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