Journal of Alzheimer's Disease - Volume 51, issue 2

Authors: Abdin, Edimansyah | Subramaniam, Mythily | Achilla, Evanthia | Chong, Siow Ann | Vaingankar, Janhavi Ajit | Picco, Louisa | Sambasivam, Rajeswari | Pang, Shirlene | Chua, Boon Yiang | Ng, Li Ling | Chua, Hong Choon | Heng, Derrick | Prince, Martin | McCrone, Paul

Article Type: Research Article

Abstract: Background: There is currently limited evidence on the economic burden that dementia exerts on multi-ethnic Asian populations. Objective: The present study aimed to estimate the economic cost of dementia in Singapore. Methods: We used data from the Well-being of the Singapore Elderly study, a nationally representative survey of the older Singapore Resident population aged 60 years and above. Generalized linear modeling was used to estimate factors associated with costs. Results: The total cost of dementia in 2013 was estimated at S$532 million (95% CI, S$361 million to S$701 million) while the annual cost per …person was estimated at S$10,245 per year (95% CI, S$6,954 to S$12,495). Apart from dementia, higher total societal cost were also significantly associated with older age, Indian ethnicity, and those who were diagnosed with heart problems, stroke, diabetes or depression, whereas being divorced/separated, lower education, and those who were diagnosed with hypertension were significantly associated with lower total societal cost. Conclusion: The study provides a rich body of information on healthcare utilization and cost of dementia, which is essential for future planning of services for the elderly population. Show more

Keywords: Cost of illness, dementia, elderly, health services, societal cost

DOI: 10.3233/JAD-150930

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 439-449, 2016

Authors: Karakis, Ioannis | Pase, Matthew P. | Beiser, Alexa | Booth, Sarah L. | Jacques, Paul F. | Rogers, Gail | DeCarli, Charles | Vasan, Ramachandran S. | Wang, Thomas J. | Himali, Jayandra J. | Annweiler, Cedric | Seshadri, Sudha

Article Type: Research Article

Abstract: Background: Identifying nutrition- and lifestyle-based risk factors for cognitive impairment and dementia may aid future primary prevention efforts. Objective: We aimed to examine the association of serum vitamin D levels with incident all-cause dementia, clinically characterized Alzheimer’s disease (AD), MRI markers of brain aging, and neuropsychological function. Methods: Framingham Heart Study participants had baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations measured between 1986 and 2001. Vitamin D status was considered both as a continuous variable and dichotomized as deficient (<10 ng/mL), or at the cohort-specific 20th and 80th percentiles. Vitamin D was related to the 9-year risk of …incident dementia (n  = 1663), multiple neuropsychological tests (n  = 1291) and MRI markers of brain volume, white matter hyperintensities and silent cerebral infarcts (n  = 1139). Results: In adjusted models, participants with vitamin D deficiency (n  = 104, 8% of the cognitive sample) displayed poorer performance on Trail Making B-A (β= –0.03 to –0.05±0.02) and the Hooper Visual Organization Test (β= –0.09 to –0.12±0.05), indicating poorer executive function, processing speed, and visuo-perceptual skills. These associations remained when vitamin D was examined as a continuous variable or dichotomized at the cohort specific 20th percentile. Vitamin D deficiency was also associated with lower hippocampal volumes (β= –0.01±0.01) but not total brain volume, white matter hyperintensities, or silent brain infarcts. No association was found between vitamin D deficiency and incident all-cause dementia or clinically characterized AD. Conclusions: In this large community-based sample, low 25(OH)D concentrations were associated with smaller hippocampal volume and poorer neuropsychological function. Show more

Keywords: Alzheimer’s disease, brain, dementia, diet, lifestyle, magnetic resonance imaging, neuropsychology, nutritional status, risk factors, vitamin D

DOI: 10.3233/JAD-150991

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 451-461, 2016

Authors: White, Matthew T. | Shaw, Leslie M. | Xie, Sharon X. | for the Alzheimer’s Disease Neuroimaging Initiative | and the National Alzheimer’s Coordinating Center

Article Type: Research Article

Abstract: Studies of cerebrospinal fluid (CSF) biomarkers in Alzheimer’s disease (AD) have indicated that much of the variability observed in the biomarkers may be due to measurement error. Biomarkers are often obtained with measurement error, which may make the diagnostic biomarker appear less effective than it truly is. In the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, technical replicates of CSF biomarkers are available; the National Alzheimer’s Coordinating Center database contains longitudinal replicates of CSF biomarkers. We focus on the area under the receiver operating characteristic curve (AUC) as the measure of diagnostic effectiveness for differentiating AD from normal cognition using CSF …biomarkers and compare AUC estimates obtained by a more standard, naïve method (which uses a single observation per subject and ignores measurement error) to a maximum likelihood (ML) based method (which uses all replicates per subject and adjusts for measurement error). The choice of analysis method depends upon the noise to signal ratio (i.e., the magnitude of the measurement error variability relative to the true biomarker variability); moderate to high ratios may significantly bias the naïve AUC estimate, and the ML-based method would be preferred. The noise to signal ratios were low for the ADNI biomarkers but high for the tTau and pTau biomarkers in NACC. Correspondingly, the naïve and ML-based AUC estimates were nearly identical in the ADNI data but dissimilar for the tTau and pTau biomarkers in the NACC data. Therefore, using the naïve method is adequate for analysis of CSF biomarkers in the ADNI study, but the ML method is recommended for the NACC data. Show more

Keywords: Alzheimer’s disease, biomarkers, diagnostic testing, maximum likelihood, measurement error, replicate data

DOI: 10.3233/JAD-151045

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 463-470, 2016

Authors: Xu, He | Perreau, Victoria M. | Dent, Krista A. | Bush, Ashley I. | Finkelstein, David I. | Adlard, Paul A.

Article Type: Research Article

Abstract: Background: There is strong evidence that iron homeostasis is impaired in the aging and Alzheimer’s disease (AD) brain and that this contributes to neurodegeneration. Apolipoprotein E (APOE) has been identified as the strongest genetic risk factor for AD. However, the interaction between the two has yet to be fully explored. Objective: This study aimed to investigate the relationship between exogenous iron levels and ApoE in neurons and astrocytes. Methods: Our study used primary cultured cortical neurons and astrocytes to investigate the changes in ApoE caused by iron. Western blot and RT-PCR were used to measure ApoE. …Results: We observed that iron upregulated intracellular ApoE levels in both neurons and astrocytes at the post-transcriptional and transcriptional level, respectively. However, there was less full-length ApoE secreted by neurons and astrocytes after iron treatment. We speculate that this might impair brain lipid metabolism and amyloid-β clearance. In terms of ApoE receptors, we observed that neuronal LRP-1 levels were increased by the addition of exogenous iron, which could contribute to Aβ PP endocytosis in neurons. However, there were no significant changes in neuronal LDLR, astrocyte LDLR, or astrocyte LRP-1. Conclusion: Our study reveals that iron may contribute to the pathogenesis of AD by affecting ApoE and its receptors and supports the notion that iron chelation should be investigated as a therapeutic strategy for AD. Show more

Keywords: Apolipoprotein E, iron, lipoprotein receptor-related protein, low-density lipoprotein receptor

DOI: 10.3233/JAD-150797

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 471-487, 2016

Authors: Aso, Ester | Andrés-Benito, Pol | Carmona, Margarita | Maldonado, Rafael | Ferrer, Isidre

Article Type: Research Article

Abstract: The endogenous cannabinoid system represents a promising therapeutic target to modify neurodegenerative pathways linked to Alzheimer’s disease (AD). The aim of the present study was to evaluate the specific contribution of CB2 receptor to the progression of AD-like pathology and its role in the positive effect of a cannabis-based medicine (1:1 combination of Δ9 -tetrahidrocannabinol and cannabidiol) previously demonstrated to be beneficial in the AβPP/PS1 transgenic model of the disease. A new mouse strain was generated by crossing AβPP/PS1 transgenic mice with CB2 knockout mice. Results show that lack of CB2 exacerbates cortical Aβ deposition and increases …the levels of soluble Aβ40 . However, CB2 receptor deficiency does not affect the viability of AβPP/PS1 mice, does not accelerate their memory impairment, does not modify tau hyperphosphorylation in dystrophic neurites associated to Aβ plaques, and does not attenuate the positive cognitive effect induced by the cannabis-based medicine in these animals. These findings suggest a minor role for the CB2 receptor in the therapeutic effect of the cannabis-based medicine in AβPP/PS1 mice, but also constitute evidence of a link between CB2 receptor and Aβ processing. Show more

Keywords: AβPP/PS1 mice, Alzheimer’s disease, amyloid, cannabinoid receptor 2, cognitive impairment, Δ9-tetrahidrocannabinol and cannabidiol, tau, therapy

DOI: 10.3233/JAD-150913

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 489-500, 2016

Authors: Luchsinger, José A. | Perez, Thania | Chang, Helena | Mehta, Pankaj | Steffener, Jason | Pradabhan, Gnanavalli | Ichise, Masanori | Manly, Jennifer | Devanand, Davangere P. | Bagiella, Emilia

Article Type: Research Article

Abstract: Diabetes and hyperinsulinemia may be risk factors for Alzheimer’s disease (AD). We conducted a pilot study of metformin, a medication efficacious in treating and preventing diabetes while reducing hyperinsulinemia, among persons with amnestic mild cognitive impairment (aMCI) with the goal of collecting preliminary data on feasibility, safety, and efficacy. Participants were 80 men and women aged 55 to 90 years with aMCI, overweight or obese, without treated diabetes. We randomized participants to metformin 1000 mg twice a day or matching placebo for 12 months. The co-primary clinical outcomes were changes from baseline to 12 months in total recall of the Selective …Reminding Test (SRT) and the score of the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog). The secondary outcome was change in relative glucose uptake in the posterior cingulate-precuneus in brain fluorodeoxyglucose positron emission tomography. Change in plasma Aβ42 was an exploratory outcome. The mean age of participants was 65 years. Fifty percent of participants were women. The only baseline variable that was different between the arms was the ADAS-Cog. Metformin could not be tolerated by 7.5% of participants; 15% tolerated 500 mg/day, 35% tolerated 1000 mg/day, 32.5% tolerated 1500 mg/day, and only 10% tolerated the maximum dose. There were no serious adverse events related to metformin. The 7.5% of persons who did not tolerate metformin reported gastrointestinal symptoms. After adjusting for baseline ADAS-cog, changes in total recall of the SRT favored the metformin group (9.7±8.5 versus 5.3±8.5; p  = 0.02). Differences for other outcomes were not significant. A larger trial seems warranted to evaluate the efficacy and cognitive safety of metformin in prodromal AD. Show more

Keywords: Amnestic mild cognitive impairment, insulin, memory, metformin, randomized clinical trial

DOI: 10.3233/JAD-150493

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 501-514, 2016

Authors: Chen, Huei-Yang | Panegyres, Peter K.

Article Type: Research Article

Abstract: Background: Ethnic minorities seem to be at an increased risk of Alzheimer’s disease (AD). However, little is known about ethnic differences and the risks of early onset AD (EOAD). Objective: Cognitive function changes over time and odds of EOAD by ethnicity were analyzed by the mixed model and the logistic regression. Methods: Information on demographics, self-reported co-morbidities, cognitive functions (MMSE and ADAS-COG), and ApoE genotypes were collected for 6,500 subjects with AD obtained from the placebo arm of clinical trials; this data was examined by ethnicities: Caucasian, Asian, African American, Hispanic, and other minorities— including Native …Alaskans, Americans, and Hawaiians. Results: Of the total subjects, Caucasians accounted for 89.0% , followed by 4.7% Asians, 2.7% African Americans, 2.4% Hispanics, and 1.2% Native Americans, Alaskans, and Hawaiians. Age, gender, EOAD status, co-morbidities, family history of AD, and ApoE genotypes were significantly different by ethnicity. ApoE ɛ 2 allele is possibly overrepresented in the Native Americans, Africans, Hawaiians, and African Americans. A significant interaction with time, ethnicity, and cognitive performance was found, indicating more cognitive deterioration in other minorities than Caucasians for mini-mental state (p  <  0.01). After adjusting for co-morbidities and gender, the odds of EOAD among African Americans (OR: 1.6, 95% CI: 1.1–2.4) and Native Alaskans, Americans, and Hispanics (OR: 2.1, 95% CI: 1.2–3.5) were significantly higher, compared with Caucasians. Conclusions: Ethnicity may impact AD through age of onset, co-morbidities, family history, ApoE gene status, and cognitive change over time. The greater odds of EOAD among African Americans, Alaskans, and Hawaiians suggest that some ethnicities may be at risk of AD at a younger age. Show more

Keywords: Alzheimer’s disease, ApoE, early onset Alzheimer’s disease, early onset dementia, ethnicity

DOI: 10.3233/JAD-151089

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 515-523, 2016

Authors: Chu, Shuguang | Xu, Feijia | Su, Ya | Chen, Hong | Cheng, Xin

Article Type: Research Article

Abstract: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a relatively rare syndrome of reversible encephalopathy and could be divided into two subtypes of inflammatory CAA (ICAA) and amyloid-β-related angiitis (ABRA) according to histopathology. We present a case of pathologically proved ABRA with partial seizures and headache, and a focal lesion in the right temporal lobes on magnetic resonance imaging. Summarized from previous 139 ABRA and ICAA cases, ABRA is preferred when the lesion is enhanced on MRI and requires combination drug therapy, while ICAA is highly suspected with ApoE genotype of ɛ 4/ɛ 4. More clinical markers for diagnosis of CAA-ri warrant …further researches. Show more

Keywords: Amyloid-β-related angiitis, cerebral amyloid angiopathy, cerebral amyloid angiopathy-related inflammation, inflammatory cerebral amyloid angiopathy

DOI: 10.3233/JAD-151036

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 525-532, 2016

Authors: Benito-León, Julián | Contador, Israel | Mitchell, Alex J. | Domingo-Santos, Ángela | Bermejo-Pareja, Félix

Article Type: Research Article

Abstract: Evidence regarding the relationship between performance on specific cognitive domains and cause of death is scarce. We assessed whether specific cognitive domains predicted mortality and the presence of any association with specific causes of death in a population-dwelling sample of non-demented older adults. In this population-based, prospective study (NEDICES), 2,390 non-demented subjects ≥65 years completed a brief neuropsychological battery. Cox’s proportional hazards models, adjusted by sociodemographic and comorbidity factors, global cognitive performance, educational level, and premorbid intelligence were used to assess the risk of death. Participants were followed for a median of 9.2 years (range 0.01–10.7), after which the death …certificates of those who died were examined. 880 (36.8%) of 2,390 participants died over a median follow-up of 5.5 years (range 0.01–10.5). Using adjusted Cox regression models, we found that hazard ratios for mortality in participants within the lowest tertiles (worse performance) were 1.31 (speed of cognitive processing, p  = 0.03); 1.22 (semantic fluency, p  = 0.04), 1.32 (delayed free recall, p  = 0.003), and 1.23 (delayed logical memory, p  = 0.03). Poor performance on delayed recall and speed of cognitive processing tests were associated with dementia and cerebrovascular disease mortality, respectively. Further, poor performance on semantic fluency was associated with decreased cancer mortality. In this study of community dwelling non-demented older adults, worse neuropsychological performance was associated with increased risk of mortality. Performance on specific cognitive domains were related to different causes of death. Of particular note there appears to be an inverse association between poor semantic fluency and cancer mortality. Show more

Keywords: Cause specific-mortality, cognitive aging, epidemiology, neuropsychology, prospective cohort, population-based study

DOI: 10.3233/JAD-150875

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 533-544, 2016

Authors: Heßmann, Philipp | Seeberg, Greta | Reese, Jens Peter | Dams, Judith | Baum, Erika | Müller, Matthias J. | Dodel, Richard | Balzer-Geldsetzer, Monika

Article Type: Research Article

Abstract: The purpose of this study is to evaluate the health-related quality of life (HrQoL) of patients with Alzheimer’s disease (AD) in different care settings (institutionalized versus community-dwelling) across all severity stages of dementia. Patients were consecutively recruited with their primary caregivers (123 inpatients and 272 outpatients), and the impact of patient-related parameters such as behavioral and psychological symptoms of dementia (BPSD) (Geriatric Depression Scale [GDS] and Neuropsychiatric Inventory [NPI]) and functional capacity (Alzheimer’s Disease Cooperative Study-Activities of Daily Living [ADCS-ADL]) on HrQoL was analyzed. Patients’ HrQoL was assessed using self-reported and caregiver-rated generic (EuroQoL Instrument) and dementia-specific (Quality of Life-Alzheimer’s …Disease [Qol-AD]) scales. Patients reported a considerably higher HrQoL than their caregivers on the QoL-AD, EQ-5D, and EQ VAS (p  <  0.001). Different dementia severity groups showed significantly worse results in HrQoL for patients with lower MMSE scores. The mean self-reported QoL-AD decreased from 32.3±5.7 in the group with the highest MMSE scores to 27.1±5.5 in patients with the lowest MMSE scores (p  <  0.001). A considerably lower HrQoL was shown for institutionalized patients versus participants in outpatient settings (proxy-rated QoL-AD 19.7±4.6 versus 26.0±7.1, p  <  0.001). Depressive symptoms (GDS), BPSD (NPI), and reduced functional capacity (ADCS-ADL) were evaluated for their impact on patients’ HrQoL. Multivariate models explained between 22% and 54% of the variance in patients’ HrQoL. To analyze the causative direction of the reported associations, further longitudinal studies should be conducted. Show more

Keywords: Alzheimer’s disease, BPSD, care, dementia, depression, quality of life

DOI: 10.3233/JAD-150835

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 545-561, 2016

Authors: Pilotto, Andrea | Turrone, Rosanna | Liepelt-Scarfone, Inga | Bianchi, Marta | Poli, Loris | Borroni, Barbara | Alberici, Antonella | Premi, Enrico | Formenti, Anna | Bigni, Barbara | Cosseddu, Maura | Cottini, Elisabetta | Berg, Daniela | Padovani, Alessandro

Article Type: Research Article

Abstract: Vascular risk factors have been associated with cognitive deficits and incident dementia in the general population, but their role on cognitive dysfunction in Parkinson’s disease (PD) is still unclear. The present study addresses the single and cumulative effect of vascular risk factors on cognition in PD patients, taking clinical confounders into account. Standardized neuropsychological assessment was performed in 238 consecutive PD patients. We evaluated the association of single and cumulative vascular risk factors (smoking, diabetes, hypercholesterolemia, hypertension, and heart disease), with the diagnosis of PD normal cognition (PDNC, n  = 94), mild cognitive impairment (PD-MCI, n  = 111), and dementia (PDD, n … = 33). The association between single neuropsychological tests and vascular risk factors was evaluated with covariance analyses adjusted for age at onset, educational levels, gender, disease duration, and motor performance. Age, educational levels, disease duration, and motor function were significantly different between PDNC, PD-MCI, and PDD. Heart disease was the only vascular factor significantly more prevalent in PDD compared with PDNC in adjusted analyses. Performance of tests assessing executive and attention functions were significantly worse in patients with hypertension, heart disease, and/or diabetes (p  <  0.05). Heart disease is associated with dementia in PD, suggesting a potential window of intervention. Vascular risk factors act especially on attention and executive functions in PD. Vascular risk stratification may be useful in order to identify PD patients with a greater risk of developing dementia. These findings need to be verified in longitudinal studies. Show more

Keywords: Dementia, heart disease, hypertension, Parkinson disease, risk factors

DOI: 10.3233/JAD-150610

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 563-570, 2016

Authors: Fang, Du | Zhang, Zhihua | Li, Hang | Yu, Qing | Douglas, Justin T. | Bratasz, Anna | Kuppusamy, Periannan | Yan, Shirley ShiDu

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized clinically by cognitive decline and memory loss. The pathological features are amyloid-β peptide (Aβ) plaques and intracellular neurofibrillary tangles. Many studies have suggested that oxidative damage induced by reactive oxygen species (ROS) is an important mechanism for AD progression. Our recent study demonstrated that oxidative stress could further impair mitochondrial function. In the present study, we adopted a transgenic mouse model of AD (mAPP, overexpressing AβPP/Aβ in neurons) and performed redox measurements using in vivo electron paramagnetic resonance (EPR) imaging with methoxycarbamyl-proxyl (MCP) as a redox-sensitive probe for studying oxidative …stress in an early stage of pathology in a transgenic AD mouse model. Through assessing oxidative stress, mitochondrial function and cognitive behaviors of mAPP mice at the age of 8-9 months, we found that oxidative stress and mitochondrial dysfunction appeared in the early onset of AD. Increased ROS levels were associated with defects of mitochondrial and cognitive dysfunction. Notably, the in vivo EPR method offers a unique way of assessing tissue oxidative stress in living animals under noninvasive conditions, and thus holds a potential for early diagnosis and monitoring the progression of AD. Show more

Keywords: Aβ accumulation, cognitive function, mitochondrial dysfunction, oxidative stress

DOI: 10.3233/JAD-150917

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 571-580, 2016

Authors: Louwersheimer, Eva | Keulen, M. Antoinette | Steenwijk, Martijn D. | Wattjes, Mike P. | Jiskoot, Lize C. | Vrenken, Hugo | Teunissen, Charlotte E. | van Berckel, Bart N.M. | van der Flier, Wiesje M. | Scheltens, Philip | van Swieten, John C. | Pijnenburg, Yolande A.L.

Article Type: Research Article

Abstract: Background: The logopenic variant of Primary Progressive Aphasia (lvPPA) is associated with underlying Alzheimer’s disease (AD) pathology and characterized by impaired single word retrieval and repetition of phrases and sentences. Objective: We set out to study whether logopenic aphasia is indeed the prototypic language profile in PPA patients with biomarker evidence of underlying AD pathology and to correlate language profiles with cortical atrophy patterns on MRI. Methods: Inclusion criteria: (I) clinical diagnosis of PPA; (II) CSF profile and/or PiB-PET scan indicative for amyloid pathology; (III) availability of expert language evaluation. Based on language evaluation, patients were …classified as lvPPA (fulfilling lvPPA core criteria), lvPPA extended (fulfilling core criteria plus other language disturbances), or PPA unclassifiable (not fulfilling lvPPA core criteria). Cortical atrophy patterns on MRI were visually rated and quantitative measurements of cortical thickness were performed using FreeSurfer. Results: We included 22 patients (age 67±7 years, 50% female, MMSE 21±6). 41% were classified as lvPPA , 36% as lvPPA extended with additional deficits in language comprehension and/or confrontation naming, and 23% as PPA unclassifiable. By both qualitative and quantitative measurements, patients with lvPPA showed mild global cortical atrophy on MRI, whereas patients with lvPPA extended showed more focal cortical atrophy, predominantly at the left tempo-parietal side. For PPA unclassifiable, qualitative measurements revealed a heterogeneous atrophy pattern. Conclusion: Although most patients fulfilled the lvPPA criteria, we found that their language profiles were heterogeneous. The clinical and radiological spectrum of PPA due to underlying AD pathology is broader than pure lvPPA. Show more

Keywords: Atypical Alzheimer’s disease, cerebral atrophy, language disorders, logopenic aphasia, neurodegenerative disorder, primary progressive aphasia

DOI: 10.3233/JAD-150812

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 581-590, 2016

Authors: Song, Jung Min | Sung, You Me | Nam, Jin Han | Yoon, Hyejin | Chung, Andrew | Moffat, Emily | Jung, Mira | Pak, Daniel T.S. | Kim, Jungsu | Hoe, Hyang-Sook

Article Type: Research Article

Abstract: Background: The accumulation of amyloid-β (Aβ ) leads to the loss of dendritic spines and synapses, which is hypothesized to cause cognitive impairments in Alzheimer’s disease (AD) patients. In our previous study, we demonstrated that a novel mercaptoacetamide-based class II histone deacetylase inhibitor (HDACI), known as W2, decreased Aβ levels and improved learning and memory in mice. However, the underlying mechanism of this effect is unknown. Objective: Because dendritic spine formation is associated with cognitive performance, here we investigated whether HDACI W2 regulates dendritic spine density and its molecular mechanism of action. Methods: To examine …the effect of HDACI W2 on dendritic spine density, we conducted morphological analysis of dendritic spines using GFP transfection and Golgi staining. In addition, to determine the molecular mechanism of W2 effects on spines, we measured the levels of mRNAs and proteins involved in the Ras signaling pathway using quantitative real-time PCR, immunocytochemistry, and western analysis. Results: We found that HDACI W2 altered dendritic spine density and morphology in vitro and in vivo . Additionally, W2 increased the mRNA or protein levels of Ras GRF1 and phospho-ERK. Moreover, knockdown of RasGRF1 and inhibition of ERK activity prevented the W2-mediated spinogenesis in primary hippocampal neurons. Conclusion: Our Class II-selective HDACI W2 promotes the formation and growth of dendritic spines in a RasGRF1 and ERK dependent manner in primary hippocampal neurons. Show more

Keywords: Alzheimer’s disease, dendritic spine, HDAC inhibitor, ras signaling

DOI: 10.3233/JAD-150717

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 591-604, 2016

Authors: Hong, Xiao-Ping | Chen, Tao | Yin, Ni-Na | Han, Yong-Ming | Yuan, Fang | Duan, Yan-Jun | Shen, Feng | Zhang, Yan-Hong | Chen, Ze-Bin

Article Type: Research Article

Abstract: Enhanced neurogenesis has been reported in the hippocampus of patients with Alzheimer’s disease (AD), the most common neurodegenerative disorder characterized with amyloid-β (Aβ) aggregation, tau hyperphosphorylation, and progressive neuronal loss. Previously we reported that tau phosphorylation played an essential role in adult hippocampal neurogenesis, and activation of glycogen synthase kinase (GSK-3), a crucial tau kinase, could induce increased hippocampal neurogenesis. In the present study, we found that treatment of D-galactose rats with Puerarin could significantly improve behavioral performance and ameliorate the enhanced neurogenesis and microtubule-associated protein tau hyperphosphorylation in the hippocampus ofD-galactose rat brains. FGF-2/GSK-3 signaling pathway might be involved …in the effects of Puerarin on hippocampal neurogenesis and tau hyperphosphorylation. Our finding provides primary in vivo evidence that Puerarin can attenuate AD-like enhanced hippocampal neurogenesis and tau hyperphosphorylation. Our finding also suggests Puerarin can be served as a treatment for age-related neurodegenerative disorders, such as AD. Show more

Keywords: Alzheimer’s disease, glycogen synthase kinase, hippocampus, neurogenesis, Puerarin, spatial memory, tau hyperphosphorylation

DOI: 10.3233/JAD-150566

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 605-617, 2016

Authors: O’Caoimh, Rónán | Timmons, Suzanne | Molloy, D. William

Article Type: Research Article

Abstract: Background: Sensitive and specific instruments are required to screen for cognitive impairment (CI) in busy clinical practice. The Montreal Cognitive Assessment (MoCA) is widely validated but few studies compare it to tests designed specifically to detect mild cognitive impairment (MCI). Objective: Comparison of two “MCI specific” screens: the Quick Mild Cognitive Impairment screen (Qmci ) and MoCA. Methods: Patients with subjective memory complaints (SMC; n  = 73), MCI (n  = 103), or dementia (n  = 274), were referred to a university hospital memory clinic and underwent comprehensive assessment. Caregivers, without cognitive symptoms, were recruited as normal controls (n  = 101). …Results: The Qmci was more accurate than the MoCA in differentiating MCI from controls, area under the curve (AUC) of 0.90 versus 0.80, p  = 0.009. The Qmci had greater (AUC 0.81), albeit non-significant, accuracy than the MoCA (AUC 0.73) in separating MCI from SMC, p  = 0.09. At its recommended cut-off (<62/100), the Qmci had a sensitivity of 90% and specificity of 87% for CI (MCI/dementia). Raising the cut-off to <65 optimized sensitivity (94%), reducing specificity (80%). At <26/30 the MoCA had better sensitivity (96%) but poor specificity (58%). A MoCA cut-off of <24 provided the optimal balance. Median Qmci administration time was 4.5 (±1.3) minutes compared with 9.5 (±2.8) for the MoCA. Conclusions: Although both tests distinguish MCI from dementia, the Qmci is particularly accurate in separating MCI from normal cognition and has shorter administration times, suggesting it is more useful in busy hospital clinics. This study reaffirms the high sensitivity of the MoCA but suggests a lower cut-off (<24) in this setting. Show more

Keywords: Cognitive screening, dementia, mild cognitive impairment, Montreal Cognitive Assessment, Quick Mild Cognitive Impairment screen

DOI: 10.3233/JAD-150881

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 619-629, 2016

Article Type: Other

DOI: 10.3233/JAD-160060

Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 631-635, 2016