Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Pan, Kuan-Yu | Xu, Weili | Mangialasche, Francesca | Dekhtyar, Serhiy | Fratiglioni, Laura | Wang, Hui-Xin

Article Type: Research Article

Abstract: While the importance of working conditions on cognitive function has been tentatively suggested previously, few studies have considered cumulative effects of exposure throughout the working life. We examined the association between job demand-control status and late-life cognitive decline, taking into account exposure durations. In the population-based cohort study, Swedish National Study on Aging and Care-Kungsholmen, 2,873 dementia-free participants aged 60+ were followed up to nine years. Cognitive function was measured using the Mini-Mental State Examination. The entire working life was outlined through interview and occupations were graded with a psychosocial job-exposure matrix. Multivariate linear mixed-effects models were used. Slower cognitive …decline was observed among people with high job control (β : 0.10, 95% CI: 0.03, 0.19) and demands (β : 0.15, 95% CI: 0.07, 0.22) in the longest-held job. Compared to active job, faster decline was shown in low strain (β : – 0.17, 95% CI: – 0.26, – 0.08), high strain (β : – 0.13, 95% CI: – 0.24, – 0.03), and passive job (β : – 0.22, 95% CI: – 0.34, – 0.11). Longer duration of active jobs was associated with slower cognitive decline (β : 0.24, 95% CI: 0.16, 0.32), whereas faster decline was associated with longer durations of low strain (β : – 0.12, 95% CI: – 0.19, – 0.05), high strain (β : – 0.13, 95% CI: – 0.21, – 0.04), and passive jobs (β : – 0.12, 95% CI: – 0.20, – 0.04). In conclusion, not only psychologically stressful jobs, but also low-stimulating and passive jobs are associated with faster cognitive decline in later life. Duration of exposure may play a role in the psychosocial working condition-cognitive decline association. Show more

Keywords: Cognition, cohort studies, epidemiology, psychosocial work condition, working life

DOI: 10.3233/JAD-180870

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2018

Authors: Farlow, Martin R. | Thompson, Richard E. | Wei, Lee-Jen | Tuchman, Alan J. | Grenier, Elaine | Crockford, David | Wilke, Susanne | Benison, Jeffrey | Alkon, Daniel L.

Article Type: Research Article

Abstract: Background: Bryostatin-activated PKC epsilon pre-clinically induces synaptogenesis, anti-apoptosis, anti-amyloid-β oligomers, and anti-hyperphosphorylated tau. Objectives: To investigate bryostatin safety, tolerability, and efficacy to improve cognition in advanced Alzheimer’s disease (AD) patients. Methods: A double-blind, randomized, placebo-controlled Phase II, 12-week trial of i.v. bryostatin for 150 advanced AD patients (55–85) with MMSE-2 of 4–15, randomized 1:1:1 into 20 μg and 40 μg bryostatin, and placebo arms. The Full Analysis Set (FAS) and the Completer Analysis Set (CAS) were pre-specified alternative assessments (1-sided, p  < 0.1 for primary efficacy, and 2-sided, p  < 0.05 for pre-specified and post hoc exploratory …analyses). Results: The safety profile was similar for 20 μg treatment and placebo patients. The 40 μg patients showed safety and drop-out issues, but no efficacy. Primary improvement of Severe Impairment Battery (SIB) scores at 13 weeks was not significant (p  = 0.134) in the FAS, although in the CAS, the SIB comparison favored 20 μg bryostatin compared to placebo patients (p  < 0.07). Secondary analyses at weeks 5 and 15 (i.e., 30 days post-final dosing) also favored 20 μg bryostatin compared to placebo patients. A pre-specified ANCOVA for baseline memantine blocking bryostatin and positive post-hoc trend analyses were statistically significant. Conclusion: Although the primary endpoint was not significant in the FAS, primary and secondary analyses in the CAS, and pre-specified and post-hoc exploratory analyses did favor bryostatin 20 μg compared to the placebo cohort. These promising Phase II results support further trials of 20 μg bryostatin— without memantine— to treat AD. Show more

Keywords: Bryostatin, memantine, neurorestorative, PKC (Protein Kinase C), severe Alzheimer’s disease, severe impairment battery, synaptic growth factors, synaptogenesis

DOI: 10.3233/JAD-180759

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2018

Authors: Torrealba, Eduardo | Garcia-Morales, Pilar | Cejudo, Juan Carlos | Diaz, Mario | Rodriguez-Esparragon, Francisco | Fabre, Oscar | Mesa-Herrera, Fatima | Marin, Raquel | Sanchez-Garcia, Florentino | Rodriguez-Perez, Aurelio | Gramunt, Nina

Article Type: Research Article

Abstract: Background: Assessment of hippocampal amnesia is helpful to distinguish between normal cognition and mild cognitive impairment (MCI), but not for identifying converters to dementia. Here biomarkers are useful but novel neuropsychological approaches are needed in their absence. The In-out-test assesses episodic memory using a new paradigm hypothesized to avoid reliance on executive function, which may compensate for damaged memory networks. Objective: To assess the validity of the In-out-test in identifying prodromal Alzheimer’s disease (PAD) in a clinical setting, by comparing this to the Free and Cued Selective Reminding Test (FCSRT) and cerebrospinal fluid biomarkers. …Methods: A cross-sectional study of 32 cognitively healthy, 32 MCI, and 30 progressive dementia subjects. All participants were given both the In-out-test and the FCSRT; 40 of them also received a lumbar puncture. Results: Internal consistency was demonstrated using Cronbach Alpha (r  = 0.81) and Inter-rater reliability with Kappa (k = 0.94). Intraclass correlation (ICC) for test-retest reliability: r  = 0.57 (p  = 0.57). ICC between the In-out-test and FCSRT r  = 0.87 (p  = 0.001). ICC between the In-out-test and Aβ 42 and P-tau/Aβ 42 for controls: 0.73 and 0.75, respectively; P-tau for MCI: 0.77 and total sample: 0.70; Aβ 42 for dementia: 0.71. All ICC measures between FCSRT and biomarkers were ≤0.264. AD diagnosis: In-out-test k = 0.71; FCSRT k = 0.49. PAD diagnosis (N = 35): In-out-test k = 0.69; FCSRT k = 0.44. Conclusions: The In-out-test detected prodromal AD with a higher degree of accuracy than a conventional hippocampal-based memory test. These results suggest that this new paradigm could be of value in clinical settings, predicting which patients with MCI will go on to develop AD. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, dementia, early diagnosis, episodic memory, mild cognitive impairment, neuropsychological tests, tau proteins

DOI: 10.3233/JAD-171007

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2018

Authors: Bonvicini, Cristian | Scassellati, Catia | Benussi, Luisa | Di Maria, Emilio | Maj, Carlo | Ciani, Miriam | Fostinelli, Silvia | Mega, Anna | Bocchetta, Martina | Lanzi, Gaetana | Giacopuzzi, Edoardo | Ferraboli, Sergio | Pievani, Michela | Fedi, Virginia | Defanti, Carlo Alberto | Giliani, Silvia | Frisoni, Giovanni Battista | Ghidoni, Roberta | Gennarelli, Massimo

Article Type: Research Article

Abstract: Background: Early onset dementias (EOD) are rare neurodegenerative dementias that present before 65 years. Genetic factors have a substantially higher pathogenetic contribution in EOD patients than in late onset dementia. Objective: To identify known and/or novel rare variants in major candidate genes associated to EOD by high-throughput sequencing. Common-risk variants of apolipoprotein E (APOE ) and prion protein (PRNP ) genes were also assessed. Methods: We studied 22 EOD patients recruited in Memory Clinics, in the context of studies investigating genetic forms of dementia. Two methodological approaches were applied for the target-Next Generation …Sequencing (NGS) analysis of these patients. In addition, we performed progranulin plasma dosage, C9Orf72 hexanucleotide repeat expansion analysis, and APOE genotyping. Results: We detected three rare known pathogenic mutations in the GRN and PSEN2 genes and eleven unknown-impact mutations in the GRN , VCP , MAPT , FUS, TREM2, and NOTCH3 genes. Six patients were carriers of only common risk variants (APOE and PRNP ), and one did not show any risk mutation/variant. Overall, 69% (n  = 9) of our early onset Alzheimer’s disease (EAOD) patients, compared with 34% (n  = 13) of sporadic late onset Alzheimer’s disease (LOAD) patients and 27% (n  = 73) of non-affected controls (ADNI, whole genome data), were carriers of at least two rare/common risk variants in the analyzed candidate genes panel, excluding the full penetrant mutations. Conclusion: This study suggests that EOD patients without full penetrant mutations are characterized by higher probability to carry polygenic risk alleles that patients with LOAD forms. This finding is in line with recently reported evidence, thus suggesting that the genetic risk factors identified in LOAD might modulate the risk also in EOAD. Show more

Keywords: Alzheimer’s disease, common variants, early onset dementia, frontotemporal dementia, Lewy body dementia, next generation sequencing, rare mutations

DOI: 10.3233/JAD-180482

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2018

Authors: de Macêdo Medeiros, André | Silva, Regina Helena

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder that drastically compromises patients’ and relatives’ quality of life, besides being a significant economic burden to global public health. Its pathophysiology is not completely elucidated yet, hence, the current therapies are restricted to treating the symptoms. Over the years, several epidemiological studies have shown disproportionalities in AD when sex is considered, which has encouraged researchers to investigate the potentiality of sex as a risk factor. Studies in rodent models have been used to investigate mechanistic basis of sex differences in AD, as well as the development of possible new sex-specific therapeutic strategies. However, …full knowledge on factors related to this sexual dimorphism remains to be unraveled. Some findings point to differences in genetic and developmental backgrounds either earlier in life or in the aging brain. Herein we summarize the multisystemic framework behind the sex differences in AD and discuss the possible mechanisms involved in these differences raised by the literature so far in an integrative perspective. Show more

Keywords: Aging, animal models, hormones, humans, immune system, oxidative stress, stress

DOI: 10.3233/JAD-180213

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-26, 2018

Authors: Hvidsten, Lara | Engedal, Knut | Selbæk, Geir | Wyller, Torgeir Bruun | Jūratė Šaltytė, Benth | Kersten, Hege

Article Type: Research Article

Abstract: Background: Cross-sectional studies of quality of life (QOL) of people with young-onset dementia shows diverging results. Objective: To identify factors associated with QOL in people with young-onset Alzheimer’s (AD) and frontotemporal dementia (FTD) and explore development in QOL over a two-year period, including differences between the two subtypes. Methods: A two-year cohort study of 88 community-dwelling people with young-onset AD and FTD recruited from Nordic memory clinics. QOL was assessed using the proxy version of the Quality of Life – Alzheimer’s Disease questionnaire, dementia severity was rated with the Clinical Dementia Rating scale, depressive symptoms by …the Cornell Scale for Depression in Dementia, awareness with the Reed anosognosia scale, and needs using the Camberwell Assessment of Needs in the Elderly questionnaire. Factors associated with QOL and development in QOL over time were explored with growth mixture model trajectories and mixed model analyses. Results: We identified two groups of people following trajectories with better (n  = 35) versus poorer (n  = 53) QOL. People with more depressive symptoms at baseline had higher odds of belonging to poorer QOL group, OR 1.2 (CI 1.1; 1.5, p  = 0.011). Having Alzheimer’s disease was associated with significantly better QOL (p  = 0.047 at baseline, p  = 0.009 at T1 and p  = 0.033 at T2). Increasing number of unmet needs was significantly associated with poorer QOL at baseline (p  = 0.007), but not later in follow-up. Conclusion: Early assessment and treatment based on dementia subtype, depression, and individual needs may enhance quality of life in young-onset dementia. Show more

Keywords: Alzheimer’s disease, depression, frontotemporal dementia, quality of life, young-onset

DOI: 10.3233/JAD-180479

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2018

Authors: Almansoub, Hasan A.M.M. | Tang, Hui | Wu, Ying | Wang, Ding-Qi | Mahaman, Yacoubou Abdoul Razak | Wei, Na | Almansob, Yusra A. M. | He, Wei | Liu, Dan

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases that is characterized by progressive memory loss and two main pathological hallmarks, including the extracellular amyloid plaques and intracellular neurofibrillary tangles. The microtubule-related protein tau is involved in the pathogenesis of many neurological diseases commonly known as tauopathies and is found to be abnormally hyperphosphorylated in AD and accumulated in neurons. Besides hyperphosphorylation, tau also undergoes abnormal glycosylation, ubiquitination, glycation, and other posttranslational modifications. These abnormalities lead to the aberrant aggregation of tau in the synaptic loci in AD. In this review, we highlighted the most recent studies about …how tau is abnormally regulated and how those abnormalities play important roles in the pathogenesis of AD. Show more

Keywords: Aggregation, Alzheimer’s disease, hyperphosphorylation, post-translational modifications, tau

DOI: 10.3233/JAD-180868

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-21, 2018

Authors: Zammit, Andrea R. | Muniz-Terrera, Graciela | Katz, Mindy J. | Hall, Charles B. | Ezzati, Ali | Bennett, David A. | Lipton, Richard B.

Article Type: Research Article

Abstract: Background: In a previous report, we used latent class analysis (LCA) to identify natural subgroups of older adults in the Einstein Aging Study (EAS) based on neuropsychological performance. These subgroups differed in demographics, genetic profile, and prognosis. Herein, we assess the generalizability of these findings to an independent sample, the Rush Memory and Aging Project (MAP), which used an overlapping, but distinct neuropsychological battery. Objective: Our aim was to identify the association of natural subgroups based on neuropsychological performance in the MAP cohort with incident dementia and compare them with the associations identified in the EAS. …Methods: MAP is a community-dwelling cohort of older adults living in the northeastern Illinois, Chicago. Latent class models were applied to baseline scores of 10 neuropsychological measures across 1,662 dementia-free MAP participants. Results were compared to prior findings from the EAS. Results: LCA resulted in a 5-class model: Mixed-Domain Impairment (n  = 71, 4.3%), Memory-specific-Impairment (n  = 274, 16.5%), Average (n  = 767, 46.1%), Frontal Impairment (n  = 222, 13.4%), and a class of Superior Cognition (n  = 328, 19.7%). Similar to the EAS, the Mixed-Domain Impairment, the Memory-Specific Impairment, and the Frontal Impairment classes had higher risk of incident Alzheimer’s disease when compared to the Average class. By contrast, the Superior Cognition had a lower risk of Alzheimer’s disease when compared to the Average class. Conclusions: Natural cognitive subgroups in MAP are similar to those identified in EAS. These similarities, despite study differences in geography, sampling strategy, and cognitive tests, suggest that LCA is capable of identifying classes that are not limited to a single sample or a set of cognitive tests. Show more

Keywords: Alzheimer’s disease, dementia, latent class analysis, neuropsychological profiles

DOI: 10.3233/JAD-180737

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2018

Authors: Reed, May J. | Damodarasamy, Mamatha | Pathan, Jasmine L. | Chan, Christina K. | Spiekerman, Charles | Wight, Thomas N. | Banks, William A. | Day, Anthony J. | Vernon, Robert B. | Keene, C. Dirk

Article Type: Research Article

Abstract: Little is known about the extracellular matrix (ECM) during progression of AD pathology. Brain ECM is abundant in hyaluronan (HA), a non-sulfated glycosaminoglycan synthesized by HA synthases (HAS) 1–3 in a high molecular weight (MW) form that is degraded into lower MW fragments. We hypothesized that pathologic severity of AD is associated with increases in HA and HA-associated ECM molecules. To test this hypothesis, we assessed HA accumulation and size; HA synthases (HAS) 1–3; and the HA-stabilizing hyaladherin, TSG-6 in parietal cortex samples from autopsied research subjects with not AD (CERAD = 0, Braak = 0– II, n  = 12–21), intermediate AD (CERAD = 2, Braak = III–IV, n … = 13–18), and high AD (CERAD = 3, Braak = V–VI, n  = 32–40) AD neuropathologic change. By histochemistry, HA was associated with deposits of amyloid and tau, and was also found diffusely in brain parenchyma, with overall HA quantity (measured by ELSA) significantly greater in brains with high AD neuropathology. Mean HA MW was similar among the samples. HAS2 and TSG-6 mRNA expression, and TSG-6 protein levels were significantly increased in high AD and both molecules were present in vasculature, NeuN-positive neurons, and Iba1-positive microglia. These results did not change when accounting for gender, advanced age (≥ 90 years versus <90 years), or the clinical diagnosis of dementia. Collectively, our results indicate a positive correlation between HA accumulation and AD neuropathology, and suggest a possible role for HA synthesis and metabolism in AD progression. Show more

Keywords: Alzheimer’s disease, extracellular matrix, hyaluronan, TSG-6

DOI: 10.3233/JAD-180797

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2018

Authors: Deckers, Kay | Nooyens, Astrid | van Boxtel, Martin | Verhey, Frans | Verschuren, Monique | Köhler, Sebastian

Article Type: Research Article

Abstract: Background: Several modifiable risk factors for cognitive decline have been identified, but whether differences by gender and educational level exist is unclear. Objective: The present study aims to clarify this by prospectively investigating the relationship between health- and lifestyle factors and cognitive functioning in different subgroups defined by gender and educational level. Methods: 2,347 cognitive healthy individuals (mean age = 54.8, SD = 6.8, range: 41–71; 51.8% female; 26.2% low education) from the Doetinchem Cohort Study were examined for cognitive function at baseline, and at 5- and 10-year follow-up. Health- and lifestyle factors were captured by a poly-environmental risk score …labelled ‘LIfestyle for BRAin Health’ (LIBRA). This score consists of 12 modifiable risk and protective factors for cognitive decline and dementia, with higher scores indicating greater risk (range: –2.7 to +12.7). Heterogeneity in associations between LIBRA and decline in verbal memory, cognitive flexibility, and mental speed between males and females and individuals with different levels of education were assessed in linear mixed models. Results: Overall, higher LIBRA scores predicted faster decline in verbal memory, cognitive flexibility, and mental speed over 10 years. Higher LIBRA scores were further associated with increased risk for incident cognitive impairment (one-point increase in LIBRA: HR = 1.09, 1.04–1.14, p  = 0.001). In general, these effects were similar across gender and educational level. Conclusion: A composite risk score comprising unhealthy lifestyle and relatively poor health in midlife is significantly associated with a worse course of cognition 10 years later. These associations were for the most part unrelated to gender or educational differences. Show more

Keywords: Aging, cognition, dementia, education, gender, lifestyle, modifiable risk factors, prevention

DOI: 10.3233/JAD-180492

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2018

Authors: Wan Nasri, Wan Nurzulaikha | Makpol, Suzana | Mazlan, Musalmah | Tooyama, Ikuo | Wan Zurinah Wan Ngah, Wan Zurinah | Damanhuri, Hanafi Ahmad

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by loss of memory and other cognitive abilities. AD is associated with aggregation of amyloid-β (Aβ ) deposited in the hippocampal brain region. Our previous work has shown that tocotrienol rich fraction (TRF) supplementation was able to attenuate the blood oxidative status, improve behavior, and reduce fibrillary-type Aβ deposition in the hippocampus of an AD mouse model. In the present study, we investigate the effect of 6 months of TRF supplementation on transcriptome profile in the hippocampus of APPswe/PS1dE9 double transgenic mice. TRF supplementation can alleviate AD conditions by …modulating several important genes in AD. Moreover, TRF supplementation attenuated the affected biological process and pathways that were upregulated in the AD mouse model. Our findings indicate that TRF supplementation can modulate hippocampal gene expression as well as biological processes that can potentially delay the progression of AD. Show more

Keywords: Alzheimer’s disease, hippocampus, microarray analysis, tocotrienol-rich fraction, transgenic mouse

DOI: 10.3233/JAD-180496

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2018

Authors: Goto, Seiko | Shen, Xuting | Sun, Minkai | Hamano, Yutaka | Herrup, Karl

Article Type: Research Article

Abstract: Dementia is highly prevalent among the worldwide elderly population. Only a small number of the currently marketed drugs are effective in controlling its symptoms, and none has any effect on its progression. Further, as the condition advances, even these pharmaceuticals lose their efficiency, and new research into interventions that might improve the life quality of patients at the end stage of dementia and their families is increasingly rare. In our previous studies, we explored the benefits of exposure to nature, in the form of Japanese garden, for persons with advanced dementia. In the current work, we extended our observations to …two new locations and a new set of subjects with a different ethnic composition with the goal of identifying interventions that might improve their quality of life. We found that, even in these new settings, garden observation not only relieved physiological stress, it improved qualitative measures such as verbalization and memory retrieval. We present data that viewing the garden is a holistic experience rather a solely visual stimulus. Our new data further support the conclusion that garden observation is worth including in the care planning schedule of advanced dementia patients. Its low cost and easy availability make it an economical adjunct to current pharmacological methods that has the potential to improve the quality of life of people with dementia. Show more

Keywords: Dementia, heart rate, Japanese garden, memory retrieval, stress relief

DOI: 10.3233/JAD-170510

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2018

Authors: Collins, Rachel | Silarova, Barbora | Clare, Linda

Article Type: Research Article

Abstract: Background: Understanding policy context and how policy is implemented at the local and clinical level is an important precursor to developing preventive strategies focusing on dementia risk reduction in primary healthcare settings. Objective: Using England as a case study, we review policies and strategies relevant to dementia prevention from the national to local level and how these are translated into primary healthcare services. Methods: We conducted a scoping review covering: 1) identification of national, regional, and local policies and strategies that include dementia prevention; 2) identification of national guidelines for implementing dementia prevention at the clinical …level; and 3) evaluation of the implementation of these at the clinical level. Results: Dementia prevention is addressed in national policy, and this filters through to regional and local levels. Focus on dementia prevention is limited and variable. Reference to modifiable risk factors is associated with other non-communicable diseases, placing less emphasis on factors more dementia specific. Evidence of implementation of dementia prevention policies at the clinical level is limited and inconsistent. Available evidence suggests messages about dementia prevention may best be delivered through primary healthcare services such as the National Health Service (NHS) Health Check. Conclusion: The limitations identified in this review could be addressed through development of a national policy focused specifically on dementia prevention. This could provide a platform for increasing knowledge and understanding among the general population and healthcare professionals. It would be important for such a policy to cover the full range of modifiable risk factors relevant to dementia. Show more

Keywords: Commissioner, government, modifiable risk, primary healthcare, policymaker

DOI: 10.3233/JAD-180608

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2018

Authors: Royall, Donald R. | Palmer, Raymond F.

Article Type: Research Article

Abstract: Dementia can be empirically described by the latent dementia phenotype “δ ” and its various composite “homologs”. We have explored δ ’s blood-based protein biomarkers in the Texas Alzheimer’s Research and Care Consortium (TARCC) study. However, it would be convenient to replicate those associations in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). To this end, we have engineered a δ homolog from observed cognitive performance measures common to both projects. Our findings were replicated in randomly selected 50% splits of TARCC data (Group 1, N = 1,747; Group 2, N = 1,755), and then independently in ADNI (N = 1,737). The new δ homolog, i.e., …“dT2A” (d-TARCC to ADNI), fit the data of both studies well, and was strongly correlated with dementia severity, as rated by the Clinical Dementia Rating Scale “sum of boxes” (TARCC: r  = 0.99, p  <  0.001; ADNI: r  = 0.96, p  <  0.001). dT2A achieved an area under the receiver operating characteristic curve of 0.981 (0.976–0.985) for the discrimination of Alzheimer’s disease from normal controls in TARCC, and 0.988 (0.983–0.993) in ADNI. dT2A is the 12th δ homolog published to date, and opens the door to independent replications across these and similar studies. Show more

Keywords: Aging, Alzheimer Disease Neuroimaging Initiative, cognition, dementia, g , intelligence, TARCC

DOI: 10.3233/JAD-171053

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2018

Authors: Javanshiri, Keivan | Landqvist Waldö, Maria | Friberg, Niklas | Sjövall, Fredrik | Wickerström, Karin | Haglund, Mattias | Englund, Elisabet

Article Type: Correction

DOI: 10.3233/JAD-189011

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-1, 2018

Authors: Radford, Kylie | Lavrencic, Louise M. | Delbaere, Kim | Draper, Brian | Cumming, Robert | Daylight, Gail | Mack, Holly A. | Chalkley, Simon | Bennett, Hayley | Garvey, Gail | Hill, Thi Yen | Lasschuit, Danielle | Broe, Gerald A.

Article Type: Research Article

Abstract: Dementia prevalence in Aboriginal and Torres Strait Islander Australians is three to five times higher than the general Australian population. A better understanding of the underlying biomedical and social risk factors is needed to guide dementia prevention in Aboriginal Australians. The current study is the first to examine potential risk factors for dementia in the majority urban and regional population, with a representative sample of 336 Aboriginal Australians aged 60 years and older. Participants included 45 people with a dementia diagnosis (n  = 27 probable/possible Alzheimer’s disease); and 286 people without dementia. Univariate logistic regression analyses (controlling for age) identified childhood …trauma, mid-life factors (history of unskilled work, past high-risk alcohol use), and medical factors (history of stroke, head injury with loss of consciousness, epilepsy) as risk factors for dementia. Multivariable analysis revealed age, childhood trauma, unskilled work, stroke, and head injury as independent predictors of all-cause dementia. A range of comorbid factors related to dementia was also identified (i.e., functional impairment, incontinence, recent hospital admission, low body mass index, living in residential care, depression, current high-risk alcohol use, social isolation, low physical activity levels). These findings extend previous outcomes in a remote Aboriginal population by highlighting that life-course social determinants of health, in addition to neurological disorders, likely play an important role in elevating dementia risk. Certain psychosocial and medical exposures are highly prevalent in Aboriginal Australians, similar to other indigenous populations, and should be considered when designing targeted and culturally appropriate prevention initiatives to reduce the burden of dementia. Show more

Keywords: Aged, Alzheimer’s disease, indigenous population, neurocognitive disorders, social determinants of health

DOI: 10.3233/JAD-180573

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2018

Authors: Zanco, Marcos | Plácido, Jessica | Marinho, Valeska | Ferreira, José Vinicius | Oliveira, Felipe | Monteiro-Junior, Renato Sobral | Barca, Maria Lage | Engedal, Knut | Laks, Jerson | Deslandes, Andrea

Article Type: Research Article

Abstract: Background: Spatial navigation is a fundamental cognitive ability that allows an individual to maintain independence by facilitating the safe movement from one place to another. It emerges as one of the first deficits in patients with Alzheimer’s disease (AD). Objective: To compare spatial navigation performance in the healthy elderly and AD patients through use of the Floor Maze Test (FMT)— an easy-to-apply two-dimensional (2D) maze— and determine which cognitive and functional capacities were associated with performance in this task. Methods: The FMT was administered to 24 AD patients and 36 healthy controls. Spatial navigation was evaluated …through the FMT. Functional capacity was evaluated through the Senior Fitness Test battery of tests. Cognitive functions were evaluated through the Mini-Mental State Examination (MMSE), verbal fluency, digit span test, and the Rey Auditory Verbal Learning Test (RAVLT). Results: The group with AD was significantly slower and presented more errors at all stages of the FMT. Planning Time (PT) performance was associated with cardiorespiratory resistance (Step test) and delayed memory according to the RAVLT (R2  = 0.395, p  <  0.001). Performance in the Immediate Maze Time (IMT) and Delayed Maze Time (DMT) was associated with global cognitive status (MMSE) (R2  = 0.509) and delayed memory (R2  = 0.540). Conclusion: Patients with AD present significant spatial navigation deficits. Their performance on the FMT is influenced by cardiorespiratory capacity, memory, and global cognitive function. As exercise helps to improve executive function and functional capacity, future intervention studies should be carried out to analyze the possible effects of physical exercise on spatial navigation. Show more

Keywords: Alzheimer’s disease, functional capacity, executive function, spatial navigation

DOI: 10.3233/JAD-180819

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2018

Authors: Thyrian, Jochen René | Michalowsky, Bernhard | Hertel, Johannes | Wübbeler, Markus | Gräske, Johannes | Holle, Bernhard | Schäfer-Walkmann, Susanne | Wolf-Ostermann, Karin | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: There is no common definition for the Dementia Care Network (DCN). They are heterogeneous and there is no general, longitudinal evidence for the effects of DCN. Objective: We describe changes in utilization of health services by people served by dementia care networks in Germany and factors associated with those changes over time. Methods: Primary data was assessed in 560 people with dementia (PwD) and their caregivers supported by DCN in Germany; sociodemographic and clinical variables, utilization of services; DCN were characterized according to governance. The design: observational study with face-to-face interviews at two time points …over a period of one year. Data was assessed via semi-structured interviews at the participants’ homes. Results: Utilization of health services in this study is consistently higher than reported for the general population and does not significantly change over time. The strongest predictor of utilization of any service after one year was the use of this service at baseline (OR from 3.23 to 44.16). Higher activities of daily functioning increased the chances to utilize specialist physicians (OR = 1.32; 95% -CI: 1.08–1.63) or occupational therapy (OR = 1.24; 95% -CI: 1.02–1.50) significantly. Being a female decreased chances to utilize specialist physicians (OR = 0.57; 95% -CI: 0.37–0.87) and increased the chances to utilize no services (OR = 2.08; 95% -CI: 1.29–3.33). Conclusion: While health care acknowledges the importance and benefits of dementia care networks (i.e., in Germany, the results were considered in new German legislation (SGB XI)), further research is needed to define this kind of service delivery to facilitate comparison as well as promote evidence-based implementation. Show more

Keywords: Care network, dementia, Germany, health services

DOI: 10.3233/JAD-180758

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2018

Authors: Smedinga, Marthe | Tromp, Krista | Schermer, Maartje H.N. | Richard, Edo

Article Type: Research Article

Abstract: Background: The shift to defining Alzheimer’s disease (AD) as a biological continuum, which is characterized by the presence of biomarkers instead of clinical symptoms, has sparked a widespread debate. Insight into the given arguments and their underlying moral values is crucial to ensure well-considered and appropriate AD biomarker testing in the future. Objective: To critically review the arguments in favor of or against AD biomarker testing in people with no or mild cognitive impairment and to explicate their underlying moral values. Methods: Seven databases were systematically searched for publications mentioning arguments of interest. Arguments are identified …using qualitative data-analysis and evaluated within an ethical framework. Results: Our search yielded 3,657 articles of which 34 met the inclusion criteria. We discuss the clusters of arguments separate from their evaluation and the assessment of the debate as a whole. The right to know, which derives from the moral value of respect for autonomy, is a central argument in favor of biomarker testing. On the other hand, fear of the disease and lack of a disease-modifying treatment may result in a negative balance of good over inflicted harms, which argues against its use. Conclusion: Critical evaluation and weighing of the given arguments in each specific context, within an ethical framework, demonstrates the necessity to differentiate between what we hope or expect from research and where we currently stand. While AD biomarkers may have an indispensable value for research, the current advantage for clinical practice appears limited. Show more

Keywords: Alzheimer’s disease, bioethical issues, biomarkers, disclosure, early diagnosis, ethics

DOI: 10.3233/JAD-180638

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2018

Authors: Menardi, Arianna | Pascual-Leone, Alvaro | Fried, Peter J. | Santarnecchi, Emiliano

Article Type: Review Article

Abstract: Comforts in modern society have generally been associated with longer survival rates, enabling individuals to reach advanced age as never before in history. With the increase in longevity, however, the incidence of neurodegenerative diseases, especially Alzheimer’s disease, has also doubled. Nevertheless, most of the observed variance, in terms of time of clinical diagnosis and progression, often remains striking. Only recently, differences in the social, educational and occupational background of the individual, as proxies of cognitive reserve (CR), have been hypothesized to play a role in accounting for such discrepancies. CR is a well-established concept in literature; lots of studies have …been conducted in trying to better understand its underlying neural substrates and associated biomarkers, resulting in an incredible amount of data being produced. Here, we aimed to summarize recent relevant published work addressing the issue, gathering evidence for the existence of a common path across research efforts that might ease future investigations by providing a general perspective on the actual state of the arts. An innovative model is hereby proposed, addressing the role of CR across structural and functional evidences, as well as the potential implementation of non-invasive brain stimulation techniques in the causal validation of such theoretical frame. Show more

Keywords: Aging, Alzheimer’s disease, cognitive reserve, diffusion tensor imaging, electroencephalography, functional magnetic resonance imaging, magnetic resonance imaging, positron emission tomography, transcranial magnetic stimulation

DOI: 10.3233/JAD-180549

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-22, 2018

Authors: Lahme, Larissa | Esser, Eliane | Mihailovic, Natasa | Schubert, Friederike | Lauermann, Jost | Johnen, Andreas | Eter, Nicole | Dunning, Thomas | Alnawaiseh, Maged

Article Type: Research Article

Abstract: Background: There is increasing evidence for the involvement of cerebrovascular factors in Alzheimer’s disease (AD). Objective: To evaluate retinal and optic nerve head perfusion in patients with AD using optical coherence tomography angiography (OCTA), and to analyze the correlations of quantitative OCTA metrics with AD pathology and vascular cerebral lesions in AD patients. Methods: 36 eyes of 36 patients with AD (study group) and 38 eyes of 38 healthy subjects (control group) were prospectively included in this study. OCTA was performed using RTVue XR Avanti with AngioVue. In addition, patients underwent a detailed ophthalmological and neurological …examination including Mini-Mental State Examination, cerebral magnetic resonance imaging, and amyloid-β (Aβ ) and tau levels in the cerebrospinal fluid (CSF). Results: The flow density in the superficial retinal OCT angiogram of the macula in the study group was significantly lower compared to the control group (p  = 0.001). There was a significant correlation between the flow density in the superficial retinal OCT angiogram of the macula, as measured using OCTA, and the Fazekas scale (Spearman’s correlation coefficient = –0.520; p  = 0.003). There was no significant correlation between the Aβ or tau levels in the CSF and the flow density data. Conclusion: Patients with AD showed a reduced flow density in the radial peripapillary capillaries layer and in the superficial retinal OCT angiogram when compared with healthy controls. The reduced retinal flow density measured using OCTA is not specifically associated with AD pathology but is associated with the vascular cerebral lesions in AD. Show more

Keywords: Alzheimer’s disease, flow density, optical coherence tomography angiography, retinal and optic nerve head perfusion

DOI: 10.3233/JAD-180738

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2018

Authors: Yaffe, Kristine | Barnes, Deborah E. | Rosenberg, Dori | Dublin, Sascha | Kaup, Allison R. | Ludman, Evette J. | Vittinghoff, Eric | Peltz, Carrie B. | Renz, Anne D. | Adams, Kristin J. | Larson, Eric B.

Article Type: Research Article

Abstract: This article describes the protocol for the Systematic Multi-domain Alzheimer’s Risk Reduction Trial (SMARRT), a single-blind randomized pilot trial to test a personalized, pragmatic, multi-domain Alzheimer’s disease (AD) risk reduction intervention in a US integrated healthcare delivery system. Study participants will be 200 higher-risk older adults (age 70–89 years with subjective cognitive complaints, low normal performance on cognitive screen, and ≥ two modifiable risk factors targeted by our intervention) who will be recruited from selected primary care clinics of Kaiser Permanente Washington, oversampling people with non-white race or Hispanic ethnicity. Study participants will be randomly assigned to a two-year Alzheimer’s …risk reduction intervention (SMARRT) or a Health Education (HE) control. Randomization will be stratified by clinic, race/ethnicity (non-Hispanic white versus non-white or Hispanic), and age (70–79, 80–89). Participants randomized to the SMARRT group will work with a behavioral coach and nurse to develop a personalized plan related to their risk factors (poorly controlled hypertension, diabetes with evidence of hyper or hypoglycemia, depressive symptoms, poor sleep quality, contraindicated medications, physical inactivity, low cognitive stimulation, social isolation, poor diet, smoking). Participants in the HE control group will be mailed general health education information about these risk factors for AD. The primary outcome is two-year cognitive change on a cognitive test composite score. Secondary outcomes include: 1) improvement in targeted risk factors, 2) individual cognitive domain composite scores, 3) physical performance, 4) functional ability, 5) quality of life, and 6) incidence of mild cognitive impairment, AD, and dementia. Primary and secondary outcomes will be assessed in both groups at baseline and 6, 12, 18, and 24 months. Show more

Keywords: Alzheimer’s disease, dementia, health promotion, integrated delivery of health care, risk reduction behavior

DOI: 10.3233/JAD-180634

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2018

Authors: Heffernan, Megan | Andrews, Gavin | Fiatarone Singh, Maria A. | Valenzuela, Michael | Anstey, Kaarin J. | Maeder, Anthony | McNeil, John | Jorm, Louisa | Lautenschlager, Nicola | Sachdev, Perminder | Ginige, Anupama | Hobbs, Megan | Boulamatsis, Christos | Chau, Tiffany | Cobiac, Lynne | Cox, Kay | Daniel, Kenneth | Flood, Victoria M. | Guerrero, Yareni | Gunn, Jane | Jain, Nidhi | Kochan, Nicole A. | Lampit, Amit | Mavros, Yorgi | Meiklejohn, Jacinda | Noble, Yian | O’Leary, Fiona | Radd-Vagenas, Sue | Walton, Courtney | Brodaty, Henry

Article Type: Research Article

Abstract: Background: Maintain Your Brain (MYB) is a randomized controlled trial of an online multi-modal lifestyle intervention targeting modifiable dementia risk factors with its primary aim being to reduce cognitive decline in an older age cohort. Methods: MYB aims to recruit 8,500 non-demented community dwelling 55 to 77 year olds from the Sax Institute’s 45 and Up Study in New South Wales, Australia. Participants will be screened for risk factors related to four modules that comprise the MYB intervention: physical activity, nutrition, mental health, and cognitive training. Targeting risk factors will enable interventions to be personalized so …that participants receive the most appropriate modules. MYB will run for three years and up to four modules will be delivered sequentially each quarter during year one. Upon completing a module, participants will continue to receive less frequent booster activities for their eligible modules (except for the mental health module) until the end of the trial. Discussion: MYB will be the largest trial to attempt to prevent cognitive decline and potentially dementia. If successful, MYB will provide a model for not just effective intervention among older adults, but an intervention that is scalable for broad use. Show more

Keywords: Alzheimer’s disease, clinical trial, cognitive decline, cognitive training, dementia, depression, non-pharmacological, physical activity, nutrition, randomized controlled trial

DOI: 10.3233/JAD-180572

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2018

Authors: Watt, Andrew D. | Jenkins, Nicole L. | McColl, Gawain | Collins, Steven | Desmond, Patricia M.

Article Type: Research Article

Abstract: There is hope that the continuing efforts of researchers will yield a disease-modifying drug for Alzheimer’s disease. Such a drug is likely to be capable of halting, or significantly slowing, the underlying pathological processes driving cognitive decline; however, it is unlikely to be capable of restoring brain function already lost through the pathological process. A therapy capable of halting Alzheimer’s disease, while not providing restoration of function, may prompt serious ethical questions. For example, is there a stage in the disease process when it becomes too late for therapeutic intervention to commence? And who bears the responsibility of making such …a decision? Conversations regarding the ethics of treating neurodegenerative conditions with non-restorative drugs have been largely absent within both clinical and research communities. Such discussions are urgently required to ensure that patients’ rights and well-being are protected when such therapeutic options become available. Show more

Keywords: Alzheimer’s disease, ethics, late-stage, restoration, palliative care, therapeutics

DOI: 10.3233/JAD-180865

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2018

Authors: Zhang, Haibo | Wang, Ding | Gong, Ping | Lin, Aihua | Zhang, Yan | Ye, Richard D. | Yu, Yang

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by progressive loss of memory and other cognitive functions. Accumulation of amyloid-β (Aβ ) and hyperphosphorylated tau are two major neuropathological features of AD. Formyl peptide receptor 2 (FPR2), contributing to innate immunity and inflammation, has been implicated in the uptake and clearance of Aβ . It remains unclear whether FPR2 affects cognition and tau phosphorylation. The effects of FPR2 in cognition and tau phosphorylation were examined using FPR2 knock-out (Fpr2 –/– ) mice receiving intracerebroventricular (ICV) injection of streptozotocin (STZ). The general behaviors and cognitive functions were evaluated using rotarod, open …field test, and Morris water maze test. The alteration in tau hyperphosphorylation and activation of astrocytes were determined by using western blotting and/or immunofluorescence staining. ICV injection of STZ impaired spatial learning and memory of mice in Morris water maze. FPR2 deficiency improved spatial learning and memory of ICV-STZ mice. In the hippocampus and cortex of ICV-STZ mice, a marked increase was observed in tau phosphorylation at Ser199, Thr205, and Ser396 compared with ICV-saline control mice. However, FPR2 deficiency attenuated the hyperphosphorylation of tau at Ser199 and Ser396. In addition, the expression of GFAP was significantly increased in hippocampus and cortex of ICV-STZ mice. FPR2 deletion reduced the increase of GFAP expression induced by ICV injection of STZ. These results indicate that FPR2 deficiency is associate with improved cognition, reduced tau hyperphosphorylation, and activation of astrocytes in the mouse AD model tested. FPR2 may be a potential target in AD prevention and therapy. Show more

Keywords: Alzheimer’s disease, astrocyte activation, formyl peptide receptor 2, tau phosphorylation

DOI: 10.3233/JAD-180823

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2018

Authors: Pappas, Colleen | Small, Brent J. | Andel, Ross | Laczó, Jan | Parizkova, Martina | Ondrej, Lerch | Hort, Jakub

Article Type: Research Article

Abstract: Background: Identifying protective factors that promote healthy cognitive aging is of importance due to the growing older adult population. Preventing chronic hyperglycemia may be one such way to preserve cognitive abilities, as high blood glucose levels have been associated with cognitive impairment and decline. Objective: To evaluate the influence of blood glucose levels on cognition among older adults using common neuropsychological tests and a spatial navigation task. Methods: The association between cognitive performance and blood glucose levels was assessed among 117 older adults classified as cognitively healthy, subjective cognitive decline, amnestic mild cognitive impairment, or Alzheimer’s …disease dementia from the Czech Brain Aging Study. Cognitive abilities were measured by tests of verbal memory, nonverbal memory, working memory, visuospatial skills, and executive function. A test of spatial navigation known as the Hidden Goal Task was also used. Blood glucose levels were measured by glycosylated hemoglobin A1c (HbA1c). Analyses were performed using multiple linear regression controlling for age, gender, education, depressive symptoms, diabetes, and cognitive status. Results: A significant relationship was observed for HbA1c and executive function performance (beta = –2.46, SE  = 0.92, p  = 0.008). Following moderation analysis, this relationship was significant only among those with cognitive impairment (beta = –4.37, SE  = 1.28, p  = 0.001, 95% CI [–6.91, –1.83]). Associations between HbA1c and other cognitive domains were not significant (p s >  0.05). Conclusions: Higher HbA1c was associated with poorer executive function among persons with cognitive impairment, but not with performance on other cognitive domains. Maintaining proper glucoregulation may help preserve executive function performance among cognitively impaired older adults. Show more

Keywords: Biomarkers, cognition, cognitive impairments, executive function

DOI: 10.3233/JAD-180693

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2018

Authors: Strobel, Sabrina | Grünblatt, Edna | Heinsen, Helmut | Riederer, Peter | Espach, Thomas | Meder, Michael | Monoranu, Camelia-Maria

Article Type: Research Article

Abstract: Oxidative stress is implicated in the pathogenesis of neurodegenerative diseases, including sporadic Alzheimer’s disease (AD). Mitochondrial DNA (mtDNA) deletions are markers of oxidative damage with an age-dependent accumulation. In a previous study, we analyzed mtDNA levels in diverse neuronal cell types in order to unravel the impact of oxidative stress in brains of AD patients. The aim of this study was to identify possible correlations between mtDNA deletion levels of selected astrocytes and microglia from three brain regions with different vulnerability to AD pathology and different stages of disease compared to controls. Our results reflect a higher vulnerability of hippocampal …astrocytes and microglia to oxidative stress compared to other brain regions, such as cerebellum and brain stem. Show more

Keywords: Alzheimer’s disease, astrocytes, brainstem, cerebellum, hippocampus, microglia, mitochondrial DNA, oxidative stress, selective vulnerability

DOI: 10.3233/JAD-180661

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2018

Authors: Guven, Gamze | Bilgic, Başar | Tufekcioglu, Zeynep | Erginel Unaltuna, Nihan | Hanagasi, Hasmet | Gurvit, Hakan | Singleton, Andrew | Hardy, John | Emre, Murat | Gulec, Cagri | Bras, Jose | Guerreiro, Rita | Lohmann, Ebba

Article Type: Research Article

Abstract: Progranulin (GRN) gene mutations are a major cause of frontotemporal dementia (FTD). Most mutations identified to date are null mutations, which are predicted to cause the pathology via haploinsufficiency. Decreased peripheral progranulin protein (PGRN) levels are associated with the presence of GRN null mutations and are accepted as reliable biomarkers. In this study, our aim was to test whether the presence of specific GRN splice site mutations (c.– 8+2T>G and c.708+6_9del), could be predicted by peripheral mRNA or protein GRN levels, by studying affected and asymptomatic individuals from FTD families. We also tested four missense GRN …variants to assess if altered GRN levels depended on the type of mutation. Our results confirmed a reduction in both mRNA and protein PGRN levels in the splice site mutation carriers, which is consistent with previous reports for null mutations. Our results also suggested that both decreased peripheral GRN mRNA and serum PGRN levels indicate the presence of pathogenic mutations in affected individuals, and identify the asymptomatic individuals at risk, without previous knowledge of genetic status. Both inferences suggest a potential use of peripheral GRN mRNA or serum PGRN levels as biomarkers for families with FTD. Show more

Keywords: ELISA, frontotemporal dementia, progranulin, serum, splice site mutation

DOI: 10.3233/JAD-180599

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2018

Authors: Syeda, Tauqeerunnisa | Sanchez-Tapia, Mónica | Pinedo-Vargas, Laura | Granados, Omar | Cuervo-Zanatta, Daniel | Rojas-Santiago, Eleazar | Díaz-Cintra, Sof&a | Torres, Nimbe | Perez-Cruz, Claudia

Article Type: Research Article

Abstract: Recent investigations have demonstrated an important role of gut microbiota (GM) in the pathogenesis of Alzheimer’s disease (AD). GM modulates a host’s health and disease by production of several substances, including lipopolysaccharides (LPS) and short-chain fatty acids (SCFAs), among others. Diet can modify the composition and diversity of GM, and ingestion of a healthy diet has been suggested to lower the risk to develop AD. We have previously shown that bioactive food (BF) ingestion can abate neuroinflammation and oxidative stress and improve cognition in obese rats, effects associated with GM composition. Therefore, BF can impact the gut-brain axis and improved …behavior. In this study, we aim to explore if inclusion of BF in the diet may impact central pathological markers of AD by modulation of the GM. Triple transgenic 3xTg-AD (TG) female mice were fed a combination of dried nopal, soy, chia oil, and turmeric for 7 months. We found that BF ingestion improved cognition and reduced Aβ aggregates and tau hyperphosphorylation. In addition, BF decreased MDA levels, astrocyte and microglial activation, PSD-95, synaptophysin, GluR1 and ARC protein levels in TG mice. Furthermore, TG mice fed BF showed increased levels of pGSK-3β . GM analysis revealed that pro-inflammatory bacteria were more abundant in TG mice compared to wild-type, while BF ingestion was able to restore the GM’s composition, LPS, and propionate levels to control values. Therefore, the neuroprotective effects of BF may be mediated, in part, by modulation of GM and the release of neurotoxic substances that alter brain function. Show more

Keywords: Lipopolysaccharide, microbiota, neuroinflammation, pro-inflammatory bacteria, propionate, sirt1

DOI: 10.3233/JAD-180556

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-26, 2018

Authors: Rizzo, Giovanni | De Blasi, Roberto | Capozzo, Rosa | Tortelli, Rosanna | Barulli, Maria Rosaria | Liguori, Rocco | Grasso, Daniela | Logroscino, Giancarlo

Article Type: Short Communication

Abstract: We assessed nigral dorsolateral hyperintensity (swallow tail sign) at susceptibility-weighted imaging using 3T-MRI in 15 dementia with Lewy bodies (DLB), 11 Alzheimer’s disease (AD), and 8 frontotemporal dementia (FTD) patients and 10 subjects with subjective memory complaint (SMC). More DLB patients lacked nigral hyperintesity (p  <  0.05). Sensitivity, specificity, and accuracy of DLB diagnosis were, respectively: 80%, 64%, and 73% versus AD; 80%, 75%, and 78% versus FTD; and 80%, 90%, and 84% versus SMC. Considering bilateral loss, sensitivity decreased (53% ) but specificity increased (82–100% ). Swallow tail sign loss, especially if bilateral, can be useful for DLB diagnosis.

Keywords: Dementia with Lewy bodies, magnetic resonance imaging, nigrosome, swallow tail sign, susceptibility-weighted imaging

DOI: 10.3233/JAD-180687

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2018

Authors: Schwarz, Christopher G. | Gunter, Jeffrey L. | Lowe, Val J. | Weigand, Stephen | Vemuri, Prashanthi | Senjem, Matthew L. | Petersen, Ronald C. | Knopman, David S. | Jack Jr , Clifford R.

Article Type: Research Article

Abstract: Longitudinal PET studies in aging and Alzheimer’s disease populations rely on accurate and precise measurements of change over time from serial PET scans. Various methods for partial volume correction (PVC) are commonly applied to such studies, but existing comparisons and validations of these PVC methods have focused on cross-sectional measurements. Rate of change measurements inherently have smaller magnitudes than cross-sectional measurements, so levels of noise amplification due to PVC must be smaller, and it is necessary to re-evaluate methods in this context. Here we compare the relative precision in longitudinal measurements from serial amyloid PET scans when using geometric transfer …matrix (GTM) PVC versus the traditional two-compartment (Meltzer-style), three-compartment (Müller-Gärtner-style), and no-PVC approaches. We used two independent implementations of standardized uptake value ratio (SUVR) measurement and PVC (one in-house pipeline based on SPM12 and ANTs, and one using FreeSurfer 6.0). For each approach, we also tested longitudinal-specific variants. Overall, we found that measurements using GTM PVC had significantly worse relative precision (unexplained within-subject variability ≈4–8%) than those using two-compartment, three-compartment, or no PVC (≈2–4%). Longitudinally-stabilized approaches did not improve these properties. This data suggests that GTM PVC methods may be less suitable than traditional approaches when measuring within-person change over time in longitudinal amyloid PET. Show more

Keywords: Amyloid PET, change over time, geometric transfer matrix, partial volume correction, Pittsburgh Compound B, precision, SUVR

DOI: 10.3233/JAD-180749

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2018

Authors: Chen, Ben | Zhong, Xiaomei | Mai, Naikeng | Peng, Qi | Zhang, Min | Chen, Xinru | Wu, Zhangying | Zou, Laiquan | Liang, Wanyuan | Ouyang, Cong | Wu, Yujie | Ning, Yuping

Article Type: Research Article

Abstract: Olfactory identification (OI) deficits have been regarded as an indicator of cognitive impairment in the elderly, but few studies have analyzed the mixed effect of depression on OI. Since depression is common in the elderly and strongly associated with OI, we aimed to explore whether the comorbidity of depression and cognitive impairment may be associated with worse outcomes. In total, 153 elderly patients with depression and 154 normal elderly were recruited. Subjects underwent assessments of depression, cognitive function, and OI. Information on the factors that may affect OI performance was collected (age, sex, smoking history, diabetes, etc.). Correlation analysis showed …that several factors had a significant influence on OI performance in the elderly, including severity of depression, cognitive scores, age, sex, and years of education (p  <  0.05). Among the different cognitive domains, OI was positively associated with global cognition, memory, language, executive function, and attention performance (p  <  0.05). The multiple linear regression analysis indicated that memory scores, age, HAMD scores, and sex were the most relevant factors to OI scores across all elderly participants. The factorial analysis suggested that elderly with comorbidity of depression and cognitive impairment (memory deficits or language deficits) had worse OI impairment, and there was an interactive effect of depression and memory deficits on OI in elderly people. The present study suggested that the coexistence of depressive symptoms and cognitive impairment was associated with worse OI in the elderly. Studies exploring the association between OI and cognitive function should include an assessment of depression and adjust the interactive effects of depression. Show more

Keywords: Cognition, depression, geriatric, neuropsychology, olfactory

DOI: 10.3233/JAD-180760

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2018

Authors: Boespflug, Erin L. | Simon, Matthew J. | Leonard, Emmalyn | Grafe, Marjorie | Woltjer, Randall | Silbert, Lisa C. | Kaye, Jeffrey A. | Iliff, Jeffrey J.

Article Type: Research Article

Abstract: Waste clearance from the brain parenchyma occurs along perivascular pathways. Enlargement of the perivascular space (ePVS) is associated with pathologic features of Alzheimer’s disease (AD), although the mechanisms and implications of this dilation are unclear. Fluid exchange along the cerebral vasculature is dependent on the perivascular astrocytic water channel aquaporin-4 (AQP4) and loss of perivascular AQP4 localization is found in AD. We directly measured ePVS in postmortem samples of pathologically characterized tissue from participants who were cognitively intact or had AD or mixed dementia (vascular lesions with AD). We found that both AD and mixed dementia groups had significantly increased …ePVS compared to cognitively intact subjects. In addition, we found increased global AQP4 expression of the AD group over both control and mixed dementia groups and a qualitative reduction in perivascular localization of AQP4 in the AD group. Among these cases, increasing ePVS burden was associated with the presence of tau and amyloid-β pathology. These findings are consistent with the existing evidence of ePVS in AD and provide novel information regarding differences in AD and vascular dementia and the potential role of astroglial pathology in ePVS. Show more

Keywords: Amyloid, aquaporin-4, astrocytes, cerebrovascular disease, glymphatic, perivascular space, virchow-robin space

DOI: 10.3233/JAD-180367

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2018

Authors: Shea, Yat-Fung | Barker, Warren | Greig-Gusto, Maria T. | Loewenstein, David A. | DeKosky, Steven T. | Duara, Ranjan

Article Type: Research Article

Abstract: Background: The impact of amyloid positron emission tomography (Aβ -PET) in a “real-world” memory disorders clinic remains poorly studied. Objective: we studied the impact of Aβ -PET in diagnosis and management in the memory clinic and factors making the most impact in diagnosis and management. Methods: We studied 102 patients who had presented at a memory disorders clinic (the Wien Center for Alzheimer’s Disease and Memory Disorders, Miami Beach, FL) and had a diagnostic work-up for cognitive complaints, including Aβ -PET scans. Results: Following Aβ -PET, changes were made in diagnosis (37.3%), in specific …treatments for Alzheimer’s disease (26.5%) and in psychiatric treatments (25.5%). The agreement between diagnosis pre-Aβ -PET versus post-Aβ -PET diagnosis was only fair, with a Cohen’s kappa of 0.23 (95% CI 0–0.42). Patients with MRI findings suggestive of AD (medial temporal and/or parietal atrophy) were more frequently amyloid positive than amyloid negative (66.2% versus 33.8%, p  = 0.04). Among patients with atypical clinical features for AD, but with MRI findings suggestive of AD, an amyloid negative PET scan had a greater impact than an amyloid positive PET scan on diagnosis (84.2% versus 17.1%, p  <  0.001), management (84.2% versus 40%, p  <  0.01) and discussion of results and advice on lifestyles (73.7% versus 22.9%, p  <  0.001). Conclusions: We conclude that MRI features suggestive of AD predict a positive amyloid PET scan. However, among those with MRI features suggestive of AD but with atypical clinical features of AD, the clinical impact on diagnosis and management is greater for an amyloid negative than an amyloid positive Aβ -PET scans. Show more

Keywords: Alzheimer’s disease, amyloid imaging, diagnosis, management, memory clinic, positron emission tomography

DOI: 10.3233/JAD-180683

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2018

Authors: Lombardi, Gemma | Polito, Cristina | Berti, Valentina | Bagnoli, Silvia | Nacmias, Benedetta | Pupi, Alberto | Sorbi, Sandro

Article Type: Short Communication

Abstract: Bilingualism is an independent component of cognitive reserve that permits to delay dementia onset up to 5 years. We describe a case of a bilingual Italian man affected by mild cognitive impairment with high cognitive reserve that, despite the presence of multiple risk factors (ApoE ɛ 4/ɛ 4 genotype, older age, untreated Obstructive Sleep Apnea Syndrome, AD-like biomarker alterations) did not convert to Alzheimer’s disease up to 5 years follow-up. The present case confirms the role of bilingualism as a strong protective factor for dementia, even in the occurrence of multiple risk factors.

Keywords: Alzheimer’s disease, bilingualism, cognitive reserve, obstructive sleep apnea, prevention

DOI: 10.3233/JAD-180736

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2018

Authors: Gu, Jianlan | Chen, Feng | Chu, Dandan | Lu, Ying | Iqbal, Khalid | Gong, Cheng-Xin | Liu, Fei

Article Type: Research Article

Abstract: Alternative splicing of tau exon 10 generates tau isoforms with three or four microtubule-binding repeats, 3R-tau or 4R-tau, which are under developmental regulation. Dysregulation of tau exon 10 splicing is sufficient to cause neurodegenerative disorders. The RNA-binding Fox3 (Rbfox3), identified as NeuN, regulates RNA processing. However, whether Rbfox3/NeuN regulates tau exon 10 splicing is unknown. In the present study, we found that the developmental expression of 4R-tau coincided with the expression of Rbfox3 in rat brains. Rbfox3 enhanced tau exon 10 inclusion. Tau intron 10 contains UGCAUG, the conservative binding sequence of Rbfox3. Intron 10 of tau pre-mRNA was co-immunoprecipitated …by Rbfox3/NeuN. Deletion mutants of the RNA recognition motif (RRM) or three RNA-binding sites of the RRM in Rbfox3/NeuN failed to enhance tau exon 10 inclusion. Rbfox3, specifically expressed in the fetal brain, did not affect tau exon 10 splicing. The level of Rbfox3/NeuN was reduced and was associated with the ratio of 4R-tau/3R-tau in the excitotoxic mouse brains induced by kainic acid. These findings suggest that Rbfox3/NeuN regulates the alternative splicing of tau exon 10 and that decreased Rbfox3/NeuN may lower the ratio of 4R-tau/3R-tau. Show more

Keywords: Alternative splicing, alzheimer’s disease, rbfox3/NeuN, tau

DOI: 10.3233/JAD-180882

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2018

Authors: Francis, Paul T. | Costello, Helen | Hayes, Gillian M.

Article Type: Research Article

Abstract: Brain banking has a long and distinguished past, contributing greatly to our understanding of human neurological and psychiatric conditions. Brain banks have been operationally diverse, collecting primarily end stage disease, with variable quality clinical data available, yet it is now recognized the most informative brain donations are from those in longitudinally studied cohorts. The Brains for Dementia Research (BDR) cohort and program was for planned brain donation across five UK brain banks and one donation point, with standardized operating procedures, following longitudinal clinical and psychometric assessments for people with no cognitive impairment as well as those with dementia. Lay …representatives with experience of dementia were involved from inception of BDR and 74.5% of all enquiries about participation came through routes that were directly attributable to or influenced by lay representatives. Ten years after inception, this ongoing project has received over 700 brain donations from the recruited cohort of 3,276 potential brain donors. At cohort census for this paper, 72.2% of the living cohort have no cognitive impairment by assessment, whereas only 28.3% of the donated cohort were without cognitive impairment. It is important that brain banks are agile and reflect the changing needs of the research community, given that ‘big data’, readiness cohorts, and GWAS demand large sample numbers of highly characterized individuals to facilitate new approaches and understanding of pathological processes in dementia. Show more

Keywords: Brain donation, cohort, control, dementia, research tissue bank

DOI: 10.3233/JAD-180699

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2018

Authors: Koseoglu, Mehmet Murat | Norambuena, Andrés | Sharlow, Elizabeth R. | Lazo, John S. | Bloom, George S.

Article Type: Review Article

Abstract: Aberrant neuronal cell cycle re-entry (CCR) is a phenomenon that precedes and may mechanistically lead to a majority of the neuronal loss observed in Alzheimer’s disease (AD). Recent developments concerning the regulation of aberrant neuronal CCR in AD suggest that there are potential intracellular signaling “hotspots” in AD, cancer, and brain insulin resistance, the latter of which is characteristically associated with AD. Critically, these common signaling nodes across different human diseases may represent currently untapped therapeutic opportunities for AD. Specifically, repurposing of existing US Food and Drug Administration-approved pharmacological agents, including experimental therapeutics that target the cell cycle in cancer, …may be an innovative avenue for future AD-directed drug discovery and development. In this review we discuss overlapping aspects of AD, cancer, and brain insulin resistance from the perspective of neuronal CCR, and consider strategies to exploit them for prevention or therapeutic intervention of AD. Show more

Keywords: Alzheimer’s disease, amyloid, cell cycle re-entry, tau

DOI: 10.3233/JAD-180874

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2018

Authors: Flanagan, Margaret E. | Cholerton, Brenna | Latimer, Caitlin S. | Hemmy, Laura S. | Edland, Steven D. | Montine, Kathleen S. | White, Lon R. | Montine, Thomas J.

Article Type: Research Article

Abstract: Transactive response binding protein-43 (TDP-43) cytoplasmic neuronal and glial aggregates (pathologic TDP-43) have been described in multiple brain diseases. We describe the associations between neuropathologically confirmed TDP-43 and cognition in two population-based cohorts: the Nun Study (NS) and the Honolulu-Asia Aging Study (HAAS). In the HAAS, there was a significant association between hippocampal sclerosis (HS) and TDP-43 (OR = 11.04, p  <  0.0001, 95% CI 3.57–34.13). In the NS, there were significant associations between TDP-43 and HS (OR = 16.44, p  >  0.001 95%, CI 7.10–38.00) and Alzheimer’s disease (AD) severity (OR = 1.74, p  = 0.009, 95% CI 1.15–2.64). When cognitive scores were added to the …model, HS remained significant but the other variables were not. When HS was removed from the model, the overall model remained significant and the associations between cognitive performance and TDP-43 (OR = 2.11, p  = 0.022, 95% CI 1.11–4.02) were significant. In the NS, there was a significant association between cognitive performance and TDP-43 (OR 1.94 p  = 0.005, 95% CI 1.22–3.09) (HS remained significant, but AD did not). When HS was removed from the model, only CERAD was significant (OR = 2.43 p  <  0.001, 95% CI 1.58–3.74). These results support a consistent association between pathologic TDP-43, HS, and the development of cognitive impairment in two large studies of brain aging, while the relationship between AD pathology and TDP-43 may vary according to cohort-specific features. Show more

Keywords: Alzheimer’s disease, associations, hippocampal sclerosis, TDP43

DOI: 10.3233/JAD-180162

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2018

Authors: Gambogi, Leandro Boson | Guimarães, Henrique Cerqueira | de Souza, Leonardo Cruz | Caramelli, Paulo

Article Type: Research Article

Abstract: Background: The behavioral variant frontotemporal dementia (bvFTD) shares some clinical features with severe mental disorders, such as bipolar affective disorder (BAD), schizophrenia (SCZ), and schizoaffective disorder (SZA), and at least for a small subgroup of patients, these conditions may share similar pathological genetic mutations. Objectives: To investigate the frequency of a past medical history satisfying diagnostic criteria for BAD, SCZ, and SZA in a bvFTD outpatient sample, and to compare the clinical profile of patients with and without a positive history. Methods: Cross-sectional study in which participants were consecutively selected after receiving a diagnosis of probable …bvFTD and had a caregiver interviewed with SCID-I. The sample was categorized into two groups: with (bvFTD+) or without (bvFTD–) prior medical history satisfying diagnostic criteria for BAD/SCZ/SZA. Subjects went through cognitive, functional, and neuropsychiatric evaluations. Results: Overall, 46 bvFTD patients were included; bvFTD+ patients accounted for 36.9% of the sample. The main nosology fulfilling criteria was BAD (76.5%). The groups differed in Neuropsychiatric Inventory scores (p  = 0.01), use of antipsychotics (p  = 0.01), family history of psychosis (p  = 0.01), presence of primitive reflexes (p  = 0.04), Frontal Assessment Battery performance (p  = 0.01), Ekman’s facial emotion recognition test (p  = 0.03), frequency of apathy (p  = 0.03), and stereotyped behavior (p  = 0.01). All these parameters were more frequent/worse in the bvFTD+ group. Conclusions: A prior medical history compatible with BAD/SCZ/SZA was found in more than 1/3 of this sample of bvFTD patients and was associated with subtle distinctive clinical features. Show more

Keywords: Bipolar disorder, dementia, schizoaffective disorder, schizophrenia

DOI: 10.3233/JAD-180528

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2018

Authors: Helman, Alex M. | Siever, Morgan | McCarty, Katie L. | Lott, Ira T. | Doran, Eric | Abner, Erin L. | Schmitt, Frederick A. | Head, Elizabeth

Article Type: Research Article

Abstract: Cerebrovascular pathology is a significant mediator in Alzheimer’s disease (AD) in the general population. In people with Down syndrome (DS), the contribution of vascular pathology to dementia may play a similar role in age of onset and/or the rate of progression of AD. In the current study, we explored the extent of microbleeds (MBs) and the link between cerebral amyloid angiopathy (CAA) and MBs in the frontal cortex (FCTX) and occipital cortex (OCTX) in an autopsy series from individuals with DS (<40 years), DS with AD pathology (DSAD), sporadic AD, and control cases (2–83 years). Sections were immunostained against Aβ …1 - 40 and an adjacent section stained using Prussian blue for MBs. MBs were both counted and averaged in each case and CAA was scored based on previously published methods. MBs were more frequent in DS cases relative to controls but present to a similar extent as sporadic AD. This aligned with CAA scores, with more extensive CAA in DS relative to controls in both brain regions. CAA was also more frequent in DSAD cases relative to sporadic AD. We found CAA to be associated with MBs and that MBs increased with age in DS after 30 years of age in the OCTX and after 40 years of age in the FCTX. MB and CAA appear to be a significant contributors to the development of dementia in people with DS and are important targets for future clinical trials. Show more

Keywords: Cerebral amyloid angiopathy, microhemorrhages, Prussian blue, trisomy 21

DOI: 10.3233/JAD-180589

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2018

Authors: Penninkilampi, Ross | Casey, Anne-Nicole | Singh, Maria Fiatarone | Brodaty, Henry

Article Type: Research Article

Abstract: It has been reported that social engagement may be associated with dementia risk. We searched PubMed, EMBASE, PsycINFO, CINAHL, LILACS, Biomed Central, Scopus, and Web of Science from January 2012 – May 2017, supplemented by extraction from previous reviews. We included cohort and case-control studies examining the association between social engagement or loneliness and dementia risk, pooling data using a random-effects model. Registered: PROSPERO (CRD42017067074). We included 31 cohort and 2 case-control studies comprising 2,370,452 participants. Poor social engagement indices were associated with increased dementia risk, including having a poor social network (RR = 1.59, 95% CI 1.31–1.96; I2  = 0.00%) and poor …social support (RR = 1.28, 95% CI 1.01–1.62; I2  = 55.51%). In long-term studies (≥10 years), good social engagement was modestly protective (RR = 0.88, 95% CI 0.80–0.96; I2  = 0.00%). Loneliness was associated with non-significantly increased risk (RR = 1.38, 95% CI 0.98–1.94; I2  = 45.32). Our findings encourage interventions targeting social isolation and disengagement for dementia prevention. Show more

Keywords: Alzheimer’s disease, dementia, engagement, loneliness, meta-analysis, socialization, social isolation, systematic review

DOI: 10.3233/JAD-180439

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2018

Authors: Choi, Hojin | Jeong, Jee Hyang | Kim, Yong Bum | Jo, Kwang Deog | Choi, Jin-Yong | Kang, Kyung-Hun | Kang, Heeyoung | Kwon, Do-Young | Yoo, Bong-Goo | Lee, Hyun Jin | Shin, Byoung-Soo | Jeon, Sung-Man | Kwon, Oh Dae | Kim, Jin-Suk | Lee, Soo-Joo | Han, Hyun Jeong | Kim, Youngsoo | Park, Tai-Hwan | Kim, Young Jin | Park, Mee Young | Yang, Hui-Jun | Park, Hyun-Young | Shin, Hae-Eun | Lee, Jung Seok | Yang, YoungSoon | Jung, Yo Han | Lee, Ae Young | Shin, Dong-Ick | Shin, Kyong Jin | Park, Kee Hyung

Article Type: Research Article

Abstract: Background: Magnetic resonance imaging (MRI) is a useful tool to predict the diagnosis and progression of Alzheimer’s disease (AD), especially for primary physicians. However, the correlation between baseline MRI findings and AD progression has not been fully established. Objective: To investigate the correlation between hippocampal atrophy (HA) and white matter hyperintensities (WMH) on initial brain MRI images and the degree of cognitive decline and functional changes over 1 year. Methods: In this prospective, 12-month observational study, dementia outpatients were recruited from 29 centers across South Korea. Baseline assessments of HA and WMH on baseline brain MRI …were derived as well as cognitive function, dementia severity, activities of daily living, and acetylcholinesterase inhibitor (AChEI) use. Follow-up assessments were conducted at 6 and 12 months. Results: Among 899 enrolled dementia patients, 748 were diagnosed with AD of whom 654 (87%) were taking AChEIs. Baseline WMH showed significant correlations with age, current alcohol consumption, and Clinical Dementia Rating score; baseline HA was correlated with age, family history, physical exercise, and the results of cognitive assessments. Among the AChEI group, changes in the Korean version of the Instrumental Activities of Daily Living (K-IADL) were correlated with the severity of HA on baseline brain MRI, but not with the baseline severity of WMH. In the no AChEI group, changes in K-IADL were correlated with the severity of WMH and HA at baseline. Conclusion: Baseline MRI findings could be a useful tool for predicting future clinical outcomes by primary physicians, especially in relation to patients’ functional status. Show more

Keywords: Atrophy, brain imaging, cognitive function, hippocampus, white matter hyperintensities

DOI: 10.3233/JAD-180565

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2018

Authors: Okuya, Makoto | Matsunaga, Shinji | Ikuta, Toshikazu | Kishi, Taro | Iwata, Nakao

Article Type: Research Article

Abstract:  A systematic review and meta-analysis of the efficacy/safety of intravenous immunoglobulin (IVIG) administration in mild-to-moderate Alzheimer’s disease (AD) patients was performed. Six randomized double-blind, placebo-controlled trials (n  = 801) were included in this study. No significant difference in cognitive function was observed between the groups. Moreover, IVIG was inferior to placebo in behavioral disturbances (mean difference = 2.19). Further, IVIG administration was associated with a higher incidence of rash than placebo. Our results do not support IVIG administration for mild-to-moderate AD, suggesting that IVIG is not effective to treat mild-to-moderate AD and that it deteriorates behavioral and psychological symptoms of dementia in mild-to-moderate …AD. Show more

Keywords: Efficacy, intravenous immunoglobulin, meta-analysis, mild-to-moderate Alzheimer’s disease, safety, systematic review

DOI: 10.3233/JAD-180888

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2018

Authors: Fan, ShuJuan | Xian, XiaoHui | Li, Li | Yao, XiaoGuang | Hu, YuYan | Zhang, Min | Li, WenBin

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by progressive impairment of learning, memory, and cognitive deficits. Glutamate is the major excitatory neurotransmitter in the central nervous system and plays an important role in learning, memory, and cognition. The homeostasis and reutilization of glutamate are dependent on astrocytic uptake by glutamate transporter-1 (GLT-1) and the subsequent glutamate-glutamine cycle. Increasing evidence showed impairments in GLT-1 expression and uptake activity and glutamate-glutamine cycle in AD. Ceftriaxone (Cef) has been reported to upregulate the expression and uptake of GLT-1. Therefore, the present study was undertaken to explore whether Cef can improve cognitive deficits of APP/PS1 mice …in early stage of AD by upregulating GLT-1 expression, and then promoting the glutamate-glutamine cycle. It was shown that Cef treatment significantly alleviated the cognitive deficits measured by Morris water maze test and upregulated GLT-1 protein expression in the hippocampus of APP/PS1 mice. Particularly, the activity of glutamine synthetase (GS) and the protein expression of system N glutamine transporter 1 (SN1), which are the key factors involved in the glutamate-glutamine cycle, were significantly upregulated as well after the Cef treatment. Furthermore, inhibition of GLT-1 uptake activity by dihydrokainic acid, an inhibitor of GLT-1, blocked the Cef-induced improvement on the cognitive deficits, GS activity, and SN1 expression. The above results suggested that Cef could improve cognitive deficits of APP/PS1 mice in early stage of AD by upregulating the GLT-1 expression, GS activity, and SN1 expression, which would lead to stimulating the glutamate-glutamine cycle. Show more

Keywords: APP/PS1 mice, ceftriaxone, DHK, GLT-1, glutamate-glutamine cycle

DOI: 10.3233/JAD-180708

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2018

Authors: Sulmont-Rossé, Claire | Gaillet, Marie | Raclot, Carine | Duclos, Michel | Servelle, Maud | Chambaron, Stéphanie

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is often associated with feeding difficulties and changes in eating behavior with may lead to malnutrition. In French nursing homes, AD patients may live in special care units that better meet dementia residents’ needs. However, meals are often delivered to AD patients by using meal trays coming from central kitchens. This led to the disappearance of cues that could help residents to foresee mealtime, such as the smell of food odors. The aim of the present study was to assess the impact of odorizing the dining room of AD Units with a meat odor before lunch on …subsequent food intake and eating behavior. Thirty-two residents (>75 years old) from three AD Units were included in the study. They participated in two control lunches and two primed lunches, for which a meat odor was diffused in the dining room 15 minutes before the arrival of the meal tray (olfactory priming). Results of the first replication showed a significant effect of olfactory priming, with a 25% increase in meat and vegetable consumption compared to the control condition. Behavioral measurements also showed a significant increase of resident’s interest toward the meal in the primed lunch. However, this effect was no longer observed when the priming session was replicated two weeks later with the same priming odor and the same menu. Although further research is needed to understand why this priming effect cannot be replicated, our experiment is one of the very first to investigate the effect of food odor priming on subsequent food intake in AD patients in a real-life setting. Show more

Keywords: 80 and over, aged, Alzheimer’s disease, dementia, eating, institutionalization, malnutrition, meals, nursing home, odor, priming

DOI: 10.3233/JAD-180465

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2018

Authors: Xie, Yan-Chun | Yao, Zhao-Hui | Yao, Xiao-Li | Pan, Jianzhen | Zhang, Shao-Feng | Zhang, Yong | Hu, Jichang

Article Type: Research Article

Abstract: Chronic cerebral hypoperfusion (CCH) affects the aging population and especially patients with neurodegenerative diseases, such as Alzheimer’s disease or Parkinson’s disease. CCH is closely related to the cognitive dysfunction in these diseases. Glucagon-like peptide-2 receptor (GLP2R) mRNA and protein are highly expressed in the gut and in hippocampal neurons. This receptor is involved in the regulation of food intake and the control of energy balance and glucose homeostasis. The present study employed behavioral techniques, electrophysiology, western blotting, immunohistochemistry, quantitative real time polymerase chain reaction (qRT-PCR), and Golgi staining to investigate whether the expression of GLP2R changes after CCH and whether …GLP2R is involved in cognitive impairment caused by CCH. Our findings show that CCH significantly decreased hippocampal GLP2R mRNA and protein levels. GLP2R upregulation could prevent CCH-induced cognitive impairment. It also improved the CCH-induced impairment of long-term potentiation and long-term depression. Additionally, GLP2R modulated after CCH the AKT-mTOR-p70S6K pathway in the hippocampus. Moreover, an upregulation of the GLP2R increased the neurogenesis in the dentate gyrus, neuronal activity, and density of dendritic spines and mushroom spines in hippocampal neurons. Our findings reveal the involvement of GLP2R via a modulation of the AKT-mTOR-p70S6K pathway in the mechanisms underlying CCH-induced impairments of spatial learning and memory. We suggest that the GLP2R and the AKT-mTOR-p70S6K pathway in the hippocampus are promising targets to treat cognition deficits in CCH. Show more

Keywords: Chronic cerebral hypoperfusion, cognitive dysfunction, glucagon-like peptide-2 receptor, neural plasticity

DOI: 10.3233/JAD-180782

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2018

Authors: Calderón-Garcidueñas, Lilian | Mukherjee, Partha S. | Waniek, Katharina | Holzer, Max | Chao, Chih-kai | Thompson, Charles | Ruiz-Ramos, Rubén | Calderón-Garcidueñas, Ana | Franco-Lira, Maricela | Reynoso-Robles, Rafael | Gónzalez-Maciel, Angélica | Lachmann, Ingolf

Article Type: Research Article

Abstract: Long-term exposure to fine particulate matter (PM2.5 ) and ozone (O3 ) above USEPA standards is associated with Alzheimer’s disease (AD) risk. Metropolitan Mexico City (MMC) children exhibit subcortical pretangles in infancy and cortical tau pre-tangles, NFTs, and amyloid phases 1-2 by the 2nd decade. Given their AD continuum, we measured in 507 normal cerebrospinal fluid (CSF) samples (MMC 354, controls 153, 12.82±6.73 y), a high affinity monoclonal non-phosphorylated tau antibody (non-P-Tau), as a potential biomarker of AD and axonal damage. In 81 samples, we also measured total tau (T-Tau), tau phosphorylated at threonine 181 (P-Tau), amyloid-β 1-42 , …BDNF, and vitamin D. We documented by electron microscopy myelinated axonal size and the pathology associated with combustion-derived nanoparticles (CDNPs) in anterior cingulate cortex white matter in 6 young residents (16.25±3.34 y). Non-P-Tau showed a strong increase with age significantly faster among MMC versus controls (p  = 0.0055). Aβ 1 - 42 and BDNF concentrations were lower in MMC children (p  = 0.002 and 0.03, respectively). Anterior cingulate cortex showed a significant decrease (p  = <0.0001) in the average axonal size and CDNPs were associated with organelle pathology. Significant age increases in non-P-Tau support tau changes early in a population with axonal pathology and evolving AD hallmarks in the first two decades of life. Non-P-Tau is an early biomarker of axonal damage and potentially valuable to monitor progressive longitudinal changes along with AD multianalyte classical CSF markers. Neuroprotection of young urbanites with PM2.5 and CDNPs exposures ought to be a public health priority to halt the development of AD in the first two decades of life. Show more

Keywords: Aβ 1-42 , air pollution, Alzheimer’s disease, axonal damage, BDNF, cerebrospinal fluid, children, combustion-derived nanoparticles, insulin, leptin, Mexico City, non-phosphorylated tau, PM2.5 , PrPC , vitamin D, Wallerian degeneration, white matter

DOI: 10.3233/JAD-180853

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2018

Authors: Soria, Jose A. | Huisa, Branko N. | Edland, Steven D. | Litvan, Irene | Peavy, Guerry M. | Salmon, David P. | Hansen, Lawrence A. | Galasko, Douglas R. | Brewer, James B. | González, Hector M. | Rissman, Robert A.

Article Type: Research Article

Abstract: Clinical, neuropsychological, and neurological procedures used to diagnose Alzheimer’s disease (AD) and related dementias were largely developed and validated in well-educated, non-Latino, English-speaking populations. Sociocultural and genetic differences in Latinos might influence the accuracy of clinical diagnosis of AD and other dementias. We aim to compare the accuracy of the clinical diagnosis of AD and related dementias in Latinos with the corresponding neuropathological diagnosis. From the UCSD Alzheimer’s Disease Research Center longitudinal cohort, we selected all Latino participants who had autopsy neuropathological studies from 1991 to 2017. Participants underwent annual neurological clinical evaluations, standard neuropsychological tests, neuroimaging, and genotyping of …the Apolipoprotein E. We calculated the sensitivity and specificity for the clinical diagnosis of AD against the primary pathological diagnosis. From the 34 participants with a primary neuropathological diagnosis of AD, 33 (97.1%) were correctly clinically diagnosed as having AD at the last clinical evaluation, and 1 was incorrectly diagnosed with dementia with Lewy bodies. Of the 19 participants without a primary neuropathological diagnosis of AD, 8 were incorrectly clinically diagnosed with probable AD at the last clinic evaluation. The clinical diagnosis of AD at the last clinical evaluation had 97.1% sensitivity and 57.9% specificity against autopsy-verified AD. In this Latino cohort, clinicians predicted AD pathological findings with high sensitivity but moderate specificity. Tangle-only dementia was the most common misdiagnosis. Our study suggests that current procedures and instruments to clinically determine AD in Latinos have high sensitivity compared with neuropathology, but specificity needs to be improved. Show more

Keywords: Alzheimer’s disease, dementia, Latino, Lewy bodies, neuropathology

DOI: 10.3233/JAD-180789

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2018

Authors: Jiang, Haowei | Jayadev, Suman | Lardelli, Michael | Newman, Morgan

Article Type: Research Article

Abstract: RESENILIN 1 (PSEN1 ) and PRESENILIN 2 (PSEN2 ) genes are loci for mutations causing familial Alzheimer’s disease (fAD). However, the function of these genes and how they contribute to fAD pathogenesis has not been fully determined. This review provides a summary of the overlapping and independent functions of the PRESENILINS with a focus on the lesser studied PSEN2 . As a core component of the γ-secretase complex, the PSEN2 protein is involved in many γ-secretase-related physiological activities, including innate immunity, Notch signaling, autophagy, and mitochondrial function. These physiological activities have all been associated with AD …progression, indicating that PSEN2 plays a particular role in AD pathogenesis. Show more

Keywords: Alzheimer’s disease, γ-secretase, PRESENILIN 1, PRESENILIN 2

DOI: 10.3233/JAD-180656

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2018