Journal of Alzheimer's Disease - Volume 62, issue 1

Authors: Jęśko, Henryk | Lukiw, Walter J. | Wilkaniec, Anna | Cieślik, Magdalena | Gąssowska-Dobrowolska, Magdalena | Murawska, Emilia | Hilgier, Wojciech | Adamczyk, Agata

Article Type: Research Article

Abstract: Urea cycle enzymes may play important yet poorly characterized roles in Alzheimer’s disease (AD). Our previous results showed that amyloid-β (Aβ) affects urea cycle enzymes in rat pheochromocytoma (PC12) cells. The aim of the present study was to investigate the changes in arginases, other urea cycle enzymes, and nitric oxide synthases (NOS s) in PC12 cells transfected with AβPP bearing the double ‘Swedish’ mutation (APPsw , K670M/N671L) and in postmortem sporadic AD brain hippocampus; the mutation intensifies Aβ production and strongly associates with AD neuropathology. mRNA expression was analyzed using real-time PCR in cell cultures and DNA microarrays in …hippocampal CA1 area of human AD brains. Arginase activity was measured spectrophotometrically, and arginine, ornithine, and citrulline levels by high-performance liquid chromatography. Our data demonstrated that the expression and activity of arginases (Arg1 and Arg2 ), as well as the expression of argininosuccinate synthase (Ass ) were significantly reduced in APPsw cells compared to control. However, argininosuccinate lyase (Asl ) was upregulated in APPsw cells. Real-time PCR analysis revealed significant elevation of neuronal nitric oxide synthase (Nnos ) mRNA in APPsw cells, without changes in the endothelial Enos , whereas inducible Inos was undetectable. The changes were found to follow closely those observed in the human hippocampal CA1 region of sporadic AD brains. The changes in enzyme expression were accompanied in APPsw cells by significantly elevated citrulline, ornithine, and arginine. Our findings demonstrate that AβPP/Aβ alters arginine metabolism and induces a shift of cellular homeostasis that may support the oxidative/nitrosative stress observed in AD. Show more

Keywords: Alzheimer’s disease, amyloid β, amyloid-β protein precursor, arginase, arginine, argininosuccinate lyase, argininosuccinate synthase, citrulline, nitric oxide synthase, ornithine

DOI: 10.3233/JAD-170427

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 279-291, 2018

Authors: Mowrey, Wenzhu B. | Lipton, Richard B. | Katz, Mindy J. | Ramratan, Wendy S. | Loewenstein, David A. | Zimmerman, Molly E. | Buschke, Herman

Article Type: Research Article

Abstract: Background: The Memory Binding Test (MBT) demonstrated good cross-sectional discriminative validity and predicted incident aMCI. Objective: To assess whether the MBT predicts incident dementia better than a conventional list learning test in a longitudinal community-based study. Methods: As a sub-study in the Einstein Aging Study, 309 participants age≥70 initially free of dementia were administered the MBT and followed annually for incident dementia for up to 13 years. Based on previous work, poor memory binding was defined using an optimal empirical cut-score of≤17 on the binding measure of the MBT, Total Items in the Paired condition (TIP). …Cox proportional hazards models were used to assess predictive validity adjusting for covariates. We compared the predictive validity of MBT TIP to that of the free and cued selective reminding test free recall score (FCSRT-FR; cut-score:≤24) and the single list recall measure of the MBT, Cued Recalled from List 1 (CR-L1; cut-score:≤12). Results: Thirty-five of 309 participants developed incident dementia. When assessing each test alone, the hazard ratio (HR) for dementia was significant for MBT TIP (HR = 8.58, 95% CI: (3.58, 20.58), p  < 0.0001), FCSRT-FR (HR = 4.19, 95% CI: (1.94, 9.04), p  = 0.0003) and MBT CR-L1 (HR = 2.91, 95% CI: (1.37, 6.18), p  = 0.006). MBT TIP remained a significant predictor of dementia (p  = 0.0002) when adjusting for FCSRT-FR or CR-L1. Conclusions: Older adults with poor memory binding as measured by the MBT TIP were at increased risk for incident dementia. This measure outperforms conventional episodic memory measures of free and cued recall, supporting the memory binding hypothesis. Show more

Keywords: Aging, Alzheimer’s disease, cognition, dementia, longitudinal studies, memory, survival analysis

DOI: 10.3233/JAD-170714

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 293-304, 2018

Authors: Mullan, Kathryn | Cardwell, Chris R. | McGuinness, Bernadette | Woodside, Jayne V. | McKay, Gareth J.

Article Type: Research Article

Abstract: Serum antioxidants may afford neuroprotection against Alzheimer’s disease (AD) via correction of the pro-oxidative imbalance but findings reported have been inconsistent. We compared the pooled mean difference in serum levels of ten dietary antioxidants between patients with AD and cognitively intact controls from 52 studies in meta-analyses using random-effects models. Patients with AD had significantly lower plasma levels of α-carotene, β-carotene, lycopene, lutein, vitamin A, C, and E, and uric acid. No significant difference was observed for plasma levels of β-cryptoxanthin and zeaxanthin. Considerable heterogeneity was detected across studies. The lower serum levels of dietary antioxidants from the carotene and …vitamin subclasses observed in individuals with AD suggest reduced systemic availability of these subclasses in this prevalent form of dementia. To our knowledge, these are the first meta-analyses to demonstrate lower serum lycopene and to evaluate β-cryptoxanthin, lutein, and zeaxanthin levels in AD. In light of the significant heterogeneity detected across studies, caution should be exercised in the interpretation of the data and therapeutic intervention approaches considered through supplementation measures. Our data may better inform interventions to improve antioxidant status in a condition of major public health importance. Show more

Keywords: Alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein, lycopene, uric acid, vitamin A, vitamin C, vitamin E, zeaxanthin

DOI: 10.3233/JAD-170758

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 305-317, 2018

Authors: Huang, Haiqing | Tanner, Jared | Parvataneni, Hari | Rice, Mark | Horgas, Ann | Ding, Mingzhou | Price, Catherine

Article Type: Research Article

Abstract:  Using resting state functional magnetic resonance imaging (RS-fMRI), we explored: 1) pre- to post-operative changes in functional connectivity in default mode, salience, and central executive networks after total knee arthroplasty (TKA) with general anesthesia, and 2) the contribution of cognitive/brain reserve metrics these resting state functional declines. Individuals age 60 and older electing unilateral total knee arthroplasty (TKA; n  = 48) and non-surgery peers with osteoarthritis (n  = 45) completed baseline cognitive testing and baseline and post-surgery (post-baseline, 48-h post-surgery) brain MRI. We acquired cognitive and brain estimates for premorbid (vocabulary, reading, education, intracranial volume) and current (working memory, processing speed, declarative …memory, ventricular volume) reserve. Functional network analyses corrected for pain severity and pain medication. The surgery group declined in every functional network of interest (p  < 0.001). Relative to non-surgery peers, 23% of surgery participants declined in at least one network and 15% of the total TKA sample declined across all networks. Larger preoperative ventricular volume and lower scores on preoperative metrics of processing speed and working memory predicted default mode network connectivity decline. Premorbid cognitive and premorbid brain reserve did not predict decline. Within 48 hours after surgery, at least one fourth of the older adult sample showed significant functional network decline. Metrics of current brain status (ventricular volume), working memory, and processing speed predicted the severity of default mode network connectivity decline. These findings demonstrate the relevance of preoperative cognition and brain integrity on acute postoperative functional network change. Show more

Keywords: Anesthesia, cognitive dysfunction, cognitive reserve, dementia, efficiency, magnetic resonance imaging, orthopedics

DOI: 10.3233/JAD-170496

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 319-333, 2018

Authors: Angulo Sevilla, David | Carreras Rodríguez, María Teresa | Heredia Rodríguez, Patricia | Fernández Sánchez, Marisa | Vivancos Mora, José Aurelio | Gago-Veiga, Ana Beatriz

Article Type: Research Article

Abstract: Background: Sundown syndrome (SS) is the onset or worsening of behavioral symptoms in the evening in patients with dementia. Objective: To identify the differential clinical profile of patients with dementia who present SS. Methods: A cross-sectional, case-control observational study was conducted by retrospectively reviewing the medical records of patients with dementia in a specialized Memory Unit. We compared the characteristics of patients with and without SS, including sociodemographic variables, etiology, and severity of the dementia, behavioral symptoms, sleep disorders (considering insomnia and hypersomnia), other diseases and treatments employed. We identified the factors related to SS and …conducted a logistic regression analysis to establish a predictive nomogram. Results: Of the 216 study patients with dementia, 41 (19%) had SS. There was a predominance of women (2.4:1), advanced age (p  = 0.0001), dependence (p  < 0.0001), institutionalization (p  < 0.0001), caregiver burden (p  < 0.0001), anxiety (p  < 0.0001), delirium (p  < 0.0001), hallucinations (p  < 0.0001), wandering (p  < 0.0001), Lewy body dementia (p  = 0.05), higher Global Deterioration Scale score (GDS; p  < 0.0001), and sleep disorders (p  < 0.0001). The multivariate analysis revealed that age (p  = 0.048), GDS score (p  = 0.01), and the presence of insomnia or hypersomnia (p  < 0.0001) independently defined the presence of SS. We established a predictive nomogram for developing SS in patients with dementia, with a predictive capacity of 80.1%. Conclusion: In our study, age, a higher score on the GDS, and the presence of insomnia or hypersomnia are differential clinical characteristics of patients with SS. We defined a nomogram that helps predicting the occurrence of SS in patients with dementia. Show more

Keywords: Behavioral disorder, clinical profile, dementia, sundown syndrome

DOI: 10.3233/JAD-170488

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 335-346, 2018

Authors: Lanzillotta, Chiara | Tramutola, Antonella | Meier, Shelby | Schmitt, Frederick | Barone, Eugenio | Perluigi, Marzia | Di Domenico, Fabio | Abisambra, Jose F.

Article Type: Research Article

Abstract: Down syndrome (DS) is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans, which results from the triplication of chromosome 21. DS individuals have an increased risk of developing Alzheimer’s disease (AD)-like pathology and dementia by the age of 40 due to the triplication of several genes involved in the formation of amyloid plaques and tau tangles. Further, DS and AD are characterized by the aberrant accumulation of unfolded/misfolded proteins resulting from over-burdened protein quality control systems. The accumulation of misfolded proteins in the endoplasmic reticulum (ER) triggers a cellular stress response called the …unfolded protein response (UPR). Long-term activation of the UPR mediates neuronal dysfunction in AD. We hypothesized that the UPR is impacted in a mouse model of DS. To test this, we performed gene and protein expression analysis of ER stress markers in the Ts65Dn mouse model of DS at 3, 9, and 18 months. We identified activation of the PERK pathway in Ts65Dn DS mice at 3 months of age compared to euploid controls. We also determined that the early and overt UPR activation decreased with age, the UPR signal was significantly reduced by 18 months. Our data suggest that UPR activation in DS mouse models occurs early before consistent brain neurodegeneration and might be an essential contributor to dys-proteostasis. Show more

Keywords: Down syndrome, eif2 alpha, PERK, Ts65Dn, unfolded protein response

DOI: 10.3233/JAD-170617

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 347-359, 2018

Authors: Xu, Lin | Zhang, Wenchao | Liu, Xianchen | Zhang, Cuili | Wang, Pin | Zhao, Xiulan

Article Type: Research Article

Abstract: Background: Environmental exposure to toxic metals has been postulated to play a role in the pathophysiological processes of Alzheimer’s disease (AD). However, the circulatory levels of toxic metals in AD patients are not consistent in previous studies. Objective: To systematically assess levels of toxic metals (aluminum, mercury, cadmium, lead) in the circulation (blood, serum/plasma) of AD patients and controls. Methods: PubMed, Web of Science, Science Direct, Cochrane Library, and the China National Knowledge Infrastructure (CNKI) were systematically searched to identify studies published up to January 1, 2017. Meta-analyses were performed using random-effects models and the pooled …standardized mean difference (SMD) were reported with 95% confidence intervals (CI). Results: We identified 17, 7, 8, and 10 studies for aluminum, mercury, cadmium, and lead, respectively. Meta-analyses showed significantly elevated circulatory levels of aluminum (SMD = 1.08, 95% CI: 0.66, 1.50), mercury (SMD = 0.55, 95% CI, 0.15, 0.95), and cadmium (SMD = 0.62, 95% CI: 0.12, 1.11), whereas lower levels of lead (SMD = –0.23, 95% CI: –0.38, –0.07) in AD patients than in controls. Publication bias was only observed for aluminum studies, but the “trim and fill” analysis showed that the publication bias did not alter the direction of the effect. Sensitivity analyses showed no studies from the pooled analysis changed the results. Conclusion: Compared to controls, circulatory levels of aluminum, mercury, and cadmium are significantly higher but the levels of lead were reduced in AD patients. These findings suggest that elevated aluminum, mercury, and cadmium in the circulation, especially in serum may play a role in the progression of AD. Show more

Keywords: Alzheimer’s disease, circulation, meta-analyses, systematic review, toxic metals

DOI: 10.3233/JAD-170811

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 361-372, 2018

Authors: Pons, Anke | LaMonica, Haley M. | Mowszowski, Loren | Köhler, Sebastian | Deckers, Kay | Naismith, Sharon L.

Article Type: Research Article

Abstract: Background: Dementia prevalence is expected to increase substantially over the next few decades. Since there is currently no cure for dementia available, there is an urgent need for the early identification of individuals at high risk for dementia, so that primary and secondary prevention strategies can be implemented. Recently, the LIfestyle for BRAin health (LIBRA) index was developed as a new dementia risk algorithm. It specifically focuses on modifiable risk and protective factors that can be targeted in midlife. Objective: The objective of this study was to evaluate the LIBRA index in relation to markers of cognitive functioning …in a clinical, health-seeking sample of community-based older adults. Methods: 484 participants (mean age 62.7 years) were recruited from the Healthy Brain Ageing Clinic at the Brain and Mind Centre, Sydney. Participants underwent comprehensive clinical and neuropsychological assessment and completed a self-report survey pack. Participants were rated via consensus as having either subjective cognitive complaints (SCC) or meeting criteria for mild cognitive impairment (MCI). The LIBRA score was calculated based on 11 available risk and protective factors. Results: 65.4% of the sample met criteria for MCI. People with MCI showed a significantly higher LIBRA score compared to people with SCC. Furthermore, multiple cognitive domains, in particular executive functioning, were associated with a higher LIBRA score, with stronger correlations in people with MCI. Conclusion: The LIBRA index might be a useful tool to determine lifestyle-attributable risk of cognitive decline in an older health-seeking population, including people with MCI. Show more

Keywords: Dementia, mild cognitive impairment, modifiable risk factors, prevention

DOI: 10.3233/JAD-170731

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 373-384, 2018

Authors: Bettcher, Brianne M. | Johnson, Sterling C. | Fitch, Ryan | Casaletto, Kaitlin B. | Heffernan, Kate S. | Asthana, Sanjay | Zetterberg, Henrik | Blennow, Kaj | Carlsson, Cynthia M. | Neuhaus, John | Bendlin, Barbara B. | Kramer, Joel H.

Article Type: Research Article

Abstract: Inflammatory markers have been shown to predict neurocognitive outcomes in aging adults; however, the degree to which peripheral markers mirror the central nervous system remains unknown. We investigated the association between plasma and cerebrospinal fluid (CSF) markers of inflammation, and explored whether these markers independently predict CSF indicators of Alzheimer’s disease (AD) pathology or neuronal damage. Plasma and CSF samples were analyzed for inflammatory markers in a cohort of asymptomatic older adults (n  = 173). CSF samples were analyzed for markers of AD pathology (Aβ42 , phosphorylated tau [p-tau], sAβPPβ) or neuronal damage (total tau; neurofilament light chain) (n  = 147). …Separate linear models for each analyte were conducted with CSF and plasma levels entered simultaneously as predictors and markers of AD pathology or neuronal damage as outcome measures. Strong associations were noted between CSF and plasma MIP-1β levels, and modest associations were observed for remaining analytes. With respect to AD pathology, higher levels of plasma and CSF IL-8, CSF MIP-1β, and CSF IP-10 were associated with higher levels of p-tau. Higher levels of CSF IL-8 were associated with higher levels of CSF Aβ42 . Higher CSF sAβPPβ levels were associated with higher plasma markers only (IL-8; MCP-1). In terms of neuronal injury, higher levels of plasma and CSF IL-8, CSF IP-10, and CSF MIP-1β were associated with higher levels of CSF total tau. Exploratory analyses indicated that CSF Aβ42 modifies the relationship between plasma inflammatory levels and CSF tau levels. Results suggest that both plasma and CSF inflammatory markers independently relay integral information about AD pathology and neuronal damage. Show more

Keywords: Aging, Alzheimer’s disease, biomarkers, neuroinflammation, preclinical AD, systemic inflammation

DOI: 10.3233/JAD-170602

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 385-397, 2018

Authors: Ben Bouallègue, Fayçal | Mariano-Goulart, Denis | Payoux, Pierre | for the Alzheimer’s Disease Neuroimaging Initiative (ADNI)

Article Type: Research Article

Abstract: Joint analysis of amyloid and metabolic PET patterns across healthy, mild cognitive impairment (MCI), and Alzheimer’s disease (AD) subjects was performed using baseline 18 F-florbetapir and 18 F-FDG PET of 684 subjects from the ADNI (251 normal, 204 stable MCI, 85 AD converters, and 144 AD). Correlation between regional amyloid and metabolic uptake was measured and predictive value of PET profile regarding AD conversion in cognitively impaired subjects was assessed using survival analysis and support vector machine classification (SVM). The highest correlations were found in the temporal cortex, precuneus, and posterior cingulum. With respect to normal controls, amyloid load increase …was diffuse and early in MCI subjects, whereas metabolism decrease occurred later and predominated in temporo-parietal, precuneus, and cingulate cortices. Five-year AD conversion rates in cognitively impaired subjects were 5%, 22%, 42%, and 78% in amyloid-/FDG-, amyloid-/FDG+, amyloid+/FDG-, and amyloid+/FDG+ subjects respectively (mean follow-up 37±14 months). Using SVM, the combination of ADAS-cog score, amyloid PET, and FDG PET yielded better performance in predicting AD conversion (77% accuracy; 58% positive predictive value; 88% negative predictive value) than ADAS-cog (72%; 52%; 86%), amyloid PET (72%; 52%; 87%), and FDG PET (67%; 47%; 84%). This study attests the complementary value of amyloid and FDG PET in MCI assessment and the efficiency of combined cognitive, amyloid, and metabolic scores to predict AD conversion. Show more

Keywords: Alzheimer’s disease, Alzheimer’s Disease Neuroimaging Initiative, amyloid PET, FDG PET, mild cognitive impairment

DOI: 10.3233/JAD-170833

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 399-408, 2018

Authors: Phua, April Ka Sin | Hiu, Shaun Kuan Wei | Goh, Win King | Ikram, Mohammad Kamran | Venketasubramanian, Narayanaswamy | Tan, Boon Yeow | Chen, Christopher Li-Hsian | Xu, Xin

Article Type: Research Article

Abstract: Background: Researchers have questioned the utility of brief cognitive tests such as the Mini-Mental Status Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) in serial administration and suggested that brief cognitive tests may not accurately track changes in Global Cognition. Objective: To examine the accuracy of longitudinal changes on brief cognitive tests in reflecting progression in Global Cognition measured using comprehensive neuropsychological assessments. Methods: Two hundred and seven participants were assessed with the MMSE, MoCA, and a validated comprehensive neuropsychological battery. Global z-scores on the battery were derived and used to assess overall and significant (≥0.5 …standard deviation) decline on Global Cognition. Different patterns of decline on MMSE/MoCA were classified. Accuracy was examined using receiver operating characteristic curve, and sensitivity, specificity, positive (PPV) and negative (NPV) predictive values were reported. Results: The overall ability of MMSE/MoCA change scores to discriminate participants who did and did not decline on Global Cognition was fair-to-moderate (AUC [95% CI] = 0.71 [0.64–0.78] & 0.73 [0.66–0.80] for overall decline; 0.78 [0.70–0.85] & 0.80 [0.73–0.86] for significant decline, respectively). Changes in MMSE/MoCA had low accuracy in identifying significant Global Cognitive Decline (PPV = 0.41 & 0.46, respectively) but high accuracy in ruling out significant decline and identifying cognitively stable participants (NPV = 0.89 & 0.88, respectively). Conclusion: There is limited utility in brief cognitive tests for tracking cognitive decline. Instead, they should be used for identifying participants who remain cognitively stable on follow up. These results accentuate the importance of acknowledging the limitations of brief cognitive tests when assessing cognitive change. Show more

Keywords: Cognitive decline, cognitive impairments, dementia, geriatric assessment, longitudinal studies, neuropsychological test, outpatient clinic

DOI: 10.3233/JAD-170831

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 409-416, 2018

Authors: Malpas, Charles B. | Saling, Michael M. | Velakoulis, Dennis | Desmond, Patricia | Hicks, Rodney J. | Zetterberg, Henrik | Blennow, Kaj | O’Brien, Terence J.

Article Type: Research Article

Abstract: The two cardinal pathologies of Alzheimer’s disease (AD) develop according to distinct anatomical trajectories. Cerebral tau-related pathology first accumulates in the mesial temporal region, while amyloid-related pathology first appears in neocortex. The eventual distributions of these pathologies reflect their anatomical origins. An implication is that the cardinal pathologies might exert preferential effects on the structurofunctional brain changes observed in AD. We investigated this hypothesis in 39 patients with dementia of the Alzheimer’s type. Interrelationships were analyzed between cerebrospinal fluid biomarkers of the cardinal pathologies, volumetric brain changes using magnetic resonance imaging, and brain metabolism using [18 F]-FDG-PET. Amyloid-related pathology was …preferentially associated with structurofunctional changes in the precuneus and lateral temporal regions. Tau-related pathology was not associated with changes in these regions. These findings support the hypothesis that tau- and amyloid-pathology exert differential effects on structurofunctional changes in the AD brain. These findings have implications for future therapeutic trials and hint at a more complex relationship between the cardinal pathologies and disruption of brain networks. Show more

Keywords: Alzheimer’s disease, amyloid-β, cerebral glucose uptake, cerebrospinal fluid, cortical thickness, P-tau

DOI: 10.3233/JAD-170250

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 417-427, 2018

Authors: Xu, Qing-qing | Shan, Chun-shuo | Wang, Yong | Shi, Yi-hua | Zhang, Qi-hao | Zheng, Guo-qing

Article Type: Research Article

Abstract: Background: Vascular dementia (VaD) is the second common form of dementia and Chinese herbal medicine (CHM) has been used for aging-related disorders for thousands of years. However, there is still a lack of scientific evidence using CHM for VaD. Objective: To conduct a systematic review to assess the current evidence available for the effectiveness and safety of CHM for VaD. Methods: Six databases were searched for high-quality randomized-controlled clinical trials that met the requirements of at least 4 of the 7 domains of the Cochrane risk of bias tool from their inception to February 2017. RevMan …5.3 was applied for data analysis. Results: Forty studies with 42 comparisons and 3,572 individuals were included. The studies investigated the CHM versus placebo (n  = 4), CHM versus western conventional treatment (WCT) (n  = 36), and CHM plus WCT versus WCT (n  = 2). Meta-analysis showed that CHM for VaD could improve Mini-Mental State Examination (MMSE), the Activities of Daily Living, Hasegawa’s dementia scale, and clinical effective rate but had statistically similar effect based on Blessed Behavior Scale (BBS) outcome when compared with WCTs. When compared with placebo, CHMs were more beneficial in improving MMSE but showed no significant difference in BBS scores. CHM as adjuvant therapy exerted an additive anti-VaD benefit on MMSE scores. The participants of CHM group had fewer adverse events than that of the placebo group or WCT group. Conclusion: The findings of the present study support, at least to an extent, that CHM can be recommended for routine use for treatment of VaD. Show more

Keywords: Chinese herbal, meta-analysis, systematic review, traditional Chinese medicine, vascular dementia

DOI: 10.3233/JAD-170856

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 429-456, 2018

Authors: Ritchie, Craig W. | Black, Christopher M. | Khandker, Rezaul K. | Wood, Robert | Jones, Eddie | Hu, Xiaohan | Ambegaonkar, Baishali M.

Article Type: Research Article

Abstract: To ensure that patients with dementia and their caregivers receive appropriate treatment and support, early diagnosis is essential but remains challenging. Real-world data from a multi-national, cross-sectional survey of physicians and their patients were analyzed to quantify the diagnostic pathway for dementia, including a focus on severity of patients’ cognitive impairment (CI) at the time of symptom onset, referral and subsequent diagnosis. Data were collected for 7,620 patients with CI. Most patients saw a healthcare professional within 1 year of first symptoms and received a diagnosis within 3–7 months of initial consultation. However, only 20% of patients received a diagnosis …before their disease progressed beyond the prodromal stage and 23.5% already had moderate CI at diagnosis. These findings show that the goal of identifying and diagnosing CI at the earliest stages of disease is, for many patients, not achieved. Efforts toward public awareness and proactive, earlier detection and intervention, must be maintained—indeed where possible invigorated. Show more

Keywords: Caregivers, cognitive impairment, consultation, diagnosis, earlier and intervention, early diagnosis, prodromal, real-world, referral

DOI: 10.3233/JAD-170864

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 457-466, 2018

Authors: Reale, Marcella | D’Angelo, Chiara | Costantini, Erica | Di Nicola, Marta | Yarla, Nagnedra Sastry | Kamal, Mohammad Amjad | Salvador, Nieves | Perry, George

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD), a neurodegenerative disease, is associated with dysfunction of the olfactory and the entorhinal cortex of the brain that control memory and cognitive functions and other daily activities. Pro-inflammatory cytokines, amyloid-β (Aβ), and the cholinergic system play vital roles in the pathophysiology of AD. However, the role of changes in cholinergic system components, Aβ accumulation, and cytokines in both the olfactory and entorhinal cortex is not known clearly. Objective: The present study is aimed to evaluate the changes of cholinergic system components, Aβ accumulation, and cytokines in both the olfactory bulb (OB) and entorhinal cortex …(EC) of young and aged APPSWE /PS1dE9 transgenic (Tg) mice. Methods: We have explored the changes of cholinergic system components, Aβ accumulation, and expression profiling of cytokines in the OB and EC of aged APPswe transgenic mice and age-matched wild type mice using quantitative Real-Time PCR assays and immunohistochemistry techniques. Results: In aged Tg mice, a significant increase of expression of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and chemokine MCP1 (p  < 0.001, p  < 0.001, and p  = 0.001, respectively) and a significant reduction of nAChRα4 (p  = 0.048) and AChE (p  = 0.023) was observed when compared with age-matched wild type mice. Higher levels of AChE and BuChE are expressed in OB and EC of the APPSWE /PS1dE9 of Tg mice. Aβ accumulation was observed in OB and EC of the APPSWE /PS1dE9 of Tg mice. Conclusion: The study demonstrates the expression profiling of pro-inflammatory cytokines and cholinergic markers as well as Aβ accumulation in OB and EC of the APPSWE /PS1dE9 Tg mice. Moreover, the study also demonstrated that the APPSWE /PS1dE9 Tg mice can be useful as a mouse model to understand the role of pro-inflammatory cytokines and cholinergic markers in pathophysiology of AD. Show more

Keywords: Aβ accumulation, Alzheimer’s disease, APPswe transgenic mice, cholinergic markers, pro-inflammatory cytokines

DOI: 10.3233/JAD-170999

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 467-476, 2018

Authors: Zhou, Futao | Chen, Shuangrong

Article Type: Research Article

Abstract: Leptin, as a link between fat mass and the brain, has been reported to be associated with gender. The gender differences in leptin levels between Alzheimer’s disease (AD) and healthy elderly controls are inconclusive so far. To quantitatively summarize the leptin data available from female and male patients with AD, we searched PubMed and EMBASE for articles published from inception to July 20, 2017. Data were extracted from 27 studies, consisting of 3,014 participants. The pooled results showed that the overall leptin levels were lower in AD (Hedges’ g  = –0.481; p  = 0.002) than in controls, and the leptin levels in …whole blood and serum were decreased with moderate and large effect sizes (g  = –0.677, –0.839; respectively; both of p -values <0.001) in AD compared with controls. In blood, there were significantly lower concentrations of leptin in female AD than in female controls (g  = –0.590; p  = 0.014), but not in male case-control group (g  = –0.666; p  = 0.067). Meta-regression analysis demonstrated that the decreased extent of leptin levels in AD paralleled the degree of the severity of dementia symptoms, as well as the alterations of body mass index (p -values ≤0.002). The findings provide strong evidence that 1) the blood concentrations of leptin are lower in female AD patients than in female controls; and 2) the greater the severity of dementia symptoms, the greater the decreases in the blood leptin levels. But more future investigations on the blood leptin levels in male AD patients is warranted. Show more

Keywords: Alzheimer’s disease, female, leptin, male, meta-analysis

DOI: 10.3233/JAD-170983

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 477-486, 2018