Journal of Alzheimer's Disease - Volume 58, issue 3

Authors: Sun, Junjun | Zhou, Hong | Bai, Feng | Zhang, Zhijun | Ren, Qingguo

Article Type: Review Article

Abstract: Myelin is a lipid-rich multilamellar membrane that wraps around long segments of neuronal axons and it increases the conduction of action potentials, transports the necessary trophic support to the neuronal axons, and reduces the energy consumed by the neuronal axons. Together with axons, myelin is a prerequisite for the higher functions of the central nervous system and complex forms of network integration. Myelin impairments have been suggested to lead to neuronal dysfunction and cognitive decline. Accumulating evidence, including brain imaging and postmortem and genetic association studies, has implicated myelin impairments in Alzheimer’s disease (AD). Increasing data link myelin impairments with …amyloid-β (Aβ) plaques and tau hyperphosphorylation, which are both present in patients with AD. Moreover, aging and apolipoprotein E (ApoE) may be involved in the myelin impairments observed in patients with AD. Decreased neuronal activity, increased Aβ levels, and inflammation further damage myelin in patients with AD. Furthermore, treatments that promote myelination contribute to the recovery of neuronal function and improve cognition. Therefore, strategies targeting myelin impairment may provide therapeutic opportunities for patients with AD. Show more

Keywords: Aging, Alzheimer’s disease, ApoE4, cognition, demyelination, remyelination

DOI: 10.3233/JAD-170036

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 597-612, 2017

Authors: Calderón-Garcidueñas, Lilian | de la Monte, Suzanne M.

Article Type: Review Article

Abstract: Given the epidemiological trends of increasing Alzheimer’s disease (AD) and growing evidence that exposure and lifestyle factors contribute to AD risk and pathogenesis, attention should be paid to variables such as air pollution, in order to reduce rates of cognitive decline and dementia. Exposure to fine particulate matter (PM2.5 ) and ozone (O3 ) above the US EPA standards is associated with AD risk. Mexico City children experienced pre- and postnatal high exposures to PM2.5 , O3, combustion-derived iron-rich nanoparticles, metals, polycyclic aromatic hydrocarbons, and endotoxins. Exposures are associated with early brain gene imbalance in oxidative stress, inflammation, innate …and adaptive immune responses, along with epigenetic changes, accumulation of misfolded proteins, cognitive deficits, and brain structural and metabolic changes. The Apolipoprotein E (APOE) 4 allele, the most prevalent genetic risk for AD, plays a key role in the response to air pollution in young girls. APOE 4 heterozygous females with >75% to <94% BMI percentiles are at the highest risk of severe cognitive deficits (1.5–2 SD from average IQ). This review focused on the relationships between gender, BMI, systemic and neural inflammation, insulin resistance, hyperleptinemia, dyslipidemia, vascular risk factors, and central nervous system involvement in APOE4 urbanites exposed to PM2.5 and magnetite combustion-derived iron-rich nanoparticles that can reach the brain. APOE4 young female heterozygous carriers constitute a high-risk group for a fatal disease: AD. Multidisciplinary intervention strategies could be critical for prevention or amelioration of cognitive deficits and long-term AD progression in young individuals at high risk. Show more

Keywords: APOE, Alzheimer’s disease, body mass index, children, cognition, dementia, diabetes, female gender, glucose, insulin resistance, leptin, metabolic syndrome, Mexico City, nanoparticles, PM 2.5

DOI: 10.3233/JAD-161299

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 613-630, 2017

Authors: Zhu, Jin-Bao | Tan, Chen-Chen | Tan, Lan | Yu, Jin-Tai

Article Type: Review Article

Abstract: Alzheimer’s disease (AD), the main form of dementia in the elderly, is the most common progressive neurodegenerative disease characterized by rapidly progressive cognitive dysfunction and behavior impairment. AD exhibits a considerable heritability and great advances have been made in approaches to searching the genetic etiology of AD. In AD genetic studies, methods have developed from classic linkage-based and candidate-gene-based association studies to genome-wide association studies (GWAS) and next generation sequencing (NGS). The identification of new susceptibility genes has provided deeper insights to understand the mechanisms underlying AD. In addition to searching novel genes associated with AD in large samples, the …NGS technologies can also be used to shed light on the ‘black matter’ discovery even in smaller samples. The shift in AD genetics between traditional studies and individual sequencing will allow biomaterials of each patient as the central unit of genetic studies. This review will cover genetic findings in AD and consequences of AD genetic findings. Firstly, we will discuss the discovery of mutations in APP , PSEN1 , PSEN2 , APOE , and ADAM10 . Then we will summarize and evaluate the information obtained from GWAS of AD. Finally, we will outline the efforts to identify rare variants associated with AD using NGS. Show more

Keywords: Alzheimer’s disease, genetics, genome-wide association studies, linkage studies, next generation sequencing

DOI: 10.3233/JAD-170062

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 631-659, 2017

Authors: Lacosta, Ana-María | Insua, Daniel | Badi, Hassnae | Pesini, Pedro | Sarasa, Manuel

Article Type: Short Communication

Abstract: The two pathognomonic lesions in the brain of AD patients are senile plaques and intraneuronal neurofibrillary tangles (NFT). Previous studies have demonstrated that amyloid-β (Aβ) is a component of both senile plaques and NFTs, and have showed that intracellular accumulation of Aβ is toxic for cells and precedes the appearance of extracellular amyloid deposits. Here we report that there are numerous intraneuronal NFT and extraneuronal NFT immunoreactive for Aβx-40 in which there is no co-localization with tau staining suggesting the existence of two different neurodegenerating populations associated with the intracellular accumulation of either tau protein or Aβx-40 in …AD. Show more

Keywords: Amyloid-β, Aβ peptides, immunohistochemistry, neurodegeneration, phosphorylated-tau, tau protein

DOI: 10.3233/JAD-170163

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 661-667, 2017

Authors: Raunio, Anna | Myllykangas, Liisa | Kero, Mia | Polvikoski, Tuomo | Paetau, Anders | Oinas, Minna

Article Type: Short Communication

Abstract: We investigated the frequency of Lewy-related pathology (LRP) in the amygdala among the population-based Vantaa 85+ study. Data of amygdala samples (N = 304) immunostained with two α-synuclein antibodies (clone 42 and clone 5G4) was compared with the previously analyzed LRP and AD pathologies from other brain regions. The amygdala LRP was present in one third (33%) of subjects. Only 5% of pure AD subjects, but 85% of pure DLB subjects had LRP in the amygdala. The amygdala LRP was associated with dementia; however, the association was dependent on LRP on other brain regions, and thus was not an independent risk factor. …The amygdala-predominant category was a rare (4%) and heterogeneous group. Show more

Keywords: 80 and over, aged, α-synuclein, Alzheimer’s disease, amygdala, amygdala-predominant, Lewy body disease, Lewy-related pathology, population-based study

DOI: 10.3233/JAD-170104

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 669-674, 2017

Authors: Babulal, Ganesh M. | Stout, Sarah H. | Head, Denise | Holtzman, David M. | Fagan, Anne M. | Morris, John C. | Roe, Catherine M.

Article Type: Research Article

Abstract: We examined whether neuropsychiatric symptoms (NPS) interact with cerebrospinal fluid (CSF) biomarkers (amyloid-β42 [Aβ42 ], tau, phosphorylated tau181 [ptau181 ], tau/Aβ42 , and ptau181 /Aβ42 ) of Alzheimer’s disease pathology to predict driving decline among cognitively-normal older adults (N  = 116) aged ≥65. Cox proportional hazards models examined time to receiving a rating of marginal or fail on the driving test. Age, education, and gender were adjusted in the models. Participants with more abnormal CSF (Aβ42 , tau/Aβ42 , ptau181 /Aβ42 ) and NPS were faster to receive a marginal/fail on the road test compared to those without NPS. …NPS interact with abnormal CSF biomarkers to impact driving performance among cognitively-normal older adults. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, depression, neuropsychology, noncognitive outcomes, preclinical

DOI: 10.3233/JAD-170067

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 675-680, 2017

Authors: Kasahata, Naoki | Sato, Tomohide | Onishi, Iichiroh | Kitagawa, Masanobu | Uchihara, Toshiki | Hirokawa, Katsuiku

Article Type: Short Communication

Abstract: We encountered an 83-year-old man with 3-repeat dominant grain-like tau deposition. Tau-positive lesions exhibited apparent similarity to argyrophilic grains in terms of their distribution in the ambient gyrus, amygdala, and dorsomedial temporal tip and the characteristic comma-like morphology. The abundant oligodendroglial tau immunoreactivities were 3-repeat dominant. Tuft-shaped astrocytes showed partial 3-repeat tau immnoreactivities. These grain-like structures, as well as tuft-shaped astrocytes and oligodendroglia, exhibited predominant 3-repeat tau immunoreactivity, suggesting that grain-like structures and their characteristic distribution are mutually linked and not unique to 4-repeat tau deposition. pTDP immunoreactivity, extensive macrophage infiltration, and spongiosis were associated with these 3-repeat tau deposits.

Keywords: 3-repeat tau, ambient gyrus, amygdala, astrocytic tau immunoreactivity, grain, oligodendroglial tau immunoreactivity, TDP-43, temporal tip

DOI: 10.3233/JAD-160672

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 681-685, 2017

Authors: Yoshino, Yuta | Yamazaki, Kiyohiro | Ozaki, Yuki | Sao, Tomoko | Yoshida, Taku | Mori, Takaaki | Mori, Yoko | Ochi, Shinichiro | Iga, Jun-Ichi | Ueno, Shu-Ichi

Article Type: Research Article

Abstract: Microglial dysfunction and inflammation have recently been shown to be related to the development of Alzheimer’s disease (AD). Inositol polyphosphate-5-phosphatase (INPP5D) functions broadly as a negative regulator of immune signaling, and its locus was associated with development of AD in a large-scale genome-wide association study. Thus, we examined INPP5D mRNA expression and methylation rates of the CpG sites in the upstream region of INPP5D exon 1 in peripheral leukocytes in 50 AD and age- and sex-matched control subjects. INPP5D mRNA expression in AD subjects was significantly higher than that in control subjects (1.16±0.39 versus 1.0±0.23, p  = 0.049) …and was correlated with the Mini-Mental State Examination score (p  = 0.002, r  = 0.426) and the total score of the Alzheimer’s Disease Assessment Scale (p  < 0.001, r  = –0.697). Methylation rates in the upstream region of INPP5D exon 1 were not significantly different between AD and control subjects (average rate: 3.5±3.0 versus 2.8±1.3, p  = 0.551). Our results suggested that INPP5D mRNA expression was elevated in the early stage and decreased with cognitive decline in AD. INPP5D mRNA expression in leukocytes may be a useful biomarker for the early stage of AD. Show more

Keywords: Alzheimer’s disease, inositol polyphosphate-5-phosphatase, methylation, microglia, pyrosequencing

DOI: 10.3233/JAD-161211

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 687-694, 2017

Authors: Ritter, Aaron | Hawley, Nanako | Banks, Sarah J. | Miller, Justin B.

Article Type: Research Article

Abstract: Despite widespread use, there have been few investigations into the neuroanatomical correlates of the Montreal Cognitive Assessment (MoCA). In a sample of 138 consecutive patients presenting with cognitive complaints, we report significant correlations between lower MoCA memory scores and smaller hippocampal volumes (r  = 0.36–0.41, p  < 0.001). We also report that the newly devised memory index score, designed to better capture encoding deficits than the standard delayed recall score, was not significantly better for predicting hippocampal volume. These initial results suggest that poor performance on the MoCA’s memory section should prompt further evaluation for hippocampal atrophy.

Keywords: Alzheimer’s disease, dementia, hippocampus, magnetic resonance imaging, neuropsychological test

DOI: 10.3233/JAD-161241

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 695-699, 2017

Authors: Yang, Yue | Halliday, Glenda M. | Hodges, John R. | Tan, Rachel H.

Article Type: Research Article

Abstract: Background: The early and selective loss of von Economo neurons in the anterior cingulate cortex has been linked to behavioral deficits in frontotemporal dementia (FTD). Importantly, whether these neurons are also targeted in patients with the C9ORF72 repeat expansion has yet to be established. This is of particular interest given the recent evidence highlighting the thalamus rather than anterior cingulate cortex as a region of significant degeneration in patients with the C9ORF72 repeat expansion. Objective: To assess the von Economo neuron density and thalamus volumes in behavioral variant FTD (bvFTD) cases with the C9ORF72 …repeat expansion, sporadic bvFTD, sporadic ALS, and controls. Methods: Volumetric and quantitative cell counting methods were employed to assess the von Economo neuron density and thalamus volumes in 37 pathologically-confirmed cases comprised of patients with bvFTD (n  = 13) cases with the C9ORF72 repeat expansion (62% with psychosis), sporadic bvFTD (n  = 8), sporadic amyotrophic lateral sclerosis (n  = 7) and controls (n  = 9). Results: von Economo neuron density was significantly reduced in sporadic bvFTD cases only. Thalamus degeneration was identified only in bvFTD cases with the C9ORF72 repeat expansion, and to a similar extent in cases with and without psychosis. No significant difference in von Economo neuron density or thalamus degeneration was seen between bvFTD cases with or without the C9ORF72 repeat expansion. Conclusion: The present histological findings converge with neuroimaging results to corroborate the anterior cingulate cortex as a core region involved in sporadic bvFTD, and the thalamus as a major region targeted in patients with the C9ORF72 expansion. Show more

Keywords: Behavioral variant frontotemporal dementia, C9ORF72, psychosis, thalamus, von Economo neurons

DOI: 10.3233/JAD-170002

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 701-709, 2017