Journal of Alzheimer's Disease - Volume 44, issue 3

Authors: West, Rebecca K. | Ravona-Springer, Ramit | Heymann, Anthony | Schmeidler, James | Leroith, Derek | Koifman, Keren | Guerrero-Berroa, Elizabeth | Preiss, Rachel | Hoffman, Hadas | Silverman, Jeremy M. | Beeri, Michal Schnaider

Article Type: Research Article

Abstract: We studied the relationship of adult body height with five cognitive outcomes (executive functioning, semantic categorization, attention/working memory, episodic memory, and an overall cognition measure) in 897 cognitively normal elderly with type 2 diabetes. Regression analyses controlling for sociodemographic, cardiovascular, and diabetes-related risk factors and depression demonstrated that in males, shorter stature was associated with poorer executive functioning (p = 0.001), attention/working memory (p = 0.007), and overall cognition (p = 0.016), but not with episodic memory (p = 0.715) or semantic categorization (p = 0.948). No relationship between height and cognition was found for females. In cognitively normal type …2 diabetes male subjects, shorter stature, a surrogate for early-life stress and poor nutrition, was associated with cognitive functions. Show more

Keywords: Cognitive performance, height, risk factors, type 2 diabetes mellitus, vascular dementia

DOI: 10.3233/JAD-142049

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 927-935, 2015

Authors: Saidi, Laiq-Jan | Polydoro, Manuela | Kay, Kevin R. | Sanchez, Laura | Mandelkow, Eva-Maria | Hyman, Bradley T. | Spires-Jones, Tara L.

Article Type: Research Article

Abstract: One of the hallmarks of Alzheimer's disease is the formation of neurofibrillary tangles, intracellular aggregates of hyperphosphorylated, mislocalized tau protein, which are associated with neuronal loss. Changes in tau are known to impair cellular transport (including that of mitochondria) and are associated with cell death in cell culture and mouse models of tauopathy. Thus clearing pathological forms of tau from cells is a key therapeutic strategy. One critical modulator in the degradation and clearance of misfolded proteins is the co-chaperone CHIP (Carboxy terminus Hsp70 interacting Protein), which is known to play a role in refolding and clearance of hyperphosphorylated tau. …Here, we tested the hypothesis that CHIP could ameliorate pathological changes associated with tau. We find that co-expressing CHIP with full-length tau, tau truncated at D421 mimicking caspase cleavage, or the short tauRD ΔK280 tau construct containing only the tau repeat domain with a tauopathy mutation, decreases tau protein levels in human H4 neuroglioma cells in a manner dependent on the Hsp70-binding TPR domain of CHIP. The observed reduction in tau levels by CHIP is associated with a decrease of tau phosphorylation and reduced levels of cleaved Caspase 3 indicating that CHIP plays an important role in preventing tau-induced pathological changes. Furthermore, tau-associated mitochondrial transport deficits are rescued by CHIP co-expression in H4 cells. Together, these data suggest that the co-chaperone CHIP can rescue the pathological effects of tau, and indicate that other diseases of protein misfolding and accumulation may also benefit from CHIP upregulation. Show more

Keywords: Alzheimer's disease, caspase, CHIP, mitochondrial transport, tau protein

DOI: 10.3233/JAD-142094

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 937-947, 2015

Authors: Barrett, James P. | Minogue, Aedín M. | Jones, Raasay S. | Ribeiro, Catia | Kelly, Ronan J. | Lynch, Marina A.

Article Type: Research Article

Abstract: Macrophages are key cells in tissue defense in the periphery and, under certain circumstances, infiltrate the central nervous system, where they may play a similar role in the brain, perhaps supporting the function of microglia. Macrophages have been shown to adopt different activation states in response to various stimuli. Specifically, when exposed to inflammatory stimuli such as interferon (IFN)γ, the cells adopt the M1 phenotype, whereas when exposed to anti-inflammatory cytokines such as interleukin (IL)-4 or IL-13, the M2 phenotype is adopted. While M1 macrophages are associated with tissue defense and destruction of invading pathogens, M2 macrophages are involved in …tissue repair and in terminating inflammation. It is well known that an inflammatory microenvironment exists in the brain of aged animals and also in the brain of mice that overexpress amyloid-β protein precursor (AβPP) and presenilin 1 (PS1; AβPP/PS1 mice), a commonly-used model of Alzheimer's disease (AD). Recent studies have revealed that immune cells, including macrophages, infiltrate the brain in both circumstances raising the possibility that these cells adopt the M1 activation state and contribute to the already-existing neuroinflammation. We set out to examine the responses of bone marrow-derived macrophages prepared from wildtype and AβPP/PS1 mice and demonstrate that cells from AβPP/PS1 mice, even after several days in culture, respond more profoundly to IFNγ than those from wildtype mice. We suggest that this propensity to respond to M1-polarizing stimuli, together with the described changes in the brain of AβPP/PS1 mice, contribute to the development of chronic neuroinflammation. Show more

Keywords: AβPP/PS1 mice, blood-brain barrier, bone marrow-derived macrophages, IFNγ, M1 and M2 phenotypes, neuroinflammation

DOI: 10.3233/JAD-142076

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 949-962, 2015

Authors: Kim, Hee Jin | Im, Kiho | Kwon, Hunki | Lee, Jong Min | Ye, Byoung Seok | Kim, Yeo Jin | Cho, Hanna | Choe, Yearn Seong | Lee, Kyung Han | Kim, Sung Tae | Kim, Jae Seung | Lee, Jae Hong | Na, Duk L. | Seo, Sang Won

Article Type: Research Article

Abstract: There is growing evidence that the human brain is a large scale complex network. The structural network is reported to be disrupted in cognitively impaired patients. However, there have been few studies evaluating the effects of amyloid and small vessel disease (SVD) markers, the common causes of cognitive impairment, on structural networks. Thus, we evaluated the association between amyloid and SVD burdens and structural networks using diffusion tensor imaging (DTI). Furthermore, we determined if network parameters predict cognitive impairments. Graph theoretical analysis was applied to DTI data from 232 cognitively impaired patients with varying degrees of amyloid and SVD burdens. …All patients underwent Pittsburgh compound-B (PiB) PET to detect amyloid burden, MRI to detect markers of SVD, including the volume of white matter hyperintensities and the number of lacunes, and detailed neuropsychological testing. The whole-brain network was assessed by network parameters of integration (shortest path length, global efficiency) and segregation (clustering coefficient, transitivity, modularity). PiB retention ratio was not associated with any white matter network parameters. Greater white matter hyperintensity volumes or lacunae numbers were significantly associated with decreased network integration (increased shortest path length, decreased global efficiency) and increased network segregation (increased clustering coefficient, increased transitivity, increased modularity). Decreased network integration or increased network segregation were associated with poor performances in attention, language, visuospatial, memory, and frontal-executive functions. Our results suggest that SVD alters white matter network integration and segregation, which further predicts cognitive dysfunction. Show more

Keywords: Amyloid, diffusion tensor imaging, graph theory, small vessel disease, white matter network

DOI: 10.3233/JAD-141623

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 963-975, 2015

Authors: Humphries, Crystal E. | Kohli, Martin A. | Nathanson, Lubov | Whitehead, Patrice | Beecham, Gary | Martin, Eden | Mash, Deborah C. | Pericak-Vance, Margaret A. | Gilbert, John

Article Type: Research Article

Abstract: Previous transcriptome studies observed disrupted cellular processes in late-onset Alzheimer's disease (LOAD), yet it is unclear whether these changes are specific to LOAD, or are common to general neurodegeneration. In this study, we address this question by examining transcription in LOAD and comparing it to cognitively normal controls and a cohort of “disease controls.” Differential transcription was examined using RNA-seq, which allows for the examination of protein coding genes, non-coding RNAs, and splicing. Significant transcription differences specific to LOAD were observed in five genes: C10orf105, DIO2, a lincRNA, RARRES3, and WIF1. These findings were replicated in two independent publicly available …microarray data sets. Network analyses, performed on 2,504 genes with moderate transcription differences in LOAD, reveal that these genes aggregate into seven networks. Two networks involved in myelination and innate immune response specifically correlated to LOAD. FRMD4B and ST18, hub genes within the myelination network, were previously implicated in LOAD. Of the five significant genes, WIF1 and RARRES3 are directly implicated in the myelination process; the other three genes are located within the network. LOAD specific changes in DNA methylation were located throughout the genome and substantial changes in methylation were identified within the myelination network. Splicing differences specific to LOAD were observed across the genome and were decreased in all seven networks. DNA methylation had reduced influence on transcription within LOAD in the myelination network when compared to both controls. These results hint at the molecular underpinnings of LOAD and indicate several key processes, genes, and networks specific to the disease. Show more

Keywords: Alzheimer's disease, dementia with Lewy bodies, DNA methylation, expression, human brain, Illumina Human Methylation 450K, late-onset transcriptome, myelination, networks, RNA-seq, splicing

DOI: 10.3233/JAD-141989

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 977-987, 2015

Authors: Chaudhry, Mamoonah | Wang, Xingbin | Bamne, Mikhil N. | Hasnain, Shahida | Demirci, F.Yesim | Lopez, Oscar L. | Kamboh, M. Ilyas

Article Type: Research Article

Abstract: Epigenetic changes including genomic imprinting may affect risk of late-onset Alzheimer's disease (LOAD). There are >100 known imprinted genes and most of them are expressed in human brain. In this study, we examined the association of single nucleotide polymorphisms (SNPs) in 93 imprinted genes with LOAD risk in 1291 LOAD cases and 958 cognitively normal controls. We performed single-site, gene-based, and haplotype analyses. Single-site analysis showed 14 significant associations at p < 0.01. The most significant SNP (rs11770199; p = 0.0003) in single-site analysis was located on chromosome 7 in the GRB10 gene. Gene-based analyses revealed four significant associations in …the WT1, ZC3H12C, DLGAP2, and GPR1 genes at p < 0.05. The haplotype analysis also revealed significant associations with three genes (ZC3H12C, DLGAP2, and GPR1). These findings suggest a possible role of imprinted genes in AD pathogenesis that show specific expression in the brain. Show more

Keywords: Brain, gene expression, imprinting, late onset Alzheimer's disease

DOI: 10.3233/JAD-142106

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 989-994, 2015

Authors: Callaway, Jennifer K. | Jones, Nigel C. | Royse, Alistair G. | Royse, Colin F.

Article Type: Research Article

Abstract: Post-operative cognitive dysfunction (POCD) predominantly affects the elderly who suffer memory and concentration deficits after anesthesia and surgery. Animal studies have demonstrated anesthetic alone may contribute to POCD but results are variable and little is known about common anesthetics other than isoflurane. The present study investigated dose-dependence of desflurane anesthesia in young adult and aged rats. We hypothesize higher concentrations of desflurane will result in memory impairment in the water maze and that impairment will be worse in aged rats. Effects of anesthesia (1 or 1.5 MAC, 4 h) desflurane, or sham exposure on cognition were investigated in young adult …(3 months) and aged (20–24 months) rats at 1, 4, and 12 weeks post-exposure. The Morris water maze was used to assess acquisition and retention of spatial reference memory. Latency to find the hidden platform and swimming speed were compared between treatments. Aged rats showed significant impairment in task acquisition after exposure to 1.5 MAC, but not 1.0 MAC desflurane anesthetic when tested 1 week following exposure. Latency to find the platform and distance travelled were significantly longer in aged rats given 1.5 MAC desflurane (latency: F(1,108) = 19.71, p < 0.0001; distance: F(1,108) = 5.79, p = 0.018). Deficits were not long-lasting and were no longer present at 4 or 12 weeks. In contrast, young adult rats performed equally as well as sham-exposed control rats irrespective of desflurane dose. This study showed the effects of desflurane on learning and memory in the water maze are age and dose dependent and are brief in duration. Show more

Keywords: Aging, anesthetics inhalation, cognitive, desflurane, memory disorders, retention disorders

DOI: 10.3233/JAD-132444

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 995-1005, 2015

Authors: Tynkkynen, Juho | Laatikainen, Tiina | Salomaa, Veikko | Havulinna, Aki S. | Blankenberg, Stefan | Zeller, Tanja | Hernesniemi, Jussi A.

Article Type: Research Article

Abstract: Background: Memory disorders and Alzheimer's disease (AD) share the same risk factors with cardiovascular diseases. Objective: We tested whether elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) levels would predict any incident dementia or AD. Methods: The association between NT-proBNP and the risk of dementia was evaluated in a total of 7,158 subjects without previous memory disorders in a prospective study with a median follow-up of 13.8 years. Results: A total of 220 new dementia cases occurred, of which 149 were AD. Baseline logNT-proBNP levels were associated significantly with the risk of dementia in the entire …study population (HR 1.32, 95%CI 1.17–1.56, p = 0.001) per 1SD difference, adjusted for multiple cardiovascular risk factors. Integrated discrimination improvement (IDI) and continuous net-reclassification improvement (continuous NRI) were improved in the study population over 40 years of age: continuous NRI was 17.5% (95%CI 4.4–30.6%, p = 0.009) and IDI was 0.005 (95%CI 0.001–0.010, p = 0.021). Regarding AD, the HR for 1SD logNT-proBNP change was 1.23 (95%CI 1.01–1.49, p = 0.040) in the entire study population, but no IDI or continuous NRI improvement was seen. Conclusion: NT-proBNP is also an independent risk marker for dementia, and patient discrimination regarding dementia risk could be improved by using it. Show more

Keywords: Alzheimer's disease, biological marker, dementia, N-terminal pro-BNP, population-based, prospective studies, risk

DOI: 10.3233/JAD-141809

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 1007-1013, 2015

Authors: Wucherer, Diana | Eichler, Tilly | Kilimann, Ingo | Hertel, Johannes | Michalowsky, Bernhard | Thyrian, Jochen René | Teipel, Stefan | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: There is a lack of knowledge about antidementia drug treatment in community dwelling people with dementia in Germany. Objective: To determine the frequency of treatment with antidementia drugs in patients in primary care, and the socio-demographic and clinical variables associated with antidementia drug treatment. Methods: Present analyses are based on preliminary data from the DelpHi-trial, an ongoing GP-based, cluster-randomized, controlled intervention trial to implement and evaluate an innovative concept of collaborative dementia care management in Germany. Our sample consists of n = 243 subjects who screened positive for dementia. Results: 29.6% (n = …72) of participants received antidementia drugs: memantine 44.5% (n = 32); donepezil 30.5% (n = 22); rivastigmine 13.9% (n = 10); galantamine 11.1% (n = 8). A total of 46.4% (n = 45) of the subgroup of participants with a formal dementia diagnosis received antidementia drug treatment. Approximately 37.5% (n = 27) of our sample received treatment with antidementia drugs without having a formal diagnosis. Treatment with antidementia drugs was significantly associated with more severe cognitive impairment and having a formal dementia diagnosis. Conclusions: One in three people who screened positive for dementia in primary care received antidementia drug treatment, indicating the frequent use of this class of drugs. For those with a formal dementia diagnosis, these drug treatment rates are more than triple, compared to those in nursing homes. Show more

Keywords: DelpHi-MV trial, dementia, donepezil, galantamine, memantine, primary health care, rivastigmine

DOI: 10.3233/JAD-142064

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 1015-1021, 2015

Authors: Jang, Jae-Won | Park, So Young | Park, Young Ho | Baek, Min Jae | Lim, Jae-Sung | Youn, Young Chul | Kim, SangYun

Article Type: Research Article

Abstract: Background: Brain magnetic resonance imaging (MRI) shows cerebral structural changes. However, a unified comprehensive visual rating scale (CVRS) has seldom been studied. Thus, we combined brain atrophy and small vessel disease scales and used an MRI template as a CVRS. Objective: The aims of this study were to design a simple and reliable CVRS, validate it by investigating cerebral structural changes in clinical groups, and made comparison to the volumetric measurements. Methods: Elderly subjects (n = 260) with normal cognition (NC, n = 65), mild cognitive impairment (MCI, n = 101), or Alzheimer's disease (AD, n …= 94) were evaluated with brain MRI according to the CVRS of brain atrophy and small vessel disease. Validation of the CVRS with structural changes, neuropsychological tests, and volumetric analyses was performed. Results: The CVRS revealed a high intra-rater and inter-rater agreement and it reflected the structural changes of subjects with NC, MCI, and AD better than volumetric measures (CVRS-coronal: F = 13.5, p < 0.001; CVRS-axial: F = 19.9, p < 0.001). The area under the receiver operation curve (aROC) of the CVRS showed higher accuracy than volumetric analyses. (NC versus MCI aROC: CVRS-coronal, 0.777; CVRS-axial, 0.773; MCI versus AD aROC: CVRS-coronal, 0.680; CVRS-axial, 0.681). Conclusion: The CVRS can be used clinically to conveniently measure structural changes of brain. It reflected cerebral structural changes of clinical groups and correlated with the age better than volumetric measures. Show more

Keywords: Alzheimer's disease, mild cognitive impairment, visual rating scale

DOI: 10.3233/JAD-142088

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 1023-1034, 2015