Journal of Alzheimer's Disease - Volume 79, issue 2

Authors: Bascuñana, Pablo | Brackhan, Mirjam | Pahnke, Jens

Article Type: Research Article

Abstract: Background: Detailed pathology analysis and morphological quantification is tedious and prone to errors. Automatic image analysis can help to increase objectivity and reduce time. Here, we present the evaluation of the DeePathology STUDIO™ for automatic analysis of histological whole-slide images using machine learning/artificial intelligence. Objective: To evaluate and validate the use of DeePathology STUDIO for the analysis of histological slides at high resolution. Methods: We compared the DeePathology STUDIO and our current standard method using macros in AxioVision for the analysis of amyloid-β (Aβ) plaques and microglia in APP-transgenic mice at different ages. We analyzed density …variables and total time invested with each approach. In addition, we correlated Aβ concentration in brain tissue measured by ELISA with the results of Aβ staining analysis. Results: DeePathology STUDIO showed a significant decrease of the time for establishing new analyses and the total analysis time by up to 90%. On the other hand, both approaches showed similar quantitative results in plaque and activated microglia density in the different experimental groups. DeePathology STUDIO showed higher sensitivity and accuracy for small-sized plaques. In addition, DeePathology STUDIO allowed the classification of plaques in diffuse- and dense-packed, which was not possible with our traditional analysis. Conclusion: DeePathology STUDIO substantially reduced the effort needed for a new analysis showing comparable quantitative results to the traditional approach. In addition, it allowed including different objects (categories) or cell types in a single analysis, which is not possible with conventional methods. Show more

Keywords: Alzheimer’s disease, amyloid-β , artificial intelligence, automated detection, histology, machine learning, microglia activation, quantification

DOI: 10.3233/JAD-201120

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 597-605, 2021

Authors: Wang, Xiuzhe | Miao, Zhijuan | Xu, Xiaofeng | Schultzberg, Marianne | Zhao, Yuwu

Article Type: Research Article

Abstract: Background: Specialized pro-resolving mediators (SPMs) are bioactive lipids derived from n-3 and n-6 polyunsaturated fatty acids. SPMs promote resolution of inflammation and are reduced in Alzheimer’s disease. It is unknown whether SPMs are associated with post-stroke cognitive impairment (PSCI). Objective: In the present report, we aimed to study the levels of SPMs in PSCI patients in the acute phase of ischemic stroke. Methods: Levels of SPMs in the plasma from 36 patients with PSCI and 33 patients with post-stroke non-cognitive impairment (PSNCI) were measured by enzyme immunoassay. Results: We found that levels of the …SPM lipoxin A4 (LXA4 ) were significantly reduced in PSCI patients compared with PSNCI patients. Interestingly, the LXA4 levels were positively correlated with Mini-Mental State Examination scores, but not with the National Institutes of Health Stroke Scale scores. Such alteration and correlation were not found in any of the other SPMs analyzed, i.e., including resolvin D1, resolvin D2, and maresin 1. Conclusion: We conclude that the plasma levels of LXA4 were reduced in PSCI patents in the acute phase of ischemic stroke and were correlated to cognitive function. Show more

Keywords: Lipoxin, maresin, post-stroke cognitive impairment, resolution of inflammation, resolvin

DOI: 10.3233/JAD-201050

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 607-613, 2021

Authors: Ailshire, Jennifer | Walsemann, Katrina M.

Article Type: Research Article

Abstract: Background: Air pollution is linked to worse cognitive function in older adults, but whether differences in this relationship exist by education, a key risk factor for cognitive decline, remains unknown. Objective: To determine if the association between fine particulate matter air pollution (PM2.5 ) and incident cognitive impairment varies by level of education in two cohorts assessed a decade apart. Methods: We used data on adults ages 60 and older from the nationally representative Health and Retirement Study (HRS) linked with tract-level annual average PM2.5 . We used mixed-effects logistic regression models to examine education differences …in the association between PM2.5 and incident cognitive impairment in two cohorts: 2004 (n  = 9,970) and 2014 (n  = 9,185). Cognitive impairment was determined with tests of memory and processing speed for self-respondents and proxy and interviewer assessments of cognitive functioning in non-self-respondents. Results: PM2.5 was unrelated to incident cognitive impairment among those with 13 or more years of education, but the probability of impairment increased with greater concentrations of PM2.5 among those with 8 or fewer years of education. The interaction between education and PM2.5 was only found in 2004, possibly because PM2.5 concentrations were much lower in 2014. Conclusion: Education is a key determinant of cognitive decline and impairment, and in higher pollution contexts may serve as a protective factor against the harms of air pollution on the aging brain. Additionally, because air pollution is ubiquitous, and particularly harmful to vulnerable populations, even small improvements in air quality may have large impacts on population health. Show more

Keywords: Aging, air pollution, cognition, dementia, education, modifiable risk factors

DOI: 10.3233/JAD-200765

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 615-625, 2021

Authors: Hasegawa, Kazuko | Kochi, Kenji | Maruyama, Hidenori | Konishi, Osamu | Toya, Shunji | Odawara, Toshinari

Article Type: Research Article

Abstract: Background: Although previous phase II and III clinical trials conducted in Japan showed that zonisamide improved parkinsonism in patients with dementia with Lewy bodies (DLB), some differences in efficacy outcomes were observed between the trials. Objective: We aimed to further examine the efficacy and safety of zonisamide in DLB patients with parkinsonism in a post hoc analysis of pooled data from the previous phase II and III trials. Methods: Both trials featured a 4-week run-in period followed by a 12-week treatment period with a double-blind, placebo-controlled, parallel-group, randomized, multicenter trial design. In our pooled analysis, …the primary outcome was the change in Unified Parkinson’s Disease Rating Scale (UPDRS) part III total score. Other outcomes included the changes in Mini-Mental State Examination (MMSE) and Neuropsychiatric Inventory-10 (NPI-10) scores, and the incidence of adverse events. Results: Zonisamide significantly decreased the UPDRS part III total and individual motor symptom scores but did not affect the MMSE or NPI-10 scores at week 12. There was no difference in the incidence of adverse events between the zonisamide and placebo groups except for decreased appetite, which had an increased frequency in the zonisamide 50 mg group compared with placebo. Conclusion: Our findings indicate that zonisamide improved parkinsonism with DLB without deterioration of cognitive function and or worsening behavioral and psychological symptoms of dementia. Show more

Keywords: Dementia, lewy bodies, parkinsonism, zonisamide

DOI: 10.3233/JAD-200893

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 627-637, 2021

Authors: Ibi, Daisuke | Hirashima, Kazuki | Kojima, Yuya | Sumiya, Kahori | Kondo, Sari | Yamamoto, Mirai | Ando, Toshihiro | Hiramatsu, Masayuki

Article Type: Research Article

Abstract: Background: The deposition of amyloid-β (Aβ) and hyperphosphorylation of tau are well-known as the pathophysiological features of Alzheimer’s disease (AD), leading to oxidative stress and synaptic deficits followed by cognitive symptoms. We already demonstrated that betaine (glycine betaine) prevented cognitive impairment and hippocampal oxidative stress in mice intracerebroventricularly injected with an active fragment of Aβ, whereas the effect of betaine in chronic models of AD remains unknown. Objective: Our objective was to investigate the effects of chronic betaine intake on cognitive impairment and aberrant expression of genes involved in synapse and antioxidant activity in the hippocampus of a …genetic AD model. Methods: We performed cognitive tests and RT-PCR in the hippocampus in 3xTg mice, a genetic AD model. Results: Cognitive impairment in the Y-maze and novel object recognition tests became evident in 3xTg mice at 9 months old, and not earlier, indicating that cognitive impairment in 3xTg mice developed age-dependently. To examine the preventive effect of betaine on such cognitive impairment, 3xTg mice were fed betaine-containing water for 3 months from 6 to 9 months old, and subsequently subjected to behavioral tests, in which betaine intake prevented the development of cognitive impairment in 3xTg mice. Additionally, the expression levels of genes involved in synapse and antioxidant activity were downregulated in hippocampus of 3xTg mice at 9 months old compared with age-matched wild-type mice, which were suppressed by betaine intake. Conclusion: Betaine may be applicable as an agent preventing the progression of AD by improving the synaptic structure/function and/or antioxidant activity. Show more

Keywords: Alzheimer’s disease, betaine, cognitive function, hippocampus

DOI: 10.3233/JAD-200972

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 639-652, 2021

Authors: Chen, Guanqun | Zhao, Mingyan | Yang, Kun | Lin, Hua | Han, Chunlei | Wang, Xiaoni | Han, Ying

Article Type: Research Article

Abstract: Background: Education plays a potential important effect on the prevalence and incidence of dementia. However, most of the evidence based on convenience sampling. Objective: To explore effects of education on cognition in individuals with subjective cognitive decline (SCD) and cognitive impairment (CI) from a population-based study. Methods: We examined the effect of education on cognition among individuals with SCD (n  = 451) and CI (n  = 280) from a population-based study. A series of neuropsychological tests of memory, executive, language, and general cognitive function were used to assess the participants. Results: Multiple regression analyses revealed that …education has a positive effect on cognition in both SCD and CI group in the population-based research. Further stratification study showed that the beneficial effect of education remains in the SCD group regardless of the education level, especially in the SCD participants with a low education level. However, that effect of education exists in the CI group with a low education level and disappears in the high education level. Conclusion: These results from a population-based sample suggest that high educational attainment may delay cognitive decline in the individuals with SCD regardless of high or low educational level, and high education only predicts cognition in those in the low educational level in CI group. Show more

Keywords: Alzheimer’s disease, cognitive reserve, dementia, education, mild cognitive impairment, subjective cognitive decline

DOI: 10.3233/JAD-201170

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 653-661, 2021

Authors: Teipel, Stefan J. | Temp, Anna Gesine Marie | Levin, Fedor | Dyrba, Martin | Grothe, Michel J. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: TAR DNA-binding protein 43 (TDP-43) has been recognized as a frequent co-pathology of Alzheimer’s disease (AD). The effect of the presence of TDP-43 pathology on in vivo measures of AD-related amyloid pathology using amyloid sensitive PET is still unresolved. Objective: To study the association of TDP-43 pathology with antemortem amyloid PET signal. Methods: We studied 30 cases from the ADNI autopsy sample with available ratings of presence of TDP-43 and antemortem amyloid sensitive 18 F-FlorbetapirPET. We used Bayesian regression to determine the effect of TDP-43 on global and regional amyloid PET signal. In a …post-hoc analysis, we assessed the association of TDP-43 pathology with antemortem memory performance. Results: We found substantial to strong evidence for a negative effect of TDP-43 (Bayes factor against the null model (BF10 ) = 9.0) and hippocampal sclerosis (BF10  = 6.4) on partial volume corrected hippocampal 18 F-Florbetapir uptake. This effect was only partly mediated by the negative effect of TDP-43 on hippocampal volume. In contrast, Bayesian regression supported that there is no effect of TDP-43 on global cortical PET-signal (BF10  = 0.65). We found an anecdotal level of evidence for a negative effect of TDP-43 pathology on antemortem memory performance after accounting for global amyloid PET signal (BF10  = 1.6). Conclusion: Presence of TDP-43 pathology does not confound the global amyloid PET-signal but has a selective effect on hippocampal PET-signal that appears only partially dependent on TDP-43 mediated atrophy. Show more

Keywords: Amyloid pathology, florbetapir PET, hippocampal sclerosis, hippocampal volume, memory, TAR DNA-binding protein 43

DOI: 10.3233/JAD-201032

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 663-670, 2021

Authors: Petersen, Melissa E. | Rafii, Michael S. | Zhang, Fan | Hall, James | Julovich, David | Ances, Beau M. | Schupf, Nicole | Krinsky-McHale, Sharon J. | Mapstone, Mark | Silverman, Wayne | Lott, Ira | Klunk, William | Head, Elizabeth | Christian, Brad | Foroud, Tatiana | Lai, Florence | Diana Rosas, H. | Zaman, Shahid | Wang, Mei-Cheng | Tycko, Benjamin | Lee, Joseph H. | Handen, Benjamin | Hartley, Sigan | Fortea, Juan | O’Bryant, Sid | for the Alzheimer’s Biomarker Consortium –Down Syndrome (ABC-DS)

Article Type: Research Article

Abstract: Background: The need for diagnostic biomarkers of cognitive decline is particularly important among aging adults with Down syndrome (DS). Growing empirical support has identified the utility of plasma derived biomarkers among neurotypical adults with mild cognitive impairment (MCI) and Alzheimer’s disease (AD); however, the application of such biomarkers has been limited among the DS population. Objective: This study aimed to investigate the cross-sectional diagnostic performance of plasma neurofilament light chain (Nf-L) and total-tau, individually and in combination among a cohort of DS adults. Methods: Plasma samples were analyzed from n  = 305 (n  = 225 cognitively stable (CS); …n  = 44 MCI-DS; n  = 36 DS–AD) participants enrolled in the Alzheimer’s Biomarker Consortium —Down Syndrome. Results: In distinguishing DS-AD participants from CS, Nf-L alone produced an AUC of 90%, total-tau alone reached 74%, and combined reached an AUC of 86%. When age and gender were included, AUC increased to 93%. Higher values of Nf-L, total-tau, and age were all shown to be associated with increased risk for DS-AD. When distinguishing MCI-DS participants from CS, Nf-L alone produced an AUC of 65%, while total-tau alone reached 56%. A combined model with Nf-L, total-tau, age, and gender produced an AUC of 87%. Both higher values in age and total-tau were found to increase risk for MCI-DS; Nf-L levels were not associated with increased risk for MCI-DS. Conclusion: Advanced assay techniques make total-tau and particularly Nf-L useful biomarkers of both AD pathology and clinical status in DS and have the potential to serve as outcome measures in clinical trials for future disease-modifying drugs. Show more

Keywords: Neurofilament light chain, proteomics, sensitivity, specificity, total-tau, trisomy 21

DOI: 10.3233/JAD-201167

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 671-681, 2021

Authors: Tagliapietra, Matteo | Frasson, Emma | Cardellini, Davide | Mariotto, Sara | Ferrari, Sergio | Zanusso, Gianluigi | Plebani, Mauro | Monaco, Salvatore

Article Type: Research Article

Abstract: Background: Anti-IgLON5 disease is a rare neurodegenerative tauopathy that displays heterogeneity in clinical spectrum, disease course, cerebrospinal fluid (CSF) findings, and variable response to immunotherapy. Sleep disorders, bulbar dysfunction, and gait abnormalities are common presenting symptoms, and conventional brain MRI scanning is often unrevealing. Objective: To provide a comprehensive overview of the literature and to assess the frequency of symptoms, MRI findings, and treatment response in patients with IgLON5 autoimmunity in the serum and CSF or restricted to serum. Methods: We examined a 65-year-old woman with bulbar-onset IgLON5 disease with serum-restricted antibodies, and we also performed …a systematic review of all confirmed cases reported in the English literature. Results: We identified 93 patients, included our case. Clinical data were obtained in 58 subjects, in whom the most frequent symptoms were sleep-disordered breathing, dysphagia, parasomnias, dysarthria, limb or gait ataxia, stridor or vocal cord paresis, movement disorders, and postural instability. Distinct MRI alterations were identified in 12.5% of cases, as opposed to unspecific or unremarkable changes in the remaining patients. T2-hyperintense non-enhancing signal alterations involving the hypothalamus and the brainstem tegmentum were observed only in the present case. Inflammatory CSF was found in half of the cases and serum-restricted antibodies in 4 patients. Treatment with immunosuppressant or immunomodulatory drugs led to sustained clinical response in 19/52 patients. Conclusion: Anti-IgLON5 autoimmunity should be considered in patients with sleep disorders, bulbar syndrome, autonomic involvement, and movement disorders, and high-field brain MRI can be of diagnostic help. Show more

Keywords: Anti-IgLON5 disease, autoimmune encephalitis, biomarkers, brain/diagnostic imaging, cerebrospinal fluid, stridor, tauopathy

DOI: 10.3233/JAD-201105

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 683-691, 2021

Authors: Keenan, Ryan J. | Oberrauch, Sara | Bron, Romke | Nowell, Cameron J. | Challis, Leesa M. | Hoyer, Daniel | Jacobson, Laura H.

Article Type: Research Article

Abstract: Background: Sleep/wake disturbances (e.g., insomnia and sleep fragmentation) are common in neurodegenerative disorders, especially Alzheimer’s disease (AD) and frontotemporal dementia (FTD). These symptoms are somewhat reminiscent of narcolepsy with cataplexy, caused by the loss of orexin-producing neurons. A bidirectional relationship between sleep disturbance and disease pathology suggests a detrimental cycle that accelerates disease progression and cognitive decline. The accumulation of brain tau fibrils is a core pathology of AD and FTD-tau and clinical evidence supports that tau may impair the orexin system in AD/FTD. This hypothesis was investigated using tau mutant mice. Objective: To characterize orexin receptor mRNA …expression in sleep/wake regulatory brain centers and quantify noradrenergic locus coeruleus (LC) and orexinergic lateral hypothalamus (LH) neurons, in tau transgenic rTg4510 and tau–/– mice. Methods: We used i n situ hybridization and immunohistochemistry (IHC) in rTg4510 and tau–/– mice. Results: rTg4510 and tau–/– mice exhibited a similar decrease in orexin receptor 1 (OX1 R) mRNA expression in the LC compared with wildtype controls. IHC data indicated this was not due to decreased numbers of LC tyrosine hydroxylase-positive (TH) or orexin neurons and demonstrated that tau invades TH LC and orexinergic LH neurons in rTg4510 mice. In contrast, orexin receptor 2 (OX2 R) mRNA levels were unaffected in either model. Conclusion: The LC is strongly implicated in the regulation of sleep/wakefulness and expresses high levels of OX1 R. These findings raise interesting questions regarding the effects of altered tau on the orexin system, specifically LC OX1 Rs, and emphasize a potential mechanism which may help explain sleep/wake disturbances in AD and FTD. Show more

Keywords: Alzheimer’s disease, frontotemporal dementia, in situ hybridization, locus coeruleus, orexin, orexin receptor, rTg4510, sleep, tau

DOI: 10.3233/JAD-201177

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 693-708, 2021