Volume 67, Number 4, IN PRESS

Review
Xiaohua Zhang*, Kejing Lao*, Zhongyin Qiu, Md Saidur Rahman, Yuelin Zhang, Xingchun Gou * These authors contributed equally to this work.
Potential Astrocytic Receptors and Transporters in the Pathogenesis of Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is the most common cause of dementia and is characterized by the progressive loss of memory and cognition in the aging population. However, the etiology of and therapies for AD remain far from understood. Astrocytes, the most abundant neuroglia in the brain, have recently aroused substantial concern due to their involvement in synaptotoxicity, amyloidosis, neuroinflammation, and oxidative stress. In this review, we summarize the candidate molecules of astrocytes, especially receptors and transporters, that may be involved in AD pathogenesis. These molecules include excitatory amino acid transporters (EAATs), metabotropic glutamate receptor 5 (mGluR5), the adenosine 2A receptor (A2AR), the α7-nicotinic acetylcholine receptor (α7-nAChR), the calcium-sensing receptor (CaSR), S100β, and cannabinoid receptors. We describe the characteristics of these molecules and the neurological and pharmacological underpinnings of these molecules in AD. Among these molecules, EAATs, A2AR, and mGluR5 are strongly related to glutamate-mediated synaptotoxicity and are involved in glutamate transmission or the clearance of extrasynaptic glutamate in the AD brain. The α7-nAChR, CaSR, and mGluR5 are receptors of Aβ and can induce a plethora of toxic effects, such as the production of excess Aβ, synaptotoxicity, and NO production triggered by changes in intracellular calcium signaling. Antagonists or positive allosteric modulators of these receptors can repair cognitive ability and modify neurobiological changes. Moreover, blocking S100β or activating cannabinoid receptors reduces neuroinflammation, oxidative stress, and reactive astrogliosis. Thus, targeting these molecules might provide alternative approaches for treating AD.

Review
Ankur Ashwin Patel, Ganepola Araccige Padmajiva Ganepola, John Raymond Rutledge, David Hsuan-sheng Chang (Handling Associate Editor: Simone Agostini)
The Potential Role of Dysregulated miRNAs in Alzheimer’s Disease Pathogenesis and Progression
Abstract: Alzheimer’s disease (AD) is a debilitating neurodegenerative disease that affects the cognitive faculties of millions of people worldwide. There is still no known cure for AD, nor a clear understanding of AD etiology. Nevertheless, researchers have made significant strides in understanding various key aspects of AD neuropathology at the cellular and molecular levels. This review is intended to provide a general survey of what is known and unknown, based on the three hallmarks of AD, combined with our knowledge from microRNA research. Our goal is to reevaluate and reassess the current direction of AD research and therapeutic insights, charting a new course and comprehensive plan to combat this imminent global health threat.

Review
Yusra Mansour, Kaitlyn Blackburn, Luis Oscar González-González, Lilian Calderón-Garcidueñas*, Randy J. Kulesza* *These authors contributed equally to this work.
Auditory Brainstem Dysfunction, Non-Invasive Biomarkers for Early Diagnosis and Monitoring of Alzheimer’s Disease in Young Urban Residents Exposed to Air Pollution
Abstract: Alzheimer’s disease (AD) is a biological construct defined by abnormal deposits of hyperphosphorylated tau and amyloid-β. The 2050 projection for AD in the USA is 14 million. There is a strong association between AD, air pollution, and traffic. Early diagnosis is imperative for intervention in the initial disease stages. Hearing and, specifically, the ability to encode complex sounds are impaired in AD. Nuclei in the auditory brainstem appear to be sensitive to neurodevelopmental and neurodegenerative disorders. Specifically, sustained exposure to air pollution is harmful to the brainstem; young residents of Metropolitan Mexico City (MMC) exposed to fine particulate matter and combustion-derived nanoparticles develop AD pathology in infancy. MMC clinically healthy children and teens have significant central delays in brainstem auditory evoked potentials (BAEPs). Herein, we review evidence that the auditory pathway is a key site of AD early pathology associated with air pollution and is significantly involved in AD patients. We strongly suggest electrophysiological screening, including BAEPs, be employed to screen individuals for early delays and to monitor progressive decline in patients diagnosed with mild cognitive impairment and AD. Understanding auditory dysfunction in early AD in pediatric and young adult populations may clarify mechanisms of disease progression. Air pollution is a risk factor for the development of AD and as the number of Americans with AD continues to grow without a cure, we need to focus on preventable, early causes of this fatal disease and intervene appropriately.

Review
George T. Grossberg, Gary Tong, Anna D. Burke, Pierre N. Tariot (Handling Associate Editor: Anne Fink)
Present Algorithms and Future Treatments for Alzheimer’s Disease
Abstract: An estimated 47 million people live with Alzheimer’s disease (AD) and other forms of dementia worldwide. Although no disease-modifying treatments are currently available for AD, earlier diagnosis and proper management of the disease could have considerable impact on patient and caregiver quality of life and functioning. Drugs currently approved for AD treat the cognitive, behavioral, and functional symptoms of the disease and consist of three cholinesterase inhibitors (ChEIs) and the N-methyl-D-aspartate receptor antagonist memantine. Treatment of patients with mild to moderate AD is generally initiated with a ChEI. Patients who show progression of symptoms while on ChEI monotherapy may be switched to another ChEI and/or memantine can be added to the treatment regimen. In recent years, putative disease-modifying therapies have emerged that aim to slow the progression of AD instead of only addressing its symptoms. However, many therapies have failed in clinical trials in patients with established AD, suggesting that, once developed, disease-modifying agents may need to be deployed earlier in the course of illness. The goal of this narrative literature review is to discuss present treatment algorithms and potential future therapies in AD.

Short Communication
Giorgio Giulio Fumagalli, Luca Sacchi, Paola Basilico, Andrea Arighi Tiziana Carandini, Marta Scarioni, Annalisa Colombi, Anna Pietroboni, Laura Ghezzi, Chiara Fenoglio, Maria Serpente, Marianna D’anca, Marina Arcaro, Matteo Mercurio, Fabio Triulzi, Elisa Scola, Giorgio Marotta, Elio Scarpini, Daniela Galimberti (Handling Associate Editor: Laura Serra)
Monozygotic Twins with Frontotemporal Dementia due to Thr272fs GRN Mutation Discordant for Age at Onset
Abstract: We report the case of two monozygotic twins with Thr272fs mutation in progranulin gene. Both patients developed frontotemporal dementia with 5 years difference in age at onset (Twin 1: 73 years, Twin 2: 68 years), with early behavioral, language, dysexecutive, and memory problems. They had the same formal education (5 years), but while Twin 1 dedicated more to social and leisure activity, Twin 2 worked all her life. At neuroimaging (MRI for Twin 1 and CT for Twin 2), they both showed asymmetric atrophy with left predominance. The two were discordant for total tau levels in cerebrospinal fluid, neuropsychological testing, and smoking habits. The description of the twins can help identify environmental factors that influence the onset and phenotype of frontotemporal dementia.

Leonardo Guzmán-Martínez, José Pablo Tapia, Gonzalo A. Farías, Andrea González, Matías Estrella, Ricardo B. Maccioni
The Alz-tau Biomarker for Alzheimer’s Disease: Study in a Caucasian Population
Abstract: The establishment of a molecular biomarker for early detection of Alzheimer’s disease (AD) is critical for diagnosis and follow up of patients, and as a quantitative parameter in the evaluation of potential new drugs to control AD. A list of blood biomarkers has been reported but none has been validated for the Alzheimer’s clinic. The changes in hyperphosphorylated tau and amyloid peptide in the cerebrospinal fluid is currently used as a tool in the clinics and for research purposes, but this method is highly invasive. Recently, we reported a non-invasive and reliable blood biomarker that correlates the increase in the ratio of heavy tau (HMWtau) and the low molecular weight tau (LMWtau) in human platelets and the decrease in the brain volume as measured by structural MRI. This molecular marker has been named Alz-tau®. Beyond the clinical trials developed with a Latin American population, the present study focuses on an evaluation of this biomarker in a Caucasian population. We examined 36 AD patients and 15 cognitively normal subjects recruited in Barcelona, Spain. Tau levels in platelets were determined by immunoreactivity and the cognitive status by using GDS and MMSE neuropsychological tests. The HMW/LMW tau ratio was statistically different between controls and AD patients. A high correlation was found between the increase in MMSD and GDS scores and HMW/LMW tau ratio. This study showed that this ratio is significantly higher in AD patients than controls. Moreover, this study on a peripheral marker of AD is valuable to understanding the AD pathogenesis.

Veronika Pražienková, Claire Schirmer, Martina Holubová, Blanka Železná, Jaroslav Kuneš, Marie-Christine Galas, Lenka Maletínská
Lipidized Prolactin-Releasing Peptide Agonist Attenuates Hypothermia-Induced Tau Hyperphosphorylation in Neurons
Abstract: Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases, characterized by the accumulation of extracellular amyloid plaques and intraneuronal neurofibrillary tangles. These tangles mainly consist of hyperphosphorylated tau protein. As it induces tau hyperphosphorylation in vitro and in vivo, hypothermia is a useful tool for screening potential neuroprotective compounds that ameliorate tau pathology. In this study, we examined the effect of prolactin-releasing peptide (PrRP), its lipidized analog palm11-PrRP31 and glucagon-like peptide 1 agonist liraglutide, substances with anorexigenic and antidiabetic properties, on tau phosphorylation and on the main kinases and phosphatases involved in AD development. Our study was conducted in a neuroblastoma cell line SH-SY5Y and rat primary neuronal cultures under normothermic and hypothermic conditions. Hypothermia induced a significant increase in tau phosphorylation at the pThr212 and pSer396/pSer404 epitopes. The palmitoylated analogs liraglutide and palm11-PrRP31 attenuated tau hyperphosphorylation, suggesting their potential use in the treatment of neurodegenerative diseases.

Daisuke Hirose, Soichiro Shimizu, Kentaro Hirao, Yusuke Ogawa, Tomohiko Satou, Yoshitsugu Kaneko, Naoto Takenoshita, Nayuta Namioka, Raita Fukasawa, Takahiko Umahara, Hirofumi Sakurai, Ryo Watanabe, Haruo Hanyu
Neuroimaging Characteristics of Frailty Status in Patients with Alzheimer’s disease
Abstract: Background/Objective: Although frailty is closely linked to dementia, particularly Alzheimer’s disease (AD), underlying pathophysiology of frailty associated with AD remains uncertain. This study aimed to investigate differences in structural and functional brain imaging abnormalities between AD with and without frailty. Methods: A total of 191 outpatients with probable AD (men: 91; women: 100; age: 80.7 ± 6.3 years) who underwent both magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT) were enrolled in this study. Frailty was determined in accordance with the Obu study Health Promotion for the Elderly. We compared numbers of small infarctions in the subcortical gray and white matter and severity of white matter abnormalities (periventricular hyperintensity [PVH] and deep white matter hyperintensity [DWMH]) on MRI, and regional cerebral blood flow (rCBF) changes on SPECT between AD with and without frailty. Results: The prevalence of frailty was 43.4% in patients with AD. PVH and DWMH scores were significantly higher in AD with frailty compared to those without frailty. AD with frailty had a trend of decreased rCBF in the bilateral anterior cingulate gyrus, whereas those without frailty tend to have decreased rCBF in the left dominant parietal lobe and precuneus. Conclusion: Our MRI and SPECT imaging studies suggest different underlying pathophysiology in the brain between AD with frailty and without frailty.

Bibek Gyanwali, Muhammad Amin Shaik, Boon Yeow Tan, Narayanaswamy Venketasubramanian, Christopher Chen*, Saima Hilal* *Joint last authors
Risk Factors for and Clinical Relevance of Incident and Progression of Cerebral Small Vessel Disease Markers in an Asian Memory Clinic Population
Abstract: Background: Cerebral small vessel disease (SVD) is one of the major contributors to cognitive impairment and dementia. However, data on the incidence and progression of SVD in an Asian population are lacking. Objective: The present study aims to investigate the incidence, progression, associated risk factors, and clinical relevance of SVD in a memory clinic setting. Methods: A prospective case-control study, where 346 patients underwent repeated brain MRI with a mean interval of 24.5 months, accessing white matter hyperintensities (WMH), lacunes and cerebral microbleeds (CMBs). Severity of cognitive impairment was assessed using Clinical Dementia Rating scale and change in clinical diagnosis. Data on demographics, vascular risk factors, and clinical history were collected at baseline. Results: The prevalence of significant WMH (Fazekas ≥2) was 56.6% at baseline which progressed to 59.0% at follow-up. Overall prevalence of CMBs increased from 42.2% to 47.4% (9% new cases) and lacunes increased from 31.8% to 33.2% (2.1% new cases). Hypertension was associated with WMH progression (OR: 1.78, 95%CI: 1.01, 2.99) and increasing age was associated with incident CMBs (OR: 1.04, 95%CI: 1.01, 1.08). Moreover, the use of lipid-lowering medications decreased the incidence of lacunes (OR: 0.15, 95% CI: 0.04, 0.61). The major risk factor for incident SVD was baseline SVD lesion load. WMH progression was associated with increased severity of cognitive impairment (OR: 1.95, 95%CI: 1.16, 3.23). Conclusion: Vascular risk factors and baseline severity of SVD lesion load were associated with progression of SVD. Furthermore, WMH progression was linked with increased severity of cognitive impairment. Future studies should be aimed to slow cognitive deterioration by preventing SVD related brain damage by targeting vascular risk factors.

Yuanxin Chen, Tianduo Wang, Kem A. Rogers, Brian K. Rutt, John A. Ronald
Close Association of Myeloperoxidase-Producing Activated Microglia with Amyloid Plaques in Hypercholesterolemic Rabbits
Abstract: Microglial activation and oxidative stress have been linked to the formation of amyloid plaques found in Alzheimer’s disease (AD). Epidemiologic and experimental evidence also suggests that cholesterol (CH) contributes to the pathogenesis of AD, particularly the formation of amyloid plaques. We have previously described the development of amyloid-β (Aβ) plaques in New Zealand white rabbits maintained on a 0.125%-0.25% w/w CH diet for extended periods of time (28 months). Here we further characterize this model with combined immunofluorescence and immunohistochemical staining to evaluate markers of immune cell activation. Five out of eight CH-fed rabbits, but not control rabbits, developed extracellular Aβ plaques in both the hippocampus and cortex. Significantly (p<0.05) higher CD11b microglial staining was found in the hippocampus, temporal cortex, and frontal cortex of CH-fed versus control rabbits. In the temporal cortex and parietal cortex, active CD-11b- and ferritin-positive microglia were found in close proximity to Aβ plaques. Classification and quantification of activated microglia in the temporal cortex showed that 68 ± 12.9%, 25 ± 7.3%, and 7 ± 2.7% of all microglia had a primed, reactive, and amoeboid phenotype, respectively. Activated microglia also expressed myeloperoxidase which was co-localized to amyloid deposits. Our findings in this dietary-based model lend further support of a role of activated microglia and oxidative stress during the development of AD and strengthens the links between hypercholesterolemia, inflammatory status, and AD.

Marco Spallazzi, Federica Barocco, Giovanni Michelini, Nicola Morelli, Maura Scarlattei, Giorgio Baldari, Livia Ruffini, Paolo Caffarra (Handling Associate Editor: Carlo Abbate)
The Incremental Diagnostic Value of [18F]Florbetaben PET and the Pivotal Role of the Neuropsychological Assessment in Clinical Practice
Abstract: Background: Amyloid pathology is a key feature of Alzheimer’s disease (AD) and can be assessed in vivo with amyloid positron emission tomography (PET) imaging. Objective: The objective of this study was to evaluate the incremental value of a PET scan with [18F]florbetaben, in terms of changes of diagnosis, diagnostic confidence, and treatment plan when added to a standardized diagnostic workup for cognitive disorders, with particular focus on the role of the neuropsychological assessment, including the Free and Cued Selective Reminding Test (FCSRT). Methods: A total of 104 patients (69 mild cognitive impairment, 35 dementia), with diagnostic uncertainty after diagnostic workup, were recruited from our memory clinic. [18F]florbetaben PET scans were interpreted as amyloid negative or positive on the basis of a semi-quantitative visual rating. Clinical diagnosis and diagnostic confidence for AD or non-AD dementia were rated before and after PET result disclosure, as was the impact of PET on the patient management plan. Results: There were 69/104 (66%) [18F]florbetaben positive scans, 51/62 (82%) patients were suspected as having AD before the PET scan and 18/42 (43%) were not. Overall, the data obtained at PET changed 18/104 diagnoses (17%) and increased diagnostic confidence from 69.1±8.1% to 83.5±9.1 (p<0.001), with the greatest impact on diagnosis and confidence in PET negative patients with an initial diagnosis of AD (p<0.01) and in early-onset patients (p=0.01). Conclusion: Amyloid PET represents a source of added value in dementia diagnosis, with a significant effect on diagnosis and diagnostic confidence. However, the use of a complete neuropsychological assessment has an add-on value on limiting the amyloid PET influence on change of diagnosis, and the real impact of amyloid PET should always be weighed up together with an accurate standardized diagnostic workup.

Anna Bebe, Volkert Siersma, Jakob Kragstrup, Anni Brit Sternhagen Nielsen, Anne Møller, Jens Søndergaard, Dagný Rós Nicolaisdóttir, Frans Boch Waldorff
The Effect of Economic Assets on Mortality in Patients with Dementia: A Population-Based Cohort Study
Abstract: Background: We investigated the effect of economic assets on mortality in patients with dementia in a national cohort of elderly individuals aged 65 or older. Objective: To examine the effect of economic assets on mortality in patients with dementia. Methods: Incidence of dementia and all-cause mortality was analyzed with incidence rate ratios (IRR) in three different categories of economic assets by means of Cox regression models. Results: A total of 874,246 individuals aged 65+ were included. The risk of receiving a dementia diagnosis was highest in the low economic asset group (IRR 1.19). Patients with dementia had a higher mortality compared to those without a diagnosis (IRR 2.85). The mortality in the dementia group was lowest in the high economic asset group (IRR 3.31). However, the increase associated with dementia was lowest within the low economic assets group (IRR 2.57). Conclusion: Mortality is increased with a dementia diagnosis and highest for the low economic asset group. However, the increase in mortality attributable to dementia was higher in the high economic assets group.

Fei Wang, Jianfeng Luo, Ding Ding, Qianhua Zhao, Qihao Guo, Xiaoniu Liang, Fen Zhou, Wei Deng, Zhen Hong
Elevated Fasting Blood Glucose Level Increases the Risk of Cognitive Decline Among Older Adults with Diabetes Mellitus: The Shanghai Aging Study
Abstract: Background: Several studies have demonstrated that the elevated fasting blood glucose (FBG) may increase the risk of incident dementia in older adults with or without diabetes mellitus (DM). However, similar results are rarely reported in Chinese population. Objective: This study aimed to demonstrate the association between FBG and risk of incident cognitive decline in older Chinese adults. Methods: We prospectively followed up 1,555 dementia-free participants with baseline FBG measurement in the Shanghai Aging Study. Results: We identified 126 incident dementia cases across a mean of 5.2 years. Cumulative dementia incidence in type II DM participants with higher FBG (>6.1 mmol/L) increased most dramatically, second with that of non-DM participants with higher FBG, than that of participants with lower FBG (≤6.1 mmol/L). DM participants had a significant higher risk of incident dementia (adjusted HR 1.51, 95%CI 1.25-1.82) by every 1 mmol/L increment of FBG. Among DM participants, baseline FBG was positively related to the rate of annual decline of MMSE (β=0.10, p=0.0018). Conclusions: Our results suggest that especially in people with type II DM, effective blood glucose control may help to prevent cognitive impairment in later life.

Antoine Garnier-Crussard*, Julien Vernaudon*, Nicolas Auguste, Claire Moutet, Virginie Dauphinot, Pierre Krolak-Salmon *These authors contributed equally to this work.
Perception of Benefits and Risks of Neurocognitive Disorders Diagnosis: A French National Survey
Abstract: Background: Neurocognitive disorders (NCD) are underdiagnosed in primary care, mainly because of the misunderstanding of benefits associated with timely diagnosis. Objective: The aim of this study was to explore the benefits and risks of diagnosis in a population of general practitioners (GPs), specialized physicians (SPs), other healthcare professionals (HPs), and informal caregivers (ICs). Methods: A questionnaire was submitted to GPs, SPs, HPs. and ICs. It aimed at evaluating benefits and risks related to NCD diagnosis associated with four prototypical clinical cases at different stages: isolated cognitive complaint/mild NCD, major NCD at mild/moderate stage, moderate stage with behavioral and psychotic symptoms, and severe stage. The concepts of early, timely, and personalized diagnosis were evaluated. Results: A total of 719 completed surveys were collected from 183 GPs, 176 SPs, 281 HPs, and 79 ICs. More than 90% of the participants considered initiating a diagnosis as relevant except at the severe stage. Benefits were superior to risks for all groups and all four cases alike (p<0.001). Benefits were lower according to GPs and higher for SPs than the other groups at the first two stages (p<0.001). At the moderate stage, there were few differences between groups. At the severe stage, GPs and SPs claimed it was less relevant to carry out a diagnosis than the other groups (p<0.001). Risks were higher for ICs and lower for SPs (p<0.001). The best diagnosis concept was the personalized diagnosis. Conclusion: Benefits appeared more relevant than risks with differences according to the stage of the disease and type of respondents.

Arushi Tripathy, Ashley Shade, Brittany Erskine, Kristi Bailey, Abigail Grande, Joyce J. deJong, George Perry, Rudy J. Castellani (Handling Editor: Massimo Tabaton)
No Evidence of Increased Chronic Traumatic Encephalopathy Pathology or Neurodegenerative Proteinopathy in Former Military Service Members: A Preliminary Study
Abstract: It is presently unknown whether military service members are at risk for chronic traumatic encephalopathy (CTE) or Alzheimer’s disease (AD) pathology, due to traumatic brain injury (TBI). Studies with respect to AD have had mixed results with respect to mild TBI, although an increased risk of clinical AD with moderate and severe TBI is more consistently demonstrated. No studies to date have demonstrated a longitudinal progression from TBI to autopsy. We therefore initiated a cross-sectional survey of former military service members. 18 brain specimens have been examined to date, with a mean age of 68.9  16 years (range 32-94). Twelve had a history of psychiatric problems; 10 had a history of PTSD specifically. Five had neurological problems including stroke and seizures. One subject had early-onset AD. Two subjects had a history of TBI and two had a history of blast exposure. Age-related proteinopathy, ranging from AD neuropathologic change A0B1C0 to A3B3C3 by NIA-AA guidelines, was identified. None of the cases showed changes specific for CTE pathology. There was no relationship between p-tau in the amygdala and psychiatric signs. There was no significant difference in phosphorylated tau (p-tau) or amyloid-β burden compared to age-matched controls. These preliminary data suggest that military service per se is not a risk factor for CTE pathology or neurodegenerative proteinopathy. More research is needed to study the relationship, if any, between TBI and neurodegenerative proteinopathy.

Chih-Chia Lai, Hsuan Lo, Hong-Guo Lin, Hsun-Hsun Lin
Potentiation of NMDA-Mediated Responses by Amyloid-β Peptide 1-40 in Rat Sympathetic Preganglionic Neurons
Abstract: The abnormal accumulation of amyloid-β peptides (Aβ) is one of the main characteristics of Alzheimer's disease (AD). Cerebro- and cardiovascular diseases may be the risk factors for developing AD. The effect of Aβ on central sympathetic control of cardiovascular function remains unclear. The present study examines the acute effects of Aβ oligomers on the function of NMDA receptors, a subtype of ionotropic glutamate receptors, in rat sympathetic preganglionic neurons (SPNs). In the in vitro electrophysiological study, Aβ1-40 but not Aβ1-42 applied by superfusion for 5 min significantly potentiated NMDA-induced depolarizations in SPNs of neonatal rat spinal cord slice preparation. Application of Aβ1-40 had little effects on AMPA-induced depolarizations or GABA-induced hyperpolarizations. Treatment with a selective protein kinase C (PKC) inhibitor applied together with Aβ1-40 blocked the augmentation by Aβ1-40 of NMDA-induced depolarizations. Western blot analysis showed an increase in the levels of phosphoserine 896, selectively regulated by PKC, without significant changes in phosphoserine 897 on GluN1 subunits in lateral horn areas of spinal cord slices following treatment with Aβ1-40. In the in vivo study, intrathecal injection of Aβ1-40 (0.2 nmol) potentiated the pressor effects induced by NMDA (2 nmol) injected intrathecally in urethane-anesthetized rats. These results suggest that different fragments of Aβ may have differential effects on the NMDA receptor function and the selective augmentation of NMDA receptor function by Aβ1-40 may involve PKC-dependent mechanisms in sympathetic preganglionic neurons.

Corinne E. Fischer, Ines Kortebi, Wael K. Karameh, Sanjeev Kumar, Damien Gallagher, Angela Golas, David Munoz, Joseph Barfett6, Meryl A. Butters, Christopher R. Bowie, Alastair Flint, Tarek Rajji, Nathan Herrmann, Bruce G. Pollock, Benoit Mulsant, Tom A. Schweizer*, Linda Mah*, and the PACT-MD Study Group *Co-senior authors
Examining the Link Between Cardiovascular Risk Factors and Neuropsychiatric Symptoms in Mild Cognitive Impairment and Major Depressive Disorder in Remission
Abstract: Background: Cardiovascular risk factors (CVRFs) have been linked to both depression and cognitive decline but their role in neuropsychiatric symptoms (NPS) has yet to be clarified. Objective: Understanding the role of CVRFs in the etiology of NPS for prospective treatments and preventive strategies to minimize these symptoms. Methods: We examined the distribution of NPS using the Neuropsychiatric Inventory (NPI) scores in three cohorts from the Prevention of Alzheimer’s Dementia with Cognitive Remediation Plus Transcranial Direct Current Stimulation in Mild Cognitive Impairment and Depression (PACt-MD) study: older patients with a lifetime history of major depressive disorder (MDD) in remission, patients with mild cognitive impairment (MCI), and patients with combined MCI and MDD. We also examined the link between individual NPS and CVRFs, Framingham risk score, and Hachinski ischemic score in a combined sample. Results: Analyses were based on a sample of 140 subjects, 70 with MCI, 38 with MCI plus MDD, and 32 with MDD. There was no effect of age, gender, education, cognition, or CVRFs on the presence (NPI>1) or absence (NPI=0) of NPS. Depression was the most prevalent affective NPS domain followed by night-time behaviors and appetite changes across all three diagnostic groups. Agitation and aggression correlated negatively while anxiety, disinhibition, night-time behaviors, and irritability correlated positively with CVRFs (all p-values <0.05). Other NPS domains showed no significant association with CVRFs. Conclusion: CVRFs are significantly associated with individual NPI sub-scores but not with total NPI scores, suggesting that different pathologies may contribute to different NPS domains.

Jens Bohlken, Karel Kostev
Coded Prevalence of Mild Cognitive Impairment in General and Neuropsychiatrists Practices in Germany between 2007 and 2017
Abstract: Background: The diagnosis of mild cognitive impairment (MCI) is becoming increasingly important for the medical treatment of dementia. Objective: The aim of this study was to investigate whether the coded prevalence of MCI changed in the period from 2007 to 2017 compared to dementia diagnoses. Methods: This was a retrospective evaluation of diagnostic data from 432 general practitioner (GP) practices and 53 neuropsychiatrist (NP) practices in Germany based on the Disease Analyzer database (IQVIA). The frequencies with which MCI and dementia were diagnosed in these practices were determined. The frequency with which dementia was diagnosed was included to determine whether the change in the frequency of MCI diagnoses was due to the increase in dementia prevalence. Results: It was found that the number of GP practices with patients receiving MCI diagnoses increased from 16% to 46%, while the number of NP practices with patients receiving MCI diagnoses increased from 55% to 75%. Moreover, the study found an increase in the coded prevalence of MCI from 0.4 to 1.9 patients/GP practice and from 6.5 to 11.1 patients/NP practice were observed. Conclusions: A growing number of GPs and NPs code MCI with increasing frequency. However, the coding frequency of MCI in 2017 corresponded to less than 10% of its true prevalence. A sharp increase in MCI diagnoses can be expected, along with the establishment of preventive and disease-modifying dementia strategies.

Eva Y.L. Tan, Sebastian Köhler, Renske E.G. Hamel, Juan Luis Muñoz-Sánchez, Frans R.J. Verhey, Inez H.G.B. Ramakers
Depressive Symptoms in Mild Cognitive Impairment and the Risk of Dementia: A Systematic Review and Comparative Meta-Analysis of Clinical and Community-Based Studies
Abstract: Background: Affective symptoms are considered a risk factor or prodromal symptom for dementia. Recent reviews indicate that depressive symptoms predict progression from mild cognitive impairment (MCI) to dementia, but results need to be further explored. Objective: To investigate the effect of depressive symptoms on the development of dementia in people with MCI, and explore potential sources of between-study variability, including study setting by a systematic review and meta-analysis. Methods: Databases were searched for prospective studies defining people with MCI at baseline, investigating dementia at follow-up and giving information about depressive symptoms. Two authors independently extracted data from the studies and rated the methodological quality. Meta-analyses were conducted using random-effect models to yield pooled risk ratios (RR). Meta-regression analyses tested differences between clinical and community-based studies and other sources of heterogeneity. Results: Thirty-five studies, representing 14,158 individuals with MCI, were included in the meta-analysis. Depressive symptoms in MCI predicted dementia in 15 community-based studies (RR = 1.69, 95% CI 1.49-1.93, I2 =0.0%), but not in 20 clinical studies (RR = 1.02, 95% CI 0.92-1.14, I2 =73.0%). Further investigation of this effect showed that the mean age of community-based studies was significantly higher than of clinical studies but neither this nor other study characteristics explained variability in study outcomes. Conclusions: Depressive symptoms are associated with an increased risk of conversion from MCI to dementia in community-based studies. In contrast, evidence in clinical populations was insufficient with high heterogeneity.

Hanna Lu, Sandra S.M. Chan, Linda C. W. Lam
Localized Analysis of Normalized Distance from Scalp to Cortex and Personalized Evaluation (LANDSCAPE): Focusing on Age- and Dementia-Specific Changes
Abstract: Background: Scalp to cortex distance (SCD), as a key technological parameter, has been highlighted in the guidelines of non-invasive brain stimulation. However, in the context of age-related brain changes, the region-specific SCD and its impact on stimulation-induced electric field remain unclear. Objective: This study aimed to investigate the region-specific SCD and its relationship with morphometric features and cognitive function in age- and disease-specific populations. Methods: We analyzed the SCD and cortical thickness (CT) of left primary motor cortex (M1) and dorsolateral prefrontal cortex (DLPFC) in 214 cognitively normal adults and 43 dementia patients. CT-adjusted SCD was used to control the influence of CT on SCD. Head model was developed to simulate the impact of SCD on the electric field induced by transcranial electrical stimulation. Results: We found age-related increased SCD in the left DLPFC (p<0.001), but not M1 (p=0.134), and dementia-related increased SCD in both left DLPFC (p<0.001) and M1 (p<0.001). CT-adjusted SCD showed greater region-specific impact on left DLPFC rather than M1. The electric field induced by stimulation was consequently decreased with the increased SCD across normal aging and dementia groups. Conclusions: Age and dementia have differential impacts on the SCDs of left DLPFC and M1. The findings suggest that it is important to be aware of region-specific distance measures when conducting neuromodulation in individuals with old age and dementia.

Juha O. Rinne, Timo Suotunen, Jaana Rummukainen, Sanna-Kaisa Herukka, Ossi Nerg, Anne M. Koivisto, Tuomas Rauramaa, Kjell Någren, Mikko Hiltunen, Irina Alafuzoff, Jaakko Rinne, Juha E. Jääskeläinen, Hilkka Soininen, Ville Leinonen
[11C]PIB PET Is Associated with the Brain Biopsy Amyloid-β Load in Subjects Examined for Normal Pressure Hydrocephalus
Abstract: Background: Idiopathic normal pressure hydrocephalus (iNPH) is frequently associated with concomitant amyloid-β (Aβ) pathology. Objective: To compare the [11C]PIB PET uptake in the patients with suspected iNPH to Aβ and hyperphosphorylated-tau (HPτ) in the right frontal cortical biopsy, the cerebrospinal fluid (CSF) Aβ, the response to a CSF shunt, and the final clinical diagnosis of Alzheimer’s disease (AD). Methods: Patients (n=21) from Kuopio NPH Registry (http://www.uef.fi/nph) with intraventricular pressure monitoring, immunostaining for Aβ and HPτ in the right frontal cortical biopsies, and a Mini-Mental State Examination and a Clinical Dementia Rating underwent [11C]PIB PET. Aβ, total tau, and Pτ181 were measured by ELISA from the ventricular (n=15) and the lumbar (n=9) CSF. Response to the shunt was seen in 13 out of the 15 shunted patients. AD was diagnosed in 8 patients during a median follow-up of 6 years (mean 7.3±2.4 years, range 3-1). Results: [11C]PIB uptake in the right frontal cortex (ρ=0.60, p<0.01) and the combined neocortical [11C]PIB uptake score (ρ=0.61, p<0.01) were associated with a higher Aβ load in the right frontal cortical biopsy. Excluding one (1/15) outlier, [11C]PIB uptake was also associated with the ventricular CSF Aβ (ρ=-0.58, p=0.03). Conclusions: The findings show that [11C]PIB PET can reliably detect simultaneous amyloid pathology among the iNPH patients. Further studies will show whether amyloid PET could predict a clinical response to the shunt operation. In addition, the presence of Aβ pathology in the patients with iNPH might also warrant treatment with current AD drugs.

Chandrakala Aluganti Narasimhulu*, Connie Mitra*, Deepshikha Bhardwaj, Kathryn Young Burge, Sampath Parthasarathy *These authors contributed equally to this work.
Alzheimer’s Disease Markers in Aged ApoE-PON1 Deficient Mice
Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disorder associated with aging. Cardiovascular risk factors like hypertension and atherosclerosis increase the risk for AD. Polymorphic alleles of apolipoprotein E (ApoE) are one of the main genetic determinants of AD. Objective: Mice, double-knockout (DKO) for ApoE (major cholesterol carrier in brain) and PON1 (paroxonase1, reduces oxidative stress), showed severe age-dependent atherosclerosis of the arteries carrying blood to the brain even on normal diet. This prompted us to investigate the possibility of an AD pathology resulting from the deficiency of ApoE and the induction of oxidative stress. Methods: Atherosclerotic lesions were quantified by ImageJ. The brain hippocampus of young and old ApoE-PON1 DKO mice and control mice were harvested. RT-PCR analysis was performed for mRNA levels of AD specific markers. Blood levels of S100 calcium-binding protein B (S100B) protein were measured by ELISA. H&E as well as immunostaining was performed to detect amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) in brain tissues. Evans blue dye was used to evaluate the vascular permeability and blood-brain barrier (BBB) dysfunction. Results: Results showed that the older DKO mice had severe carotid atherosclerosis, increased mRNA levels of AD markers in brain tissue, and elevated levels of serum S100B protein. Immunological staining confirmed the characteristics of AD. Ex-vivo imaging showed higher levels of Evans blue dye in the ApoE-PON1 DKO mice brain tissues, pointing toward impaired vasculature. Conclusion: Aged ApoE-PON1 DKO mice displaying AD specific markers along with Aβ plaques, NFTs, and disrupted BBB suggests the animals are suffering from AD.

Amy Jenkins, Jeremy Tree, Ian Michael Thornton, Andrea Tales
Subjective Cognitive Impairment in 55-65-Year-Old Adults Is Associated with Negative Affective Symptoms, Neuroticism, and Poor Quality of Life
Abstract: Although subjective cognitive impairment (SCI) is increasingly recognized clinically and in research as a risk factor for mild cognitive impairment and dementia (particularly Alzheimer’s disease), it is etiologically heterogeneous and potentially treatable. Compared to mild cognitive impairment and Alzheimer’s disease, SCI however remains poorly characterized with debate continuing regarding its clinical relevance. The primary aim of this study was to improve the characterization of SCI within the general public by investigating functions sometimes omitted clinically or in research, namely visual attention-related information processing speed (RT) and its intra-individual variability (IIVRT), general cognition, depression, anxiety, memory, quality of life (QOL), and neuroticism. Compared to individuals without SCI, those with SCI were more likely to reveal higher scores of anxiety, depression, and neuroticism and poorer perceived physical, psychological, and environmental QOL. Within-group analysis identified no significant relationships between any of the above variables for the non-SCI group whereas for the SCI group, poorer Cognitive Change Index scores were significantly correlated with slower RT, raised IIVRT, poorer memory, negative affective symptoms, higher neuroticism scores, and poorer QOL. This indicates that reports of perceived memory changes in SCI can also be associated with other characteristics, namely objectively measured detrimental change in other aspects of brain function and behavior. This outcome emphasizes the importance of a multi-function approach to characterizing and understanding SCI. Thus, although the effect of RT and IIVRT is not strong enough to differentiate SCI from non-SCI at group level, slowing and raised IIVRT do appear to characterize some people with SCI.

Roberta Rizzo, Daria Bortolotti, Valentina Gentili, Antonella Rotola, Silvia Bolzani, Elisabetta Caselli, Maria Rosaria Tola, Dario Di Luca (Handling Associate Editor: Tamás Fülöp)
KIR2DS2/KIR2DL2/HLA-C1 Haplotype Is Associated with Alzheimer’s Disease: Implication for the Role of Herpesvirus Infections
Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, where neuroinflammation and immune cells are key pathological factors. Recently it was suggested a possible association between AD and human herpesvirus 6 (HHV-6) infection. Since we recently observed that multiple sclerosis patients with KIR2DL2 expression on natural killer (NK) cells are more susceptible to herpesvirus infection, we tested the possible implication of KIR/HLA genetic for HHV-6A infection. We identified, for the first time, a possible implication of a specific KIR/HLA subset in AD. The combination KIR2DS2/KIR2DL2/C1 correlated with a lower MMSEDi score, representative of a severe AD status and an increased susceptibility to HHV-6A infection. Therefore, the results seem to converge on the hypothesis that herpesvirus infection might play a role in AD. If this hypothesis finds experimental confirmation, a new therapeutic strategy, modulating KIR2DL2 expression on NK cells, for AD might be envisaged.

Michael Evgen’ev*, Natalia Bobkova*, George Krasnov*, David Garbuz, Sergei Funikov, Anna Kudryavtseva, Alexei Kulikov, Alexander Samokhin, Andrey Maltsev , Inna Nesterova *These authors contributed equally to this work.
The Effect of Human HSP70 Administration on a Mouse Model of Alzheimer’s Disease Strongly Depends on Transgenicity and Age
Abstract: In humans, heat shock protein 70 is a key component of the machinery that protects neuronal cells from various stress conditions and whose production significantly declines during aging. Herein, we investigated the protective effect of sub-chronic intranasal administration of human Hsp70 on the state of neurons in the temporal cortex and areas of the hippocampus of old transgenic (Tg) 5XFAD mice (11-13 months), representing a late-onset model of hereditary Alzheimer’s disease. Quantitative analysis of the various neuronal pathologies between the two groups (Tg versus nTg) revealed maximal levels of abnormalities in the brains of aged Tg mice. Importantly, intranasal application of HSP70 had profound beneficial effects on neuron morphology in the temporal cortex and hippocampal regions when applied to the aged Tg mice but not in the case of age-matched, non-transgenic, littermate animals. Furthermore, the effect of HSP70 administration on neurons in the hippocampus and temporal cortex differed characteristically between the groups. Using RNA-Seq, we identified a lot of differentially expressed genes in the hippocampus of old Tg mice compared with those of nTg mice. Most importantly, we observed HSP70-induced upregulation of multiple genes participating in antigen processing and presentation especially the members of major histocompatibility complex (class I and II) in the brains of old 5XFAD Tg animals, suggesting that Hsp70 executes its beneficial role via activation of adaptive immunity. Overall, our data enable to conclude that Hsp70 treatment may be a safe and effective therapeutic application against Alzheimer-type neuropathologies manifested at the late stages of the disease.