Journal of Alzheimer's Disease - Volume 63, issue 3

Authors: Huang, Yangmei | Guo, Baihong | Shi, Bihua | Gao, Qingtao | Zhou, Qiang

Article Type: Research Article

Abstract: Reduced cerebral blood flow in Alzheimer’s disease (AD) may occur in early AD, which contributes to the pathogenesis and/or pathological progression of AD. Reversing this deficit may have therapeutic potential. Certain traditional Chinese herbal medicines (e.g., Saponin and its major component Xueshuantong [XST]) increase blood flow in humans, but whether they could be effective in treating AD patients has not been tested. We found that systemic XST injection elevated cerebral blood flow in APP/PS1 transgenic mice using two-photon time-lapse imaging in the same microvessels before and after injection. Subchronic XST treatment led to improved spatial learning and memory and motor …performance in the APP/PS1 mice, suggesting improved neural plasticity and functions. Two-photon time lapse imaging of the same plaques revealed a reduction in plaque size after XST treatment. In addition, western blots experiments showed that XST treatment led to reduced processing of amyloid-β protein precursor (AβPP) and enhanced clearance of amyloid-β (Aβ) without altering the total level of AβPP. We also found increased synapse density in the immediate vicinity of amyloid plaques, suggesting enhanced synaptic function. We conclude that targeting cerebral blood flow can be an effective strategy in treating AD. Show more

Keywords: Aβ plaque, Alzheimer’s disease, cerebral blood flow, Chinese herbal medicine, synapse, two-photon imaging

DOI: 10.3233/JAD-170763

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 1089-1107, 2018

Authors: Gil, María José | Manzano, María Sagrario | Cuadrado, María Luz | Fernández, Cristina | Góméz, Elena | Matesanz, Carmen | Calero, Miguel | Rábano, Alberto

Article Type: Research Article

Abstract: Frontotemporal lobar degeneration (FTLD) is a clinically, pathologically, and genetically heterogeneous group of disorders that affect the frontal and temporal lobes of the brain. FTLD classification distinguishes three main neuropathological groups: FTLD-tau, FTLD-TDP, and FTLD-FUS. As a four-repeat tauopathy, argyrophilic grain disease (AGD) is included in the FTLD-tau group. AGD may also appear in association with other neuropathological disorders. We describe the demographic, clinical, neuropathological, and genetic characteristics of a series of FTLD cases presenting with AGD. For this purpose, a clinico-pathological study of 71 autopsy-confirmed FTLD cases from different tissue banks was performed. AGD was found in 52.1% of …FTLD cases. The presence of AGD increased with the increasing age (up to 88.9% in cases older than 80 years; p  < 0.001) and was associated with higher ages at onset (p  < 0.001) and death (p  < 0.001). In AGD cases, progressive supranuclear palsy (PSP) was the most frequent clinical diagnosis (29.7%) and gait disturbance was the most common symptom (64.5%); behavioral and language symptoms were less frequent as compared with non-AGD cases (p  = 0.055; p  = 0.012). PSP was the most frequent neuropathological diagnosis among cases with AGD (32.4%). This group also showed less brain atrophy (p  = 0.094) and higher prevalence of Alzheimer (p  = 0.002) and vascular pathology (p  = 0.047) as compared to the non-AGD group. We also observed that H1/H1 genotype was overrepresented in AGD cases (p  = 0.018) and that there was no association with any specific APOE allele. A subanalysis of PSP cases according to the AGD status was carried out, yielding no significant differences. Show more

Keywords: Argyrophilic grain disease, frontotemporal dementia, frontotemporal lobar degeneration, tauopathy

DOI: 10.3233/JAD-171115

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 1109-1117, 2018

Authors: Li, Jinlei | Ogrodnik, Matthew | Kolachalama, Vijaya B. | Lin, Honghuang | Au, Rhoda

Article Type: Research Article

Abstract: Background: Dementia is the leading cause of dependence and disability in the elderly population worldwide. However, currently there is no effective medication for dementia treatment. Therefore, identifying lifestyle-related risk factors including some that are modifiable may provide important strategies for reducing risk of dementia. Objective: This study aims to highlight associations between easily obtainable lifestyle risk factors in mid-life and dementia in later adulthood. Methods: Using data from the Framingham Heart Study Offspring cohort, we leveraged well-known classification models (decision tree classifier and random forests) to associate demographic and lifestyle behavioral data with dementia status. We …then evaluated model performance by computing area under receiver operating characteristic (ROC) curve. Results: As expected, age was strongly associated with dementia. The analysis also identified ‘widowed’ marital status, lower BMI, and less sleep at mid-life as risk factors of dementia. The areas under the ROC curves were 0.79 for the decision tree, and 0.89 for the random forest model. Conclusion: Demographic and lifestyle factors that are non-invasive and inexpensive to implement can be assessed in midlife and used to potentially modify the risk of dementia in late adulthood. Classification models can help identify associations between dementia and midlife lifestyle risk factors. These findings inform further research, in order to help public health officials develop targeted programs for dementia prevention. Show more

Keywords: Dementia, demographic factors, lifestyle, mid-life

DOI: 10.3233/JAD-170917

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 1119-1127, 2018

Authors: Claus, Jules J. | Coenen, Mirthe | Staekenborg, Salka S. | Schuur, Jacqueline | Tielkes, Caroline E.M. | Koster, Pieter | Scheltens, Philip

Article Type: Research Article

Abstract: Background: Evidence suggests that cerebral white matter lesions (WML) play a role in cognitive decline. Objective: To assess the impact of cerebral WML on cognitive function relative to absence or presence of medial temporal atrophy (MTA) in a large single-center memory clinic population. Methods: Patients included had subjective cognitive impairment (SCI, n  = 333), mild cognitive impairment (MCI, n  = 492) and Alzheimer’s disease (AD, n  = 832). The relationships between visually rated WML (Fazekas scale, 0–3) on brain Computed Tomography and CAMCOG memory and non-memory function were investigated with regression analysis adjusted for age, gender and education in …combined patient groups. We assessed possible interaction versus addition effects of these relationships with visually rated MTA (Scheltens scale). Results: The highly statistical significant relationship between WML and memory function was no longer significant when MTA was taken into account. However, the strong significant relationship between WML and non-memory function remained significant after adjustment for MTA, but the explained variance attributed to WML was only 1.3%. There was no interaction between WML and MTA on CAMCOG test scores. In addition, shown by a 2×2 factorial model by presence versus absence of WML and MTA, WML affected non-memory function only in the presence of MTA. Conclusion: Our data suggest that presence of WML is associated with lower non-memory cognitive function but this effect is conditional on the presence of pre-existing MTA. The very small explained variance suggests little impact of WML to the clinical profile of a memory clinic patient. Show more

Keywords: Alzheimer’s disease, computed tomography, Fazekas score, memory clinic, mild cognitive impairment, subjective cognitive impairment, white matter lesions

DOI: 10.3233/JAD-171111

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 1129-1139, 2018

Authors: Mahaman, Yacoubou Abdoul Razak | Huang, Fang | Wu, Mengjuan | Wang, Yuman | Wei, Zhen | Bao, Jian | Salissou, Maibouge Tanko Mahamane | Ke, Dan | Wang, Qun | Liu, Rong | Wang, Jian-Zhi | Zhang, Bin | Chen, Dan | Wang, Xiaochuan

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is multifactorial with unclear etiopathology. Due to the complexity of AD, many attempted single therapy treatments, like Aβ immunization, have generally failed. Therefore, there is a need for drugs with multiple benefits. Naturally occurring phytochemicals with neuroprotective, anti-amyloidogenic, antioxidative, and anti-inflammatory properties could be a possible way out. In this study, the effect of Moringa oleifera (MO), a naturally occurring plant with high antioxidative, anti-inflammatory, and neuroprotective effects, was evaluated on hyperhomocysteinemia (HHcy) induced AD-like pathology in rats. Homocysteine (Hcy) injection for 14 days was used to induce AD-like pathology. Simultaneous MO extract gavage followed the …injection as a preventive treatment or, after injection completion, MO gavage was performed for another 14 days as a curative treatment. MO was found to not only prevent but also rescue the oxidative stress and cognitive impairments induced by Hcy treatment. Moreover, MO recovered the decreased synaptic proteins PSD93, PSD95, Synapsin 1 and Synaptophysin, and improved neurodegeneration. Interestingly, MO decreased the Hyc-induced tau hyperphosphorylation at different sites including S-199, T-231, S-396, and S-404, and at the same time decreased Aβ production through downregulation of BACE1. These effects in HHcy rats were accompanied by a decrease in calpain activity under MO treatment, supporting that calpain activation might be involved in AD pathogenesis in HHcy rats. Taken together, our data, for the first time, provided evidence that MO alleviates tau hyperphosphorylation and Aβ pathology in a HHcy AD rat model. This and previous other studies support MO as a good candidate for, and could provide new insights into, the treatment of AD and other tauopathies. Show more

Keywords: Alzheimer’s disease, amyloid-β, BACE1, calpain, homocysteine, Moringa oleifera (MO), tau

DOI: 10.3233/JAD-180091

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 1141-1159, 2018

Authors: Nardiello, Pamela | Pantano, Daniela | Lapucci, Andrea | Stefani, Massimo | Casamenti, Fiorella

Article Type: Research Article

Abstract: Alzheimer’s disease is the most common form of dementia affecting a large proportion of aged people. Plant polyphenols have been reported to be potentially useful in the prevention of AD due to their multiple pharmacological activities. The aim of the present study was to assess whether the previously reported neuroprotective and anti-inflammatory effects resulting from oleuropein aglycone administration were reproduced by diet supplementation with similar amounts of its metabolite hydoxytyrosol (HT). Four-month-old TgCRND8 and wild type mice were treated for 8 weeks with a low-fat diet (5%) supplemented with HT (50 mg/kg of diet). We found that HT supplementation significantly improved …cognitive functions of TgCRND8 mice and significantly reduced Aβ42 and pE3-Aβ plaque area and number in the cortex; in the hippocampal areas of HT-fed TgCRND8 mice, we found a significant reduction in the pE3-Aβ plaque number together with a tendency toward a reduction in Aβ42 load and pE3-Aβ plaque area, associated with a marked reduction of TNF-α expression and astrocyte reaction. Macroautophagy induction and modulation of MAPKs signaling were found to underlie the beneficial effects of HT. Our findings indicate that HT administration reproduces substantially the beneficial effects on behavioral performance and neuropathology previously reported in TgCRND8 mice fed with oleuropein aglycone, resulting in comparable neuroprotection. Show more

Keywords: Amyloid plaques, autophagy, hydoxytyrosol, MAPKs signaling, memory function

DOI: 10.3233/JAD-171124

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 1161-1172, 2018

Authors: Sen, Abhik | Nelson, Thomas J. | Alkon, Daniel L. | Hongpaisan, Jarin

Article Type: Research Article

Abstract: Oxidative stress and amyloid-β (Aβ) oligomers have been implicated in Alzheimer’s disease (AD). The growth and maintenance of neuronal networks are influenced by brain derived neurotrophic factor (BDNF) expression, which is promoted by protein kinase C epsilon (PKCɛ ). We investigated the reciprocal interaction among oxidative stress, Aβ, and PKCɛ levels and subsequent PKCɛ -dependent MnSOD and BDNF expression in hippocampal pyramidal neurons. Reduced levels of PKCɛ , MnSOD, and BDNF and an increased level of Aβ were also found in hippocampal neurons from autopsy-confirmed AD patients. In cultured human primary hippocampal neurons, spherical aggregation of Aβ (amylospheroids) decreased …PKCɛ and MnSOD. Treatment with t-butyl hydroperoxide (TBHP) increased superoxide, the oxidative DNA/RNA damage marker, 8-OHG, and Aβ levels, but reduced PKCɛ , MnSOD, BDNF, and cultured neuron density. These changes were reversed with the PKCɛ activators, bryostatin and DCPLA-ME. PKCɛ knockdown suppressed PKCɛ , MnSOD, and BDNF but increased Aβ. In cultured neurons, the increase in reactive oxygen species (ROS) associated with reduced PKCɛ during neurodegeneration was inhibited by the SOD mimetic MnTMPyP and the ROS scavenger NAc, indicating that strong oxidative stress suppresses PKCɛ level. Reduction of PKCɛ and MnSOD was prevented with the PKCɛ activator bryostatin in 5–6-month-old Tg2576 AD transgenic mice. In conclusion, oxidative stress and Aβ decrease PKCɛ expression. Reciprocally, a depression of PKCɛ reduces BDNF and MnSOD, resulting in oxidative stress. These changes can be prevented with the PKCɛ -specific activators. Show more

Keywords: Alzheimer’s disease, BDNF, hippocampus, MnSOD, oxidative stress, PKCɛ

DOI: 10.3233/JAD-171008

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 1173-1189, 2018

Authors: Kapadia, Minesh | Mian, M. Firoz | Michalski, Bernadeta | Azam, Amber B. | Ma, Donglai | Salwierz, Patrick | Christopher, Adam | Rosa, Elyse | Zovkic, Iva B. | Forsythe, Paul | Fahnestock, Margaret | Sakic, Boris

Article Type: Research Article

Abstract: The triple-transgenic (3xTg-AD) mouse strain is a valuable model of Alzheimer’s disease (AD) because it develops both amyloid-β (Aβ) and tau brain pathology. However, 1-year-old 3xTg-AD males no longer show plaques and tangles, yet early in life they exhibit diverse signs of systemic autoimmunity. The current study aimed to address whether females, which exhibit more severe plaque/tangle pathology at 1 year of age, show similar autoimmune phenomena and if so, whether these immunological changes coincide with prodromal markers of AD pathology, markers of learning and memory formation, and epigenetic markers of neurodegenerative disease. Six-month-old 3xTg-AD and wild-type mice of both …sexes were examined for T-cell phenotype (CD3+ , CD8+ , and CD4+ populations), serological measures (autoantibodies, hematocrit), soluble tau/phospho-tau and Aβ levels, brain-derived neurotrophic factor (BDNF) expression, and expression of histone H2A variants. Although no significant group differences were seen in tau/phospho-tau levels, 3xTg-AD mice had lower brain mass and showed increased levels of soluble Aβ and downregulation of BDNF expression in the cortex. Splenomegaly, depleted CD+ T-splenocytes, increased autoantibody levels and low hematocrit were more pronounced in 3xTg-AD males than in females. Diseased mice also failed to exhibit sex-specific changes in histone H2A variant expression shown by wild-type mice, implicating altered nucleosome composition in these immune differences. Our study reveals that the current 3xTg-AD model is characterized by systemic autoimmunity that is worse in males, as well as transcriptional changes in epigenetic factors of unknown origin. Given the previously observed lack of plaque/tangle pathology in 1-year-old males, an early, sex-dependent autoimmune mechanism that interferes with the formation and/or deposition of aggregated protein species is hypothesized. These results suggest that more attention should be given to studying sex-dependent differences in the immunological profiles of human patients. Show more

Keywords: 3xTg-AD mice, Alzheimer’s disease, autoantibodies, BDNF, histone variants, protective autoimmunity, soluble amyloid-beta, tau protein, T-lymphocytes

DOI: 10.3233/JAD-170779

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 1191-1205, 2018

Article Type: Correction

DOI: 10.3233/JAD-189002

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 1207-1207, 2018