Journal of Alzheimer's Disease - Volume 52, issue 2

Authors: Küster, Olivia C. | Kösel, Jonas | Spohn, Stephanie | Schurig, Niklas | Tumani, Hayrettin | von Arnim, Christine A.F. | Uttner, Ingo

Article Type: Research Article

Abstract: Individuals with higher cognitive reserve are more able to cope with pathological brain alterations, potentially due to the application of more efficient cognitive strategies. The extent to which an individual’s cognitive performance can be increased by advantageous conditions differs substantially between patients with Alzheimer’s dementia (AD) and healthy older adults and can be assessed with the Testing-the-Limits (TtL) approach. Thus, TtL has been proposed as a tool for the early diagnosis of AD. Here, we report the diagnostic accuracy of a memory TtL paradigm to discriminate between AD patients and controls. The TtL paradigm was administered to 57 patients with …clinically diagnosed AD and 94 controls. It consisted of a pre-test condition, representing baseline cognitive performance, the presentation of an encoding strategy, and two subsequent post-test conditions, representing learning potential. Receiver operating characteristic (ROC) curves were analyzed for each condition in order to receive optimal cutoff points along with their sensitivity and specificity and to compare the diagnostic accuracy of the conditions. Differentiation between AD patients and controls, indicated by the area under the ROC curve, increased significantly for the TtL post-test and total error scores compared to the pre-test score. The combined error score in the two post-tests could differentiate between AD patients and controls with a sensitivity of 0.93 and a specificity of 0.80. The presented approach can be carried out in 25 minutes and thus constitutes a time- and cost-effective way to diagnose AD with high accuracy. Show more

Keywords: Alzheimer’s disease, cognition, cognitive reserve, dementia, diagnosis, neuropsychology

DOI: 10.3233/JAD-151141

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 519-528, 2016

Authors: Heffernan, Megan | Mather, Karen A. | Xu, Jing | Assareh, Amelia A. | Kochan, Nicole A. | Reppermund, Simone | Draper, Brian | Trollor, Julian N. | Sachdev, Perminder | Brodaty, Henry

Article Type: Research Article

Abstract: Alcohol consumption is a potentially modifiable risk factor for dementia, but the literature is not completely consistent. This inconsistency may be partly due to an interaction with the apolipoprotein E (APOE ) genotype, an established risk factor for Alzheimer’s dementia. The aim of this study was to examine whether alcohol consumption is associated with incident dementia or decline in specific cognitive domains over 4 years, and if this effect is modified by APOE ɛ 4 status. Non-demented community dwelling older adults (70-90 years) from an ongoing longitudinal study were assessed for cognitive impairment in attention/processing speed, language, executive function, …visuospatial ability, and memory. Incident dementia was diagnosed according to DSM-IV criteria. Compared to those who did not drink in the previous 12 months, neither low consumption (HR 0.64 95% CI 0.3-1.4) or risky consumption (HR 0.58 95% CI 0.2-1.5) was associated with incident dementia. Carriers of the APOE ɛ 4 allele were more likely to develop dementia, but there was no significant interaction with alcohol consumption. Show more

Keywords: Alcohol, Alzheimer’s disease, cognitive decline, cognitive impairment, dementia

DOI: 10.3233/JAD-150537

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 529-538, 2016

Authors: Jefferson, Angela L. | Gifford, Katherine A. | Acosta, Lealani Mae Y. | Bell, Susan P. | Donahue, Manus J. | Davis, L. Taylor | Gottlieb, JoAnn | Gupta, Deepak K. | Hohman, Timothy J. | Lane, Elizabeth M. | Libon, David J. | Mendes, Lisa A. | Niswender, Kevin | Pechman, Kimberly R. | Rane, Swati | Ruberg, Frederick L. | Su, Yan Ru | Zetterberg, Henrik | Liu, Dandan

Article Type: Research Article

Abstract: Background: Vascular health factors frequently co-occur with Alzheimer’s disease (AD). A better understanding of how systemic vascular and cerebrovascular health intersects with clinical and pathological AD may inform prevention and treatment opportunities. Objective: To establish the Vanderbilt Memory & Aging Project, a case-control longitudinal study investigating vascular health and brain aging, and describe baseline methodology and participant characteristics. Methods: From September 2012 to November 2014, 335 participants age 60– 92 were enrolled, including 168 individuals with mild cognitive impairment (MCI, 73±8 years, 41% female) and 167 age-, sex-, and race-matched cognitively normal controls (NC, 72±7 years, …41% female). At baseline, participants completed a physical and frailty examination, fasting blood draw, neuropsychological assessment, echocardiogram, cardiac MRI, and brain MRI. A subset underwent 24-hour ambulatory blood pressure monitoring and lumbar puncture for cerebrospinal fluid (CSF) collection. Results: As designed, participant groups were comparable for age (p  = 0.31), sex (p  = 0.95), and race (p  = 0.65). MCI participants had greater Framingham Stroke Risk Profile scores (p  = 0.008), systolic blood pressure values (p  = 0.008), and history of left ventricular hypertrophy (p  = 0.04) than NC participants. As expected, MCI participants performed worse on all neuropsychological measures (p -values < 0.001), were more likely to be APOE ɛ 4 carriers (p  = 0.02), and had enhanced CSF biomarkers, including lower Aβ42 (p  = 0.02), higher total tau (p  = 0.004), and higher p-tau (p  = 0.02) compared to NC participants. Conclusion: Diverse sources of baseline and longitudinal data will provide rich opportunities to investigate pathways linking vascular and cerebrovascular health, clinical and pathological AD, and neurodegeneration contributing to novel strategies to delay or prevent cognitive decline. Show more

Keywords: Alzheimer’s disease, biomarkers, brain MRI, cardiac MRI, mild cognitive impairment, vascular risk factors

DOI: 10.3233/JAD-150914

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 539-559, 2016

Authors: Westwood, Sarah | Leoni, Emanuela | Hye, Abdul | Lynham, Steven | Khondoker, Mizanur R. | Ashton, Nicholas J. | Kiddle, Steven J. | Baird, Alison L. | Sainz-Fuertes, Ricardo | Leung, Rufina | Graf, John | Hehir, Cristina Tan | Baker, David | Cereda, Cristina | Bazenet, Chantal | Ward, Malcolm | Thambisetty, Madhav | Lovestone, Simon

Article Type: Research Article

Abstract: Increasingly, clinical trials for Alzheimer’s disease (AD) are being conducted earlier in the disease phase and with biomarker confirmation using in vivo amyloid PET imaging or CSF tau and Aβ measures to quantify pathology. However, making such a pre-clinical AD diagnosis is relatively costly and the screening failure rate is likely to be high. Having a blood-based marker that would reduce such costs and accelerate clinical trials through identifying potential participants with likely pre-clinical AD would be a substantial advance. In order to seek such a candidate biomarker, discovery phase proteomic analyses using 2DGE and gel-free LC-MS/MS for high …and low molecular weight analytes were conducted on longitudinal plasma samples collected over a 12-year period from non-demented older individuals who exhibited a range of 11 C-PiB PET measures of amyloid load. We then sought to extend our discovery findings by investigating whether our candidate biomarkers were also associated with brain amyloid burden in disease, in an independent cohort. Seven plasma proteins, including A2M, Apo-A1, and multiple complement proteins, were identified as pre-clinical biomarkers of amyloid burden and were consistent across three time points (p  <  0.05). Five of these proteins also correlated with brain amyloid measures at different stages of the disease (q  <  0.1). Here we show that it is possible to detect a plasma based biomarker signature indicative of AD pathology at a stage long before the onset of clinical disease manifestation. As in previous studies, acute phase reactants and inflammatory markers dominate this signature. Show more

Keywords: KeywordsAlzheimer’s disease, amyloid, biological markers, blood, plasma, preclinical, proteomics

DOI: 10.3233/JAD-151155

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 561-572, 2016

Authors: Hirni, Daniela I. | Kivisaari, Sasa L. | Krumm, Sabine | Monsch, Andreas U. | Berres, Manfred | Oeksuez, Fatma | Reinhardt, Julia | Ulmer, Stephan | Kressig, Reto W. | Stippich, Christoph | Taylor, Kirsten I.

Article Type: Research Article

Abstract: Neurofibrillary pathology in Alzheimer’s dementia (AD) is associated with cognitive impairments and cortical thinning, and begins in medial perirhinal cortex (mPRC) before entering entorhinal cortex (ERC). Thus, mPRC dysfunction (e.g., semantic object memory impairments) may predate or accompany ERC (i.e., episodic memory) dysfunction in the preclinical course of typical AD. We developed formulae estimating mPRC and ERC integrity (i.e., cortical thickness) using common neuropsychological tests in 31 healthy individuals and 58 early AD patients. These formulae estimated the longitudinal courses of mPRC and ERC functioning in independent groups of 28 optimally healthy individuals who developed AD (NC-AD) over 2.8–13.4 years …and 28 pairwise-matched, stable, healthy individuals (NC-NC). Mixed models demonstrated significantly worse NC-AD than NC-NC estimated mPRC and ERC functioning at the earliest observation, 12 years preceding diagnosis, and a significant decline 4 years preceding the AD diagnosis. These findings demonstrate that specific neuropsychological impairments occur early in the course of preclinical AD and that tasks measuring mPRC functioning may serve as additional, powerful markers of preclinical AD. Show more

Keywords: Episodic memory, longitudinal, neurofibrillary pathology, preclinical cognitive marker, rhinal cortex, semantic memory

DOI: 10.3233/JAD-150158

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 573-580, 2016

Authors: Ebrahimie, Esmaeil | Moussavi Nik, Seyyed Hani | Newman, Morgan | Van Der Hoek, Mark | Lardelli, Michael

Article Type: Research Article

Abstract: Dominant mutations in the PRESENILIN genes PSEN1 and PSEN2 cause familial Alzheimer’s disease (fAD) that usually shows onset before 65 years of age. In contrast, genetic variation at the PSEN1 and PSEN2 loci does not appear to contribute to risk for the sporadic, late onset form of the disease (sAD), leading to doubts that these genes play a role in the majority of AD cases. However, a truncated isoform of PSEN2 , PS2V, is upregulated in sAD brains and is induced by hypoxia and high cholesterol intake. PS2V can increase γ -secretase activity and suppress …the unfolded protein response (UPR), but detailed analysis of its function has been hindered by lack of a suitable, genetically manipulable animal model since mice and rats lack this PRESENILIN isoform. We recently showed that zebrafish possess an isoform, PS1IV, that is cognate to human PS2V. Using an antisense morpholino oligonucleotide, we can block specifically the induction of PS1IV that normally occurs under hypoxia. Here, we exploit this ability to identify gene regulatory networks that are modulated by PS1IV. When PS1IV is absent under hypoxia-like conditions, we observe changes in expression of genes controlling inflammation (particularly sAD-associated IL1B and CCR5 ), vascular development, the UPR, protein synthesis, calcium homeostasis, catecholamine biosynthesis, TOR signaling, and cell proliferation. Our results imply an important role for PS2V in sAD as a component of a pathological mechanism that includes hypoxia/oxidative stress and support investigation of the role of PS2V in other diseases, including schizophrenia, when these are implicated in the pathology. Show more

Keywords: Gene regulatory networks, neurodegenerative diseases, transcriptome profiling, zebrafish

DOI: 10.3233/JAD-150678

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 581-608, 2016

Authors: Thyrian, Jochen René | Eichler, Tilly | Michalowsky, Bernhard | Wucherer, Diana | Reimann, Melanie | Hertel, Johannes | Richter, Steffen | Dreier, Adina | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: Efficient help and care for people with dementia (PWD) is dependent on knowledge about PWD in primary care. Objective: This analysis comprehensively describes community-dwelling PWD in primary care with respect to various dementia care specific variables. Methods: The analyses are based on baseline data of the ongoing general practitioner-based, randomized, controlled intervention trial DelpHi-MV (Dementia: life- and person-centered help). 6,838 patients were screened for dementia in 136 GP practices; 17.1% were screened positive, 54.4% of those agreed to participate and data could be assessed in n  = 516 subjects. We assessed age, sex, living situation, cognitive …status, functional status, level of impairment, comorbidities, formal diagnosis of dementia, depression, neuropsychiatric symptoms, quality of life, utilization of medical support, and pharmacological therapy. Results: Concerning clinical-, dementia-, and health-related variables, the sample under examination was on average mildly cognitively and functionally impaired (MMSE, m = 22.2; BADL, m = 3.7). A level of care was assigned in 38.0%. Depression was identified in 15.4% and other frequent comorbidities were high blood pressure (83.3%), coronary heart diseases (37.1%), cerebrovascular diseases (22.3%), among others. In 48.6%, neuropsychiatric symptoms were present in a clinically relevant severity. Pharmacological treatment with antidementia medication was received by 25.8% and antidepressant medication by 14.0%. Utilization of services was generally low. Conclusion: The comprehensive description of people screened positive for dementia in primary care reveals a complex and unique population of patients. They are considerably underdiagnosed and in their majority mildly to moderately affected. More in-depth analyses are needed to study relations, associations and interactions between different variables. Show more

Keywords: Dementia, primary care, primary health care, screening

DOI: 10.3233/JAD-151076

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 609-617, 2016

Authors: Eichler, Tilly | Hoffmann, Wolfgang | Hertel, Johannes | Richter, Steffen | Wucherer, Diana | Michalowsky, Bernhard | Dreier, Adina | Thyrian, Jochen René

Article Type: Research Article

Abstract: Background: Little is known about the proportion and the characteristics of community-dwelling people with dementia (PWD) living alone in Germany. Objectives: To analyze the prevalence of PWD living alone (with and without the support of an informal caregiver) and socio-demographical and clinical characteristics as well as health and nursing care utilization associated with living alone. Methods: DelpHi-MV (Dementia: Life- and person-centered help in Mecklenburg-Western Pomerania) is a general practitioner-based, randomized controlled intervention trial. The present analyses are based on baseline data of 511 patients (≥70 years, community-dwelling) who had screened positive for dementia (DemTect <9). …Results: N  = 251 (51%) of the patients lived alone. PWD living alone were statistically significantly more often female, older, and more often widowed than those not living alone. About 9% of the patients (n  = 24) were not supported by any informal caregiver. Regarding the clinical variables (cognitive and functional impairment, depression, falls, number of drug-related problems, malnutrition, quality of life), there were no statistically significant group differences. Patients living alone utilized professional services such as home care, help with medication, home-delivered meals, or housekeeping assistance significantly more often. Multivariate analyses confirmed these findings. Conclusion: Our results reveal the high proportion of PWD living alone in Germany. PWD living alone did not seem to be at an increased health risk. Our findings indicate that living alone with dementia is possible. In order to ensure the sufficient provision of health and nursing care services for PWD living alone, providers should consider the present results for future planning. Show more

Keywords: Ambulatory care, dementia, living arrangements, primary health care

DOI: 10.3233/JAD-151058

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 619-629, 2016

Authors: Zhai, Yaoming | Yin, Song | Zhang, Dongfeng

Article Type: Research Article

Abstract: Antipsychotic drugs have been inconsistently associated with death risk of Alzheimer’s disease (AD) patients. Herein we review and quantitatively summarize the evidence from epidemiological studies. Pertinent studies were identified by searching PubMed and Cochrane Library Register of Controlled Trials through 20 December 2015. The DerSimonian and Laird random effect model was adopted as the pooling method. Twelve studies from nine articles with 11,463 participants were included. The pooled RR of observational studies was 1.36 (95% CI, 0.83–2.24; I2  = 94.9%) for antipsychotic drugs users versus individuals who were not exposed to antipsychotic drugs. When the three studies that were key contributors …to the high heterogeneity were excluded, the pooled RR was 2.08 (95% CI 1.39 to 3.13). The result of one double-blind randomized clinical trial indicated that antipsychotic drugs nearly doubled the risk of death in AD patients. In conclusion, there is no evidence of absence of association between antipsychotic drugs’ use with death risk of AD patients. Careful assessments of potential benefits and risks should be made before prescribing antipsychotics for treatment of psychosis symptoms and behavioral problems of AD patients. Show more

Keywords: Alzheimer’s disease, antipsychotic agents, epidemiology, meta-analysis

DOI: 10.3233/JAD-151207

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 631-639, 2016

Authors: Vidal, Jean-Sébastien | Hanon, Olivier | Funalot, Benoît | Brunel, Nadège | Viollet, Cécile | Rigaud, Anne-Sophie | Seux, Marie-Laure | le-Bouc, Yves | Epelbaum, Jacques | Duron, Emmanuelle

Article Type: Research Article

Abstract: Background: The relationship between the insulin-like growth factor-I (IGF-I) system and Alzheimer’s disease (AD) is mostly based on transversal studies. It remains, however, to demonstrate whether IGF-I is associated with cognitive decline over time in AD. Objective: The objective of the study was to analyze the course of cognitive decline of AD subjects over a 24-month period in relation to serum IGF-I and insulin-like growth factor binding protein-3 (IGFBP-3) measured at baseline. Methods: Data are from the SIGAL follow-up study. IGF-I and IGFBP-3 were measured in AD subjects who performed a Mini-Mental State Examination (MMSE) every …6 months for 2 years. MMSE course was analyzed using a mixed model with random intercept and slope function. Results: Among the 200 AD participants, 146 (mean age = 81.1 (standard deviation (SD) = 5.9) years, 62.6% of women) had at least one follow-up visit. Mean IGF-I at baseline was 147.8 (74.2) ng/mL. Hundred forty-six participants (62.6%) had at least one follow-up visit. Mean MMSE was 21.7 (4.7)/30 and dropped on average by 2.28 points per year. MMSE decline was steeper among participants with lower IGF-I. For each decrease of 1 SD of IGF-I, subjects lost an additional 0.63 points per year in MMSE, e.g., participants with IGF-I level of 74 ng/mL lost 2.91 MMSE points per year whereas participants with IGF-I of 222 ng/mL lost 1.65 MMSE points per year. There was no association between IGFBP-3 and cognitive decline. Conclusion: Lower baseline serum IGF-I was associated with faster cognitive decline in AD over a 2-year period. Show more

Keywords: Alzheimer’s disease, cognitive decline, insulin-like growth factor-I

DOI: 10.3233/JAD-151162

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 641-649, 2016