Journal of Alzheimer's Disease - Volume 56, issue 1

Authors: Zerah, Lorene | Cohen-Bittan, Judith | Raux, Mathieu | Meziere, Anthony | Tourette, Cendrine | Neri, Christian | Verny, Marc | Riou, Bruno | Khiami, Frederic | Boddaert, Jacques

Article Type: Research Article

Abstract: Background: Dementia is associated with a worse prognosis of hip fracture, but the impact of a dedicated geriatric care pathway on the prognosis of these patients has not been evaluated. Objective: According to the cognitive status before surgery, our main objective was to compare mortality rate at 6 months; secondary outcomes were to compare in-hospital complications, the risk of new institutionalization, and the ability to walk at 6 months. Methods: Between 2009 and 2015, all patients (>70 years) admitted after hip fracture surgery into a dedicated unit of peri-operative geriatric care were included: patients with …dementia (DP), without dementia (NDP), and with cognitive status not determined (CSND). Data are expressed as hazard ratio (HR) for multivariate cox analysis or odds ratio (OR) for multivariate logistic regression analysis and their 95% confidence interval (CI). Results: We included 650 patients (86±6 years): 168 DP, 400 NDP, and 82 CSND. After adjustment for age, sex, comorbidities, polypharmacy, pre-fracture autonomy, time-to-surgery, and delirium, there were no significant differences for 6-month mortality (DP versus NDP: HR = 0.7[0.4–1.2], DP versus CSND: HR = 0.6[0.3–1.4], CSND versus NDP: HR = 0.8[0.4–1.7]); but DP and CSND were more likely to be newly institutionalized after 6 months compared to NDP (OR DP = 2.6[1.4–4.9], p  = 0.003, OR CSND = 2.9[1.4–6.1], p  = 0.004). 92% of population was walking after 6 months (63% with assistance): no difference was found between the three groups. Conclusion: In a dedicated geriatric care pathway, DP and CSND undergoing hip surgery have the same 6-month mortality and walking ability as NDP. Show more

Keywords: Dementia, elderly, hip fracture, unit of peri-operative geriatric care

DOI: 10.3233/JAD-160655

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 145-156, 2017

Authors: Chong, Joyce R. | Chai, Yuek Ling | Lee, Jasinda H. | Howlett, David | Attems, Johannes | Ballard, Clive G. | Aarsland, Dag | Francis, Paul T. | Chen, Christopher P. | Lai, Mitchell K.P.

Article Type: Research Article

Abstract: 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. Show more

Keywords: Alzheimer’s disease, amyloid-β, dementia with Lewy bodies, Parkinson’s disease dementia, transforming growth factor β2

DOI: 10.3233/JAD-160781

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 157-166, 2017

Authors: Heath, Matthew | Shellington, Erin | Titheridge, Sam | Gill, Dawn P. | Petrella, Robert J.

Article Type: Research Article

Abstract: Exercise programs involving aerobic and resistance training (i.e., multiple-modality) have shown promise in improving cognition and executive control in older adults at risk, or experiencing, cognitive decline. It is, however, unclear whether cognitive training within a multiple-modality program elicits an additive benefit to executive/cognitive processes. This is an important question to resolve in order to identify optimal training programs that delay, or ameliorate, executive deficits in persons at risk for further cognitive decline. In the present study, individuals with a self-reported cognitive complaint (S CC) participated in a 24-week multiple-modality (i.e., the M2 group) exercise intervention program. In addition, a …separate group of individuals with a S CC completed the same aerobic and resistance training as the M2 group but also completed a cognitive-based stepping task (i.e., multiple-modality, mind-motor intervention: M4 group). Notably, pre- and post-intervention executive control was examined via the antisaccade task (i.e., eye movement mirror-symmetrical to a target). Antisaccades are an ideal tool for the study of individuals with subtle executive deficits because of its hands- and language-free nature and because the task’s neural mechanisms are linked to neuropathology in cognitive decline (i.e., prefrontal cortex). Results showed that M2 and M4 group antisaccade reaction times reliably decreased from pre- to post-intervention and the magnitude of the decrease was consistent across groups. Thus, multi-modality exercise training improved executive performance in persons with a S CC independent of mind-motor training. Accordingly, we propose that multiple-modality training provides a sufficient intervention to improve executive control in persons with a S CC. Show more

Keywords: Executive-control, exercise, mind-motor training, multiple-modality training, subjective cognitive complaint

DOI: 10.3233/JAD-160627

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 167-183, 2017

Authors: Brooks, Sylwia W. | Dykes, Ava C. | Schreurs, Bernard G.

Article Type: Research Article

Abstract: Hypercholesterolemia has been implicated in numerous health problems from cardiovascular disease to neurodegeneration. High serum cholesterol levels in midlife have been associated with an increased risk of developing Alzheimer’s disease (AD) later in life which suggests that the pathways leading to AD pathology might be activated decades before the symptoms of the disease are detected. Cholesterol-fed animals, particularly cholesterol-fed rabbits, exhibit brain pathology similar to the changes found in brains of AD patients. Dietary cholesterol, which cannot pass the blood-brain barrier, is thought to influence central nervous system homeostasis by increased transport of its circulatory breakdown product, 27-hydroxycholesterol (27-OHC), into …the brain. 27-OHC is an endogenous selective estrogen receptor modulator. Estrogen-mediated non-reproductive functions require estrogen receptors (ERs) and include modulation of mitochondrial function and structure, as well as regulation of synaptogenesis in the brain. ERs are located in brain areas affected early in AD pathogenesis, including the hippocampus. Here we report that increase in serum cholesterol, induced by feeding rabbits a high-cholesterol diet, is associated with higher levels of 27-OHC in the brain as well as increased levels of neurodegeneration in the hippocampus. Furthermore, these results are accompanied by changes in expression of ERs in the hippocampus as well as a decrease in hippocampal mitochondria. These findings provide an important insight into one of the possible mechanisms involved in the development of AD, and shed light on the processes that may antedate amyloid-β and tau phosphorylation changes currently hypothesized to cause AD symptomology and pathology. Show more

Keywords: Alzheimer’s disease, cholesterol, cholesterol-fed rabbit, estrogen receptors, ERα, ERβ, 27-hydroxycholesterol, mitochondria, oxysterol, PSD-95, synapse

DOI: 10.3233/JAD-160725

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 185-196, 2017

Authors: Apostolova, Ivayla | Lange, Catharina | Roberts, Anna | Igel, Hans Joachim | Mäurer, Anja | Liese, Stephanie | Estrella, Melanie | Prasad, Vikas | Stechl, Elisabeth | Lämmler, Gernot | Steinhagen-Thiessen, Elisabeth | Buchert, Ralph

Article Type: Research Article

Abstract: Background: Neuroimaging-based biomarkers have the potential to improve etiological diagnosis of cognitive impairment in elderly inpatients. However, there is a relative lack of studies on neuroimaging-based biomarkers in hospitalized geriatric patients, as the vast majority of neuroimaging studies in dementia have focused on memory clinic outpatients. An important aspect of study planning is a priori estimation of the rate of screen failures. Objective: To report on the rate and causes of screen failures in a prospective study on the utility of neuroimaging (PET, MRI) for the etiological diagnosis of newly manifested cognitive impairment in acutely hospitalized …geriatric patients. Methods: Ten acute care geriatrics clinics with 802 beds participated in the study. The potential recruitment rate had been estimated to 5 patients/100 beds/week. Results: Seventeen months of pre-screening resulted in 322 potential participants. 109 of these patients were enrolled, i.e., the screen failure rate was 66%. 58% of the screen failures were due to refusal of participation by the patient, most often due to lack of interest in clarifying the cause of the cognitive impairment or due to reluctance to engage in additional diagnostic procedures associated with physical stress. 42% of pre-screened patients were excluded because of violation of the eligibility criteria. Conclusion: Enrollment for neuroimaging studies presents considerable additional challenges in acutely hospitalized geriatric patients compared to outpatient settings. Low rate of approaching potential candidates by attending geriatricians and a high rate of screen failures have to be anticipated in the study design. Show more

Keywords: Clinical trial, cognitive impairment, geriatric inpatients, neuroimaging, recruitment failure

DOI: 10.3233/JAD-160797

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 197-204, 2017

Authors: Agyemang, Charles | van de Vorst, Irene E. | Koek, Huiberdina L. | Bots, Michiel L. | Seixas, Azizi | Norredam, Marie | Ikram, Umar | Stronks, Karien | Vaartjes, Ilonca

Article Type: Research Article

Abstract: Background: Data on dementia prognosis among ethnic minority groups are limited in Europe. Objective: We assessed differences in short-term (1-year) and long-term (3-year) mortality and readmission risk after a first hospitalization or first ever referral to a day clinic for dementia between ethnic minority groups and the ethnic Dutch population in the Netherlands Methods: Nationwide prospective cohorts of first hospitalized dementia patients (N = 55,827) from January 1, 2000 to December 31, 2010 were constructed. Differences in short-term and long-term mortality and readmission risk following hospitalization or referral to the day clinic between ethnic minority groups (Surinamese, …Turkish, Antilleans, Indonesians) and the ethnic Dutch population were investigated using Cox proportional hazard regression models with adjustment for age, sex, and comorbidities. Results: Age-sex-adjusted short-term and long-term risks of death following a first hospitalization with dementia were comparable between the ethnic minority groups and the ethnic Dutch. Age- and sex-adjusted risk of admission was higher only in Turkish compared with ethnic Dutch (HR 1.57, 95% CI,1.08–2.29). The difference between Turkish and the Dutch attenuated and was no longer statistically significant after further adjustment for comorbidities. There were no ethnic differences in short-term and long-term risk of death, and risk of readmission among day clinic patients. Conclusion: Compared with Dutch patients with a comparable comorbidity rate, ethnic minority patients with dementia did not have a worse prognosis. Given the poor prognosis of dementia, timely and targeted advance care planning is essential, particularly in ethnic minority groups who are mired by cultural barriers and where uptake of advance care planning is known to be low. Show more

Keywords: Dementia, ethnic minority groups, ethnicity, Netherlands

DOI: 10.3233/JAD-160897

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 205-213, 2017

Authors: Anstey, Kaarin J. | Ashby-Mitchell, Kimberly | Peters, Ruth

Article Type: Research Article

Abstract: Background: Cohort studies have reported that midlife high total serum cholesterol (TC) is associated with increased risk of Alzheimer’s disease (AD) in late-life but findings have been based on few studies and previous reviews have been limited by a lack of compatible data. Objective: We synthesized all high quality data from cohort studies reporting on the association between total serum cholesterol measured and late-life cognitive outcomes including Alzheimer’s disease (AD), vascular dementia (VaD), any dementia, mild cognitive impairment (MCI), and cognitive decline. Methods: The literature was searched up to October 2016 using a registered protocol. …Thirty-four articles meeting study criteria were identified. Seventeen studies published from 1996 to 2014, including 23,338 participants were included in meta-analyses. Results: Relative risk of developing AD for adults with high TC in midlife was 2.14 (95% CI 1.33–3.44) compared with normal cholesterol. Individual studies that could not be pooled also reported high TC in midlife increased the risk of MCI and cognitive decline in late-life. High TC in late-life was not associated with MCI, AD, VaD, any dementia, or cognitive decline. Late-life measured HDL cholesterol and triglycerides were not associated with increased risk of VaD, and HDL was not associated with risk of MCI, AD, or any dementia. There were insufficient data to examine other cholesterol sub-fractions, sex differences, or APOE interactions. Conclusions: Significant gaps in the literature regarding TC and late-life dementia remain. Evidence suggests that high midlife TC increases risk of late-life AD, and may correlate with the onset of AD pathology. Show more

Keywords: Cholesterol, cognitive decline, dementia, lipids, review, risk factors

DOI: 10.3233/JAD-160826

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 215-228, 2017

Authors: Sokolow, Sophie | Li, Xiaohui | Chen, Lucia | Taylor, Kent D. | Rotter, Jerome I. | Rissman, Robert A. | Aisen, Paul S. | Apostolova, Liana G.

Article Type: Research Article

Abstract: Background: Donepezil is an acetylcholinesterase inhibitor frequently prescribed for the treatment of mild cognitive impairment (MCI) though not approved by the Food and Drug Administration for this indication. In Alzheimer’s disease, butyrylcholinesterase (BChE) activity increases with disease progression and may replace acetylcholinesterase function. The most frequent polymorphism of BChE is the K-variant, which is associated with lower acetylcholine-hydrolyzing activity. BChE-K polymorphism has been studied in Alzheimer’s disease progression and donepezil therapy, and has led to contradictory results. Objectives: To determine whether BChE-K genotype predicts response to donepezil in MCI. Methods: We examined the association between …BChE-K genotype and changes in cognitive function using the data collected during the ADCS vitamin E/donepezil clinical trial in MCI. Results: We found significant interactions between BChE-K genotype and the duration of donepezil treatment, with increased changes in MMSE and CDR-SB scores compared to the common allele in MCI subjects treated during the 3-year trial. We found faster MMSE decline and CDR-SB rise in BChE-K homozygous individuals treated with donepezil compared to the untreated. We observed similar interactions between BChE-K genotype and steeper changes in MMSE and CDR-SB scores in APOE4 carriers treated with donepezil compared to controls. Conclusion: BChE-K polymorphisms are associated with deleterious changes in cognitive decline in MCI patients treated with donepezil for 3 years. This indicates that BChE-K genotyping should be performed to help identify subsets of subjects at risk for donepezil therapy, like those carrying APOE4. BChE-K and APOE4 carriers should not be prescribed off-label donepezil therapy for MCI management. Show more

Keywords: Alzheimer’s disease, butyrylcholinesterase, clinical trial, donepezil, mild cognitive impairment, pharmacogenetics, therapeutics

DOI: 10.3233/JAD-160562

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 229-237, 2017

Authors: Boccardi, Virginia | Baroni, Marta | Smirne, Nicoletta | Clodomiro, Alessandra | Ercolani, Sara | Longo, Annalisa | Ruggiero, Carmelinda | Bruni, Amalia C. | Mecocci, Patrizia

Article Type: Research Article

Abstract: Background: Most of clinical guidelines recommend discontinuing treatment with cholinesterase inhibitors (ChEIs) in patients with Alzheimer’s disease (AD) who do not show an initial response to therapy as evaluated with the Mini-Mental State Examination (MMSE) scale. However, understanding the relationship between the initial response to ChEI treatment and the subsequent course of the disease is extremely important in clinical practice, but evidence is limited, particularly in the old-old population. Objective: We aimed at investigating the relationship between short-term and long-term response to ChEI therapy in old age subjects with AD in a “real life” setting. Methods: …This is a retrospective longitudinal study of 628 old age subjects (≥65 years old) with AD and treated with ChEIs over three year follow-up. The sample was divided into “young-old” (≤75 years) and “old-old” (≥76 years) according to age, and as “responder” and “non-responder” according to the initial (i.e., after three months) response to treatment. Cognitive and functional evaluation was performed by means of MMSE and ADL/IADL, respectively. Results: In the long run, subjects considered as non-responders showed a lower rate of cognitive decline as compared with responders, with a mean annual decline at MMSE of 1.0 point versus 1.6 points (p  < 0.0001), respectively. Old-old non-responders had a slower rate of cognitive (p  < 0.0001) and functional decline (p  < 0.0001) as compared with responders after three years of observation. Conclusion: Discontinuing ChEI treatment solely for the absence of an initial response is not appropriate, especially in old-old subjects. Show more

Keywords: Age groups, aged, Alzheimer’s disease, cognition, therapeutics

DOI: 10.3233/JAD-160904

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 239-248, 2017

Authors: Van Mierlo, Lisa D. | Wouters, Hans | Sikkes, Sietske A.M. | Van der Flier, Wiesje M. | Prins, Niels D. | Bremer, Jonne A.E. | Koene, Teddy | Van Hout, Hein P.J.

Article Type: Research Article

Abstract: Background: Many older people worry about cognitive decline. Early cognitive screening in an anonymous and easily accessible manner may reassure older people who are unnecessarily worried about normal cognitive aging while it may also expedite help seeking in case of suspicious cognitive decline. Objective: To develop and validate online and telephone-based automated self-tests of cognitive function. Methods: We examined the feasibility and validity of the self-tests in a prospective study of 117 participants of whom 34 had subjective cognitive decline (SCD), 30 had mild cognitive impairment (MCI), and 53 had dementia. The ability of these …self-tests to accurately distinguish MCI and dementia from SCD was examined with ROC curves. Convergent validity was examined by calculating rank correlations between the self-tests and neuropsychological tests. Results: Both the online and telephone cognitive self-tests were feasible, because the majority of participants (86% and 80%, respectively) were able to complete them. The online self-test had adequate diagnostic accuracy in the screening for MCI and dementia versus SCD with an Area under the Curve (AUC) of 0.86 (95% CI: 0.78–0.93). The AUC of the MMSE was 0.82 (95% CI: 0.74–0.89). By contrast, the telephone self-test had lower diagnostic accuracy (AUC = 0.75, 95% CI: 0.64–0.86). Both self-tests had good convergent validity as demonstrated by moderate to strong rank correlations with neuropsychological tests. Conclusion: We demonstrated good diagnostic accuracy and convergent validity for the online self-test of cognitive function. It is therefore a promising tool in the screening for MCI and dementia. Show more

Keywords: Alzheimer’s disease, cognitive screening, online and telephone cognitive self-test, sensitivity, specificity

DOI: 10.3233/JAD-160566

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 249-259, 2017

Authors: Amen, Daniel G. | Darmal, Borhan | Raji, Cyrus A. | Bao, Weining | Jorandby, Lantie | Meysami, Somayeh | Raghavendra, Cauligi S.

Article Type: Research Article

Abstract: Background: Few studies have evaluated the impact of marijuana use on regional cerebral blood flow. Objective: To determine whether perfusion in specific brain regions on functional neuroimaging, including those affected by Alzheimer’s disease pathology, are abnormal in marijuana users compared to controls. Method: Persons with a diagnosis of cannabis use disorder by DSM-IV and DSM-V criteria (n  = 982) were compared to controls (n  = 92) with perfusion neuroimaging with SPECT at rest and at a concentration task. Perfusion estimates were quantified using a standard atlas. Cerebral perfusion differences were calculated using one-way ANOVA. Diagnostic separation was …determined with discriminant analysis of all subjects. Feature selection with a minimum redundancy maximum relevancy (mRMR) identified predictive regions in a subset of marijuana users (n  = 436) with reduced psychiatric co-morbidities. Results: Marijuana users showed lower cerebral perfusion on average (p  < 0.05). Discriminant analysis distinguished marijuana users from controls with correct classification of 96% and leave one out cross-validation of 92%. With concentration SPECT regions, there was correct classification of 95% with a leave-one-out cross validation of 90%. AUC analysis for concentration SPECT regions showed 95% accuracy, 90% sensitivity, and 83% specificity. The mRMR analysis showed right hippocampal hypoperfusion on concentration SPECT imaging was the most predictive in separating marijuana subjects from controls. Conclusion: Multiple brain regions show low perfusion on SPECT in marijuana users. The most predictive region distinguishing marijuana users from healthy controls, the hippocampus, is a key target of Alzheimer’s disease pathology. This study raises the possibility of deleterious brain effects of marijuana use. Show more

Keywords: Hippocampus, imaging, marijuana, SPECT

DOI: 10.3233/JAD-160833

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 261-273, 2017

Authors: Last, Nicole | Tufts, Emily | Auger, Leslie E.

Article Type: Research Article

Abstract: The present systematic review is based on the premise that a variety of neurodegenerative diseases are accompanied by grey matter atrophy in the brain and meditation may impact this. Given that age is a major risk factor for many of these progressive and neurodegenerative diseases and that the percentage of the population over the age of 65 is quickly increasing, there is an obvious need for prompt treatment and prevention advances in research. As there is currently no cure for Alzheimer’s disease and other neurodegenerative diseases, many are seeking non-pharmacological treatment options in attempts to offset the disease-related cognitive and functional declines. …On the basis of a growing body of research suggesting that meditation is effective in increasing grey matter volume in healthy participants, this paper systematically reviewed the literature regarding the effects of meditation on restoring grey matter volume in healthy individuals and those affected by neurodegeneration. This review searched PubMed, CINAHL, and APA PsycNET to identify original studies that included MRI imaging to measure grey matter volume in meditators and post-mindfulness-based intervention participants compared to controls. Thirteen studies were considered eligible for review and involved a wide variety of meditation techniques and included participants with and without cognitive impairment. All studies reported significant increases in grey matter volume in the meditators/intervention group, albeit in assorted regions of the brain. Limited research exists on the mechanisms through which meditation affects disease-related neurodegeneration, but preliminary evidence suggests that it may offset grey matter atrophy. Show more

Keywords: Alzheimer’s disease, dementia, grey matter, meditation, mindfulness, neurodegenerative diseases, neuroprotection, Parkinson’s disease

DOI: 10.3233/JAD-160899

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 275-286, 2017

Authors: Glozman, Tanya | Solomon, Justin | Pestilli, Franco | Guibas, Leonidas | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: We describe a fully automatic framework for classification of two types of dementia based on the differences in the shape of brain structures. We consider Alzheimer’s disease (AD), mild cognitive impairment of individuals who converted to AD within 18 months (MCIc), and normal controls (NC). Our approach uses statistical learning and a feature space consisting of projection-based shape descriptors, allowing for canonical representation of brain regions. Our framework automatically identifies the structures most affected by the disease. We evaluate our results by comparing to other methods using a standardized data set of 375 adults available from the Alzheimer’s Disease Neuroimaging …Initiative (ADNI). Our framework is sensitive to identifying the onset of Alzheimer’s disease, achieving up to 88.13% accuracy in classifying MCIc versus NC, outperforming previous methods. Show more

Keywords: Alzheimer’s disease, classification, mild cognitive impairment, shape descriptors, support vector machine

DOI: 10.3233/JAD-160900

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 287-295, 2017

Authors: Fenesi, Barbara | Fang, Hanna | Kovacevic, Ana | Oremus, Mark | Raina, Parminder | Heisz, Jennifer J.

Article Type: Research Article

Abstract: Genetics and lifestyle independently determine dementia risk, but the interaction is unclear. We assessed the interactive relationship of apolipoprotein E (APOE) genotype and physical exercise on dementia risk over a 5-year period in 1,646 older adults from the Canadian Study of Health and Aging who were dementia-free at baseline. Physical exercise moderated the relationship between genotype and dementia (p  < 0.01). Specifically, for APOE ɛ4 non-carriers, the odds of developing dementia were higher in non-exercisers than exercisers (OR = 1.98, 95% CI = 1.44, 2.71, p  < 0.001), whereas, for APOE ɛ4 carriers, the odds of developing dementia were not significantly different between non-exercisers and exercisers …(OR = 0.71, 95% CI = 0.46, 1.31, p  = 0.34). Given that most individuals are not at genetic risk, physical exercise may be an effective strategy for preventing dementia. Show more

Keywords: Alzheimer’s disease, apolipoprotein E4, dementia, exercise, physical activity, prevention

DOI: 10.3233/JAD-160424

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 297-303, 2017

Authors: Ho, Lap | Legere, Marc | Li, Tongbin | Levine, Samara | Hao, Ke | Valcarcel, Breanna | Pasinetti, Giulio M.

Article Type: Research Article

Abstract: Autonomic dysfunction is very common in patients with dementia, and its presence might also help in differential diagnosis among dementia subtypes. Various central nervous system structures affected in Alzheimer’s disease (AD) are also implicated in the central autonomic nervous system (ANS) regulation. For example, deficits in central cholinergic function in AD could likely lead to autonomic dysfunction. We recently developed a simple, readily applicable evaluation for monitoring ANS disturbances in response to traumatic brain injury (TBI). This ability to monitor TBI allows for the possible detection and targeted prevention of long-term, detrimental brain responses caused by TBI that lead to …neurodegenerative diseases such as AD. We randomly selected and extracted de-identified medical record information from subjects who have been assessed using the ANS evaluation protocol. Using machine learning strategies in the analysis of information from individual as well as a combination of ANS evaluation protocol components, we identified a novel prediction model that is effective in correctly segregating between cases with or without a documented history of TBI exposure. Results from our study support the hypothesis that trauma-induced ANS dysfunctions may contribute to clinical TBI features. Because autonomic dysfunction is very common in AD patients it is possible that TBI may also contribute to AD and/or other forms of dementia through these novel mechanisms. This study provides a novel prediction model to physiologically assess the likelihood of subjects with prior history of TBI to develop clinical TBI complications, such as AD. Show more

Keywords: Alzheimer’s disease, autonomic nervous system, biomarker, neurodegenerative disorders, risk factor, traumatic brain injury

DOI: 10.3233/JAD-160948

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 305-315, 2017

Authors: Jurjević, Ivana | Miyajima, Masakazu | Ogino, Ikuko | Akiba, Chihiro | Nakajima, Madoka | Kondo, Akihide | Kikkawa, Mika | Kanai, Mitsuyasu | Hattori, Nobutaka | Arai, Hajime

Article Type: Research Article

Abstract: Background: Patients presenting with the classical idiopathic normal pressure hydrocephalus (iNPH) triad often show additional parkinsonian spectrum signs. Accurate differential diagnosis strongly influences the long-term outcome of cerebrospinal fluid (CSF) shunting. Objective: The aim of this study was to find potential CSF microRNA (miRNA) biomarkers for NPH mimics with parkinsonian syndromes that can reliably distinguish them from iNPH patients. Methods: Two cohorts of 81 patients (cohort 1, n  = 55; cohort 2, n  = 26) with possible iNPH who were treated in two centers between January 2011 and May 2014 were studied. In both cohorts, CSF samples …were obtained from patients clinically diagnosed with iNPH (n  = 21 and n  = 10, respectively), possible iNPH with parkinsonian spectrum (PS) (n  = 18, n  = 10, respectively), possible iNPH with Alzheimer’s disease (AD) (n  = 16), and non-affected elderly individuals (NC) (n  = 6). A three-step qRT-PCR analysis of the CSF samples was performed to detect miRNAs that were differentially expressed in the groups. Results: The expression of hsa-miR-4274 in CSF was decreased in both cohorts of PS group patients (cohort 1: p  < 0.0001, cohort 2: p  < 0.0001), and was able to distinguish PS from iNPH with high accuracy (area under the curve = 0.908). The CSF concentration of hsa-miR-4274 also correlated with the specific binding ratio of ioflupane (123 I) dopamine transporter scan (r  = –0.494, p  = 0.044). By contrast, the level of hsa-miR-4274 was significantly increased in the PS group after CSF diversion. Conclusion: Levels of CSF hsa-miR-4274 can differentiate PS from patients with iNPH, AD, and NC. This may be clinically useful for diagnostic purposes and predicting shunt treatment responses. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, idiopathic normal pressure hydrocephalus, microRNAs, parkinsonian syndrome

DOI: 10.3233/JAD-160848

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 317-325, 2017

Authors: Li, Xiaozhen | Westman, Eric | Thordardottir, Steinunn | Ståhlbom, Anne Kinhult | Almkvist, Ove | Blennow, Kaj | Wahlund, Lars-Olof | Graff, Caroline

Article Type: Research Article

Abstract: Familial Alzheimer’s disease (FAD) mutations have very high penetrance but age at onset and rate of disease progression differ. Neuroimaging and cerebrospinal fluid (CSF) examinations in mutation carriers (MCs) may provide an opportunity to identify early biomarkers that can be used to track disease progression from presymptomatic to the dementia stages of disease. The default mode network (DMN) is a resting state neuronal network composed of regions known to associate with amyloid deposition in AD. We hypothesized that functional connectivity in the DMN might change at pre-clinical stages in FAD MCs and correlate with changes in CSF biomarkers as a …consequence of AD brain pathology. To test the hypothesis, we compared the functional connectivity in DMN between pre-MCs/MCs and non-carriers (NCs). No significant differences between pre-MCs and NCs were observed. When comparing all MCs with NCs, significant decreased functional connectivity in the right inferior parietal lobule, right precuneus, and left posterior cingulate cortex were found. We also found statistically significant correlations between CSF amyloid-β 42 and tau protein levels and average Z-score, a resting-state functional MRI measurement reflecting the degree of the correlation between a given voxel’s time courses and the time courses corresponding to DMN, from the region with statistical difference. The observed disruption of DMN and pathological levels of AD CSF-biomarkers in FAD MCs are similar to the changes described in sporadic AD, which give further support that amyloid and tau pathology impairs neuronal and synaptic function. Show more

Keywords: Cerebrospinal fluid biomarkers, default mode network, familial Alzheimer’s disease, mutation carrier, resting-state functional MRI, synaptic function

DOI: 10.3233/JAD-160730

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 327-334, 2017

Authors: Shukla, Varsha | Seo, Jinsoo | Binukumar, B.K. | Amin, Niranjana D. | Reddy, Preethi | Grant, Philip | Kuntz, Susan | Kesavapany, Sashi | Steiner, Joseph | Mishra, Santosh K. | Tsai, Li-Huei | Pant, Harish C.

Article Type: Research Article

Abstract: It has been reported that cyclin-dependent kinase 5 (cdk5), a critical neuronal kinase, is hyperactivated in Alzheimer’s disease (AD) and may be, in part, responsible for the hallmark pathology of amyloid plaques and neurofibrillary tangles (NFTs). It has been proposed by several laboratories that hyperactive cdk5 results from the overexpression of p25 (a truncated fragment of p35, the normal cdk5 regulator), which, when complexed to cdk5, induces hyperactivity, hyperphosphorylated tau/NFTs, amyloid-β plaques, and neuronal death. It has previously been shown that intraperitoneal (i.p.) injections of a modified truncated 24-aa peptide (TFP5), derived from the cdk5 activator p35, penetrated the blood-brain …barrier and significantly rescued AD-like pathology in 5XFAD model mice. The principal pathology in the 5XFAD mutant, however, is extensive amyloid plaques; hence, as a proof of concept, we believe it is essential to demonstrate the peptide’s efficacy in a mouse model expressing high levels of p25, such as the inducible CK-p25Tg model mouse that overexpresses p25 in CamKII positive neurons. Using a modified TFP5 treatment, here we show that peptide i.p. injections in these mice decrease cdk5 hyperactivity, tau, neurofilament-M/H hyperphosphorylation, and restore synaptic function and behavior (i.e., spatial working memory, motor deficit using Rota-rod). It is noteworthy that TFP5 does not inhibit endogenous cdk5/p35 activity, nor other cdks in vivo suggesting it might have no toxic side effects, and may serve as an excellent therapeutic candidate for neurodegenerative disorders expressing abnormally high brain levels of p25 and hyperactive cdk5. Show more

Keywords: Alzheimer’s disease, cyclin-dependent kinase 5, hyperphosphorylation, synaptic function, TFP5

DOI: 10.3233/JAD-160916

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 335-349, 2017

Authors: Law, Lena L. | Schultz, Stephanie A. | Boots, Elizabeth A. | Einerson, Jean A. | Dougherty, Ryan J. | Oh, Jennifer M. | Korcarz, Claudia E. | Edwards, Dorothy F. | Koscik, Rebecca L. | Dowling, N. Maritza | Gallagher, Catherine L. | Bendlin, Barbara B. | Carlsson, Cynthia M. | Asthana, Sanjay | Hermann, Bruce P. | Sager, Mark A. | Johnson, Sterling C. | Cook, Dane B. | Stein, James H. | Okonkwo, Ozioma C.

Article Type: Research Article

Abstract: The objective of this study was to examine the association of chronotropic response (CR) and heart rate (HR) recovery— two indices of cardiovascular function within the context of a graded exercise test— with cognitive performance in a cognitively healthy, late-middle-aged cohort at risk for Alzheimer’s disease (AD). Ninety participants (age = 63.52±5.86 years; 65.6% female) from the Wisconsin Registry for Alzheimer’s Prevention participated in this study. They underwent graded exercise testing and a comprehensive neuropsychological assessment that assessed the following four cognitive domains: Immediate Memory, Verbal & Learning Memory, Working Memory, and Speed & Flexibility. Regression analyses, adjusted for age, sex, and …education, were used to examine the association between CR, HR recovery, and cognition. We found significant associations between CR and cognitive performance in the domains of Immediate Memory, Verbal Learning & Memory, and Speed & Flexibility. In contrast, HR recovery was not significantly associated with cognitive function. The association between CR and cognition persisted even after controlling for HR recovery. Together, these findings indicatethat, in a cognitively normal, late-middle-aged cohort, CR is a stronger correlate of cognitive performance than HR recovery. Overall, this study reinforces the idea that cardiovascular health plays an important role in cognitive function, specifically in a cohort at risk for AD; and that interventions that promote vascular health may be a viable pathway to preventing or slowing cognitive decline due to AD. Show more

Keywords: Alzheimer disease, cardiopulmonary exercise test, cardiovascular health, cognition, heart rate

DOI: 10.3233/JAD-160642

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 351-359, 2017

Authors: Shen, Liming | Liao, Liping | Chen, Cheng | Guo, Yi | Song, Dalin | Wang, Yong | Chen, Youjiao | Zhang, Kaoyuan | Ying, Ming | Li, Shuiming | Liu, Qiong | Ni, Jiazuan

Article Type: Research Article

Abstract: Alzheimer’ disease (AD) is the most common form of dementia affecting up to 6% of the population over the age of 65. In order to discover differentially expressed proteins that might serve as potential biomarkers, the serums from AD patients and healthy controls were compared and analyzed using the proteomics approach of isobaric tagging for relative and absolute quantitation (iTRAQ). For the first time, AD biomarkers in serums are investigated in the Han Chinese population using iTRAQ labeled proteomics strategy. Twenty-two differentially expressed proteins were identified and out of which nine proteins were further validated with more sample test. Another …three proteins that have been reported in the literature to be potentially associated with AD were also investigated for alteration in expression level. Functions of those proteins were mainly related to the following processes: amyloid-β (Aβ) metabolism, cholesterol transport, complement and coagulation cascades, immune response, inflammation, hemostasis, hyaluronan metabolism, and oxidative stress. These results support current views on the molecular mechanism of AD. For the first time, differential expression of zinc-alpha-2-glycoprotein (AZGP1), fibulin-1 (FBLN1), platelet basic protein (PPBP), thrombospondin-1 (THBS1), S100 calcium-binding protein A8 (S100A8), and S100 calcium-binding protein A9 (S100A9) were detected in the serums of AD patients compared with healthy controls. These proteins might play a role in AD pathophysiology and serve as potential biomarkers for AD diagnosis. Specifically, our results strengthened the crucial role of Aβ metabolism and blood coagulation in AD pathogenesis and proteins related to these two processes may be used as peripheral blood biomarkers for AD. Show more

Keywords: Alzheimer’ disease, biomarker, iTRAQ, proteomics, serum

DOI: 10.3233/JAD-160913

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 361-378, 2017

Authors: Jacob, Louis | Bohlken, Jens | Kostev, Karel

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) is a common mental disorder affecting around 16% of elderly people without dementia. MCI is considered an intermediate state between normal cognition and dementia. Objective: To analyze risk factors for the development of MCI in German primary care practices. Methods: In total, 3,604 MCI patients and 3,604 controls without MCI were included between January 2010 and December 2015. Several disorders potentially associated with MCI were determined. Multivariate logistic regression models were fitted with MCI as a dependent variable and other disorders as potential predictors. Results: The mean age …was 75.2 years and 45.3% of patients were men. MCI development was found to be associated with 12 disorders: intracranial injury, anxiety disorder, depression, mental and behavioral disorders due to alcohol use, stroke, hyperlipidemia, obesity, hypertension, Parkinson’s disease, sleep disorder, coronary heart disease, and diabetes with odds ratios ranging from 1.13 (diabetes) to 2.27 (intracranial injury). Conclusion: Intracranial injury, anxiety, and depression showed the strongest association with MCI. Further analyses are needed to gain a better understanding of the MCI risk factors. Show more

Keywords: Germany, mild cognitive impairment, primary practices, risk factors

DOI: 10.3233/JAD-160875

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 379-384, 2017

Authors: Shen, Liang | Liu, Lu | Ji, Hong-Fang

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative brain disease and is the most common form of dementia. In recent years, many studies indicated the association of gut microbiota changes with metabolic diseases. However, the gut microbiota of AD has not been investigated. The present study aims to compare the gut microbiota in APP/PS1 transgenic mice of AD and C57/Bl6 wild-type (WT) mice by pyrosequencing the V3 and V4 regions of the bacterial 16S ribosomal RNA genes. The 3-, 6-, and 8-month-old APP/PS1 and WT mice were used to explore the effects of age on the gut microbiota. First, the results indicated …that impaired spatial learning and memory appeared in 6-month-old APP/PS1 mice and was further aggravated in the 8-month-old group, which was consistent with immunohistochemical studies of amyloid plaque. Second, AD histological and behavioral manifestations in the APP/PS1 mice were found to be correlated with a specific gut microbiome state. Third, the microbiota diversity of APP/PS1 mice decreased with increased age. Fourth, further inspection showed that the abundance of Helicobacteraceae and Desulfovibrionaceae at the family level and Odoribacter and Helicobacter at the genus level increased significantly in APP/PS1 mice than in WT mice, while Prevotella abundance in WT mice was significantly higher than in APP/PS1 mice. More human studies are warranted to explore the potential of gut microbiota as diagnostic biomarkers or therapeutic target for AD. Show more

Keywords: 16S ribosomal RNA, Alzheimer’s disease, APP/PS1 mice, gut microbiota

DOI: 10.3233/JAD-160884

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 385-390, 2017

Authors: Xie, Bing | Xu, Yao | Liu, Zanchao | Liu, Wenxuan | Jiang, Lei | Zhang, Rui | Cui, Dongsheng | Zhang, Qingfu | Xu, Shunjiang

Article Type: Research Article

Abstract: Epigenetic aberrations have been identified as biomarkers to predict the risk of Alzheimer’s disease (AD). This study aimed to evaluate whether altered DNA methylation status of BDNF promoter could be used as potential epigenetic biomarkers for predicting the progression from amnestic mild cognitive impairment (aMCI) to AD. A total of 506 aMCI patients and 728 cognitively normal controls were recruited in the cross-sectional analyses. Patients (n  = 458) from aMCI cohort were classified into two groups after 5-year follow-up: aMCI-stable group (n  = 330) and AD-conversion group (n  = 128). DNA methylation of BDNF promoter was detected by bisulfite-PCR amplification and pyrosequencing. The …DNA methylation levels of CpG1 and CpG2 in promoter I and CpG5 and CpG6 in promoter IV of BDNF gene were significantly higher in the aMCI group than in the control group at baseline and also were increased in the conversion group compared with the non-conversion group at 5-year follow up time point. CpG5 in BDNF promoter IV had the highest AUC of 0.910 (95% CI: 0.817–0.983, p  < 0.05). Kaplan-Meier analysis showed a significant AD conversion propensity for aMCI patients with high methylation levels of CpG5 (HR  = 1.96, 95% CI: 1.07–2.98, p  < 0.001). Multivariate Cox regression analysis revealed elevated methylation status of CpG5 was a significant independent predictor for AD conversion (HR  = 3.51, p  = 0.013). These results suggest that elevation of peripheral BDNF promoter methylation might be used as potential epigenetic biomarkers for predicting the conversion from aMCI to AD. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, BDNF promoter, DNA methylation, follow-up study

DOI: 10.3233/JAD-160954

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 391-401, 2017

Authors: McLimans, Kelsey E. | Willette, Auriel A. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Obesity and insulin resistance are associated with neuropathology and cognitive decline in Alzheimer’s disease (AD). Objective: Ecto-nucleotide pyrophosphatase/phosphodiesterase 2, also called autotaxin, is produced by beige adipose tissue, regulates metabolism, and is higher in AD prefrontal cortex (PFC). Autotaxin may be a novel biomarker of dysmetabolism and AD. Methods: We studied Alzheimer’s Disease Neuroimaging Initiative participants who were cognitively normal (CN; n  = 86) or had mild cognitive impairment (MCI; n  = 135) or AD (n  = 66). Statistical analyses were conducted using SPSS software. Multinomial regression analyses tested if higher autotaxin was associated with higher relative …risk for MCI or AD diagnosis, compared to the CN group. Linear mixed model analyses were used to regress autotaxin against MRI, FDG-PET, and cognitive outcomes. Spearman correlations were used to associate autotaxin and CSF biomarkers due to non-normality. FreeSurfer 4.3 derived mean cortical thickness in medial temporal lobe and prefrontal regions of interest. Results: Autotaxin levels were significantly higher in MCI and AD. Each point increase in log-based autotaxin corresponded to a 3.5 to 5 times higher likelihood of having MCI and AD, respectively. Higher autotaxin in AD predicted hypometabolism in the medial temporal lobe [R2  = 0.343, p  < 0.001] and PFC [R2  = 0.294, p  < 0.001], and worse performance on executive function and memory factors. Autotaxin was associated with less cortical thickness in PFC areas like orbitofrontal cortex [R2  = 0.272, p < 0.001], as well as levels of total tau, p-tau181, and total tau/Aβ1–42 . Conclusions: These results are comparable to previous reports using insulin resistance. CSF autotaxin may be a useful dysmetabolism biomarker for examining AD outcomes and risk. Show more

Keywords: Diabetes mellitus, fluorodeoxyglucose F18, insulin resistance, mild cognitive impairment, MRI, positron emission tomography

DOI: 10.3233/JAD-160891

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 403-413, 2017

Authors: Wang, Zan | Dai, Zhengjia | Shu, Hao | Liu, Duan | Guo, Qihao | He, Yong | Zhang, Zhijun

Article Type: Research Article

Abstract: Both the apolipoprotein E (APOE) ɛ 4 allele and amnestic mild cognitive impairment (aMCI) are considered to be risk factors for Alzheimer’s disease (AD). The primary aim of this study was to determine whether the aMCI-related abnormality in gray matter (GM) cortical thickness and white matter (WM) tracts integrity would be modified by the APOE genotype. A total of 146 older adults, including 64 aMCI patients (28 ɛ 4 carriers and 36 non-carriers) and 82 healthy controls (39 ɛ 4 carriers and 43 non-carriers), underwent a standardized clinical interview, neuropsychological battery assessment, and multi-modal brain magnetic resonance imaging scans. Compared …with control subjects, the patients with aMCI showed significantly reduced cortical thickness bilaterally in the parahippocampal gyrus and disrupted WM integrity in the limbic tracts (e.g., increased mean diffusivity in the right parahippocampal cingulum and bilateral uncinate fasciculus). However, no significant main effects of the APOE genotype and diagnosis-by-genotype interaction on GM thickness and WM integrity were observed. Further, diffusivity measures of the limbic WM tracts were significantly correlated with the parahippocampal atrophy in aMCI. Importantly, the parahippocampal thickness and diffusivity measures of the limbic WM tracts were significantly correlated with the cognitive performance (i.e., episodic memory Z score) in patients with aMCI. These results demonstrate that WM microstructural disruptions in the limbic tracts are present at the early stage of AD in an APOE-independent manner; and this degeneration may occur progressively, in parallel with parahippocampal atrophy, and may specifically contribute to early initial impairment in episodic memory. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, apolipoprotein E, cortical thickness, white matter integrity

DOI: 10.3233/JAD-160724

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 415-428, 2017