by many factors, including serotonin transporter (SERT), monoamine oxidase enzyme (MAO), and several 5-HT receptors, including the 5-HT1B. There is little knowledge how the dynamics of this system is affected by the amyloid-β (Aβ) burden of Alzheimer's disease (AD) pathology. SH-SY5Y neuroblastoma cells transfected with the amyloid precursor protein (APP) gene containing the Swedish mutations causing familial AD (APPswe), were used as a model to explore the effect of Aβ pathology on 5-HT1B and related molecules including the receptor adaptor protein (p11), SERT and MAOA gene expression, and MAOA activity after treatment with selective serotonin reuptake inhibitor (SSRI) (sertraline), and a 5-HT1B receptor antagonist. Sertraline led more than 70 fold increase of 5-HT1B gene expression (p < 0.001), an increased serotonin turnover in both APPswe and control cells and reduced intracellular serotonin levels by 75% in APPswe cells but not in controls (p > 0.05). Treatment with the 5-HT1B receptor antagonist increased SERT gene-expression in control cells but not in the APPswe cells. 5-HT and 5-HT1B antagonist treatment resulted in different p11 expression patterns in APPswe cells compared to controls. Although MAOA gene expression was not changed by APPswe overexpression, adding 5-HT lead to a significant increase in MAOA gene expression in APPswe but not control cells. These findings suggest that the sensitivity of the 5-HT1B receptor and related systems is affected by APPswe overexpression, with potential relevance for pharmacologic intervention in AD. This may at least partly explain the lack of effect of SSRIs in patients with AD and depression.

%B J Alzheimers Dis %V 53 %P 349-61 %8 2016 May 07 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163814?dopt=Abstract %R 10.3233/JAD-160046