Journal of Alzheimer's Disease - Volume 71, issue 4

Authors: Hashimoto, Masakazu | Yamazaki, Akira | Ohno, Atsushi | Kimura, Toru | Winblad, Bengt | Tjernberg, Lars O.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease without a cure. The pathological process starts decades before clinical onset, and thus clinical trials of drugs aimed at treating AD should start at a presymptomatic stage. Therefore, it is critical to diagnose AD at an early stage. Tau, phosphorylated tau, and amyloid-β peptide (Aβ) in cerebrospinal fluid (CSF), and positron emission tomography (PET) imaging of Aβ or tau accumulation are supportive biomarkers for AD diagnosis, but there is no reliable presymptomatic diagnostic marker. Since CSF sampling is invasive, and PET imaging is expensive and available only at specialized centers, a reliable …blood biomarker has long been sought for. Here we describe a novel extramembrane fragment from solute carrier family 38 member 10 (SLC38A10, S38AA) that we found to be decreased in pyramidal neurons in AD cases by proteomics and immunohistochemical analysis. We detected a S38AA fragment in CSF and found the levels to correlate with severity of AD and APOE genotype. Importantly, the plasma levels of the fragment also showed a significant correlation with Mini-Mental State Examination scores in AD. Moreover, plasma from other neurodegenerative disease was analyzed and the fragment was found to be increased specifically in AD. Interestingly, the fragment is detected in mouse, rat, and monkey, and increases in amyloid precursor protein transgenic mice as the AD-like pathology progresses. We propose that the S38AA fragment in plasma could be a novel quantitative diagnostic marker for AD and potentially a marker of disease progression in AD. Show more

Keywords: Alzheimer’s disease, APOE, cerebrospinal fluid, diagnosis, mouse, neurodegenerative disease, plasma

DOI: 10.3233/JAD-190700

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1163-1174, 2019

Authors: Guo, Zongjun | Peng, Xing | Li, Hui-Yun | Wang, Yunlai | Qian, Ying | Wang, Zhihong | Ye, Dongqing | Ji, Xiaoyun | Wang, Zhixin | Wang, Yanjiang | Chen, Dongwan | Lei, Hongxing

Article Type: Research Article

Abstract: Immune dysregulation has been observed in the brain and blood of patients with Alzheimer’s disease (AD). However, a convenient assay to evaluate peripheral immune dysregulation in AD has not been developed, partly due to the inconsistent observations from different studies. We hypothesized that peripheral immune dysregulation may only exist in a subpopulation of AD patients; therefore it may be valuable to identify this subpopulation with a convenient assay. Along this line, we selected 14 candidate genes based on our analysis of microarray data on peripheral blood of AD and other diseases. We used RT-qPCR to examine the expression of these …14 genes in a cohort of 288 subjects, including 74 patients with AD, 64 patients with mild cognitive impairment (MCI), 51 patients with vascular dementia (VaD), and 99 elderly controls with no cognitive dysfunction/impairment. Seven of these 14 genes displayed significant difference in group comparison. Switching from group comparison to individualized evaluation revealed more in-depth information. First, there existed a wide dynamic range for the expression of these immune genes in peripheral blood even within the control group. Second, for the vast majority of the patients (AD, VaD, and MCI patients), the expression of these genes fell within the dynamic range of the control group. Third, a small portion of outliers were observed in the patient groups, more so in the VaD group than that in the AD or MCI groups. This is our first attempt to conduct personalized evaluation of peripheral immune dysregulation in AD and VaD. These findings may be applicable to the identification of peripheral immune dysregulation in AD and VaD patients which may lead to tailored treatment toward those patients. Show more

Keywords: Alzheimer’s disease, immune dysregulation, peripheral blood, precision medicine, vascular dementia

DOI: 10.3233/JAD-190666

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1175-1186, 2019

Authors: Yokoyama, Shunichi | Yoshinaga, Takuma | Matsuzaki, Juntaro | Suzuki, Hidekazu

Article Type: Research Article

Abstract: Background: Teprenone (geranylgeranylacetone), an anti-ulcer agent, has been reported to inhibit amyloid-β increase, senile plaque formation, and neuronal degeneration, and improve memory in mouse models of Alzheimer’s disease (AD). Objective: We conducted a randomized, double-blind, placebo-controlled study to ascertain teprenone’s therapeutic ability for AD. Methods: Patients with mild to moderate AD, with a Mini-Mental State Examination (MMSE) score of 13 to 26, were randomly allocated into two groups depending on the administered drug: donepezil +  placebo (placebo group) and donepezil + teprenone (teprenone group). The primary and secondary endpoints included changes in scores of the Japanese version of …the AD Assessment Scale-cognitive subscale (ADAS-J cog) and other evaluations, respectively, including MMSE scores, during a 12-month period after the first administration. Results: Forty-two and thirty-seven patients were allocated to the teprenone and placebo groups, respectively. ADAS-J cog score changes were not different between groups (placebo, 0.6±0.8; teprenone, 0.4±0.8; p  = 0.861). However, MMSE scores significantly improved in the teprenone group (placebo, – 1.2±0.5; teprenone, 0.2±0.5; p  = 0.044). Subgroup analysis considering the severity of medial temporal area atrophy revealed that this improvement by teprenone was significant in patients with mild (p  = 0.013) but not with severe atrophy (p  = 0.611). Adverse events were observed in 17.8 and 10.4% of patients in the placebo and teprenone group, respectively. Conclusion: Teprenone may be effective for AD when administered before atrophy progression in the medial temporal areas. Trial Registration: UMIN ID: UMIN000016843 Show more

Keywords: Alzheimer’s disease, dementia, donepezil, drug repositioning, geranylgeranylacetone

DOI: 10.3233/JAD-190305

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1187-1199, 2019

Authors: Iliadou, Paraskevi | Kladi, Anastasia | Frantzidis, Christos A. | Gilou, Sotiria | Tepelena, Ioanna | Gialaouzidis, Moses | Papaliagkas, Vasileios | Nigdelis, Vasilis | Nday, Christiane M. | Kiosseoglou, Grigorios | Papantoniou, Georgia | Bamidis, Panagiotis D. | Tsolaki, Magda | Moraitou, Despina

Article Type: Research Article

Abstract: Leading theories of affect development and empirical studies suggest that emotion can enhance memory in older adults. Destination memory which is defined as the ability to remember to whom we told a piece of information is being found to be compromised in aging. In the present study, we sought to assess destination memory using emotional stimuli (Emotional Destination Memory, EDM) in 16 older adults with mild cognitive impairment (MCI) and 16 healthy controls and shed light onto its potential neurophysiological aspects. We measured Mu suppression in frontal and temporal regions via EEG in real time while participants performed the task …of EDM. Results showed no group differences in task performance but significant differences in fronto-temporal activations, specifically in electrodes F7 and F8. Differential Mu rhythm pattern was observed between healthy controls and MCI with the first exhibiting Mu suppression and the last Mu enhancement. Furthermore, Mu enhancement in temporal electrodes within the MCI group was associated with lower scores on EDM. The absence of group differences in the task can be explained by the fact that even if there are underlying structural or functional deficits in the MCI group, these deficits are manifested only at neurophysiological level and not at a behavioral level, which is a common pattern in the process of cognitive decline in its initial phases. The overall findings reveal that, even if there are not any behavioral decrements in MCI patients, they show reduced activations in fronto-temporal regions and this can be attributed to general impairment in emotional destination memory due to possible mirror neuron deficiency. Show more

Keywords: Emotional destination memory, fronto-temporal, mild cognitive impairment, mirror neurons, Mu suppression

DOI: 10.3233/JAD-190311

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1201-1215, 2019

Authors: Patra, Kalicharan | Giannisis, Andreas | Edlund, Anna K. | Sando, Sigrid Botne | Lauridsen, Camilla | Berge, Guro | Grøntvedt, Gøril Rolfseng | Bråthen, Geir | White, Linda R. | Nielsen, Henrietta M.

Article Type: Research Article

Abstract: The APOE ɛ 4 gene variant is the strongest genetic risk factor for Alzheimer’s disease (AD), whereas APOE ɛ 3 conventionally is considered as ‘risk neutral’ although APOE ɛ 3-carriers also develop AD. Previous studies have shown that the apolipoprotein E3 (apoE3) isoform occurs as monomers, homodimers and heterodimers with apolipoprotein A-II in human body fluids and brain tissue, but the relevance of a plasma apoE3 monomer/dimer profile to AD is unknown. Here we assessed the distribution of monomers, homodimers and heterodimers in plasma from control subjects and patients with mild cognitive impairment (MCI) and AD with …either a homozygous APOE ɛ 3 (n  = 31 control subjects, and n  = 14 MCI versus n  = 5 AD patients) or APOE ɛ 4 genotype (n  = 1 control subject, n  = 21 MCI and n  = 7 AD patients). Total plasma apoE levels were lower in APOE ɛ 4-carriers and overall correlated significantly to CSF Aβ42 , p(Thr181)-tau and t-tau levels. Apolipoprotein E dimers were only observed in the APOE ɛ 3-carriers and associated with total plasma apoE levels, negatively correlated to apoE monomers, but were unrelated to plasma homocysteine levels. Importantly, the APOE ɛ 3-carrying AD patients versus controls exhibited a significant decrease in apoE homodimers (17.8±9.6% versus 26.7±6.3%, p  = 0.025) paralleled by an increase in apoE monomers (67.8±18.3% versus 48.5±11.2%, p  = 0.008). In the controls, apoE monomers and heterodimers were significantly associated with plasma triglycerides; the apoE heterodimers were also associated with levels of high-density lipoprotein cholesterol. The physiological relevance of apoE dimer formation needs to be further investigated, though the distribution of apoE in monomers and dimers appears to be of relevance to AD in APOE ɛ 3 subjects. Show more

Keywords: Alzheimer’s disease, apolipoprotein A-II, apolipoprotein E, biomarkers, dementia, dimers

DOI: 10.3233/JAD-190175

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1217-1231, 2019

Authors: Luikku, Antti J. | Hall, Anette | Nerg, Ossi | Koivisto, Anne M. | Hiltunen, Mikko | Helisalmi, Seppo | Herukka, Sanna-Kaisa | Junkkari, Antti | Sutela, Anna | Kojoukhova, Maria | Korhonen, Ville | Mattila, Jussi | Lötjönen, Jyrki | Rummukainen, Jaana | Alafuzoff, Irina | Jääskeläinen, Juha E. | Remes, Anne M. | Solomon, Alina | Kivipelto, Miia | Soininen, Hilkka | Rauramaa, Tuomas | Leinonen, Ville

Article Type: Research Article

Abstract: Background: Idiopathic normal pressure hydrocephalus (iNPH) patients often develop Alzheimer’s disease (AD) related brain pathology. Disease State Index (DSI) is a method to combine data from various sources for differential diagnosis and progression of neurodegenerative disorders. Objective: To apply DSI to predict clinical AD in shunted iNPH-patients in a defined population. Methods: 335 shunted iNPH-patients (median 74 years) were followed until death (n  = 185) or 6/2015 (n  = 150). DSI model (including symptom profile, onset age of NPH symptoms, atrophy of medial temporal lobe in CT/MRI, cortical brain biopsy finding, and APOE genotype) was applied. Performance …of DSI model was evaluated with receiver operating characteristic (ROC) curve analysis. Results: A total of 70 (21%) patients developed clinical AD during median follow-up of 5.3 years. DSI-model predicted clinical AD with moderate effectiveness (AUC = 0.75). Significant factors were cortical biopsy (0.69), clinical symptoms (0.66), and medial temporal lobe atrophy (0.66). Conclusion: We found increased occurrence of clinical AD in previously shunted iNPH patients as compared with general population. DSI supported the prediction of AD. Cortical biopsy during shunt insertion seems indicated for earlier diagnosis of comorbid AD. Show more

Keywords: Alzheimer’s disease, computer-assisted diagnosis, normal pressure hydrocephalus, Data and results has been partly presented as an abstract at Hydrocephalus 2017, Kobe, Japan

DOI: 10.3233/JAD-190334

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1233-1243, 2019

Authors: Ledreux, Aurélie | Håkansson, Krister | Carlsson, Roger | Kidane, Mhretab | Columbo, Laura | Terjestam, Yvonne | Ryan, Eliza | Tusch, Erich | Winblad, Bengt | Daffner, Kirk | Granholm, Ann-Charlotte | Mohammed, Abdul Kadir H.

Article Type: Research Article

Abstract: Previous studies have indicated that an active lifestyle is associated with better brain health and a longer life, compared to a more sedentary lifestyle. These studies, both on human and animal subjects, have typically focused on a single activity, usually physical exercise, but other activities have received an increasing interest. One proposed mechanism is that physical exercise increases levels of brain-derived neurotrophic factor (BDNF) in the brain. For the first time, the long-term effects on serum BDNF levels were compared in persons who engaged in either physical exercise training, cognitive training, or mindfulness practice during 5 weeks, and compared with …an active control group. Two cohorts of healthy older individuals, one from the Boston area in the US and one from the Växjö area in Sweden, participated. A total of 146 participants were randomly assigned to one of the four groups. All interventions were structurally similar, using interactive, computer-based software that directed participants to carry out specified activities for 35 minutes/day, 5 days per week for 5 weeks. Blood samples were obtained at baseline and soon after the completion of the 5-week long intervention program, and serum BDNF levels were measured using a commercially available ELISA. Only the group that underwent cognitive training increased their serum BDNF levels after 5 weeks of training (F1,74  = 4.22, p  = 0.044, partial η 2  = 0.054), corresponding to an average 10% increase. These results strongly suggest that cognitive training can exert beneficial effects on brain health in an older adult population. Show more

Keywords: Aging, brain-derived neurotrophic factor, cognitive training, mindfulness, physical exercise

DOI: 10.3233/JAD-190756

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1245-1261, 2019

Authors: Chanteloup, Gäetan | Cordonnier, Marine | Moreno-Ramos, Teresa | Pytel, Vanesa | Matías-Guiu, Jorge | Gobbo, Jessica | Cabrera-Martín, María Nieves | Gómez-Pinedo, Ulises | Garrido, Carmen | Matías-Guiu, Jordi A.

Article Type: Research Article

Abstract: We aimed to study the expression of circulating heat-shock protein HSP70 and exosomes in plasma of a cohort of patients with Alzheimer’s disease (AD) and frontotemporal dementia (FTD) at different stages. We performed correlations with clinical scales and FDG-PET. HSP70 levels were higher within exosomes than free in plasma. Moderate correlations were found between exosomal HSP70 and CDR, FTLD-CDR, and extension of hypometabolism. Our results suggest modifications in the level of exosomal HSP70 during the course of neurodegeneration, regardless of AD or FTD, and therefore HSP70 could have a potential role in the follow-up of these disorders.

Keywords: Alzheimer’s disease, biomarkers, exosomes, frontotemporal dementia, PET

DOI: 10.3233/JAD-190545

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1263-1269, 2019

Authors: Lamar, Melissa | León, Adeline | Romo, Karina | Durazo-Arvizu, Ramon A. | Sachdeva, Shruti | Lipton, Richard B. | Perreira, Krista M. | Gallo, Linda C. | Cai, Jianwen | Khambaty, Tasneem | Carrasco, Jessica | Llabre, Maria M. | Eyler, Lisa T. | Daviglus, Martha L. | González, Hector M.

Article Type: Research Article

Abstract: Sixty percent of Hispanics/Latinos are bilingual which research suggests may confer certain cognitive advantages. Female sex confers cognitive advantages in verbal learning and memory compared to male sex, regardless of race or ethnicity. Understanding the independent and interactive associations of bilingualism and sex with cognition may aid in predicting cognitive aging in Hispanics/Latinos. We examined baseline (2008–2011) data from the Hispanic Community Health Study/Study of Latinos, a multicenter, prospective community-based study. Our analyses included 6,110 males and females ≥45 years old who self-reported birth and parents’ origin outside of the continental US, Spanish as their first language, and were evaluated …in Spanish. Bilingualism was assessed along a Likert scale (1 = only Spanish to 4 = English>Spanish) for language proficiency (reading/spoken) and patterns of use (thinking/socializing). Cognitive testing included verbal learning, memory, fluency, and Digit Symbol Substitution (DSS). Linear regression models adjusted for relevant confounders, the complex survey design, and sampling weights. Participants’ self-reported language proficiency was Spanish better than English, while patterns of use suggested more Spanish than English. Higher language proficiency was associated with higher performance on all cognitive indices while higher patterns of use associated with higher fluency and DSS scores (p -values < 0.01). Female sex was associated with higher performance on all cognitive indices (p -values < 0.05). There were no significant interactions with bilingualism (regardless of metric) by sex on cognition. For Hispanics/Latinos residing in the continental US and reporting birth and parents’ origin elsewhere, bilingualism and female sex have independent cognitive benefits that are important to consider when evaluating cognitive performance. Show more

Keywords: Bilingualism, cognition, Hispanics/Latinos, memory, serial learning, sex differences

DOI: 10.3233/JAD-190019

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1271-1283, 2019

Authors: Suarez-Gonzalez, Aida | Ocal, Dilek | Pavisic, Ivanna | Peacock, Ashley | Naessens, Michelle | Ahmed, Samrah | Butler, Christopher R. | Leff, Alexander P. | Yong, Keir X.X. | Crutch, Sebastian J.

Article Type: Research Article

Abstract: Background: Progressive reading impairment is an early and debilitating symptom of posterior cortical atrophy (PCA) arising from the progressive deterioration of visual processing skills. Objective: The goal of this study was to test the effectiveness of a purpose-built reading app (ReadClear) co-produced with people living with PCA and designed to reduce the reading difficulties experienced by this population (e.g., getting lost in the page and missing words when reading). Methods: Twenty subjects with PCA were included in a cross-over design home-based study aimed at determining whether ReadClear could 1) enhance the subjective reading experience (reading pleasantness) …and 2) improve reading accuracy (reducing the number of reading errors) compared with a sham condition (a standard e-reader). Results: Reading using ReadClear provided a better subjective reading experience than sham (p  = 0.018, d = 0.5) and significantly reduced the percentage of reading errors (p  < 0.0001, r  = 0.82), particularly errors due to omissions (p  = 0.01, r  = 0.50), repeated words (p  = 0.002, r  = 0.69), and regressions in the text (p  = 0.003, r  = 0.69). We found that different kinds of reading errors were related to specific neuropsychological profiles. Conclusion: ReadClear can assist reading in people living with PCA by reducing the number of reading errors and improving the subjective reading experience of users. Show more

Keywords: Assistive technology, dyslexia, posterior cortical atrophy, reading

DOI: 10.3233/JAD-190335

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1285-1295, 2019