Journal of Alzheimer's Disease - Volume 68, issue 2

Authors: Mandal, Pravat K. | Shukla, Deepika | Tripathi, Manjari | Ersland, Lars

Article Type: Editorial

Abstract: Alzheimer’s disease (AD) is a devastating neurodegenerative disorder affecting millions of people worldwide. The actual cause of AD is still unknown. Oxidative stress is believed to be important player in AD pathology. Glutathione (GSH) is a major antioxidant, and it is already known that GSH is depleted significantly in the hippocampal regions in mild cognitive impairment (MCI) and AD patients compared to healthy old subjects. Hence there is a serious discussion to improve the brain GSH level by supplementation. This editorial highlights the need for GSH supplementation for the cognitive enhancement in MCI and AD.

DOI: 10.3233/JAD-181054

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 531-535, 2019

Authors: Devanarayan, Priya | Devanarayan, Viswanath | Llano, Daniel A. | and for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: The 2018 NIA-AA research framework proposes a classification system with Amyloid-β deposition, pathologic Tau, and Neurodegeneration (ATN) for diagnosis and staging of Alzheimer’s disease (AD). Data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database can be utilized to identify diagnostic signatures for predicting AD progression, and to determine the utility of this NIA-AA research framework. Profiles of 320 peptides from baseline cerebrospinal fluid (CSF) samples of 287 normal, mild cognitive impairment (MCI), and AD subjects followed over a 3–10-year period were measured via multiple reaction monitoring mass spectrometry. CSF Aβ42 , total-Tau (tTau), phosphorylated-Tau (pTau-181), and hippocampal volume were also …measured. From these candidate markers, optimal signatures with decision thresholds to separate AD and normal subjects were first identified via unbiased regression and tree-based algorithms. The best performing signature determined via cross-validation was then tested in an independent group of MCI subjects to predict future progression. This multivariate analysis yielded a simple diagnostic signature comprising CSF pTau-181 to Aβ42 ratio, MRI hippocampal volume, and low CSF levels of a novel PTPRN peptide, with a decision threshold on each marker. When applied to a separate MCI group at baseline, subjects meeting these signature criteria experience 4.3-fold faster progression to AD compared to a 2.2-fold faster progression using only conventional markers. This novel 4-marker signature represents an advance over the current diagnostics based on widely used markers, and is easier to use in practice than recently published complex signatures. This signature also reinforces the ATN construct from the 2018 NIA-AA research framework. Show more

Keywords: Biomarker, mild cognitive impairment, PTPRN, receptor-type tyrosine-phosphatase-like N

DOI: 10.3233/JAD-180905

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 537-550, 2019

Authors: Liu, Jia | Wang, Qianqian | Jing, Donglai | Gao, Ran | Zhang, Jing | Cui, Chunlei | Qiao, Hongwen | Liang, Zhigang | Wang, Chaodong | Rosa-Neto, Pedro | Wu, Liyong | Jia, Jianping | Gauthier, Serge

Article Type: Research Article

Abstract: For early-onset Alzheimer’s disease (EOAD) cases with unclear family history, most cases are sporadic. Some cases are positive in genetic findings, that is, either incomplete penetrance or de novo mutation. We aimed to focus on EOAD cases with de novo mutations. Case reports and literature review were performed. The implication for diagnostic approach of early-onset dementia with negative family history was developed. We reported two Chinese EOAD cases with de novo mutations. The genotype PSEN1 G206S appeared to correlate with the phenotype of EOAD with pure cognitive problems. The second case had a PSEN1 M233V mutation with …an earlier age of onset of 25 with cognitive decline, parkinsonism, and epilepsy. Although EOAD due to de novo mutations is not common, it should be considered in patients with a phenotype of progressive cognitive decline and amyloid positivity on PET or CSF analysis. Show more

Keywords: De novo PSEN1 mutation, diagnostic approach, early-onset Alzheimer’s disease, early-onset dementia with negative family history

DOI: 10.3233/JAD-181108

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 551-558, 2019

Authors: Marjańska, Małgorzata | McCarten, J. Riley | Hodges, James S. | Hemmy, Laura S. | Terpstra, Melissa

Article Type: Research Article

Abstract: This study’s objective was to increase understanding of biological mechanisms underlying clinical Alzheimer’s disease (AD) by noninvasively measuring an expanded neurochemical profile and exploring how well this advanced technology distinguishes AD from cognitively normal controls. We measured concentrations of 14 neurochemicals using ultra-high field (7 T) ultra-short echo time (8 ms) magnetic resonance spectroscopy (MRS) in 16 participants with mild to moderate clinical AD and 33 age- and gender-matched control participants. MRS was localized to the posterior cingulate cortex (PCC), a region known to be impacted by AD, and the occipital cortex (OCC), a control region. Participants with AD were recruited …from dementia specialty clinics. Concentration of the antioxidant ascorbate was higher (p  < 0.0007) in both brain regions. Concentrations of the glial marker myo -inositol and the choline-containing compounds involved in membrane turnover were higher (p ≤0.0004) in PCC of participants with AD. Ascorbate and myo -inositol concentrations were strongly associated, especially in the PCC. Random forests, using the 14 neurochemicals in the two regions, distinguished participants with AD from controls: same-sample sensitivity and specificity were 88% and 97%, respectively, though out-of-sample-values would be lower. Ultra-high field ultra-short echo time MRS identified the co-occurrence of elevated ascorbate and myo -inositol in the PCC as markers that distinguish participants with mild to moderate AD from controls. While elevated myo -inositol may be a surrogate marker of neuroinflammation, the unexpected elevation of the antioxidant ascorbate may reflect infiltration of ascorbate-rich leukocytes. Show more

Keywords: Ascorbate, myo-inositol, neurochemical profile, neuroinflammation, posterior cingulate cortex, ultra-high field, ultra-short echo time

DOI: 10.3233/JAD-180861

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 559-569, 2019

Authors: Tiiman, Ann | Jelić, Vesna | Jarvet, Jüri | Järemo, Petter | Bogdanović, Nenad | Rigler, Rudolf | Terenius, Lars | Gräslund, Astrid | Vukojević, Vladana

Article Type: Research Article

Abstract: Background: Biomarkers are central to current research on molecular mechanisms underlying Alzheimer’s disease (AD). Their further development is of paramount importance for understanding pathophysiological processes that eventually lead to disease onset. Biomarkers are also crucial for early disease detection, before clinical manifestation, and for development of new disease modifying therapies. Objective: The overall aim of this work is to develop a minimally invasive method for fast, ultra-sensitive and cost-effective detection of structurally modified peptide/protein self-assemblies in the peripheral blood and in other biological fluids. Specifically, we focus here on using this method to detect structured amyloidogenic oligomeric aggregates …in the blood serum of apparently healthy individuals and patients in early AD stage, and measure their concentration and size. Methods: Time-resolved detection of Thioflavin T (ThT) fluorescence intensity fluctuations in a sub-femtoliter observation volume element was used to identify in blood serum ThT-active structured amyloidogenic oligomeric aggregates, hereafter called nanoplaques, and measure with single-particle sensitivity their concentration and size. Results: The concentration and size of structured amyloidogenic nanoplaques are significantly higher in the blood serum of individuals diagnosed with AD than in control subjects. Conclusion: A new method with the ultimate, single-particle sensitivity was successfully developed. The proposed approach neither relies on the use of immune-based probes, nor on the use of radiotracers, signal-amplification or protein separation techniques, and provides a minimally invasive test for fast and cost-effective early determination of structurally modified peptides/proteins in the peripheral blood, as shown here, but also in other biological fluids. Show more

Keywords: Alzheimer’s disease, amyloidogenic aggregates, β-pleated sheet, blood serum, early diagnosis, florescence intensity fluctuation analysis, fluorescence correlation spectroscopy, single-molecule sensitivity, Thioflavin T

DOI: 10.3233/JAD-181144

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 571-582, 2019

Authors: Marksteiner, Josef | Oberacher, Herbert | Humpel, Christian

Article Type: Research Article

Abstract: Diagnosis of Alzheimer’s disease (AD) is still a challenge. Salivary analysis could produce an easily accessible and inexpensive possibility to study metabolic changes in AD. In the present pilot study, we show for the first time using targeted metabolomics that acyl-alkyl phosphatidylcholines (PCae C34:1-2; PCae C36:1-2-3; PCaeC38:1c3; PCae C40:2-3) are significantly reduced in saliva of AD patients (n  = 25) compared to healthy controls (n  = 25). Saliva levels of PCae C36Λ 1-2-3) were also decreased in patients with mild cognitive impairment (n  = 25). No changes were seen for saliva diacyl-phosphatidylcholines, lyso-acyl-phosphatidylcholines, and sphinogomyelins. These data suggest specific lipid changes in the …saliva of AD patients, thus salivary measures could establish new biomarkers. However, these preliminary results have to be established in larger scale studies. Show more

Keywords: Alzheimer’s disease, biomarkers, diagnosis, metabolomics, phosphatidylcholines, saliva

DOI: 10.3233/JAD-181278

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 583-589, 2019

Authors: Brett, Benjamin L. | Wilmoth, Kristin | Cummings, Peter | Solomon, Gary S. | McCrea, Michael A. | Zuckerman, Scott L.

Article Type: Research Article

Abstract: This work critically reviews chronic traumatic encephalopathy (CTE), with a specific focus on the single criterion necessary and sufficient for diagnosis. Herein, CTE is compared to other well-established neurodegenerative entities including Alzheimer’s disease and dementia with Lewy bodies. Each neurodegenerative disorder is reviewed in five pertinent areas: 1) historical perspective, 2) guideline formation process, 3) clinical diagnostic criteria, 4) pathological diagnostic criteria, and 5) validation of previously described diagnostic criteria (e.g., sensitivity and specificity). These comparisons indicate that CTE is a disease in the earliest stages of formation and has yet to undergo rigorous development and refinement similar to other …neurodegenerative diseases. Suggested future revisions to the diagnostic criterion of CTE include establishing a lower threshold for accumulation of pathology, as well as accounting for the presence of concomitant neuropathology and comorbid neurodegenerative disorders. Currently, while initial efforts have been attempted, agreed upon antemortem clinical criteria do not exist. As has been the scientific standard with similar neurodegenerative disorders, antemortem diagnostic guidelines should first be refined through subcommittees of neuroscientists from diverse institutional backgrounds with a subclassification of levels of diagnostic certainty (possible, probably, and definite). Validation studies should then assess the predictive value and accuracy of proposed antemortem diagnostic criteria in relation to potential pathological criteria. Show more

Keywords: Chronic traumatic encephalopathy, concussion, football, neurodegenerative diseases, sports, traumatic brain injury

DOI: 10.3233/JAD-181058

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 591-608, 2019

Authors: Ameen-Ali, Kamar E. | Simpson, Julie E. | Wharton, Stephen B. | Heath, Paul R. | Sharp, Paul S. | Brezzo, Gaia | Berwick, Jason

Article Type: Research Article

Abstract: The role of cellular changes in the neurovascular unit is increasingly being investigated to understand the pathogenesis of Alzheimer’s disease (AD). The aim of the current study was to determine the time course of recognition memory impairment in the J20 mouse model of AD, in relation to neuroinflammatory responses and the pathology of amyloid-β (Aβ). Male hAPP-J20 and wild-type mice were assessed at 3, 6, 9, and 12 months of age. The spontaneous object recognition (SOR) task provided a measure of memory, with assessment of both a short delay (1 min) and a long delay (4 h). Immunohistochemistry was used to characterize …Aβ deposition, and quantify astrocyte and microglial responses. At all ages tested, J20 mice had impaired long-term, but preserved short-term, recognition memory. Wild-types demonstrated preserved long-term memory up to 9 months of age, and preserved short-term memory at all ages tested. Plaque pathology in the J20 mice was present from 6 months onwards, with co-localization of reactive microglia and activated astrocytes. Reactive microglia and astrocyte activation in the hippocampus were significantly greater in the J20 mice at 9 months, compared to wild-types. This study contributes to our understanding of the pathological and cognitive mechanisms at play in AD. J20 mice showed impairment in retaining information over longer periods from an early age, preceding the deposition of Aβ and glial activation. Defining early physiological changes in relation to cognitive decline could provide insight into new therapeutic targets early in the disease process, when intervention is most likely to effectively slow disease progression. Show more

Keywords: Alzheimer’s disease, amyloid, astrocytes, hAPP-J20, microglia, recognition memory

DOI: 10.3233/JAD-181238

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 609-624, 2019

Authors: Abner, Erin L. | Nelson, Peter T. | Jicha, Gregory A. | Cooper, Gregory E. | Fardo, David W. | Schmitt, Frederick A. | Kryscio, Richard J.

Article Type: Research Article

Abstract: Tobacco smoking was examined as a risk for dementia and neuropathological burden in 531 initially cognitively normal older adults followed longitudinally at the University of Kentucky’s Alzheimer’s Disease Center. The cohort was followed for an average of 11.5 years; 111 (20.9%) participants were diagnosed with dementia, while 242 (45.6%) died without dementia. At baseline, 49 (9.2%) participants reported current smoking (median pack-years = 47.3) and 231 (43.5%) former smoking (median pack-years = 24.5). The hazard ratio (HR) for dementia for former smokers versus never smokers based on the Cox model was 1.64 (95% CI: 1.09, 2.46), while the HR for current smokers versus never …smokers was 1.20 (0.50, 2.87). However, the Fine-Gray model, which accounts for the competing risk of death without dementia, yielded a subdistribution hazard ratio (sHR) = 1.21 (0.81, 1.80) for former and 0.70 (0.30, 1.64) for current smokers. In contrast, current smoking increased incidence of death without dementia (sHR = 2.38; 1.52, 3.72). All analyses were adjusted for baseline age, education, sex, diabetes, head injury, hypertension, overweight, APOE ɛ 4, family history of dementia, and use of hormone replacement therapy. Once adjusted for the competing risk of death without dementia, smoking was not associated with incident dementia. This finding was supported by neuropathology on 302 of the participants. Show more

Keywords: Competing risks, dementia, dementia free death, lifetime smoking

DOI: 10.3233/JAD-181119

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 625-633, 2019

Authors: Kaczynski, Anika | Michalowsky, Bernhard | Eichler, Tilly | Thyrian, Jochen René | Wucherer, Diana | Zwingmann, Ina | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: People with dementia (PwD) suffer from coexisting medical conditions, creating complex clinical challenges and increasing the risk of poor outcomes, which could be associated with high healthcare cost. Objective: To describe the prevalence of comorbidity in PwD and to analyze the association between comorbidity in dementia diseases and healthcare costs from a payer’s perspective. Methods: This cross-sectional analysis was based on n  = 362 PwD of the DelpHi-MV trial (Dementia: Life-and person-centered help in Mecklenburg-Western Pomerania). Comorbidity was assessed using the Charlson comorbidity index (CCI) and was categorized into low, high, and very high comorbidity. Healthcare …resource utilization and unit costs were used to calculate costs. Multivariable regression models were applied to analyze the association between comorbidity and costs. Results: Comorbidity was highly prevalent in the sample. 47% of PwD had a very high, 37% a high, and 16% a low comorbidity in addition to dementia. The most prevalent co-existing comorbidity were diabetes mellitus (42%), peripheral vascular disease (28%) and cerebrovascular disease (25%). Total costs significantly increased by 528€ (SE  = 214, CI95  = 109–947, p  = 0.014) with each further comorbidity, especially due to higher cost for medication and medical aids. Compared with a low comorbidity, a very high comorbidity was significantly associated with 818€ (SE  = 168, CI95  = 489–1147, p  < 0.001) higher medication costs and 336€ (SE  = 161, CI95  = 20–652, p  = 0.037) higher cost for medical aids. There were no significant association between a higher comorbidity and cost for formal care services. Conclusions: Comorbidity in PwD represents a substantial financial burden on healthcare payers and is a challenge for patients, healthcare providers, and the health systems. Innovative approaches are needed to achieve a patient-oriented management of treatment and care in comorbid PwD to reduce long-term costs. Show more

Keywords: Alzheimer’s disease, comorbidity, dementia, economics, health care costs, health care resources

DOI: 10.3233/JAD-180896

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 635-646, 2019