Volume 74, Number 3, IN PRESS

Review
Elham Teimouri, Stephanie R. Rainey-Smith, Prashant Bharadwaj, Giuseppe Verdile, Ralph N. Martins
Amla Therapy as a Potential Modulator of Alzheimer’s Disease Risk Factors and Physiological Change
Abstract: There is currently no effective treatment for Alzheimer’s disease (AD), the most common form of dementia. It has been proposed, however, that a modest delay in onset can significantly reduce the number of cases. Thus, prevention and intervention strategies are currently the focus of much research. In the search for compounds that potentially confer benefit, the Amla fruit and its extracts have drawn attention. Amla preparations have been used for centuries in traditional Indian medicine systems such as Ayurveda, with various parts of the plant used to treat a variety of diseases. Here we review many animal-based studies, and some clinical trials, which have shown that Amla, and its extracts, exert many positive effects on dyslipidemia, hyperglycemia, inflammation, oxidative stress, apoptosis, and autophagy, that contribute to AD risk. Collectively, this evidence suggests that Amla may be of value as part of an effective disease-delaying treatment for AD.

Short Communication
Anna Sundström, Daniel Eriksson Sörman, Patrik Hansson, Jessica Körning Ljungberg, Rolf Adolfsson
Mental Demands at Work and Risk of Dementia
Abstract: High mental demands at work was examined as a possible protective factor to reduce the risk of dementia in 1,277 initially dementia-free participants, aged 60 years and older. The cohort was followed for a mean of 13.6 years. During follow-up, 376 participants developed all-cause dementia (Alzheimer’s disease=199; vascular dementia=145). The association between mental demands at work and dementia was analyzed with Cox hazard models, adjusted for a range of covariates. The results revealed no significant association between mental demands at work and incidence of dementia. Based on the measures used in this study, it was concluded that high mental demands at work may not reduce the risk of dementia later on in life.

Short Communication
Yasuharu Tabara, Mikihiro Yamanaka, Kazuya Setoh, Hiroaki Segawa, Takahisa Kawaguchi, Shinji Kosugi, Takeo Nakayama, Fumihiko Matsuda, and the Nagahama Study Group
Advanced Glycation End Product Accumulation Is Associated with Lower Cognitive Performance in an Older General Population: The Nagahama Study
Abstract: Accumulation of advanced glycation end products (AGEs) has been linked with cognitive decline as a risk factor based on the analysis in small populations. We investigated the association between skin autofluorescence of AGEs and global cognitive function in a Japanese older (≥60 years) population (n = 4,041). The AGEs quartiles were inversely associated with the Revised Hasegawa’s Dementia Scale score (Q1: reference, Q2: β = −0.011, p = 0.537, Q3: β = −0.043, p = 0.016, Q4: β = −0.064, p <0.001) independent of major risk factors. Accumulation of AGEs was associated with lower cognitive performance in older adults.

Arunima Kapoor, Robert Bartha, Sandra E. Black, Michael Borrie, Morris Freedman, Fuqiang Gao, Nathan Herrmann, Jennifer Mandzia, Miracle Ozzoude, Joel Ramirez, Christopher J.M Scott, Sean Symons, Corinne E. Fischer, Andrew Frank, Dallas Seitz, Michael Uri Wolf, Nicolaas Paul L.G. Verhoeff, Gary Naglie, William Reichman, Mario Masellis, Sara Berman Mitchell, David F. Tang-Wai, Carmela Tartaglia, Sanjeev Kumar, Bruce G. Pollock, Tarek K. Rajji, Elizabeth Finger, Stephen H. Pasternak, ONDRI Investigators, Richard H. Swartz
Structural Brain Magnetic Resonance Imaging to Rule Out Comorbid Pathology in the Assessment of Alzheimer’s Disease Dementia: Findings from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) Study and Clinical Trials Over the Past 10 Years
Abstract: Background/Objective: Structural brain magnetic resonance imaging (MRI) is not mandatory in Alzheimer’s disease (AD) research or clinical guidelines. We aimed to explore the use of structural brain MRI in AD/mild cognitive impairment (MCI) trials over the past 10 years and determine the frequency with which inclusion of standardized structural MRI acquisitions detects comorbid vascular and non-vascular pathologies. Methods: We systematically searched ClinicalTrials.gov for AD clinical trials to determine their neuroimaging criteria and then used data from an AD/MCI cohort who underwent standardized MRI protocols, to determine type and incidence of clinically relevant comorbid pathologies. Results: Of 210 AD clinical trials, 105 (50%) included brain imaging in their eligibility criteria. Only 58 (27.6%) required MRI. 16,479 of 53,755 (30.7%) AD participants were in trials requiring MRI. In the observational AD/MCI cohort, 141 patients met clinical criteria; 22 (15.6%) had relevant MRI findings, of which 15 (10.6%) were exclusionary for the study. Discussion: In AD clinical trials over the last 10 years, over two-thirds of participants could have been enrolled without brain MRI and half without even a brain CT. In a study sample, relevant comorbid pathology was found in 15% of participants, despite careful screening. Standardized structural MRI should be incorporated into NIA-AA diagnostic guidelines (when available) and research frameworks routinely to reduce diagnostic heterogeneity.

Peng Liu*, Beiyu Zhao*, Meng Wei, Yanbo Li, Jie Liu, Louyan Ma, Suhang Shang, Kang Huo, Jin Wang, Rui Li, Qiumin Qu *These authors contributed equally to this work.
Activation of Inflammation Is Associated with Amyloid-β Accumulation Induced by Chronic Sleep Restriction in Rats
Abstract: Alzheimer’s disease (AD) is the most common age-associated neurodegenerative disease featured by progressive learning and memory deficit, and Aβ was identified as playing a key role in the process of AD and was theorized to be caused by the imbalance of production and clearance. Increasing evidence suggested an association between sleep deprivation and AD. Our recent study found that chronic sleep restriction (CSR) caused cognitive impairment and Aβ accumulation in rats, but the underlining mechanism was unclear. In the present study, we investigated the effects of inflammation on Aβ accumulation induced by CSR. We found that CSR significantly increased the expression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), and nitric oxide (NO) in brain, and the inflammatory factors levels were positively correlated with Aβ42 deposition. Additionally, the inflammatory factors were correlated with BACE1, LRP-1, and RAGE levels in both the hippocampus and the prefrontal cortex. Furthermore, the plasma levels of IL-1β, TNF-α, and NO were elevated after CSR, and the concentration of plasma inflammatory mediators were correlated with plasma levels of sLRP1 and sRAGE. These results suggested that the inflammation in brain and plasma might be involved in the CSR-induced Aβ accumulation.

Mitsuhiro Sado, Kei Funaki, Akira Ninomiya, Martin Knapp, Masaru Mimura (Handling Associate Editor: Rebecca Palm)
Does the Combination of the Cognitive Interventions Improve the Function of Daily Living and Save the Long-Term Care Cost? A Pilot Study of Effectiveness and Cost Saving Analysis of “Learning Therapy” for People with Dementia
Abstract: Background: Although the effects of various types of cognitive interventions have been evaluated, effectiveness and cost-saving effect of the combination of the different cognitive interventions is unknown. Objective: This study aimed to evaluate the feasibility of conducting a definitive trial to assess the effectiveness of combined cognitive intervention. Methods: A matched controlled trial of learning therapy (LT), a combination of cognitive training and stimulation, was conducted. The samples were recruited from the nursing homes. Inclusion criteria were as follows: age 65 years or older, clinical diagnosis of dementia, level of activities of daily living at II or above, Mini-Mental State Examination score between 10 and 26, receiving long-term-care services without history of LT, and provision of written consent. The primary outcomes were safety, validity of eligibility, retention rate, and effect on the functions of daily living represented by Criterion Time for Certification of Needed Long-Term-Care (CT for CNLTC) at 12 months. Cost-benefit analysis was also conducted to assess the cost saving effect of LT. Results: No serious adverse events were detected. The exclusion rate at the screening phase was 5% and the retention rate was 77% at 12 months. LT demonstrated statistically significant improvement in CT for CNLTC at 12 months (Δ=18.8, almost equivalent to “one” degree of the care needed level) and saved the long-term-care cost by JPY 200,000 (USD 1,618). Conclusions: LT is effective for improving care recipients’ level of care needed and has a cost saving effect. A randomized controlled trial is required to verify these findings.

Dina Silva, Sandra Cardoso, Manuela Guerreiro, João Maroco, Tiago Mendes, Luísa Alves, Joana Nogueira, Inês Baldeiras, Isabel Santana, Alexandre de Mendonça (Handling Associate Editor: Thomas Beach)
Neuropsychological Contribution to Predict Conversion to Dementia in Patients with Mild Cognitive Impairment due to Alzheimer’s Disease
Abstract: Background: Diagnosis of Alzheimer’s disease (AD) confirmed by biomarkers allows the patient to make important life decisions. However, doubt about the fleetness of symptoms progression and future cognitive decline remains. Neuropsychological measures were extensively studied in prediction of time to conversion to dementia for mild cognitive impairment (MCI) patients in the absence of biomarker information. Similar neuropsychological measures might also be useful to predict the progression to dementia in patients with MCI due to AD. Objective: To study the contribution of neuropsychological measures to predict time to conversion to dementia in patients with MCI due to AD. Methods: Patients with MCI due to AD were enrolled from a clinical cohort and the effect of neuropsychological performance on time to conversion to dementia was analyzed. Results: At baseline, converters scored lower than non-converters at measures of verbal initiative, non-verbal reasoning, and episodic memory. The test of non-verbal reasoning was the only statistically significant predictor in a multivariate Cox regression model. A decrease of one standard deviation was associated with 29% of increase in the risk of conversion to dementia. Approximately 50% of patients with more than one standard deviation below the mean in the z score of that test had converted to dementia after 3 years of follow-up. Conclusion: In MCI due to AD, lower performance in a test of non-verbal reasoning was associated with time to conversion to dementia. This test, that reveals little decline in the earlier phases of AD, appears to convey important information concerning conversion to dementia.

Aleksandra Popovac, Irena Mladenović, Jelena Krunić, Branka Trifković, Ana Todorović, Jelena Milašin, Nebojša Despotović, Ivica Stančić
Apolipoprotein E4 Allele and Dental Occlusion Deficiency as Risk Factors for Alzheimer’s Disease
Abstract: Compromised dentition has been suggested to pose a significant risk factor for dementia. It was mainly investigated through insufficient tooth number, disregarding contact between opposing teeth (dental occlusion). The E4 allele of apolipoprotein (APOE4) is the primary genetic marker for the late onset of Alzheimer’s disease (AD). However, APOE4 and dental occlusion have not yet been investigated as possible associated risk factors for AD. The study was aimed to examine the impact of dental status and different APOE gene variants on AD occurrence. Secondly, sociodemographic variables were investigated as factors potentially associated with AD. The case-control study included two groups: 116 patients with AD (according to the NINDS-ADRDA criteria) and 63 controls (Mini-Mental State Examination scores ≥24). The analysis of APOE gene polymorphism was conducted through PCR reaction. Dental examination included recording of number of teeth, presence of fixed or removable dentures, and number of functional tooth units (FTU). Regression analysis was used to investigate the joint effect of the clinical and genetic variables on AD. Results showed that patients with AD were more often carriers of E3/E4 genotype and E4 allele, had lower number of teeth and FTU, and were less likely to be married, live in home, and had less chronic diseases, compared to the controls. Regression analysis showed that presence of APOE4 allele and the number of total FTU remained associated with AD, even when adjusted for age, sex, and level of education. In conclusion, deficient dental occlusion and presence of APOE4 may independently increase risk for AD.

Maria Basta, Eirini Koutentaki, Alexandros Vgontzas, Ioannis Zaganas, Emmanouela Vogiatzi, Garyfalia Gouna, Mara Bourbouli, Symeon Panagiotakis, Stefania Kapetanaki, Julio Fernandez-Mendoza, Panagiotis Simos (Handling Associate Editor: Elissaios Karageorgiou)
Objective Daytime Napping Is Associated with Disease Severity and Inflammation in Patients with Mild to Moderate Dementia
Abstract: Background: Patients with dementia report excessive daytime sleep/sleepiness, which is associated with worse cognitive performance. Inflammatory markers may be elevated in patients with dementia and have been proposed as mediators of sleep/sleepiness. Objective: To examine the association of objective daytime napping with cognitive performance and peripheral markers of inflammation in patients with dementia as compared to not cognitively impaired (NCI) controls. Methods: A sub-sample of 46 patients with mild-to-moderate dementia and 85 NCI controls, were recruited from a large, population-based cohort of 3,140 elders (≥60 years) in Crete, Greece. All participants underwent medical history/physical examination, extensive neuropsychiatric and neuropsychological evaluation, 3-day 24-h actigraphy and a single morning measure of IL-6 and TNFα plasma levels. Comparisons of sleep parameters and inflammation markers between diagnostic groups, and between nappers and non-nappers within each diagnostic group, were conducted using ANCOVA controlling for demographics/related clinical factors. Associations between inflammatory markers, sleep variables, and neuropsychological performance were assessed within each group using partial correlation analysis controlling for confounders. Results: Patients with dementia slept 15 minutes longer during the day than NCI. Within dementia patients, nappers had significantly worse performance on autobiographic memory (p=0.002), working memory (p=0.007), episodic memory (p=0.010), and assessment of daily function (p=0.012) than non-nappers. Finally, IL-6 levels were significantly associated with nap duration within dementia patients who napped (r=0.500, p=0.01). Conclusions: Daytime napping in patients with dementia is associated with worse cognitive performance and increased IL-6 levels. In dementia, objective daytime napping, may be a marker of the severity of the disease.

Luciano Inácio Mariano, Paulo Caramelli, Henrique Cerqueira Guimarães, Leandro Boson Gambogi, Millena Vieira Brandão Moura, Mônica Sanches Yassuda, Antônio Lúcio Teixeira, Leonardo Cruz de Souza (Handling Associate Editor: Michael Hornberger)
Can Social Cognition Measurements Differentiate Behavioral Variant Frontotemporal Dementia from Alzheimer’s Disease Regardless of Apathy?
Abstract: Background: Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD) share cognitive and behavioral symptoms, such as apathy. Social cognition measurements are useful in distinguishing bvFTD from AD, but their accuracies may be affected by apathy. Objective: To investigate whether social cognition measurements can distinguish bvFTD from either apathetic or non-apathetic AD patients. Methods: Three groups of participants were enrolled in the present study: bvFTD (n = 22), AD (n = 20), and healthy controls (HC, n = 23). The AD group was divided into apathetic (n=10) and non-apathetic (n=10). All subjects underwent comprehensive neuropsychological examination, including the short version of the Social and Emotional Assessment (Mini-SEA), which comprises the facial emotion recognition test and the faux-pas recognition test (Faux-Pas Test). Apathy was assessed according to the Starkstein’s Apathy (SA) Scale. Results: The bvFTD and AD groups did not differ on global cognitive efficiency and on executive functions. In comparison to the whole AD group, bvFTD displayed lower Faux-Pas Test and Mini-SEA scores. Both AD subgroups, apathetic or non-apathetic, exhibited similar performance on all social cognition measurements. In comparison to either apathetic AD or non-apathetic AD, bvFTD patients underperformed on the Faux-Pas Test and on the Mini-SEA. The area under the curve values for the Mini-SEA total score were 0.87 (bvFTD versus AD), 0.90 (bvFTD versus apathetic AD), and 0.83 (bvFTD versus non-apathetic AD). Conclusion: Social cognition tests provide accurate distinction between bvFTD against either apathetic AD or non-apathetic AD. Social cognition measurements did not correlate with apathy severity.

Gøril Rolfseng Grøntvedt, Camilla Lauridsen, Guro Berge, Linda R. White, Øyvind Salvesen, Geir Bråthen, Sigrid Botne Sando
The Amyloid, Tau, and Neurodegeneration (A/T/N) Classification Applied to a Clinical Research Cohort with Long-Term Follow-Up
Abstract: Background: The unbiased amyloid, tau, and neurodegeneration (A/T/N) classification is designed to characterize individuals in the Alzheimer continuum and is currently little explored in clinical cohorts. Objective: A retrospective comparison of the A/T/N classification system with the results of a two-year clinical study, with extended follow-up up to 10 years after inclusion. Methods: Patients (n=102) clinically diagnosed as Alzheimer’s disease (AD) with dementia or amnestic mild cognitive impairment (MCI), and 61 cognitively healthy control individuals were included. Baseline cerebrospinal fluid core biomarkers for AD (Aβ42, phosphorylated tau, and total tau) were applied to the A/T/N classification using the final clinical diagnosis at extended follow-up as the gold standard. Results: A+T+N+ was a strong predictor for AD dementia, even among cognitively healthy individuals. Amnestic MCI was heterogenous, considering both clinical outcome and distribution within A/T/N. Some individuals with amnestic MCI progressed to clinical AD dementia within all four major A/T/N groups. The highest proportion of progression was among triple positive cases, but progression was also common in individuals with suspected non-Alzheimer pathophysiology (A-T+N+), and those with triple negative status. A-T-N- individuals who were cognitively healthy overwhelmingly remained cognitively intact over time, but in amnestic MCI the clinical outcome was heterogenous, including AD dementia, other dementias, and recovery. Conclusion: The A/T/N framework accentuates biomarkers over clinical status. However, when selecting individuals for research, a combination of the two may be necessary since the prognostic value of the A/T/N framework depends on clinical status.

Adrienne L. Atayde, Corinne E. Fischer, Tom A. Schweizer, David G. Munoz (Handling Associate Editor: Shireen Sindi)
Neuropsychiatric Inventory-Assessed Nighttime Behavior Accompanies, but Does Not Precede, Progressive Cognitive Decline Independent of Alzheimer’s Disease Histopathology
Abstract: Background: The relationship between sleep, neuropathology, and clinical manifestations of Alzheimer’s disease (AD) remains controversial. Objective: To determine whether nighttime behaviors (NTB) are associated with the development of AD histopathology or cognitive decline. Methods: We compared NTB prevalence in subjects with or without AD lesions, and with or without progressive cognitive decline. Subjects with either absent or severe plaques and tangles were identified from the National Alzheimer’s Disease Coordinating Center data sets and classified as cognitively declining if the standard deviation from their individual mean Mini-Mental Status Examination score was ≥ 2, and stable if < 2 regardless of their initial score. NTB was assessed using the Neuropsychiatric Inventory Questionnaire Quick Version (NPI-Q). Results: NTB was significantly greater in decliners than stable subjects in the group with severe histopathology as determined by frequent plaques (p = 0.003) or high Braak stage (p = 0.002). A similar significant trend was observed in subjects with absent plaques (p = 0.019) or tangles (p = 0.006). The prevalence of NTB was comparable between stable AD and non-AD subjects. NTB severity scores showed a similar pattern. Conclusion: The development of NTB as assessed by NPI-Q in subjects with or without AD lesions occurred concurrently with cognitive decline. Among cognitively stable subjects, the presence of AD histopathology did not alter NTB prevalence. Thus, NTB disruptions at the gross granularity level assessed by NPI-Q were much more closely related to cognitive decline than the formation of pathological lesions. Factors other than AD histopathology may mediate the association between NTB and cognitive decline.

Jin Zhang, Xue-feng Hua, Jinhua Gu, Feng Chen, Jianlan Gu, Cheng-Xin Gong, Fei Liu, Chun-Ling Dai (Handling Associate Editor: Xiaochuan Wang)
High Mobility Group Box 1 Ameliorates Cognitive Impairment in the 3xTg-AD Mouse Model
Abstract: Background: Alzheimer’s disease (AD) is the most common cause of dementia. Studies indicate that neuroinflammation plays an important role in the pathophysiology of AD. High-mobility group box 1 (HMGB1) is an important chromatin protein. It can be secreted by immune cells and passively released from damaged cells to promote inflammation. HMGB1 also can recruit stem cells and promote their proliferation and tissue repairing. However, the role of HMGB1 in the progression of AD is currently unknown. Objective: The aims were to investigate the effect of HMGB1 on the AD-related pathologies and cognitive function using 3xTg-AD mouse model. Methods: Female 5-6-month-old 3xTg-AD mice were intracerebroventricularly injected with 4.5 µg of HMGB1 or with saline as a control. The levels of interesting protein were assessed by western blots or immunofluorescence. The effect of HMGB1 on the cognitive function was evaluated by one-trial novel object recognition test and Morris water maze. Results: Intracerebroventricular injection of recombinant HMGB1 ameliorated cognitive impairment in 5-6-month-old 3xTg-AD mice. The levels of synapsin 1, synaptophysin, MAP2, NeuN, and phosphorylated CREB were increased in HMGB1-treated 3xTg-AD mouse brains. HMGB1 decreased intracellular amyloid-β level but did not affect tau phosphorylation. HMGB1 treatment also promoted neurogenesis in the dentate gyrus and increased the level of GFAP in the 3xTg-AD mouse brains. Conclusion: These results reveal a novel function of HMGB1 in enhancing neuroplasticity and improving cognitive function in 3xTg-AD mice.

Dario Arnaldi, Andrea Donniaquio, Pietro Mattioli, Federico Massa, Matteo Grazzini, Riccardo Meli, Laura Filippi, Stefano Grisanti, Francesco Famà, Michele Terzaghi, Nicola Girtler, Andrea Brugnolo, Elisa Doglione, Matteo Pardini, Flavio Villani, Flavio Nobili
Epilepsy in Neurodegenerative Dementias: A Clinical, Epidemiological, and EEG Study
Abstract: Background: Seizures are common in patients with dementia but precise epidemiologic data of epilepsy in neurodegenerative dementia is lacking. Objective: The first aim of the study was to investigate prevalence and clinical characteristics of epilepsy in a large cohort of patients with neurodegenerative dementias. Subsequently, we explored clinical, neuropsychological, and quantitative electroencephalogram (qEEG) data of Alzheimer’s disease (AD) patients with epilepsy (AD-EPI) as compared to AD patients without epilepsy (AD-CTR). Methods: We retrospectively evaluated consecutive patients with a diagnosis of a neurodegenerative dementia and a clinically diagnosed epilepsy that required antiepileptic drugs (AED). All patients underwent baseline comprehensive neuropsychological assessment. A follow-up of at least one year was requested to confirm the dementia diagnosis. In AD patients, qEEG power band analysis was performed. AD-CTR and AD-EPI patients were matched for age, Mini-Mental State Examination score, and gender. Results: Thirty-eight out of 2,054 neurodegenerative dementia patients had epilepsy requiring AED. The prevalence of epilepsy was 1.82% for AD, 1.28% for the behavioral variant of frontotemporal dementia (bvFTD), 2.47% for dementia with Lewy bodies (DLB), and 12% for primary progressive aphasia. Epilepsy were more drug-responsive in AD than in non-AD dementias. Finally, no significant differences were found in neuropsychological and qEEG data between AD-EPI and AD-CTR patients. Conclusion: In our cohort, AD, FTD, and DLB dementias have similar prevalence of epilepsy, even if AD patients were more responsive to AED. Moreover, AD-EPI patients did not have significant clinical, neuropsychological qEEG differences compared with AD-CTR patients.

Aimin Yang*, Hongwei Wang*, Xiaoxiao Zuo, Jianjun Yang (Handling Associate Editor: Weicheng Yao) *These authors contributed equally to this work.
Potassium Chloride Cotransporter 2 Inhibits Neuropathic Pain and Future Development of Neurodegeneration
Abstract: Persistent neuropathic pain (NP) causes future development of neurodegenerative diseases, e.g., Alzheimer’ disease, and thus needs to be optimally treated. Surgically-induced neuropathic pain (SNPP) is a persistent pain that occurs in nearly half of the individuals after common operations. Here, we showed that specific activation of 5-hydroxytryptamine (5-HT) type 2A receptors by systemic administration of TCB-2 [(4-bromo-3,6-dimethoxybenzocyclobuten-1-yl) methylamine hydrobromide] improved the function of potassium chloride cotransporter 2 (KCC2), resulting in reduction in neuropathic pain after chronic constriction injury (CCI), a rat model that mimics SNPP. Moreover, TCB-2 administration attenuated both mechanical and thermal hyperalgesia, likely through augmentation of dorsal horn KCC2 levels, since this effect was abolished by intrathecal provision of dihydroindenyl oxy alkanoic acid (DIOA), which blocked the effects of KCC2. Furthermore, TCB-2-mediated re-activation of KCC2 likely reduces future development of neurodegeneration in rats. Together, our data support further studies on the possibility of using this strategy to reduce postoperative pain and future neurodegenerative disorders in clinic.

Hasan A.M.M. Almansoub, Hui Tang, Ying Wu, Ding-Qi Wang, Yacoubou Abdoul Razak Mahaman, Maibouge Tanko Mahamane Salissou, Youming Lu, Fan Hu, Lan-Ting Zhou, Yusra A.M. Almansob, Dan Liu (Handling Associate Editor: Jin-Tai Yu)
Oxytocin Alleviates MPTP-Induced Neurotoxicity in Mice by Targeting MicroRNA-26a/Death-Associated Protein Kinase 1 Pathway
Abstract: Neurotoxicity is one of the major pathological changes in multiple neurological disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), the second popular neurodegenerative disease in aged people. It is known that the AD and PD share the similar neuropathological hallmarks, such as the oxidative stress, loss of specific neurons, and aggregation of specific proteins. However, there are no effective therapeutic drugs for both AD and PD yet. Oxytocin (OXT) is a small peptide with 9 amino acids that is neuroprotective to many neurological disorders. Whether OXT administration confers neuroprotection to 1-methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine (MPTP)-induced neurotoxicity in mice are still not known. In this study, we first found that the OXT levels are decreased in MPTP mice. Supplementation with OXT effectively rescues the locomotor disabilities and anxiety-like behaviors in MPTP mice. OXT also alleviates the hyperphosphorylation of α-synuclein at S129 site and the loss of dopaminergic neurons in the substantia nigra pars compacta, as well as the oxidative stress in the MPTP mice, and alleviates both oxidative stress and cell cytotoxicity in vitro. Furthermore, we found that OXT could inhibit the miR-26a/DAPK1 signal pathway in MPTP mice. In summary, our study demonstrates protective effects of OXT in MPTP mice and that miR-26a/DAPK1 signaling pathway may play an important role in mediating the protection of OXT.

Cecilia Marelli, Claire Hourregue, Laure-Anne Gutierrez, Claire Paquet, Nicolas Menjot de Champfleur, Delphine De Verbizier, Melissa Jacob, Jonathan Dubois, Aleksandra Maceski Maleska, Christophe Hirtz, Sophie Navucet, Karim Bennys, Julien Dumurgier, Emmanuel Cognat, Claudine Berr, Eloi Magnin, Sylvain Lehmann, Audrey Gabelle (Handling Associate Editor: Barbara Borroni)
Cerebrospinal Fluid and Plasma Biomarkers Do Not Differ in the Presenile and Late-Onset Behavioral Variants of Frontotemporal Dementia
Abstract: Background: Memory troubles and hippocampal atrophy are considered more frequent and focal atrophy less severe in late-onset (>65 years) than in presenile behavioral variant frontotemporal dementia (bvFTD). Objective: To compare cerebrospinal fluid (CSF) and plasma biomarkers in late-onset and presenile bvFTD. Methods: Multicentric retrospective study (2007-2017) on patients with clinical diagnosis of bvFTD. Results: This study included 44 patients (67%) with presenile and 22 (33%) with late-onset bvFTD (comparable mean disease duration; n=11 with causal mutations). Hippocampal atrophy was more frequent (80% versus 25.8%) and severe in late-onset bvFTD (median Scheltens score: 3 [0-4] versus 1 [0-3]), without difference after adjustment for age. Lobar atrophy and focal hypometabolism/hypoperfusion were not different between groups. The median CSF Aβ1-42 and phosphorylated tau (P-tau) concentrations were in the normal range and comparable between groups. Axonal neurodegeneration biomarkers were within the normal range (CSF T-tau; plasma T-tau in late-onset bvFTD) or higher (plasma neurofilament light chain (NFL); plasma T-tau in presenile bvFTD) than the normal values, but globally not different between bvFTD groups. Plasma glial fibrillary acid protein (GFAP) was strongly increased in both bvFTD groups compared with the values in controls of the same age. Conclusion: The CSF and plasma biomarker profiles did not suggest a more aggressive neurodegeneration in the presenile group (comparable T-tau, NFL, and GFAP levels) or the co-existence of Alzheimer’s disease in the late-onset group (comparable and within normal range CSF Aβ1-42 and P-tau). The severity of the neurodegenerative process seems comparable in presenile and late-onset bvFTD.

Eva Mª Arroyo-Anlló, Jorge Chamorro Sánchez, Alejandra R. Melero Ventola, Pierre Ingrand, Jean-Philippe Neau, Roger Gil
Procedural Learning Improves Cognition in Multiple Sclerosis
Abstract: Background: Multiple sclerosis (MS) is considered a neurodegenerative disease and an inflammatory demyelinating neuropathology in young population. Procedural memory has been poorly investigated in MS. Objective: We assessed whether the MS group was able to develop a motor-cognitive skill, using a procedural task (PLSC) developed in our laboratory, applying a manual and serial reaction time (RT) paradigm to semantic categorization. Methods: We evaluated 26 MS patients and 26 socio-demographic matched control participants using the PLSC task. Results: Using non-parametric statistical analyses, we observed a significant improvement of semantic categorization RTs with practice (p=0.002), even with new verbal material to categorize in MS patients (p=0.006), despite their motor and executive moderate deficits. This same profile of semantic procedural learning in MS was observed in previous studies carried out with Alzheimer’s and Parkinson’s diseases. Moreover, the visual-motor RTs remained stable or slightly improved over the five blocks in both groups, as well as in the AD groups of previous studies. The MS group showed longer visual-motor reaction times than those of the control group (p<0.042), except in motor initiation aspect (p=0.064). Both groups showed no significant differences for any type of error. Additionally, disability level and cognitive performances were not associated with the ratio of semantic procedural learning. Conclusion: The present results support the notion that MS patients may be capable of acquiring semantic skill, despite their motor disabilities and executive troubles. This work also addresses the possibilities to improve motor-cognitive skill RTs in neurodegenerative diseases.

Evan P. Pasha, Elmer Rutjes, Tsubasa Tomoto, Takashi Tarumi, Ann Stowe, Jurgen A.H.R. Claassen, C. Munro Cullum, David C. Zhu, Rong Zhang
Carotid Stiffness Is Associated with Brain Amyloid-β Burden in Amnestic Mild Cognitive Impairment
Abstract: Background: Vascular dysfunction has been implicated in the onset and progression of Alzheimer’s disease (AD), yet the relationship of arterial stiffening with brain amyloid-β (Aβ) burden in at risk patients is unclear. Objective: We aimed to determine the relationship of aortic and carotid arterial stiffening with Aβ burden in patients with amnestic mild cognitive impairment (aMCI), a proposed transitional stage between normal aging and AD. Methods: Thirty-two older adults with aMCI underwent 18Florbetapir PET amyloid imaging to ascertain Aβ burden via standardized uptake value ratio (SUVR). Carotid-femoral pulse wave velocity (cfPWV), which reflects aortic stiffness, and carotid β stiffness index and distensibility, which reflect local cerebral arterial stiffness, thus having direct impact on the cerebral circulation, were measured using applanation tonometry and ultrasonography. Results: Region-of-interest based analysis showed that precuneus and mean cortex Aβ SUVR were correlated positively with carotid β stiffness index and negatively with carotid distensibility after adjusting for age, sex, mean arterial pressure (MAP), pulse pressure (PP), and APOE4 status. Whole-brain voxel-wise analysis showed that Aβ SUVR was positively correlated with carotid β stiffness index, and negatively with carotid distensibility at the precuneus/cingulate gyrus after multiple comparison correction. cfPWV was not correlated with Aβ SUVR. Conclusions: Carotid rather than aortic stiffening is independently associated with brain Aβ burden in patients with aMCI after adjusting for age, sex, MAP, PP, and APOE4 status. These findings provide evidence that arterial stiffening, particularly carotid artery stiffening, may contribute to AD pathology in patients with aMCI.

Georgia Watt*, Kani Shang*, Jerzy Zieba, Juan Olaya, Henry Li, Brett Garner**, Tim Karl** *,**These authors contributed equally to this work.
Chronic Treatment with 50 mg/kg Cannabidiol Improves Cognition and Moderately Reduces Aβ42 Levels in 12-Month-Old Male AβPPswe/PS1∆E9 Transgenic Mice
Abstract: Alzheimer’s disease (AD) is characterized by progressive cognitive decline and pathologically by the accumulation of amyloid-β (Aβ) and tau hyperphosphorylation causing neurodegeneration and neuroinflammation. Current AD treatments do not stop or reverse the disease progression, highlighting the need for more effective therapeutics. The phytocannabinoid cannabidiol (CBD) has demonstrated antioxidant, anti-inflammatory, and neuroprotective properties. Furthermore, chronic CBD treatment (20 mg/kg) reverses social and object recognition memory deficits in the AβPPxPS1 transgenic mouse model with only limited effects on AD-relevant brain pathology. Importantly, studies have indicated that CBD works in a dose-dependent manner. Thus, this study determined the chronic effects of 50 mg/kg CBD in male AβPPxPS1 mice. 12-month-old mice were treated with 50 mg/kg CBD or vehicle via daily intraperitoneal injections for 3 weeks prior to behavioral testing. A variety of cognitive domains including object and social recognition, spatial and fear-associated memory were evaluated. Pathological brain analyses for AD-relevant markers were conducted using ELISA and western blot. Vehicle-treated male AβPPxPS1 mice demonstrated impaired social recognition memory and reversal spatial learning. These deficits were restored after CBD treatment. Chronic CBD tended to reduce insoluble Aβ40 levels in the hippocampus of AβPPxPS1 mice but had no effect on neuroinflammation, neurodegeneration, or PPARγ markers in the cortex. This study demonstrates that therapeutic-like effects of 50 mg/kg CBD on social recognition memory and spatial learning deficits in AβPPxPS1 mice are accompanied by moderate brain region-specific reductions in insoluble Aβ40 levels. The findings emphasize the clinical relevance of CBD treatment in AD; however, the underlying mechanisms involved require further investigation.

Zuzana Stozicka*, Miroslava Korenova*, Ivana Uhrinova, Veronika Cubinkova, Martin Cente, Branislav Kovacech, Nikoleta Babindakova, Katarina Matyasova, Greta Vargova, Michal Novak, Petr Novak, Norbert Zilka, Santosh Jadhav (Handling Associate Editor: Alejandra Alonso) *These authors contributed equally to this work.
Environmental Enrichment Rescues Functional Deficit and Alters Neuroinflammation in a Transgenic Model of Tauopathy
Abstract: Alzheimer’s disease (AD) is the most frequent neurodegenerative disorder, affecting over 44 million people worldwide. There are no effective pharmaco-therapeutic options for prevention and treatment of AD. Non-pharmacological approaches may help patients suffering from AD to significantly ameliorate disease progression. In this study, we exposed a transgenic rat model (tg) of human tauopathy to enriched environment for 3 months. Behavioral testing at 6 months of age revealed improvement in functional deficits of tg rats reared under enriched conditions, while sedentary tg rats remained severely impaired. Interestingly, enriched environment did not reduce tau pathology. Analysis of neurotrophic factors revealed an increase of nerve growth factor (NGF) levels in the hippocampus of both enriched groups (tg and non-tg rats), reflecting a known effect of enriched environment on the hippocampal formation. On the contrary, NGF levels decreased markedly in the brainstem of enriched groups. The non-pharmacological treatment also reduced levels of tissue inhibitor of metalloproteinase 1 in the brainstem of transgenic rats. Expression analysis of inflammatory pathways revealed upregulation of microglial markers, such as MHC class II and Cd74, whereas levels of pro inflammatory cytokines remained unaffected by enriched environment. Our results demonstrate that exposure to enriched environment can rescue functional impairment in tau transgenic rats without reducing tau pathology. We speculate that non pharmacological treatment modulates the immune response to pathological tau protein inclusions, and thus reduces the damage caused by neuroinflammation.

Hailey A. Kresge, Dandan Liu, Deepak K. Gupta, Elizabeth E. Moore, Katie E. Osborn, Lealani Mae Y. Acosta, Susan P. Bell, Kimberly R. Pechman, Katherine A. Gifford, Lisa A. Mendes, Thomas J. Wang, Kaj Blennow, Henrik Zetterberg, Timothy J. Hohman, Angela L. Jefferson
Lower Left Ventricular Ejection Fraction Relates to Cerebrospinal Fluid Biomarker Evidence of Neurodegeneration in Older Adults
Abstract: Background: Subclinical cardiac dysfunction is associated with decreased cerebral blood flow, placing the aging brain at risk for Alzheimer’s disease (AD) pathology and neurodegeneration. Objective: This study investigates the association between subclinical cardiac dysfunction, measured by left ventricular ejection fraction (LVEF), and cerebrospinal fluid (CSF) biomarkers of AD and neurodegeneration. Methods: Vanderbilt Memory & Aging Project participants free of dementia, stroke, and heart failure (n=152, 72±6 years, 68% male) underwent echocardiogram to quantify LVEF and lumbar puncture to measure CSF levels of amyloid-β42 (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau). Linear regressions related LVEF to CSF biomarkers, adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, cognitive diagnosis, and apolipoprotein E ε4 status. Secondary models tested an LVEF x cognitive diagnosis interaction and then stratified by diagnosis (normal cognitive (NC), mild cognitive impairment (MCI)). Results: Higher LVEF related to decreased CSF Aβ42 levels (β=-6.50, p=0.04) reflecting greater cerebral amyloid accumulation, but this counterintuitive result was attenuated after excluding participants with cardiovascular disease and atrial fibrillation (p=0.07). We observed an interaction between LVEF and cognitive diagnosis on CSF t-tau (p=0.004) and p-tau levels (p=0.002), whereas lower LVEF was associated with increased CSF t-tau (β=-9.74, p=0.01) and p-tau in the NC (β=-1.41, p=0.003) but not MCI participants (p-values>0.13). Conclusions: Among cognitively normal older adults, subclinically lower LVEF relates to greater molecular evidence of tau phosphorylation and neurodegeneration. Modest age-related changes in cardiovascular function may have implications for pathophysiological changes in the brain later in life.

Natalie Tomaszewski*, Xulei He*, Victoria Solomon, Mitchell Lee, Wendy J. Mack, Joseph F. Quinn, Meredith N. Braskie, Hussein N. Yassine *These authors contributed equally to this work.
Effect of APOE Genotype on Plasma Docosahexaenoic Acid (DHA), Eicosapentaenoic Acid, Arachidonic Acid, and Hippocampal Volume in the Alzheimer’s Disease Cooperative Study-Sponsored DHA Clinical Trial
Abstract: Background: Docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (AA) play key roles in several metabolic processes relevant to Alzheimer’s disease (AD) pathogenesis and neuroinflammation. Carrying the APOE ε4 allele (APOE4) accelerates omega-3 polyunsaturated fatty acid (PUFA) oxidation. In a pre-planned subgroup analysis of the Alzheimer’s Disease Cooperative Study-sponsored DHA clinical trial, APOE4 carriers with mild probable AD had no improvements in cognitive outcomes compared to placebo, while APOE4 non-carriers showed a benefit from DHA supplementation. Objective: We sought to clarify the effect of APOE ε4/ε4 on both the ratio of plasma DHA and EPA to AA, and on hippocampal volumes after DHA supplementation. Methods: Plasma fatty acids and APOE genotype were obtained in 275 participants randomized to 18 months of DHA supplementation or placebo. A subset of these participants completed brain MRI imaging (n=86) and lumbar punctures (n=53). Results: After the intervention, DHA-treated APOE ε3/ε3 and APOE ε2/ε3 carriers demonstrated significantly greater increase in plasma DHA/AA compared to ε4/ε4 carriers. APOE ε2/ε3 had a greater increase in plasma EPA/AA and less decline in left and right hippocampal volumes compared to compared to ε4/ε4 carriers. The change in plasma and cerebrospinal fluid DHA/AA was strongly correlated. Greater baseline and increase in plasma EPA/AA was associated with a lower decrease in the right hippocampal volume, but only in APOE4 non-carriers. Conclusion: The lower increase in plasma DHA/AA and EPA/AA in APOE ε4/ε4 carriers after DHA supplementation reduces brain delivery and affects the efficacy of DHA supplementation.

Haihua Zhang, Tao Wang, Zhifa Han, Longcai Wang, Yan Zhang, Lijun Wang, Guiyou Liu (Handling Associate Editor: Jin-Tai Yu)
Impact of Vitamin D Binding Protein Levels on Alzheimer’s Disease: A Mendelian Randomization Study
Abstract: Until now, observational studies, randomized controlled trials (RCTs), and Mendelian randomization (MR) studies have explored the impact of vitamin D on Alzheimer’s disease (AD), and reported inconsistent findings. In MR studies, the sensitivity analysis by removing GC rs2282679 variant highlighted no association of 25OHD levels with AD risk, which indicates that vitamin D-binding protein (DBP) encoded by GC may have distinct effects on AD risk. Here, we aim to clarify this assumption. We selected the GC rs2282679 variant associated with DBP levels (p=3.30E-76) as the instrumental variable, and extracted the summary statistics of rs2282679 variant in multiple AD GWAS datasets from IGAP, Complex Trait Genetics (CTG) lab, and UK Biobank. We then performed a MR study to investigate the causal association between DBP levels and AD. In IGAP, MR analysis showed that the genetically DBP levels (per 1 standard deviation (SD) increase 50 mg/L) were significantly associated with reduced AD risk (OR=0.63, 95% CI: 0.45-0.89, p=0.009). Importantly, the estimates from two sensitivity analyses were consistent with the main estimate in terms of direction and magnitude. Meanwhile, we found no causal association between DBP levels and other four AD phenotypes in CTG lab and UK Biobank. In summary, we highlight the role of DBP levels in AD risk, and provide strong support evidence that DBP may be the therapeutic agent for the treatment of AD. Meanwhile, our findings clarify the assumption that DBP may drive the observed relationship between 25OHD levels and AD.

Kathryn Richardson, Stephen B. Wharton, Carlota M. Grossi, Fiona E. Matthews, Chris Fox, Ian Maidment, Yoon K. Loke, Nicholas Steel, Antony Arthur, Phyo Kyaw Myint, Malaz Boustani, Noll Campbell, Louise Robinson, Carol Brayne, George M. Savva
Neuropathological Correlates of Cumulative Benzodiazepine and Anticholinergic Drug Use
Abstract: Background: Benzodiazepines and anticholinergic drugs have been implicated in causing cognitive decline and potentially increasing dementia risk. However, evidence for an association with neuropathology is limited. Objective: To estimate the correlation between neuropathology at death and prior use of benzodiazepines and anticholinergic drugs. Methods: We categorized 298 brain donors from the population-based Medical Research Council Cognitive Function and Ageing Study, according to their history of benzodiazepine (including Z-drugs) or anticholinergic medication (drugs scoring 3 on the Anticholinergic Cognitive Burden scale) use. We used logistic regression to compare dichotomized neuropathological features for those with and without history of benzodiazepine and anticholinergic drug use before dementia, adjusted for confounders. Results: Forty-nine (16%) and 51 (17%) participants reported benzodiazepine and anticholinergic drug use. Alzheimer’s disease neuropathologic change was similar whether or not exposed to either drug, for example 46% and 57% had intermediate/high levels among those with and without anticholinergic drug use. Although not significant after multiple testing adjustments, we estimated an odds ratio (OR) of 0.40 (95% confidence interval [95%CI] 0.18-0.87) for anticholinergic use and cortical atrophy. For benzodiazepine use, we estimated ORs of 4.63 (1.11-19.24) and 3.30 (1.02–10.68) for neuronal loss in the nucleus basalis and substantial nigra. There was evidence of neuronal loss in the nucleus basalis with anticholinergic drug use, but the association reduced when adjusted for confounders. Conclusions: We found no evidence that benzodiazepine or anticholinergic drug use is associated with typical pathological features of Alzheimer’s disease; however, we cannot rule out effects owing to small numbers.