Volume 72, Number 3, 2018

Pages 663-675

David R. Pepperberg
Amyloid-β-Dependent Inactivation of the Mitochondrial Electron Transport Chain at Low Transmembrane Potential: An Ameliorating Process in Hypoxia-Associated Neurodegenerative Disease?
Abstract: Cerebral hypoperfusion-induced hypoxia, a condition that impairs oxygen utilization and thus ATP production by mitochondrial oxidative phosphorylation (oxphos), is thought to contribute to neural degeneration in Alzheimer’s disease. However, hypoxia upregulates the generation of amyloid-β (Aβ), a group of peptides known to impair/inhibit the electron transport chain (ETC) of reactions that support oxphos in the inner mitochondrial membrane (IMM). This is a hypothesis paper that reconciles the hypoxia-induced upregulation of Aβ with Aβ’s ETC-inhibiting action and, specifically, posits an oxphos-enhancing effect of this inhibition under conditions of newly developing or otherwise mild hypoxia. This effect is typically transient; that is, under conditions of prolonged or severe hypoxia, the oxphos-enhancing activity is overwhelmed by Aβ’s well-known toxic actions on mitochondria and other cellular components. The hypothesis is motivated by evidence that the IMM transmembrane potential Ψm, an important determinant of ETC activity, exhibits heterogeneity, i.e., a range of values, among a given local population of mitochondria. It specifically proposes that during oxygen limitation, Aβ selectively inactivates ETC complexes in mitochondria that exhibit relatively low absolute values of Ψm, thereby suppressing oxygen binding and consumption by complex IV of the ETC in these mitochondria. This effect of Aβ on low-Ψm mitochondria is hypothesized to spare hypoxia-limited oxygen for oxphos-enabling utilization by the ETC of the remaining active, higher-Ψm local mitochondria, and thereby to increase overall ATP generated collectively by the local mitochondrial population, i.e., to ameliorate hypoxia-induced oxphos reduction. The protective action of Aβ hypothesized here may slow the early development of hypoxia-associated cellular deterioration/loss in Alzheimer’s disease and perhaps other neurodegenerative diseases.

Pages 677-681
Short Communication

Laura Bermejo-Guerrero*, Daniel Sánchez-Tejerina*, Mario Sánchez-Tornero, María del Carmen Sánchez-Sánchez, Adolfo Gómez-Grande, Alberto Villarejo-Galende, Alejandro Octavio Herrero-San Martín, Marta González-Sánchez (Handling Associate Editor: Colin Masters) *These authors contributed equally to this work.
Low Amyloid-PET Uptake in Iowa-Type Cerebral Amyloid Angiopathy with Cerebral Venous Thrombosis
Abstract: Hereditary cerebral amyloid angiopathies (CAA) are rare disorders of early onset and severe course. We describe a 47-year-old patient with Iowa-type amyloid precursor protein (APP) mutation-related hereditary CAA that manifested with concomitant lobar hemorrhage and venous sinus thrombosis. To analyze the cerebral amyloid-β burden, an amyloid-PET was performed, demonstrating low cortical retention except for the calcarine cortex. High amyloid retention was also found in the thalamus and pallidum. The co-occurrence of CAA and venous thrombosis has not been previously reported in Iowa CAA and its mechanism is yet to be elucidated. Low cortical florbetapir-PET uptake does not rule out CAA in young patients, who may benefit from genetic testing to reach diagnosis when suspicion is strong.

Pages 683-691
Rudy J. Castellani, Margaret Smith, Kristi Bailey, George Perry, Joyce L. deJong (Handling Editor: Jesus Avila)
Neuropathology in Consecutive Forensic Consultation Cases with a History of Remote Traumatic Brain Injury
Abstract: Traumatic brain injury (TBI) is widely assumed to be causal in neurodegenerative disease, based on epidemiological surveys demonstrating an increased risk of Alzheimer disease (AD) following TBI, and on recent theories surrounding repetitive head movement. We tested this assumption by evaluating 30 consecutive forensic examinations in which neuropathology consultation was sought, and in which a history of remote TBI was uncovered during the course of the investigation. In this series, there was a high frequency of psychiatric co-morbidities (100%), remote contusion (90%), and seizures (63%). Extent of proteinopathy showed no differences with age-matched controls. A subset of the cases showed focal geographic tauopathy that correlated with older age at autopsy, but had no correlation with clinical signs, and was minimal in comparison with the encephalomalacia secondary to trauma. The results suggest that cerebral contusion and post-traumatic epilepsy may be over-represented in civilian TBI, while structural brain damage from trauma is the predominant cause of morbidity following TBI. We found no evidence that TBI initiates a progressive proteinopathy.

Pages 693-701
Dominika Seblova, Carol Brayne, Vendula Machů, Marie Kuklová, Miloslav Kopecek, Pavla Cermakova (Handling Associate Editor: Karel Kostev)
Changes in Cognitive Impairment in the Czech Republic
Abstract: Background: Studies from North America and Western Europe suggest stable or declining trends in impaired cognition across birth cohorts. Objective: We aimed to examine changes in the age-specific prevalence of cognitive impairment in the Czech Republic. Methods: The study used two samples from the population-based Czech Survey on Health, Ageing and Retirement in Europe. Age-specific prevalence of cognitive impairment (defined based on scores in verbal fluency, immediate recall, delayed recall, and temporal orientation) was compared between participants in wave 2 (2006/2007; n=1,107) and wave 6 (2015; n=3,104). Logistic regression was used to estimate the association between the wave and cognitive impairment, step-wise adjusting for sociodemographic and clinical characteristics. Multiple sensitivity analyses, focusing on alternative operationalizations of relative cognitive impairment, impact of missing cognitive data, and survival bias, were carried out. Results: The most conservative estimate suggested that the age-specific prevalence of cognitive impairment declined by one fifth, from 11% in 2006/2007 to 9% in 2015. Decline was observed in all sensitivity analyses. The change was associated with differences in physical inactivity, management of high blood cholesterol, and increases in length education. Conclusion: Older adults in the Czech Republic, a country situated in the Central and Eastern European region, have achieved positive developments in cognitive aging. Longer education, better management of cardiovascular factors, and reduced physical inactivity seem to be of key importance.

Pages 703-716
Matthew Wai Kin Wong, Nady Braidy, John Crawford, Russell Pickford, Fei Song, Karen A. Mather, John Attia, Henry Brodaty, Perminder Sachdev, Anne Poljak (Handling Associate Editor: Maheen Adamson)
APOE Genotype Differentially Modulates Plasma Lipids in Healthy Older Individuals, with Relevance to Brain Health
Abstract: Apolipoprotein E (APOE) genotype is an established genetic risk factor for sporadic Alzheimer’s disease (AD) but the extent to which APOE genotype influences the plasma lipidome is unknown, even though lipids are potential diagnostic or prognostic biomarkers for AD. We quantified plasma lipids using untargeted liquid chromatography coupled mass spectrometry in a total of 152 non-demented participants aged 65-100 years carrying at least one ε2 or ε4 allele (ε2/ε2 or ε2/ε3, n=38: ε4/ε3 or ε4/ε4, n=38), who were roughly matched to an ε3/ε3 control by age, sex, and lipid-lowering medication (n=76). Low density lipoprotein cholesterol levels were genotype dependent (ε4/ε4>ε4/ε3>ε3/ε3>ε2/ε3>ε2/ε2). The greatest variation in lipids was related to the ε2 isoform, where various lysophosphatidylcholines and all phosphatidylethanolamine (PE) subclasses were elevated relative to ε3/ε3 and ε4 carriers. APOE ε4 carriers had reduced phosphatidylinositol relative to ε3/ε3 and ε2 carriers. Logistic regression revealed that ε2 carriers were at least 4 times higher odds of being in the highest tertile of PE lipid level relative to ε3/ε3. The elevation in PE and other phospholipids in ε2 carriers may indicate the protective effect of ε2 is linked to these phospholipids. Additionally, high baseline PE in cognitively normal participants predicted protection against cognitive decline six years later. Our data suggest substantial modulation of plasma lipids by APOE genotype and therefore indicates possible lipid targets and pathomechanisms involved in AD risk.

Pages 717-731
Flaminia Franchini, Massimo Musicco, Federica Ratto, Gabriele Storti, Jacob Shofany, Carlo Caltagirone, Simona Gabriella Di Santo
The LIBRA Index in Relation to Cognitive Function, Functional Independence, and Psycho-Behavioral Symptoms in a Sample of Non-Institutionalized Seniors at Risk of Dementia
Abstract: Background: Alzheimer’s disease is the principal cause of dementia and is determined, in at least one third cases, by modifiable risk factors (MRF). The “Lifestyle for Brain Health (LIBRA)” index was recently developed to quantify the individual risk of progression to dementia ascribable to MRF. Objective: The aim of this study was to investigate the association between LIBRA scores and markers of cognitive performance, functional independence, and psycho-behavioral symptoms in a community-based sample of Italian elders. Methods: 308 senior participants with mild cognitive impairment (MCI) or subjective cognitive decline (SCD) were evaluated with a complete neuropsychological battery and semi-structured interviews for the assessment of depression, apathy, and functional autonomy. All the 12 LIBRA MRF were available for the calculation of LIBRA scores. A modified version of the index (LIBRA-2) was calculated by removing depression weight from the LIBRA index. Partial correlation analyses, controlling for age and education, assessed the association between LIBRA indices and cognitive, functional, and behavioral outcomes. Separate analyses were repeated in the MCI and SCD subgroups. Results: In participants with SCD (SCDp), significant correlations existed between LIBRA and markers of impairment in global cognition, visuo-spatial attention, and semantic fluency. LIBRA-2 associated with psycho-behavioral symptoms in the whole sample and in SCDp. LIBRA-2 only associated with apathy in the MCI subgroup. Conclusions: The LIBRA index might be useful to determine the lifestyle-attributable risk of cognitive and psycho-behavioral decline in Italian seniors at risk, while in those with overt cognitive impairment, these outcomes are presumably mainly associated with non-modifiable factors.

Pages 733-749
Gita A. Pathak, Talisa K. Silzer, Jie Sun, Zhengyang Zhou, Ann A. Daniel, Leigh Johnson, Sid O'Bryant, Nicole R. Phillips, Robert C. Barber
Genome-Wide Methylation of Mild Cognitive Impairment in Mexican Americans Highlights Genes Involved in Synaptic Transport, Alzheimer’s Disease-Precursor Phenotypes, and Metabolic Morbidities
Abstract: The Mexican American population is among the fastest growing aging population and has a younger onset of cognitive decline. This group is also heavily burdened with metabolic conditions such as hypertension, diabetes, and obesity. Unfortunately, limited research has been conducted in this group. Understanding methylation alterations, which are influenced by both genetic and lifestyle factors, is key to identifying and addressing the root cause for mild cognitive impairment, a clinical precursor for dementia. We conducted an epigenome-wide association study on a community-based Mexican American population using the Illumina EPIC array. Following rigorous quality control measures, we identified 10 CpG sites to be differentially methylated between normal controls and individuals with mild cognitive impairment annotated to PKIB, KLHL29, SEPT9, OR2C3, CPLX3, BCL2L2-PABPN1, and CCNY. We found four regions to be differentially methylated in TMEM232, SLC17A8, ALOX12, and SEPT8. Functional gene-set analysis identified four gene-sets, RIN3, SPEG, CTSG, and UBE2L3, as significant. The gene ontology and pathway analyses point to neuronal cell death, metabolic dysfunction, and inflammatory processes. We found 1,450 processes to be enriched using empirical Bayes gene-set enrichment. In conclusion, the functional overlap of differentially methylated genes associated with cognitive impairment in Mexican Americans implies cross-talk between metabolically-instigated systemic inflammation and disruption of synaptic vesicular transport.

Pages 751-760
Conrad N. Trumbore, Jennie Paik, David Fay, Richard W. Vachet
Preliminary Capillary Flow Experiments with Amyloid-β, Possible Needle and Capillary Aβ Adsorption, and a Proposal for Drug Evaluation Under Shear Conditions
Abstract: Amyloid-β (Aβ) solution injections into an aqueous mobile phase moving through narrow bore stainless-steel capillary tubing results in adsorption of at least 99% Aβ within the tubing or injection valve. However, if flow is stopped for a period of 5-10 minutes, then started, wall desorption yields Aβ-containing molecules in the new effluent. The amount of desorbed Aβ-containing effluent depends on flow rate, period of flow cessation, and number of successive Aβ injections into the same tube without cleaning between injections. Unexpected multiple chromatographic peaks in these experiments seem to imply “separation” of released, previously adsorbed Aβ-containing products in the empty capillary tubing. These preliminary experiments raise questions about possible errors in Alzheimer's disease (AD) spinal tap analyses, which use stainless-steel needles of approximately the same inner diameter and encounter similar flow rates as those in our capillary experiments. Microliter syringes and HPLC connectors also contain stainless-steel tubing that have similar inner diameter dimensions and similar flow rates. The capillary system involved in these experiments has previously been proposed as a model system for studying the effects of shear on Aβ within the brain because it offers a research environment that provides highly restrictive flow through very small dimension channels. A suggestion is made for the use of this system in exploratory anti-amyloid drug studies in which both the drug and Aβ are injected in the same solution so that both drug and Aβ are subjected to the same shear environment. Reduction in adsorbed Aβ is suggested as an indicator of effective anti-Aβ drugs.

Pages 761-771
Yu Wan, Yingxia Liang, Feng Liang, Nolan Shen, Kenneth Shinozuka, Jin-Tai Yu, Chongzhao Ran, Qimin Quan, Rudolph E. Tanzi, Can Zhang (Handling Associate Editor: Ling-Qiang Zhu)
A Curcumin Analog Reduces Levels of the Alzheimer’s Disease-Associated Amyloid-β Protein by Modulating AβPP Processing and Autophagy
Abstract: Alzheimer’s disease (AD) is a devastating neurodegenerative disease with no cure currently available. A pathological hallmark of AD is accumulation and deposition of amyloid-β protein (Aβ), a ~4 kDa peptide generated through serial cleavage of the amyloid-β protein precursor (AβPP) by β- and γ-secretases. Curcumin is a natural compound primarily found in the widely used culinary spice, turmeric, which displays therapeutic potential for AD. Recently, we reported the development of curcumin analogs and identified a lead compound, curcumin-like compound-R17 (CLC-R17), that significantly attenuates Aβ deposition in an AD transgenic mouse model. Here, we elucidated the mechanisms of this analog on Aβ levels and AβPP processing using cell models of AD. Using biochemical methods and our recently developed nanoplasmonic fiber tip probe technology, we showed that the lead compound potently lowers Aβ levels in conditioned media and reduces oligomeric amyloid levels in the cells. Furthermore, like curcumin, the lead compound attenuates the maturation of AβPP in the secretory pathway. Interestingly, it upregulated α-secretase processing of AβPP and inhibited β-secretase processing of AβPP by decreasing BACE1 protein levels. Collectively, our data reveal mechanisms of a promising curcumin analog in reducing Aβ levels, which strongly support its development as a potential therapeutic for AD.

Pages 773-782
Jordi A. Matías-Guiu, Ulises Gómez-Pinedo, Lucía Forero, Vanesa Pytel, Fátima Cano, Teresa Moreno-Ramos, María Nieves Cabrera-Martín, Jorge Matías-Guiu, Javier J. González-Rosa
Plasma Neurofilament Light Chain in Primary Progressive Aphasia and Related Disorders: Clinical Significance and Metabolic Correlates
Abstract: Background: Primary progressive aphasia (PPA) is a heterogeneous syndrome that is difficult to diagnose at early stages. Plasma neurofilament light chain (NFL) has been proposed as a potential biomarker for PPA. Objective: To examine the diagnostic properties of plasma NFL in PPA and to evaluate its association with clinical stages of the disease and brain metabolism. Methods: Our study included 80 participants (13 with non-fluent, 12 with semantic, and 16 with logopenic variant PPA; 13 with amnestic Alzheimer’s disease [AD]; 13 with behavioral variant frontotemporal dementia; and 13 healthy controls). Plasma NFL concentration was measured using a high-sensitivity enzyme-linked immunosorbent assay (ELISA) kit. PET imaging was performed in a subgroup of patients. Results: NFL discriminated patients from controls with an area under the curve of 0.914 (95% CI, 0.843-0.984; p < 0.001) (cut-off: 76.46 pg/mL; 94% sensitivity, 76.9% specificity). There were no significant differences between clinical syndromes (PPA subtypes), the main clinical forms of dementia (frontotemporal dementia and AD), or the expected pathological groups (frontotemporal lobar degeneration-tau [FTLD-tau], FTLD-TDP43, and AD). NFL levels showed weak to moderate correlations with age and functional scale score. We found no significant correlation with the extent of hypometabolism observed on FDG-PET images. Conclusion: Plasma NFL is a non-specific marker of neurodegeneration, and may be helpful in the diagnosis of PPA. However, NFL does not permit differential diagnosis between PPA subtypes and is not correlated with the extent of neurodegeneration.

Pages 783-801
Eleni Poptsi, Emmanouil Tsardoulias, Despina Moraitou, Andreas L. Symeonidis, Magda Tsolaki
REMEDES for Alzheimer-R4Alz Battery: Design and Development of a New Tool of Cognitive Control Assessment for the Diagnosis of Minor and Major Neurocognitive Disorders
Abstract: Background: Subjective cognitive decline (SCD) and mild cognitive impairment (MCI) are acknowledged stages of the clinical spectrum of Alzheimer’s disease (AD), and cognitive control seems to be among the first neuropsychological predictors of cognitive decline. Existing tests are usually affected by educational level, linguistic abilities, cultural differences, and social status, constituting them error-prone when differentiating between the aforementioned stages. Creating robust neuropsychological tests is therefore prominent. Objective: The design of a novel psychometric battery for the cognitive control and attention assessment, free of demographic effects, capable to discriminate cognitively healthy aging, SCD, MCI, and mild Dementia (mD). Methods: The battery initial hypothesis was tuned using iterations of administration on random sampling healthy older adults and people with SCD, MCI, and mD, from the area of Thessaloniki, Greece. This resulted in the first release of the REflexes MEasurement DEviceS for Alzheimer battery (REMEDES for Alzheimer-R4Alz). Results: The first release lasts for almost an hour. The battery was design to assess working memory (WM) including WM storage, processing, and updating, enriched by episodic buffer recruitment. It was also designed to assess attention control abilities comprising selective, sustained, and divided attention subtasks. Finally, it comprises an inhibitory control, a task/rule switching or set-shifting, and a cognitive flexibility subtask as a combination of inhibition and task/rule switching abilities. Conclusion: The R4Alz battery is an easy to use psychometric battery with increasing difficulty levels and assumingly ecological validity, being entertaining for older adults, potentially free of demographic effects, and promising as a more accurate and early diagnosis tool of neurodegeneration.

Pages 803-814
Hong-Bae Kim, Byoungjin Park, Jae-Yong Shim (Handling Associate Editor: Tobias Möllers)
Anemia in Association with Cognitive Impairment: A Systematic Review and Meta-Analysis
Abstract: Background: Prevalence of both anemia and cognitive impairment tends to increase with age. Individual studies have recently shown that anemia could be associated with cognitive impairment. Objective: To investigate the association between anemia and cognitive impairment including dementia. Methods: Two of the authors systematically searched PubMed, EMBASE, and the Cochrane library to retrieve observational studies reporting a relationship between anemia and cognitive impairment from 1964 to July 10, 2019. Case-control and cohort studies were included, and odds ratios (ORs) or relative risks (RRs) with 95% confidence intervals (CIs) for the risk of cognitive impairment were calculated using a random-effects model. Results: In total, 16 observational studies including eight case-control studies and eight cohort studies were included in the final analysis. Anemia was significantly linked to cognitive impairment (OR or RR 1.51; 95% CI: 1.32–1.73) in a random-effects meta-analysis, albeit with medium heterogeneity (I2 = 47.8%). Meta-estimates of dementia from prospective population-based cohort studies were similar (RR 1.46; 95% CI: 1.22–1.76) without substantial heterogeneity (I2 = 23.2%). Conclusion: Our meta-analysis indicates that anemia is associated with cognitive impairment. Further prospective research is warranted to determine the cause-effect relationship of anemia with cognitive impairment and whether treatment of anemia might reduce the risk of dementia.

Pages 815-822
Bing Chen, Weiming Zheng (Handling Associate Editor: Yong Guo)
Epigenetic Control of Rho-Associated Protein Kinase 2 in Neurodegeneration
Abstract: Upregulation of Rho-associated protein kinase 2 (ROCK2) hallmarks the progression of neurodegenerative diseases. However, the molecular mechanisms underlying the regulation of ROCK2 expression are not clear and thus addressed in the current study. We generated a subacute model of Parkinson’s disease in mice with a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) method. The MPTP model was validated by impaired rotational behavior of the mice upon apomorphine exposure, astrocytic activation, and reduction in tyrosine-hydroxylase-positive neurons in the mouse striatum. Moreover, MPTP induced increases in ROCK2 protein but not in ROCK2 mRNA. Further analysis showed that MPTP inhibited the expression of microRNA-291 (miR-291), which suppressed ROCK2 mRNA via 3’-UTR-binding in neuronal cells to increase ROCK2 protein. Intracranial injection of miR-291 four days before MPTP alleviated the impaired rotational behavior of the mice upon apomorphine exposure, MPTP-induced astrocytic activation, and the reduction in tyrosine-hydroxylase-positive neurons in the mouse striatum. Together, these data suggest that miR-291 has a protective role in neurodegeneration, likely through regulation of ROCK2.

Pages 823-833
Yangfei Ji, Dan Wang, Boai Zhang, Hong Lu
Bergenin Ameliorates MPTP-Induced Parkinson’s Disease by Activating PI3K/Akt Signaling Pathway
Abstract: Background: Parkinson’s disease (PD) is the second most prevalent progressive neurodegenerative disease with motor disorders and cognitive impairment. Bergenin (Berg), extracted from the herb of Saxifrage stolonifera Curt. (Hu-Er-Cao), has anti-tumor, anti-inflammation, anti-oxidative stress, and neuroprotective properties. Objective: In this study, we wanted to investigate the effects of Berg on PD and the underlying mechanisms. Methods: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was used to introduce PD symptoms in mice. The expression levels of tyrosine hydroxylase, dopamine, and Iba-1 were examined. The levels of a series of inflammatory mediators were measured by qPCR. In addition, the PI3K/Akt signaling pathway was investigated to illustrate the underlying mechanism. In vitro, PC12 cells subjected to lipopolysaccharide (LPS) were treated with Berg. Results: We found that MPTP injection introduced motor deficits, apoptosis of neurons and inflammation, as well as inhibited the PI3K/Akt signaling pathway. However, Berg treatment suppressed the MPTP-induced alterations. In vitro, Berg attenuated the cytotoxic effects on PC12 cells induced by the culture supernatants derived from LPS-induced microglial cells. Conclusion: Berg attenuated the PD symptoms via activating the PI3K/Akt signaling pathway in vivo and in vitro.

Pages 835-843
Miharu Nakanishi, Syudo Yamasaki, Atsushi Nishida, Marcus Richards (Handling Associate Editor: Linda Ernstsen)
Midlife Psychological Well-Being and Its Impact on Cognitive Functioning Later in Life: An Observational Study Using a Female British Birth Cohort
Abstract: Background: There is growing interest in public health strategies to modify dementia risk in midlife to reduce the burden of cognitive impairment in subsequent decades. Risk reduction messages should include key recommendations for women in response to the high prevalence of dementia observed in this population. Midlife is a critical period for dementia-related brain changes and psychosocial crises. Psychological well-being can improve resilience to crises, yet it is not well understood with respect to dementia risk reduction. Objective: This study aimed to examine the association between midlife psychological well-being and cognitive function in later life in women. Methods: The study included 703 women from the British 1946 birth cohort in the Medical Research Council’s National Survey of Health and Development. Psychological well-being at 52 years was assessed using the Ryff Scales of Psychological Well-being over six dimensions: autonomy, environmental mastery, personal growth, positive relations with others, purpose in life, and self-acceptance. Cognitive function at 69 years was measured using the Addenbrooke’s Cognitive Examination, Third Edition. Results: After controlling for cognitive ability at eight years, educational attainment by 26 years, occupational attainment and marital status by 53 years, depression, smoking, and physical exercise at 60–64 years, there was a significant association between greater personal growth and lower self-acceptance at 52 years, and better cognition at 69 years. However, there was no association between cognition and the other four Ryff scales. Conclusion: Most aspects of midlife psychological well-being, except for personal growth and self-acceptance, were not prospectively associated with cognition.

Pages 845-857
Emma Richards, Antony Bayer, Jeremy Tree, Claire Hanley, Jade Norris, Andrea Tales
Subcortical Ischemic Vascular Cognitive Impairment: Insights from Reaction Time Measures
Abstract: In this study, reaction time (RT), intraindividual variability (IIV), and errors, and the effects of practice and processing load upon such function, were compared in patients with subcortical ischemic vascular cognitive impairment (SIVCI) [n=27] and cognitively healthy older adults (CH) [n = 26]. Compared to CH aging, SIVCI was characterized by a profile of significantly slowed RT, raised IIV, and higher error levels, particularly in the presence of distracting stimuli, indicating that the integrity and/or accessibility of the additional functions required to support high processing load, serial search strategies, are reduced in SIVCI. Furthermore, although practice speeded RT in SIVCI, unlike CH, practice did not lead to an improvement in IIV. This indicates that improvement in RT in SIVCI can in fact mask an abnormally high degree of IIV. Because IIV appears more related to disease, function, and health than RT, its status and potential for change may represent a particularly meaningful, and relevant, disease characteristic of SIVCI. Finally, a high level of within-group variation in the above measures was another characteristic of SIVCI, with such processing heterogeneity in patients with ostensibly the same diagnosis, possibly related to individual variation in pathological load. Detailed measurement of RT, IIV, errors, and practice effects therefore reveal a degree of functional impairment in brain processing not apparent by measuring RT in isolation.

Pages 859-865
Emma Richards, Antony Bayer, Claire Hanley, Jade E. Norris, Jeremy Tree, Andrea Tales
Reaction Time and Visible White Matter Lesions in Subcortical Ischemic Vascular Cognitive Impairment
Abstract: Slowed behavioral reaction time is associated with pathological brain changes, including white matter lesions, the common clinical characteristic of subcortical ischemic vascular cognitive impairment (SIVCI). In the present study, reaction time (RT) employing Trails B of the Trail Making Test, with responses capped at 300 s, was investigated in SIVCI (n=27) compared to cognitively healthy aging (CH) (n= 26). RT was significantly slowed in SIVCI compared to CH (Cohen’s d effect size = 1.26). Furthermore, failure to complete Trails B within 300 s was also a characteristic of SIVCI although some ostensibly cognitively healthy older adults also failed to complete within this time limit. Within the SIVCI group, RT did not differ significantly with respect to whether the patients were classified as having moderate/severe or mild, periventricular white matter changes visible on their diagnostic CT/MRI scans. This, together with the high degree of overlap in RT between the two SIVCI subgroups, raises the possibility that using visible ratings scales in isolation may lead to the underestimation of disease level.

Pages 867-884
Kazuki Yokokawa*, Naotoshi Iwahara*, Shin Hisahara, Miho C. Emoto, Taro Saito, Hiromi Suzuki, Tatsuo Manabe, Akihiro Matsumura, Takashi Matsushita, Syuuichirou Suzuki, Jun Kawamata, Hideo Sato-Akaba, Hirotada G. Fujii, Shun Shimohama *These authors contributed equally to this work.
Transplantation of Mesenchymal Stem Cells Improves Amyloid-β Pathology by Modifying Microglial Function and Suppressing Oxidative Stress
Abstract: Mesenchymal stem cells (MSC) are increasingly being studied as a source of cell therapy for neurodegenerative diseases, and several groups have reported their beneficial effects on Alzheimer’s disease (AD). In this study using AD model mice (APdE9), we found that transplantation of MSC via the tail vein improved spatial memory in the Morris water maze test. Using electron paramagnetic resonance imaging to evaluate the in vivo redox state of the brain, we found that MSC transplantation suppressed oxidative stress in AD model mice. To elucidate how MSC treatment ameliorates oxidative stress, we focused on amyloid-β (Aβ) pathology and microglial function. MSC transplantation reduced Aβ deposition in the cortex and hippocampus. Transplantation of MSC also decreased Iba1-positive area in the cortex and reduced activated ameboid shaped microglia. On the other hand, MSC transplantation accelerated accumulation of microglia around Aβ deposits and prompted microglial Aβ uptake and clearance as shown by higher frequency of Aβ-containing microglia. MSC transplantation also increased CD14-positive microglia in vivo, which play a critical role in Aβ uptake. To confirm the effects of MSC on microglia, we co-cultured the mouse microglial cell line MG6 with MSC. Co-culture with MSC enhanced Aβ uptake by MG6 cells accompanied by upregulation of CD14 expression. Additionally, co-culture of MG6 cells with MSC induced microglial phenotype switching from M1 to M2 and suppressed production of proinflammatory cytokines. These data indicate that MSC treatment has the potential to ameliorate oxidative stress through modification of microglial functions, thereby improving Aβ pathology in AD model mice.

Pages 885-899
Maria Lo Giudice, Balázs Mihalik, Zsófia Turi, András Dinnyés, Julianna Kobolák (Handling Associate Editor: Diego Albani)
Calcilytic NPS 2143 Reduces Amyloid Secretion and Increases sAβPPα Release from PSEN1 Mutant iPSC-Derived Neurons
Abstract: Despite numerous efforts and studies over the last three decades, Alzheimer’s disease (AD) remains a disorder not fully understood and incurable so far. Development of induced pluripotent stem cell (iPSC) technology to obtain terminally differentiated neurons from adult somatic cells revolutionized the study of AD, providing a powerful tool for modelling the disease and for screening candidate drugs. Indeed, iPSC reprogramming allowed generation of neurons from both sporadic and familial AD patients with the promise to recapitulate the early pathological mechanisms in vitro and to identify novel targets. Interestingly, NPS 2143, a negative allosteric modulator of the calcium sensing receptor, has been indicated as a possible therapeutic for AD. In the present study, we assessed the potential of our iPSC-based familial AD cellular model as a platform for drug testing. We found that iPSC-derived neurons respond to treatment with γ-secretase inhibitor, modifying the physiological amyloid-β protein precursor (AβPP) processing and amyloid-β (Aβ) secretion. Moreover, we demonstrated the expression of calcium sensing receptor (CaSR) protein in human neurons derived from healthy and familial AD subjects. Finally, we showed that calcilytic NPS 2143 induced a changing of Aβ and sAβPPα secreted into conditioned media and modulation of CaSR and PSEN1 expression at the plasma membrane of AD neurons. Overall, our findings suggest that NPS 2143 affects important AD processes in a relevant in vitro system of familial AD.

Pages 901-910
David A. Geier, Janet K. Kern, Kristin G. Homme, Mark R. Geier
A Cross-Sectional Study of Blood Ethylmercury Levels and Cognitive Decline Among Older Adults and the Elderly in the United States
Abstract: Cognitive health is an emerging public health concern for the aging American population. Mercury (Hg) is a toxic element that can cause nervous system damage. This hypothesis-testing study evaluated the relationship between blood ethyl-Hg levels and cognitive decline in an older adult and elderly American population. A total of 1,821,663 weighted-persons between 60-80 years old with detectable blood ethyl-Hg levels within the 2011-2012 National Health and Nutritional Examination Survey were examined. Those persons with blood ethyl-Hg levels greater than the median were deemed the higher ethyl-Hg exposure group and those with ethyl-Hg levels less than the median were deemed the lower ethyl-Hg exposure group. Three tests were utilized to measure cognitive function: 1) Consortium to Establish a Registry for Alzheimer’s Disease - Word List Learning (CERAD W-L) delayed recall test, 2) animal fluency test, and 3) Digit Symbol Substitution Test. Each cognitive test score was categorized as higher for those with scores greater than the median and lower for those with scores less than the median. Survey logistic regression modeling with covariates was used to analyze the data for the relationship between blood ethyl-Hg levels and cognitive function scores. Significantly increased risks for lower animal fluency test (odds ratio (OR)=13.652, p=0.0029) and CERAD W-L delayed recall test (OR=6.401, p=0.0433) scores were observed among the higher ethyl-Hg exposure group as compared to the lower ethyl-Hg exposure group. This study supports the hypothesis that increased ethyl-Hg exposure is associated with significant cognitive decline in older adult and elderly Americans.

Pages 911-918
Virginia Boccardi, Lucia Paolacci, Daniel Remondini, Enrico Giampieri, Giulia Poli, Nico Curti, Roberta Cecchetti, Alfredo Villa, Carmelinda Ruggiero, Stefano Brancorsini, Patrizia Mecocci (Handling Associate Editor: M. Cristina Polidori)
Cognitive Decline and Alzheimer’s Disease in Old Age: A Sex-Specific “Cytokinome Signature”
Abstract: Background: Elevated peripheral levels of different cytokines and chemokines in subjects with Alzheimer's disease (AD), as compared with healthy controls (HC), have emphasized the role of inflammation in such a disease. Considering the cross-talking between the central nervous system and the periphery, the inflammatory analytes may provide utility as biomarkers to identify AD at earlier stages. Objective: Using an advanced statistical approach, we can discriminate the interactive network of cytokines/chemokines and propose a useful tool to follow the progression and evolution of AD, also in light of sex differences. Methods: A cohort of 289 old-age subjects was screened for cytokine and chemokine profiling, measured in plasma, after a thorough clinical and neuropsychological evaluation. A custom algorithm based on Fisher linear discriminant analysis was applied to ascertain a classification signature able to discriminate HC from mild cognitive impairment (MCI) and AD. Results: We observed that a joint expression of three proteins (a “signature” composed by IFN-α2, IL-1α, TNFα) can discriminate HC from AD with an accuracy of 65.24%. Using this signature on MCI samples, 84.93% of them were classified as “non-HC”. Stratifying MCI samples by sex, we observed that 87.23% of women were classified as “non-HC”, and only 57.69% of males. Indeed, in a scatter plot of IFN-α2 and IL-1α, the HC group was better separated from MCI and AD in women as compared with men. Conclusion: These findings suggest that AD is accompanied by a peripheral inflammatory response that can already be present in MCI subjects, thus providing a mean for detecting this at-risk status and allow an anticipated intervention.

Pages 919-929
Lindsay R. Clark, Derek Norton, Sarah E. Berman, Sterling C. Johnson, Barbara B. Bendlin, Oliver Wieben, Patrick Turski, Cynthia Carlsson, Sanjay Asthana, Carey E. Gleason, Heather M. Johnson
Association of Cardiovascular and Alzheimer’s Disease Risk Factors with Intracranial Arterial Blood Flow in Whites and African Americans
Abstract: Background: Alzheimer’s disease (AD) has a higher prevalence among African Americans. Targeting cardiovascular and metabolic risk factors may be potential mechanisms to modify AD risk and address racial/ethnic disparities in AD dementia. Objective: This study investigated relationships among cardiovascular and metabolic risk factors, APOE genotype, AD biomarkers, and intracranial arterial blood flow in Whites and African Americans enriched for AD risk. Methods: 399 cognitively unimpaired adults from the Wisconsin Alzheimer’s Disease Research Center completed physical and neuroimaging examinations. A 4D Flow MRI sequence (phase-contrast vastly under sampled isotropic projection imaging) measured intracranial arterial flow in the Circle of Willis. Linear mixed-effects regression models estimated relationships between risk factors and intracranial arterial flow and tested interactions with racial group, APOE genotype, and AD biomarkers, with separate models per risk factor. Results: Higher fasting glucose was associated with lower intracranial arterial flow; no additional relationships between flow and risk factors were observed. Main effects of racial group were observed, without an interaction, indicating lower flow in African Americans compared to Whites. In race-stratified analyses, higher glucose and triglycerides were associated with lower flow for African Americans, but not for Whites. No main effects or interactions among risk factors, APOE, or AD biomarkers, and flow were observed. Conclusion: Elevated fasting glucose and triglycerides were associated with lower intracranial arterial flow; these relationships were more prominent in African Americans. Targeting metabolic risk factors may impact intracranial arterial health. Additional research is needed to determine if this will impact disparities in dementia prevalence.

Pages 931-946
Bjoern O. Schelter, Helen Shiells, Thomas C. Baddeley, Christopher M. Rubino, Harish Ganesan, Jeffrey Hammel, Vesna Vuksanovic, Roger T. Staff, Alison D. Murray, Luc Bracoud, Gernot Riedel, Serge Gauthier, Jianping Jia, Peter Bentham, Karin Kook, John M.D. Storey, Charles R. Harrington, Claude M. Wischik
Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer’s Disease
Abstract: Background: Although hydromethylthionine is a potent tau aggregation inhibitor, no difference was found in either of two Phase III trials in mild to moderate Alzheimer’s disease (AD) comparing doses in the range 150-250 mg/day with 8 mg/day intended as a control. Objective: To determine how drug exposure is related to treatment response. Methods: A sensitive plasma assay for the drug was used in a population pharmacokinetic analysis of samples from 1,162 of the 1,686 patients who participated in either of the Phase III trials with available samples and efficacy outcome data. Results: There are steep concentration-response relationships for steady state plasma levels in the range 0.3–0.8 ng/ml at the 8 mg/day dose. Using a threshold based on the lower limit of quantitation of the assay on Day 1, there are highly significant differences in cognitive decline and brain atrophy in patients with above threshold plasma levels, both for monotherapy and add-on therapy, but with effect sizes reduced by half as add-on. Plasma concentrations in the range 4–21 ng/ml produced by the high doses are not associated with any additional benefit. Conclusions: Hydromethylthionine has pharmacological activity on brain structure and function at the 8 mg/day dose as monotherapy or as add-on to symptomatic treatments. This combined with a plateau at higher doses is consistent with the lack of dose-response seen in the Phase III trials. Treatment benefit is predicted to be maximal at 16 mg/day as monotherapy. A placebo-controlled trial in mild/moderate AD is now ongoing to confirm efficacy at this dose.

Pages 947-956
Nayan Huang*, Wenjie Li*, Xiangjiang Rong, Mei Champ, Lian Wei, Mo Li, Haiyan Mu, Yueqing Hu, Zongjuan Ma, Jihui Lyu (Handling Associate Editor: Dharma Singh Khalsa) *These authors contributed equally to this work.
Effects of a Modified Tai Chi Program on Older People with Mild Dementia: A Randomized Controlled Trial
Abstract: Background: Tai Chi exercise is a non-pharmacological therapy that has received increased attention in recent years. A Tai Chi program has been specifically modified for older people with cognitive impairments by the research team. Objective: We aim to assess the effects of this Tai Chi program on mild dementia. Methods: Eighty older people with mild dementia were recruited and randomly assigned to a Tai Chi group or a control group. The Tai Chi group practiced the Tai Chi program three times a week for 10 months, while the control group continued receiving routine treatments. All participants were assessed for cognitive function, behavior/mood, and activities of daily living at baseline, 5 months, and 10 months. Results: The Tai Chi group performed better than the control group. Repeated measures ANOVA revealed a significant group × time interaction in the Montreal Cognitive Assessment (MoCA). Further analysis of sub-items of the MoCA showed a significant time effect in naming and abstraction. It was statistically significant in both main effect of time and group × time interaction in the Neuropsychiatric Inventory (NPI) and Geriatric Depression Scale (GDS). Paired sample t test showed the Tai Chi group scored lower at 5 and 10 months in the NPI and at 10 months in the GDS compared with baseline. The Tai Chi group scored lower than the control group at 10 months in the NPI and GDS. Conclusion: The results suggest this Tai Chi program may help improve cognitive function and mental well-being for older adults with mild dementia.

Pages 957-975
Tanja Fuchsberger, Raquel Yuste, Sergio Martinez-Bellver, Mari-Carmen Blanco-Gandia, Isabel Torres-Cuevas, Arantxa Blasco-Serra, Román Arango, Jose Miñarro, Marta Rodríguez-Arias, Vicent Teruel-Marti, Ana Lloret, Jose Viña
Oral Monosodium Glutamate Administration Causes Early Onset of Alzheimer’s Disease-Like Pathophysiology in APP/PS1 Mice
Abstract: Glutamate excitotoxicity has long been related to Alzheimer’s disease (AD) pathophysiology, and it has been shown to affect the major AD-related hallmarks, amyloid-β peptide (Aβ) accumulation and tau phosphorylation (p-tau). We investigated whether oral administration of monosodium glutamate (MSG) has effects in a murine model of AD, the double transgenic mice APP/PS1. We found that AD pathogenic factors appear earlier in APP/PS1 when supplemented with MSG, while wildtype mice were essentially not affected. Aβ and p-tau levels were increased in the hippocampus in young APP/PS1 animals upon MSG administration. This was correlated with increased Cdk5-p25 levels. Furthermore, in these mice, we observed a decrease in the AMPA receptor subunit GluA1 and they had impaired long-term potentiation. The Hebb-Williams maze revealed that they had memory deficits. We show here for the first time that oral MSG supplementation can accelerate AD-like pathophysiology in a mouse model of AD.