Volume 81, Number 4, 2021

Pages 1345-1360

Mónica De la Fuente
The Role of the Microbiota-Gut-Brain Axis in the Health and Illness Condition: A Focus on Alzheimer’s Disease
Abstract: Trillions of commensal microbes live in our body, the majority in the gut. This gut microbiota is in constant interaction with the homeostatic systems, the nervous, immune and endocrine systems, being fundamental for their appropriate development and function as well as for the neuroimmunoendocrine communication. The health state of an individual is understood in the frame of this communication, in which the microbiota-gut-brain axis is a relevant example. This bidirectional axis is constituted in early age and is affected by many environmental and lifestyle factors such as diet and stress, among others, being involved in the adequate maintenance of homeostasis and consequently in the health of each subject and in his/her rate of aging. For this, an alteration of gut microbiota, as occurs in a dysbiosis, and the associated gut barrier deterioration and the inflammatory state, affecting the function of immune, endocrine and nervous systems, in gut and in all the locations, is in the base of a great number of pathologies as those that involve alterations in the brain functions. There is an age-related deterioration of microbiota and the homeostatic systems due to oxi-inflamm-aging, and thus the risk of aging associated pathologies such as the neurodegenerative illness. Currently, this microbiota-gut-brain axis has been considered to have a relevant role in the pathogenesis of Alzheimer’s disease and represents an important target in the prevention and slowdown of the development of this pathology. In this context, the use of probiotics seems to be a promising help.

Pages 1361-1367

Fahad Somaa
A Review of the Application of Hyperbaric Oxygen Therapy in Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is considered as the most common cause of dementia in elderly population. While the exact mechanism of AD has not been discovered, hyperbolic oxygen therapy (HBOT) has been proven to be effective in the treatment of this degenerative disease. The objectives of this article are to review the literature available on molecular and physiological mechanisms underlying HBOT and its efficacy in treating AD and to review the effectiveness of HBOT as an alternate treatment intervention in both human and animal models. 391 full text articles were included in the review after literature search between 1980-2021 from two online data base (ScienceDirect and PubMed). The following key words were used: ‘hyperbaric oxygen therapy’ and 'Alzheimer disease.' Based on the outcomes of clinical and experimental studies, this review advocates the use of HBOT for the treatment of AD. This review explores future directions and recommends further research into a treatment protocol that will maintain long-term cognitive health of AD patients.

Pages 1369-1373
Short Communication

Anja Hviid Simonsen, Christian Sandøe Musaeus, Gitte Lund Christensen, Steen Gregers Hasselbalch, Gunhild Waldemar
Upwards Drift of Cerebrospinal Fluid Amyloid-β 42 Over Twelve Years in a Consecutive Clinical Cohort
Abstract: Amyloid-β 1-42 (Aβ1-42) measured in the cerebrospinal fluid (CSF) can be used as a diagnostic biomarker for Alzheimer’s disease (AD) but an upward drift when using the INNOTEST ELISA has been suggested. We investigated the upwards drift of Aβ1-42 levels over a period of twelve years in a consecutive memory clinic cohort. We found a significant increase in Aβ1-42 from 2008 to 2019 independent of changes in tau. New methods for the quantification of CSF Aβ1-42 levels are being implemented but awareness of this upwards drift is crucial during the diagnostic work-up and when selecting historical samples for research.

Pages 1375-1379
Short Communication

Mohamad El Haj, Ahmed A. Moustafa, Karim Gallouj
Higher Depression of Patients with Alzheimer’s Disease During than Before the Lockdown
Abstract: We assessed depression in 72 patients with Alzheimer’s disease (AD) who live in retirement homes during the COVID-19-related lockdown. We invited caregivers of 72 patients with AD who live in retirement homes to rate depression in the patients both before and during the lockdown. Analysis demonstrated increased depression in the patients during the lockdown. We attribute this increased depression to the restrictive measures on activities, visits, and physical contact between patients with AD and family members during the lockdown.

Pages 1381-1389
Wonjeong Jeong, Jae Hong Joo, Hyunkyu Kim, Yun Kyung Kim, Eun-Cheol Park, Sung-In Jang
Association Between the Use of Hypnotics and the Risk of Alzheimer’s Disease
Abstract: Background: Hypnotics, including benzodiazepines, are extensively and inappropriately prescribed for older people to treat anxiety and sleep disorders, despite the adverse health outcomes associated with their use. Objective: This study aimed to examine the association of the use of long- and short-acting hypnotics with the risk of Alzheimer’s disease. Methods: Data from 234,634 participants, derived from the Korean National Health Insurance Service National Sample Cohort from 2002 to 2013, were examined. Individuals over the age of 50 years were included in the study. The dependent variable was the risk of Alzheimer’s disease. Hypnotics were categorized by the period of the prescription of benzodiazepines, i.e., either till the participants were diagnosed with Alzheimer’s disease or the end of the study period (December 31, 2013). Cox regression model was built to analyze the association between variables. Results: Individuals who used long-acting hypnotics were found to have a higher risk of Alzheimer’s disease than non-users. Moreover, among individuals with sleep disorders, those who used hypnotics had a higher risk of Alzheimer’s disease than those who did not. Conclusion: This study identified an association between the use of hypnotics and the risk of Alzheimer’s disease among South Korean middle-aged and older people.

Pages 1391-1401
Li Huang*, Xuan Yin*, Wei Li, Yan Cao, Yueqi Chen, Lixing Lao, Zhangjin Zhang, Yiqun Mi, Shifen Xu (Handling Associate Editor: Dharma Khalsa) *These authors contributed equally to this work.
Effects of Acupuncture on Vascular Cognitive Impairment with No Dementia: A Randomized Controlled Trial
Abstract: Background: Acupuncture has been used for treating vascular cognitive impairment, but evidence for its effectiveness remains limited. Objective: This single-center, patient-accessor blinded, randomized controlled trial was designed to assess whether acupuncture could improve the cognitive function of patients with vascular cognitive impairment with no dementia (VCIND). Methods: 120 VCIND patients were randomly assigned to the electro-acupuncture (EA) or sham acupuncture (SA) group at a 1:1 ratio, with treatment conducted thrice weekly for 8 weeks. The primary outcome was the changes of cognitive function measured by the Montreal Cognitive Assessment (MoCA) from baseline to week 8. The secondary outcomes included the scores of the Mini-Mental State Examination (MMSE), the Modified Barthel Index (MBI) and the Self-rating Depression Scale (SDS). Follow-up assessments were performed with MoCA and MMSE at week 16 and 32. Linear mixed-effects models were used for analysis and all statistical tests were two-sided. Results: The results showed that patients in the EA group had a significantly greater improvement in MoCA score (23.85±4.18) than those in the SA group (21.48±4.44) at week 8 (95% CI=0.81, 3.93, p = 0.04), as well as higher MoCA scores over time (p<0.001 for interaction). Patients who received EA showed a greater increase in MMSE scores (26.42±3.47) than those who received SA (24.40±3.85) along 8 weeks (95% CI= 0.69, 3.34, p=0.0036). However, results diminished over time. No serious adverse events occurred during the trial. Conclusion: EA is a safe and effective technique to improve cognition over the short term of 8 weeks in VCIND patients.

Pages 1403-1418
Xin Wang, Qian Liu, Xiao-Guang Li, Qiu-Zhi Zhou, Dong-Qin Wu, Shi-Hong Li, Yan-Chao Liu, Jian-Zhi Wang
T217-Phosphorylation Exacerbates Tau Pathologies and Tau-Induced Cognitive Impairment
Abstract: Background: Recent studies show that an increased T217-phosphorylation of tau in plasma could diagnose AD at an early stage with high accuracy and high specificity, while the potential toxic role of tau T217-phosphorylation is not known. Objective: To study the potential toxic role of tau T217-phosphorylation. Methods: We performed stereotactic brain injection, behavioral testing, immunohistochemistry and immunofluorescence, western blotting, Golgi staining, in vitro recombinant tau polymerization, and other measurements. Results: We first constructed tau T217-wild-type (T217), T217-phospho-mimic (T217E), and T217-non-phospho-mimic (T217A) plasmids or their virus vectors on the basis of wild-type tau. We found that expressing tau-T217E induced a significantly increased tau phosphorylation at multiple AD-associated sites with inhibited proteolysis and increased cleavage/fibrillization of tau, while expressing tau-T217A abolished the above changes of tau both in vitro and in vivo. By mutating T217E on tau-P301L, a dominant mutation identified in patients with frontotemporal dementia, we did not observe significant exacerbation of tau-P301L phosphorylation and cognitive impairment although the increased tau cleavage and propagation were shown. Conclusion: T217-phosphorylation exacerbates wild-type tau hyperphosphorylation with aggravated tau cleavage/fibrillization and cognitive impairments, while overexpressing T217E on the basis P301L does not exacerbate tau phosphorylation or the P301L-induced cognitive deficits, although it aggravates tau cleavage and propagation.

Pages 1419-1428
Wyllians Vendramini Borelli, Eduardo Leal-Conceição, Michele Alberton Andrade, Nathalia Bianchini Esper, Paula Kopschina Feltes, Ricardo Bernardi Soder, Cristina Sebastião Matushita, Louise Mross Hartmann, Graciane Radaelli, Lucas Porcello Schilling, Cristina Moriguchi-Jeckel, Ana Maria Marques da Silva, Mirna Wetters Portuguez, Alexandre Rosa Franco, Jaderson Costa da Costa
Increased Glucose Activity in Subgenual Anterior Cingulate and Hippocampus of High Performing Older Adults, Despite Amyloid Burden
Abstract: Background: Individuals at 80 years of age or above with exceptional memory are considered SuperAgers (SA), an operationalized definition of successful cognitive aging. SA showed increased thickness and altered functional connectivity in the anterior cingulate cortex as a neurobiological signature. However, their metabolic alterations are yet to be uncovered. Objective: Herein, a metabolic (FDG-PET), amyloid (PIB-PET), and functional (fMRI) analysis of SA were conducted. Methods: Ten SA, ten age-matched older adults (C80), and ten cognitively normal middle-aged (C50) adults underwent cognitive testing and multimodal neuroimaging examinations. Anterior and posterior regions of the cingulate cortex and hippocampal areas were primarily examined, then subregions of anterior cingulate were segregated. Results: The SA group showed increased metabolic activity in the left and right subgenual anterior cingulate cortex (sACC, p0.05). The SA group also presented decreased connectivity between right sACC and posterior cingulate (p<0.005, corrected) as compared to that of the C80 group. Conclusion: These results support the key role of sACC and hippocampus in SA, even in the presence of amyloid deposition. It also suggests that sACC may be used as a potential biomarker in older adults for exceptional memory ability. Further longitudinal studies measuring metabolic biomarkers may help elucidate the interaction between these areas in the cognitive aging process.

Pages 1429-1443
Vasily Vorobyov, Alexander Deev, Frank Sengpiel, Vladimir Nebogatikov, Aleksey A. Ustyugov
Cortical and Striatal Electroencephalograms and Apomorphine Effects in the FUS Mouse Model of Amyotrophic Lateral Sclerosis
Abstract: Background: Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons resulting in muscle atrophy. In contrast to the lower motor neurons, the role of upper (cortical) neurons in ALS is yet unclear. Maturation of locomotor networks is supported by dopaminergic (DA) projections from substantia nigra to the spinal cord and striatum. Objective: To examine the contribution of DA mediation in the striatum-cortex networks in ALS progression. Methods: We studied electroencephalogram (EEG) from striatal putamen (Pt) and primary motor cortex (M1) in ΔFUS(1-359)-transgenic (Tg) mice, a model of ALS. EEG from M1 and Pt were recorded in freely moving young (2-month-old) and older (5-month-old) Tg and non-transgenic (nTg) mice. EEG spectra were analyzed for 30 min before and for 60 min after systemic injection of a DA mimetic, apomorphine (APO), and saline. Results: In young Tg versus nTg mice, baseline EEG spectra in M1 were comparable, whereas in Pt, beta activity in Tg mice was enhanced. In older Tg versus nTg mice, beta dominated in EEG from both M1 and Pt, whereas theta and delta 2 activities were reduced. In younger Tg versus nTg mice, APO increased theta and decreased beta 2 predominantly in M1. In older mice, APO effects in these frequency bands were inversed and accompanied by enhanced delta 2 and attenuated alpha in Tg versus nTg mice. Conclusion: We suggest that revealed EEG modifications in ΔFUS(1-359)-transgenic mice are associated with early alterations in the striatum-cortex interrelations and DA transmission followed by adaptive intracerebral transformations.

Pages 1445-1451
Maria Serpente, Chiara Fenoglio, Andrea Arighi, Giorgio G. Fumagalli, Marina Arcaro, Federica Sorrentino, Caterina Visconte, Elio Scarpini, Daniela Galimberti (Handling Associate Editor: Beatrice Arosio)
Analysis of C9orf72 Intermediate Alleles in a Retrospective Cohort of Neurological Patients: Risk Factors for Alzheimer’s Disease?
Abstract: Background: C9orf72 hexanucleotide GGGGCC (G4C2) large repeat expansions within the first intron of the gene are a major cause of familial frontotemporal dementia, but also of apparently sporadic cases. Alleles with >30 repeats are often considered pathogenic, but the repeat length threshold is still undefined. It is also unclear if C9orf72 intermediate alleles (9-30 repeats) have clinically significant effects. Objectives: We correlated the presence of C9orf72 intermediate alleles with clinical diagnoses in a perspective cohort referred to a secondary memory clinic. Methods: All samples were genotyped with AmplideXPCR/CE C9ORF72 Kit (Asuragen, Inc), an optimized C9orf72 PCR amplification reagent. Results: We showed that in patients with Alzheimer’s disease (AD) the frequency of the intermediate repeat allele was significantly increased versus controls (34/54, 63% AD versus 16/39, 41% CTRLs, *p=0.01, OR 2.91 CI 95% 1.230-6.077), whereas no significant differences (p>0.05) were observed when comparing all other dementias with non-demented individuals. Conclusion: Our findings suggest that C9orf72 intermediate repeat units may represent a genetic risk factor, contributing to the occurrence of AD. Nevertheless, further longitudinal studies, including larger cohort of subjects with intermediate alleles with long-term follow-up, would be needed to confirm these results.

Pages 1453-1468
Jonathan A. Zweig, Mikah S. Brandes, Barbara H. Brumbach, Maya Caruso, Kirsten M. Wright, Joseph F. Quinn, Amala Soumyanath, Nora E. Gray
Prolonged Treatment with Centella asiatica Improves Memory, Reduces Amyloid-β Pathology, and Activates NRF2-Regulated Antioxidant Response Pathway in 5xFAD Mice
Abstract: Background: The medicinal herb Centella asiatica has been long been used for its neuroprotective and cognitive enhancing effects. We have previously shown that two weeks of treatment with a water extract of Centella asiatica (CAW) improves cognition and activates the endogenous antioxidant response pathway without altering amyloid-β (Aβ) plaque burden. Objective: Here, we assess the effect of long-term treatment of CAW in the 5xFAD mouse model of Aβ accumulation. Methods: Four-month-old 5xFAD mice were treated with CAW in their drinking water (2 g/L) for three months at which point they underwent cognitive testing as well as analysis of Aβ plaque levels and antioxidant and synaptic gene expression. In order to confirm the involvement of the antioxidant regulatory transcription factor NRF2 on the effects of CAW on synaptic plasticity, neurons isolated from 5xFAD mice were also treated with CAW and the targeted inhibitor ML385. Results: Three months of treatment with CAW improved spatial and contextual memory as well as executive function in 5xFAD mice. This improvement was accompanied by increased antioxidant gene expression and a decrease in Aβ plaque burden relative to untreated 5xFAD animals. In isolated neurons, treatment with ML385 blocked the effects of CAW on dendritic arborization and synaptic gene expression. Conclusion: These results suggest that prolonged CAW exposure could be beneficial in Alzheimer’s disease and that these effects likely involve NRF2 activation. Moreover, these findings suggest that targeting NRF2 itself may be a relevant therapeutic strategy for improving synaptic plasticity and cognitive function in Alzheimer’s disease.

Pages 1469-1482
Qingwei Huo*, Sidra Tabassum*, Ming Chen, Mengyao Sun, Yueming Deng, Xingzhi Zheng, Yi Li, Jian Chen, Cheng Long, Li Yang (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
Amyloid-β Protein Precursor Deficiency Changes Neuronal Electrical Activity and Levels of Mitochondrial Proteins in the Medial Prefrontal Cortex
Abstract: Background: Neuropathological features of Alzheimer's disease are characterized by the deposition of amyloid-β (Aβ) plaques and impairments in synaptic activity and memory. However, we know little about the physiological role of amyloid-β protein precursor (AβPP) from which Aβ derives. Objective: Evaluate APP deficiency induced alterations in neuronal electrical activity and mitochondrial protein expression. Methods: Utilizing electrophysiological, biochemical, pharmacological, and behavioral tests, we revealed aberrant local field potential (LFP), extracellular neuronal firing and levels of mitochondrial proteins. Result: We show that APP knockout (APP-/-) leads to increased gamma oscillations in the medial prefrontal cortex (mPFC) at 1-2 months old, which can be restored by baclofen (Bac), a γ-aminobutyric acid type B receptor (GABABR) agonist. A higher dose and longer exposure time is required for Bac to suppress neuronal firing in APP-/- mice than in wild type animals, indicating enhanced GABABR mediated activity in the mPFC of APP-/- mice. In line with increased GABABR function, the glutamine synthetase inhibitor, L-methionine sulfonate, significantly increases GABABR levels in the mPFC of APP-/- mice and this is associated with a significantly lower incidence of death. The results suggest that APP-/- mice developed stronger GABABR mediated inhibition. Using HEK 293 as an expression system, we uncover that AβPP functions to suppress GABABR expression. Furthermore, APP-/- mice show abnormal expression of several mitochondrial proteins. Conclusion: APP deficiency leads to both abnormal network activity involving defected GABABR and mitochondrial dysfunction, suggesting critical role of AβPP in synaptic and network function.

Pages 1483-1491
Victoire Leroy, Yaohua Chen, Naiara Demnitz, Florence Pasquier, Pierre Krolak-Salmon, Bertrand Fougère, François Puisieux
Is Fall Risk Systematically Evaluated in Memory Clinics? A National Survey of Practice in France
Abstract: Background: Falls are a major health problem in older persons but are still under-diagnosed and challenging to prevent. Current guidelines do not target high-risk populations, especially people living with dementia. In France, people with neurocognitive disorders are mainly referred to memory clinics (MCs). Objective: We aimed to survey the routine practice of physicians working in MCs regarding fall risk assessment. Methods: We conducted a cross-sectional survey in France from January to May 2019 among physicians working in MCs, through an anonymous online questionnaire: twenty-seven questions about the physician’s background and their practice of fall risk assessment, especially use of clinical and paraclinical tools. We compared the results according to the age and the specialty of the physician. Results: We obtained 171 responses with a majority of women (60%) and geriatricians (78%). All age classes and all French regions were represented. Most of respondents (98.8%) stated that they address gait and/or falls in outpatient clinic and 95.9% in day hospitals. When asked about how they assess fall risk, fall history (83%) and gait examination (68.4%) were the most widely used, while orthostatic hypotension (24%) and clinical standardized tests (25.7%) were less common. Among standardized tests, One-leg Balance, Timed Up and Go Test, and gait speed measurements were the most used. Geriatricians had more complete fall risk assessment than neurologists (e.g., 56% versus 13% for use of standardized tests, p<0.0001). Conclusion: Almost all physicians addressed the question of fall in MC, but practices are widely heterogeneous. Further investigations are needed to standardize fall risk assessment in MCs.

Pages 1493-1504
Jagan A. Pillai, Kou Lei, James Bena, Lisa Penn, James B. Leverenz (Handling Associate Editor: Tania Alves)
Hypertension and Hypercholesterolemia Modify Dementia Risk in Relation to APOE ε4 Status
Abstract: Background: There is significant interest in understanding the role of modifiable vascular risk factors contributing to dementia risk across age groups. Objective: Risk of dementia onset was assessed in relation to vascular risk factors of hypertension and hypercholesterolemia among cognitively normal APOE ε4 carriers and non-carriers. Methods: In a sample of prospectively characterized longitudinal cohort from the National Alzheimer’s Coordinating Center database, 9,349 participants met criteria for normal cognition at baseline, had a CDR-Global (CDR-G) score of zero, and had concomitant data on APOE ε4 status and medical co-morbidities including histories of hypertension and hypercholesterolemia. Multivariable Cox proportional hazards models adjusted for well-known potential confounders were used to compare dementia onset among APOE ε4 carriers and non-carriers by young (≤65 years) and old (>65 year) age groups. Results: 519 participants converted to dementia within an average follow up of 5.97 years. Among older APOE ε4 carriers, hypercholesterolemia was related to lower risk of dementia (HR (95% CI), 0.68 (0.49-0.94), p = 0.02). Among older APOE ε4 non-carriers, hypertension was related to higher risk of dementia (HR (95% CI), 1.44 (1.13-1.82), p = 0.003). These results were corroborated among a subset with autopsy data characterizing underlying neuropathology. Among younger participants, vascular risk factors did not impact dementia risk, likely from a lower frequency of vascular and Alzheimer’s as etiologies of dementia among this cohort. Conclusion: A history of hypercholesterolemia related to a lower risk of dementia among older APOE ε4 carriers, while hypertension related to a higher risk of dementia among older APOE ε4 non-carriers.

Pages 1505-1527
Alain D. Dekker, Aurora M. Ulgiati, Henk Groen, Vincent A. Boxelaar, Silvia Sacco, Ségolène Falquero, Angelo Carfi, Antonella di Paola, Bessy Benejam, Silvia Valldeneu, Roelie Fopma, Marjo Oosterik, Marloes Hermelink, Gonny Beugelsdijk, Mieke Schippers, Hepie Henstra, Martine Scholten-Kuiper, Judith Willink-Vos, Lisa de Ruiter, Liesbeth Willems, Anneke Loonstra-de Jong, Antonia M.W. Coppus, Marleen Tollenaere, Juan Fortea, Graziano Onder, Anne-Sophie Rebillat, Debby Van Dam, Peter P. De Deyn (Handling Associate Editor: Elizabeth Head)
The Behavioral and Psychological Symptoms of Dementia in Down Syndrome scale (BPSD-DS II): Optimization and Further Validation
Abstract: Background: People with Down syndrome (DS) are at high risk to develop Alzheimer’s disease dementia (AD). Behavioral and psychological symptoms of dementia (BPSD) are common and may also serve as early signals for dementia. However, comprehensive evaluation scales for BPSD, adapted to DS, are lacking. Therefore, we previously developed the BPSD-DS scale to identify behavioral changes between the last six months and pre-existing life-long characteristic behavior. Objective: To optimize and further study the scale (discriminative ability and reliability) in a large representative DS study population. Methods: Optimization was based on item irrelevance and clinical experiences obtained in the initial study. Using the shortened and refined BPSD-DS II, informant interviews were conducted to evaluate 524 individuals with DS, grouped according to dementia status: no dementia (DS, N=292), questionable dementia (DS+Q, N=119), and clinically diagnosed dementia (DS+AD, N=113). Results: Comparing item change scores between groups revealed prominent changes in frequency and severity for anxious, sleep-related, irritable, restless/stereotypic, apathetic, depressive, and eating/drinking behavior. For most items, the proportion of individuals displaying an increased frequency was highest in DS+AD, intermediate in DS+Q, and lowest in DS. For various items within sections about anxious, sleep-related, irritable, apathetic, and depressive behaviors, the proportion of individuals showing an increased frequency was already substantial in DS+Q, suggesting that these changes may serve as early signals of AD in DS. Reliability data were promising. Conclusion: The optimized scale yields largely similar results as obtained with the initial version. Systematically evaluating BPSD in DS may increase understanding of changes among caregivers and (timely) adaptation of care/treatment.

Pages 1529-1540
Claudia Szlejf, Claudia Kimie Suemoto, Carolina Castro Porto Silva Janovsky, Laiss Bertola, Sandhi Maria Barreto, Paulo Andrade Lotufo, Isabela Martins Benseñor
Subtle Thyroid Dysfunction Is Not Associated with Cognitive Decline: Results from the ELSA-Brasil
Abstract: Background: Subtle thyroid alterations have a controversial role in cognition. Objective: We investigated the longitudinal association of baseline thyroid function, thyrotropin (TSH), and thyroxine (FT4) levels with cognitive performance after 4 years of follow-up in middle-aged and older adults without overt thyroid dysfunction. Methods: We included 4,473 individuals, age ≥55 years at the second study wave, without overt thyroid dysfunction at baseline. Individuals were divided according to thyroid function and TSH and FT4 tertiles. Cognition was assessed at baseline and after 4 years of follow-up by the word recall (DWR), semantic verbal fluency (SVF), and trail making (TMT) tests. The longitudinal association of thyroid function and TSH and FT4 tertiles with cognitive performance was investigated using generalized estimating equations adjusted for sociodemographic characteristics, lifestyle, cardiovascular risk factors and depression. Results: There was no longitudinal association of thyroid function and TSH and FT4 baseline levels with performance on the cognitive tests. However, there was a baseline cross-sectional U-shaped association of FT4 tertiles with poorer performance in the SVF (first FT4 tertile: β = -0.11, 95% CI = -0.17; -0.04; third FT4 tertile: β = -0.10, 95% CI = -0.17; -0.04) and of the third FT4 tertile with poorer performance in the DWR (β = -0.09, 95% CI = -0.16; -0.02). Conclusion: Thyroid function and hormone levels were not associated with cognitive decline during 4 years of follow-up in middle-aged and older adults without overt thyroid dysfunction. Future studies with longer follow-up could clarify the implications of subtle thyroid alterations in cognition.

Pages 1541-1553
Montserrat Alegret, Ana Espinosa, Gemma Ortega, Alba Pérez-Cordón, Ángela Sanabria, Isabel Hernández, Marta Marquié, Maitée Rosende-Roca, Ana Mauleón, Carla Abdelnour, Liliana Vargas, Ester Esteban de Antonio, Rogelio López-Cuevas, Juan Pablo Tartari, Emilio Alarcón-Martín, Lluís Tárraga, Agustín Ruiz, Mercè Boada, Sergi Valero
From Face-to-Face to Home-to-Home: Validity of a Teleneuropsychological Battery
Abstract: Background: Over the last decade, teleneuropsychology has increased substantially. There is a need for valid neuropsychological batteries to be administered home-to-home. Since 2006, the neuropsychological battery of Fundació ACE (NBACE) has been administered face-to-face in our clinical settings. Recently, we adapted the NBACE for teleneuropsychology use to be administered home-to-home (NBACEtn). Objective: The aims of the present study are: 1) to determine the home-to-home NBACE equivalence compared to its original face-to-face version; and 2) to examine home-to-home NBACE discriminant capacity by differentiating among cognitively healthy, mild cognitive impairment, or mild dementia subjects and comparing it with the face-to-face version. Methods: Data from 338 individuals assessed home-to-home (NBACEtn) were contrasted with 7,990 participants assessed with its face-to-face version (NBACE). Exploratory and confirmatory factorial structure, and invariance analysis of the two versions of the battery were performed. Results: Exploratory and confirmatory factor analysis supported the four-factor model (attention, memory, executive, and visuospatial/constructional functions). Configural, metric, and scalar measurement invariance was found between home-to-home and face-to-face NBACE versions. Significant differences in most of the neuropsychological variables assessed were observed between the three clinical groups in both versions of administration. No differences were found between the technological devices used by participants (computer or tablet and mobile devices). Conclusion: For the first time, invariance analysis findings were addressed by determining a teleneuropsychological battery’s equivalence in comparison with its face-to-face version. This study amplifies the neuropsychological assessment’s applicability using a home-to-home format, maintaining the original measure’s structure, interpretability, and discriminant capacity.

Pages 1555-1566
Jeremy Molad, Hen Hallevi, Amos D. Korczyn, Estelle Seyman, Natan M. Bornstein, Dana Niry, Roy Eldor, Einor Ben-Assayag
The Interrelation Between Chronic Headache, Cognitive Scores, and MRI Markers Among Stroke Survivors
Abstract: Background: Migraine is known to mildly increase the risk for ischemic stroke and is associated with vascular MRI markers. However, the potential effect of chronic headache (CH) on stroke outcomes has not been studied. Objective: We aimed to assess the interrelation between CH and post-stroke cognitive impairment. Methods: Data from 455 patients with a first ever stroke from the TABASCO study was available. All patients underwent 3T brain MRI, blood analysis, and a serial cognitive assessment at baseline and 6, 12, and 24 months after. Results: Eighty-five (18.7%) patients reported suffering from CH, of whom 53 (62.4%) reported symptoms of photophobia or nausea, and 34 (40%) reported an aura. CH was associated with female sex, lower prevalence of T2DM (p<0.001), and lower HbA1C levels (p<0.001). Multiple regression analysis, controlling for age, sex, education, vascular risk factors, and the presence of acute lesions in MRI, revealed that CH was an independent predictor of better cognitive scores 6, 12, and 24 months post-stroke (p=0.015, p=0.01, and p=0.012, respectively). Stroke patients suffering from CH had also higher normalized gray, white matter, and thalamus volumes, and better white matter microstructural integrity (p<0.001, p=0.037, p<0.001, p=0.008, respectively) Conclusion: In this study, CH was consistently associated with better long term cognitive scores among post stroke subjects. These surprising findings may partially arise from the higher prevalence of T2DM among subjects without CH, that may represent the existence of chronic cerebrovascular disease, and may reflect mechanisms involving glucose metabolism.

Pages 1567-1578
Farid Chekani, James Pike, Eddie Jones, Joseph Husbands, Rezaul K. Khandker
Impact of Dementia-Related Behavioral Symptoms on Healthcare Resource Use and Caregiver Burden: Real-World Data from Europe and the United States
Abstract: Background: Dementia is commonly accompanied by neurobehavioral symptoms; however, the relationship between such symptoms and health-related outcomes is unclear. Objective: To investigate the impact of specific neurobehavioral symptoms in dementia on healthcare resource use (HCRU), patient quality of life (QoL), and caregiver burden. Methods: Data were taken from the 2015/16 Adelphi Real World Dementia Disease Specific Programme™, a point-in-time survey of physicians and their consulting dementia patients. Multiple regression analyses were used to examine associations between patient symptom groups and health related outcomes. Results: Each patient symptom group of interest (patients with agitation/aggression and related symptoms [AARS] with psychosis, patients with AARS without psychosis, and patients with other behavioral symptoms) had a positive association with HCRU variables (i.e., HCRU was greater), a negative association with proxy measures of patient QoL (i.e., QoL was decreased), and a positive association with caregiver burden (i.e., burden was greater) compared with patients with no behavioral symptoms (control group). The magnitude of effect was generally greatest in patients with AARS with psychosis. Regression analysis covariates that were found to be most often significantly related to the outcomes were dementia severity and the patients’ living situation (i.e., whether they were in nursing homes or living in the community). Conclusion: Combinations of behavioral symptoms, particularly involving AARS plus psychosis, may have a detrimental impact on health-related outcomes such as HCRU, patient QoL, and caregiver burden in dementia. Our results have implications for intervention development in patients who report clusters of symptoms and caregivers, and for identifying at-risk individuals.

Pages 1579-1588
Shin Nakamura, Satoshi Yomota, Hitomi Ito, Nobuyuki Akinaga, Ayaka Hori, Kenta Chinomi, Hideaki Suzuki, Kazuhiko Uchida, Takashi Asada
A Novel Cognitive Function Scale Using Functional Near-Infrared Spectroscopy for Evaluating Cognitive Dysfunction
Abstract: Background: Maintaining cognitive function is integral to a healthy social life in the aged. Although neuropsychological tests and brain imaging methods can assess cognitive dysfunction, these techniques are subjective, psychologically burdensome, and cannot be conducted easily. Objective: We sought to develop an objective, low-burden novel cognitive function scale based on functional near-infrared spectroscopy (fNIRS) of hemodynamic changes in the cerebral cortex during daily task performance. Methods: A total of 63 participants (aged 60-80 years) identified as non-dementia controls (NDC) or with mild cognitive impairment (MCI) were recruited and randomly assigned to training and test data sets. Explanatory variables were hemodynamic responses during low-burden sensory and simple tasks without higher-order brain functioning. Results: A logistic regression analysis of the fNIRS index in NDCs and MCI patients revealed area under the curve, sensitivity, specificity, and holdout results of 0.98, 94%, 88%, and 62% respectively. Correlation between fNIRS index and MCI odds showed positive linearity (R2 = 0.96). Conclusion: Positive correlation between the fNIRS index and MCI odds indicated effectiveness of this fNIRS measurement. Although additional experiments are necessary, the fNIRS index representing degree of cognitive decline can be an onsite monitoring tool to assess cognitive status.

Pages 1589-1599
Michael Waller, Rachel F. Buckley, Colin L. Masters, Francis R. Nona, Sandra Eades, Annette J. Dobson (Handling Associate Editor: Matthew Lennon)
Deaths with Dementia in Indigenous and Non-Indigenous Australians: A Nationwide Study
Abstract: Background: The prevalence of dementia is generally reported to be higher among Indigenous peoples. Objective: The rates and coding of dementia mortality were compared between Indigenous and non-Indigenous Australians. Methods: De-identified individual records on causes of death for all people aged 40 years or more who died in Australia between 2006 and 2014 (n = 1,233,084) were used. There were 185,237 records with International Classification of Diseases, Tenth Revision, codes for dementia (Alzheimer’s Disease, vascular dementia, or unspecified dementia) as the underlying cause of death or mentioned elsewhere on the death certificate. Death rates were compared using Poisson regression. Logistic regression was used to assess whether dementia was more likely to be classified as ‘unspecified’ type in Indigenous Australians. Results: The rates of death with dementia were 57% higher in Indigenous Australians, compared to non-Indigenous, relative rate (RR) 1.57, 95% confidence interval (CI) (1.48, 1.66), p < 0.0001. This excess of deaths was highest at ages below 75 (RRs > 2, test for interaction p < 0.0001), and among men (test for interaction p < 0.0001). When the underreporting of Indigenous status on the death certificate was taken into account the relative rate increased to 2.17, 95% CI (2.07, 2.29). Indigenous Australians were also more likely to have their dementia coded as ‘unspecified’ on their death certificate (Odds Ratio 1.92, 95% CI (1.66, 2.21), p < 0.0001), compared to the non-Indigenous group. Conclusion: This epidemiological analysis based on population level mortality data demonstrates the higher dementia-related mortality rate for Indigenous Australians especially at younger ages.

Pages 1601-1611
Nobuyuki Kobayashi, Shunichiro Shinagawa, Tomoyuki Nagata, Kenji Tagai, Kazuya Shimada, Azusa Ishii, Naomi Oka, Masahiro Shigeta, Kazuhiro Kondo
Blood DNA Methylation Levels in the WNT5A Gene Promoter Region: A Potential Biomarker for Agitation in Subjects with Dementia
Abstract: Background: Behavioral and psychological symptoms of dementia (BPSD) cause a heavy burden for both patient and caregivers. These symptoms are diverse, and their mechanism is still unclear. Agitation is the most common and difficult to treat among BPSD. In recent years, while changes in DNA methylation levels have been receiving attention as a biomarker of aging and dementia, associations with BPSD have not been examined. Objective: Focusing on agitation, the objective of the present study was to identify a region where changes in DNA methylation levels are associated with agitation. Methods: Using genome-wide DNA methylation analysis data for 7 dementia subjects with agitation, 5 dementia subjects without agitation, and 4 normal elderly controls, we determined a signaling pathway in the WNT5A gene promoter region to be associated with agitation. Based on this result, we measured DNA methylation levels in this region for 26 dementia subjects with agitation and 82 dementia subjects without agitation by means of methylation-sensitive high-resolution melting (MS-HRM) analysis. Results: The WNT5A DNA methylation level in dementia subjects with agitation was significantly lower than in those without agitation (p = 0.001). Changes in WNT5A DNA methylation levels were not influenced by age, sex, body mass index, APOE ε4, medication, or inflammatory cytokines. Conclusion: Our results suggested an association of agitation with Wnt signaling, in particular with changes in WNT5A DNA methylation levels, which could be a potentially useful biomarker for predicting the appearance of agitation. It may contribute to the elucidation of the mechanism of BPSD.

Pages 1613-1624
Ove Almkvist, Katharina Brüggen, Agneta Nordberg
Subcortical and Cortical Regions of Amyloid-β Pathology Measured by 11C-PiB PET Are Differentially Associated with Cognitive Functions and Stages of Disease in Memory Clinic Patients
Abstract: Background: The effect of regional brain amyloid-β (Aβ) pathology on specific cognitive functions is incompletely known. Objective: The relationship between Aβ and cognitive functions was investigated in this cross-sectional multicenter study of memory clinic patients. Methods: The participants were patients diagnosed with Alzheimer’s disease (AD, n=83), mild cognitive impairment (MCI, n=60), and healthy controls (HC, n=32), who had been scanned by 11C-PiB PET in 13 brain regions of both hemispheres and who had been assessed by cognitive tests covering seven domains. Results: Hierarchic multiple regression analyses were performed on each cognitive test as dependent variable, controlling for demographic characteristics and APOE status (block 1) and PiB measures in 13 brain regions (block 2) as independent variables. The model was highly significant for each cognitive test and most strongly for tests of episodic memory (learning and retention) versus PiB in putamen, visuospatially demanding tests (processing and retention) versus the occipital lobe, semantic fluency versus the parietal lobe, attention versus posterior gyrus cinguli, and executive function versus nucleus accumbens. In addition, education had a positively and APOE status a negatively significant effect on cognitive tests. Conclusion: Five subcortical and cortical regions with Aβ pathology are differentially associated with cognitive functions and stages of disease in memory clinic patients.

Pages 1625-1647
Matthew B. Hunter, Natalie Jenkins, Clare Dolan, Hannah Pullen, Craig Ritchie, Graciela Muniz-Terrera
Reliability of Telephone and Videoconference Methods of Cognitive Assessment in Older Adults with and without Dementia
Abstract: Background: Telephone and videoconference administration of cognitive tests introduce additional sources of variance compared to in-person testing. Reviews of test-retest reliability have included mixed neurocognitive and psychiatric populations with limited consideration of methodological and statistical contributions. Objective: We reviewed reliability estimates from comparison studies of older adults with and without dementia, considering test-retest analyses and study methods. Methods: Medline, Embase, PsycINFO, and Web of Science were systematically searched from 1 January 2000 to 9 June 2020 for original articles comparing telephone or videoconference administered cognitive instruments to in-person administration in older adults with and without dementia or mild cognitive impairment. Results: Of 4,125 articles, 23 were included: 11 telephone (N=2 dementia cohorts) and 12 videoconference (N=4 dementia cohorts). Telephone administered subtest scores trended in the same direction as in-person with comparable means. Person-level data were scarce. Data on dementia was only available for MMSE, with resulting subtle modality bias. MMSE, SMMSE, Letter Fluency, and HVLT-R in healthy to mild-moderate Alzheimer’s disease were particularly reliable for videoconference administration. Other tests show promise but require more observations and comprehensive analyses. Most studies used high-speed stable videoconferencing hardware resulting in a lack of ecological validity for home administration. Conclusion: Remote administration is often consistent with in-person administration but variable and limited at the person/test level. Improved statistical design and inclusion of dementia related cohorts in telephone studies is recommended. Reliability evidence is stronger for videoconferencing but with limited applicability to home administration and severe dementia. Improved reporting of administrative procedures is recommended.

Pages 1649-1662
Jonas Hannestad, Tiffanie Duclos, Whitney Chao, Katie Koborsi, Vicki Klutzaritz, Brian Beck, Ashok K. Patel, James Scott, Stephen G. Thein, Jeffrey L. Cummings, Gary Kay, Steven Braithwaite, Karoly Nikolich (Handling Associate Editor: Benedict Albensi)
Safety and Tolerability of GRF6019 Infusions in Severe Alzheimer’s Disease: A Phase II Double-Blind Placebo-Controlled Trial
Abstract: Background: The plasma fraction GRF6019 shows multiple benefits on brain aging in mice, including enhanced cognition, neurogenesis, and synaptic density, as well as reduced neuroinflammation. Objective: To evaluate the safety, tolerability, and preliminary efficacy of GRF6019 in patients with severe Alzheimer’s disease (AD). Methods: A phase II, double-blind, placebo-controlled study in patients with severe AD (Mini-Mental State Examination score 0-10). Patients were randomized 2:1 to GRF6019 (N=18) or placebo (N=8) and received daily 250 mL intravenous infusions over 5 days. The primary endpoints were the rates of adverse events (AEs) and the tolerability of GRF6019 as assessed by the number of patients completing the study. Change from baseline in cognitive and functional assessments was also evaluated. Results: All patients completed 100% of study visits and infusions. The rate of AEs was similar in the GRF6019 (8/18 patients [44.4%]) and placebo (3/8 patients [37.5%]) groups, and there were no deaths or serious AEs. The most common AEs considered related to treatment were mild, transient changes in blood pressure in the GRF6021 group (hypotension: 2 patients [11.1%]; hypertension: 1 patient [5.6%]); there were no related AEs in the placebo group. The trial was not powered to detect statistically significant differences between treatment groups. At the end of the study, patients in both treatment groups remained stable or improved on all cognitive and functional endpoints. Conclusion: GRF6019 demonstrated excellent safety, feasibility, and tolerability. Future trials designed to characterize the potential functional benefits of GRF6019 and related plasma fractions in severe AD are warranted.

Pages 1663-1671
Arsenije Subotic, Cheryl R. McCreary, Feryal Saad, Amanda Nguyen, Ana Alvarez-Veronesi, Angela M. Zwiers, Anna Charlton, Andrew E. Beaudin, Zahinoor Ismail, G. Bruce Pike, Eric E. Smith
Cortical Thickness and Its Association with Clinical Cognitive and Neuroimaging Markers in Cerebral Amyloid Angiopathy
Abstract: Background: Cerebral amyloid angiopathy (CAA) contributes to brain neurodegeneration and cognitive decline, but the relationship between these two processes is incompletely understood. Objective: The purpose of this study is to examine cortical thickness and its association with cognition and neurodegenerative biomarkers in CAA. Methods: Data were collected from the Functional Assessment of Vascular Reactivity study and the Calgary Normative Study. In total, 48 participants with probable CAA, 72 cognitively normal healthy controls, and 24 participants with mild dementia due to AD were included. Participants underwent an MRI scan, after which global and regional cortical thickness measurements were obtained using FreeSurfer. General linear models, adjusted for age and sex, were used to compare cortical thickness globally and in an AD signature region. Results: Global cortical thickness was lower in CAA compared to healthy controls (mean difference (MD) -0.047 mm, 95% confidence interval (CI) -0.088, -0.005, p=0.03), and lower in AD compared to CAA (MD -0.104 mm, 95% CI -0.165, -0.043, p=0.001). In the AD signature region, cortical thickness was lower in CAA compared to healthy controls (MD -0.07 mm, 95% CI -0.13 to -0.01, p=0.02). Within the CAA group, lower cortical thickness was associated with lower memory scores (R2=0.10; p=0.05) and higher white matter hyperintensity volume (R2=0.09, p=0.04). Conclusion: CAA contributes to neurodegeneration in the form of lower cortical thickness, and this could contribute to cognitive decline. Regional overlap with an AD cortical atrophy signature region suggests that co-existing AD pathology may contribute to lower cortical thickness observed in CAA.

Pages 1673-1684
Yan Du, Brittany Dennis, Jia Liu, Kylie Meyer, Nazish Siddiqui, Katrina Lopez, Carole White, Sahiti Myneni, Mitzi Gonzales, Jing Wang
A Conceptual Model to Improve Care for Individuals with Alzheimer’s Disease and Related Dementias and Their Caregivers: Qualitative Findings in an Online Caregiver Forum
Abstract Background: As the population rapidly ages, a growing number of families are engaging in care for individuals living with Alzheimer’s disease and related dementias (ADRD). The perceived challenges and burdens that face informal caregivers are enormous. Objective: The objective of this study was to 1) explore from the family caregivers’ perspective, the daily lives of individuals living with ADRD, and the challenges family caregivers encounter when caring for a family member with ADRD; and 2) to develop a comprehensive model with the endeavor to improve care for individuals with ADRD and their family caregivers. Methods: Posts were extracted from the ALZConnected online caregiving forum in May 2019. Guided by a triangular model focused on Caregiver, Individual with ADRD, and Context of Care, two researchers independently analyzed 654 posts with a combination of deductive and inductive thematic analysis approach. Researchers all agreed on finalized codes and themes. Results: Thematic analysis resulted in four themes: Individual with ADRD, Caregiver, Dynamic between Caregiver and Individual with ADRD, and Context of Care. The most frequently discussed topics among caregivers were informational and emotional support for caregivers, and the capabilities and functioning of individuals with ADRD. Conclusion: Online forums provide a valuable platform for caregivers to support each other informationally and emotionally, share care strategies, and navigate caregiving burdens. An expanded model was derived to support a comprehensive and dynamic approach to improve care for both caregivers and individuals with ADRD. The unique nature of the caregiver forum data is worthy of further data mining using a novel analysis approach.

Pages 1685-1699
Mu-huo Ji, Xue He, Jin-chun Shen, Jian-jun Yang
Aging-Related Neural Disruption Might Predispose to Postoperative Cognitive Impairment Following Surgical Trauma
Abstract: Background: Accumulating evidence has demonstrated that aging is associated with an exaggerated response to surgical trauma together with cognitive impairments. This has significant implications for the development of clinical phenotype such as perioperative neurocognitive disorders (PND), which is a common complication following surgery, especially for the elderly. However, the mechanism by which aging brain is vulnerable to surgical trauma remains to be elucidated. Objective: To test whether age-related alterations in hippocampal network activities contribute to increased risk of PND following surgery. Methods: Thirty-two adult and seventy-two aged male C57BL/6 mice undergone sevoflurane anesthesia and exploratory laparotomy were used to mimic human abdominal surgery. For the interventional study, mice were treated with minocycline. Behavioral tests were performed post-surgery with open field, novel object recognition and fear conditioning tests, respectively. The brain tissues were then harvested and subjected to biochemistry studies. Local field potential (LFP) recording was performed in another separate experiment. Results: Aged mice displayed signs of neuroinflammation, as reflected by significantly increased proinflammatory mediators in the hippocampus. Also, aged mice displayed persistently decreased oscillation activities under different conditions, both before and after surgery. Further correlation analysis suggested that theta power was positively associated with time with novel object, while γ oscillation activity was positively associated with freezing time to context. Of note, downregulation of neuroinflammation by microglia inhibitor minocycline reversed some of these abnormities. Conclusion: Our study highlights that age-related hippocampal oscillation dysregulation increases the risk of PND incidence, which might provide diagnostic/prognostic biomarkers for PND and possible other neurodegenerative diseases.

Pages 1701-1710
Wei Xu, Chen-Chen Tan, Juan-Juan Zou, Xi-Peng Cao, Lan Tan, for the Alzheimer’s Disease Neuroimaging Initiative
Insomnia Moderates the Relationship Between Amyloid-β and Cognitive Decline in Late-Life Adults without Dementia
Abstract: Background: It is suggested that not all individuals with elevated Aβ will develop dementia or cognitive impairment. Environment or lifestyle might modulate the association of amyloid pathology with cognition. Insomnia is a risk factor of cognitive disorders including Alzheimer’s disease. Objective: To investigate if insomnia moderated the relationship between amyloid-β (Aβ) and longitudinal cognitive performance in non-demented elders. Methods: A total of 385 Alzheimer’s Disease Neuroimaging Initiative participants (mean age = 73 years, 48% females) who completed 4+ neuropsychological evaluations and a [18F] florbetapir positron emission tomography scan were followed up to 8 years. Linear mixed-effects regression models were used to examine the interactions effect between insomnia and Aβ on longitudinal cognitive sores, including four domains (memory [MEM], executive function [EF], language [LAN], and visuospatial function [VS]). Results: The Aβ-positive status (A+) but not insomnia independently predicted faster cognitive decline in all domains. Furthermore, the relationship between Aβ and cognitive decline was moderated by insomnia (MEM: χ2= 4.05, p = 0.044, EF: χ2= 4.38, p = 0.036, LAN: χ2= 4.56, p = 0.033, and VS: χ2= 4.12, p = 0.042). Individuals with both elevated Aβ and insomnia experienced faster cognitive decline than those with only elevated Aβ or insomnia. Conclusion: These data reinforced the values of insomnia management in preventing dementia, possibly by interacting Aβ metabolism. Future efforts are warranted to determine whether sleep improvement will postpone the onset of dementia, specifically among populations in stages of preclinical or prodromal AD.

Pages 1711-1725
Katherine J. Bangen, Kelsey R. Thomas, Danielle L. Sanchez, Emily C. Edmonds, Alexandra J. Weigand, Lisa Delano-Wood, Mark W. Bondi, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Laura Zahodne)
Entorhinal Perfusion Predicts Future Memory Decline, Neurodegeneration, and White Matter Hyperintensity Progression in Older Adults
Abstract: Background: Altered cerebral blood flow (CBF) has been linked to increased risk for Alzheimer’s disease (AD). However, whether altered CBF contributes to AD risk by accelerating cognitive decline remains unclear. It also remains unclear whether reductions in CBF accelerate neurodegeneration and development of small vessel cerebrovascular disease. Objective: To examine associations between CBF and trajectories of memory performance, regional brain atrophy, and global white matter hyperintensity (WMH) volume. Method: 147 Alzheimer’s Disease Neuroimaging Initiative participants free of dementia underwent arterial spin labeling (ASL) magnetic resonance imaging (MRI) to measure CBF and serial neuropsychological and structural MRI examinations. Linear mixed effects models examined 5-year rate of change in memory and 4-year rate of change in regional brain atrophy and global WMH volumes as a function of baseline regional CBF. Entorhinal and hippocampal CBF were examined in separate models. Results: Adjusting for demographic characteristics, pulse pressure, apolipoprotein E ε4 positivity, cerebrospinal fluid p-tau/Aβ ratio, and neuronal metabolism (i.e., fluorodeoxyglucose standardized uptake value ratio), lower baseline entorhinal CBF predicted faster rates of decline in memory as well as faster entorhinal thinning and WMH progression. Hippocampal CBF did not predict cognitive or brain structure trajectories. Conclusion: Findings highlight the importance of early cerebrovascular dysfunction in AD risk and suggest that entorhinal CBF as measured by noninvasive ASL MRI is a useful biomarker predictive of future cognitive decline and of risk of both cerebrovascular and neuronal changes, even after adjusting for well-established AD risk factors and in a sample with relatively low vascular risk burden.

Pages 1727-1735
Aldo Camargo, Ze Wang, for the Alzheimer’s Disease Neuroimaging Initiative
Longitudinal Cerebral Blood Flow Changes in Normal Aging and the Alzheimer's Disease Continuum Identified by Arterial Spin Labeling MRI
Abstract: Background: Cross-sectional studies have shown lower cerebral blood flow (CBF) in Alzheimer’s disease (AD), but longitudinal CBF changes in AD are still unknown. Objective: To reveal the longitudinal CBF changes in normal control (NC) and the AD continuum using arterial spin labeling perfusion magnetic resonance imaging (ASL MRI). Methods: CBF was calculated from two longitudinal ASL scans acquired 2.22 ± 1.43 years apart from 140 subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). At the baseline scan, the cohort contained 41 NC, 74 mild cognitive impairment patients (MCI), and 25 AD patients. 21 NC converted into MCI and 17 MCI converted into AD at the follow-up. Longitudinal CBF changes were assessed using paired-t test for non-converters and converters separately at each voxel and in the meta-ROI. Age and sex were used as covariates. Results: CBF reductions were observed in all subjects. Stable NC (n=20) showed CBF reduction in the hippocampus and precuneus. Stable MCI patients (n=57) showed spatially more extended CBF reduction patterns in hippocampus, middle temporal lobe, ventral striatum, prefrontal cortex, and cerebellum. NC-MCI converters showed CBF reduction in hippocampus and cerebellum and CBF increase in caudate. MCI-AD converters showed CBF reduction in hippocampus and prefrontal cortex. CBF changes were not related with longitudinal neurocognitive changes. Conclusion: Normal aging and AD continuum showed common longitudinal CBF reductions in hippocampus independent of disease and its conversion. Disease conversion independent longitudinal CBF reductions escalated in MCI subjects.

Pages 1737-1747
Ai Koyanagi, Lee Smith, Jae Il Shin, Hans Oh, Karel Kostev, Louis Jacob, Adel S. Abduljabbar, Josep Maria Haro (Handling Associate Editor: Jianping Jia)
Multimorbidity and Subjective Cognitive Complaints: Findings from 48 Low- and Middle-Income Countries of the World Health Survey 2002-2004
Abstract: Background: Data on the association between multimorbidity and subjective cognitive complaints (SCC) are lacking from low- and middle-income countries (LMICs). Objective: To assess the association between multimorbidity and SCC among adults from 48 LMICs. Methods: Cross-sectional, community-based data were analyzed from the World Health Survey 2002-2004. Ten chronic conditions (angina, arthritis, asthma, chronic back pain, depression, diabetes, edentulism, hearing problems, tuberculosis, visual impairment) were assessed. Two questions on subjective memory and learning complaints in the past 30 days were used to create a SCC scale ranging from 0 (No SCC) to 100 (worse SCC). Multivariable linear regression and mediation analyses were conducted to explore the associations. Results: A total of 224,842 individuals aged ≥18 years [mean (SD) age 38.3 (16.0) years; 49.3% males] constituted the final sample. Compared to no chronic conditions, the mean SCC score was higher by 7.13 (95%CI=6.57-7.69), 14.84 (95%CI=13.91-15.77), 21.10 (95%CI=19.49-22.70), 27.48 (95%CI=25.20-29.76), and 33.99 (95%CI=31.45-36.53) points for 1, 2, 3, 4, and ≥5 chronic conditions. Estimates by sex and age groups (18-44, 45-64, ≥65 years) were similar. Nearly 30% of the association between multimorbidity (i.e., ≥2 chronic conditions) and SCC was explained by psychological factors (i.e., perceived stress, sleep problems, anxiety symptoms). Conclusion: Multimorbidity is associated with SCC among adults in LMICs. Future studies should investigate whether addressing psychological factors in people with multimorbidity can improve cognitive function, and whether screening for SCC in individuals with multimorbidity can be a useful tool to identify individuals at particularly high risk for future cognitive decline.

Pages 1749-1761
Fang Du*, Qing Yu*, Shirley ShiDu Yan *These authors contributed equally to this work.
PINK1 Activation Attenuates Impaired Neuronal-Like Differentiation and Synaptogenesis and Mitochondrial Dysfunction in Alzheimer’s Disease Trans-Mitochondrial Cybrid Cells
Abstract: Background: Mitochondrial dysfunction, bioenergetic deficit, and extensive oxidative stress underlie neuronal perturbation during the early stage of Alzheimer’s disease (AD). Previously, we demonstrated that decreased PTEN-induced putative kinase 1 (PINK1) expression is associated with AD pathology in AD-affected human brains and AD mice. Objective: In the present study, we highlight the essential role of PINK1 in AD-relevant mitochondrial perturbation and neuronal malfunction. Methods: Using trans-mitochondrial “cybrid” (cytoplasmic hybrid) neuronal cells, whose mitochondria are transferred from platelets of patients with sporadic AD, we observed the effect of PINK1 in neuronal-like differentiation and synaptogenesis and mitochondrial functions. Results: In AD cybrid cells, the downregulation of PINK1 is correlated to the alterations in mitochondrial morphology and function and deficit in neuronal-like differentiation. Restoring/increasing PINK1 by lentivirus transduction of PINK1 robustly attenuate mitochondrial defects and rescue neurite-like outgrowth. Importantly, defective PINK1 kinase activity fails to reverse these detrimental effects. Mechanistically, AD cybrid cells reveal a significant decrease in PINK1-dependent phosphorylated mitofusin (Mfn) 2, a key mitochondrial membrane protein that participates in mitochondrial fusion, and an insufficient autophagic activity for clearance of dysfunctional mitochondria. Overexpression of PINK1, but not mutant PINK1 elevates phosphorylation of Mfn2 and autophagy signaling LC3-II. Accordingly, PINK1-overexpressed AD cybrids exhibit increases in mitochondrial length and density and suppressed reactive oxygen species. These results imply that activation of PINK1 protects against AD-affected mitochondrial dysfunction and impairment in neuronal maturation and differentiation. Conclusion: PINK1-mediated mitophagy is important for maintaining mitochondrial health by clearance of dysfunctional mitochondria and therefore, improves energy homeostasis in AD.

Pages 1763-1779
Joseph A. Hirsch, George M. Cuesta, Pasquale Fonzetti, Joseph Comaty, Barry D. Jordan, Rosanna Cirio, Leanne Levin, Alex Abrahams, Kathleen M. Fry
Expanded Exploration of the Auditory Naming Test in Patients with Dementia
Abstract: Background: Auditory naming tests are superior to visual confrontation naming tests in revealing word-finding difficulties in many neuropathological conditions. Objective: To delineate characteristics of auditory naming most likely to reveal anomia in patients with dementia, and possibly improve diagnostic utility, we evaluated a large sample of patients referred with memory impairment complaints. Methods: Patients with dementia (N = 733) or other cognitive impairments and normal individuals (N = 69) were evaluated for frequency of impairment on variables of the Auditory Naming Test (ANT) of Hamberger & Seidel versus the Boston Naming Test (BNT). Results: Naming impairment occurred more frequently using the ANT total score (φ = 0.41) or ANT tip-of-the tongue score (TOT; φ = 0.19) but not ANT mean response time compared to the BNT in patients with dementia (p < 0.001). Significantly more patients were impaired on ANT variables than on the BNT in Alzheimer’s disease (AD), vascular dementia (VaD), mixed AD/VaD, and multiple domain mild cognitive impairment (mMCI) but not in other dementias or amnestic MCI (aMCI). This differential performance of patients on auditory versus visual naming tasks was most pronounced in older, well-educated, male patients with the least cognitive impairment. Impaired verbal comprehension was not contributory. Inclusion of an ANT index score increased sensitivity in the dementia sample (92%). Poor specificity (41%) may be secondary to the inherent limitation of using the BNT as a control variable. Conclusion: The ANT index score adds diagnostic utility to the assessment of naming difficulties in patients with suspected dementia.

Pages 1781-1792
Jessica Hoffmann*, Stefan Busse*, Franz von Hoff, Katrin Borucki, Thomas Frodl, Mandy Busse *These authors contributed equally to this work.
Association Between Homocysteine and Vitamin Levels in Demented Patients
Abstract: Background: Although it is known that the nutritional status among elderly persons and, in particular, patients with dementia, is compromised, malnutrition that results in insufficient uptake of several vitamins is often not diagnosed. Objective: An elevated homocysteine level is a known strong risk factor for vascular dementia (VaD) and Alzheimer's disease (AD). Several B vitamins are involved in the metabolism of homocysteine. Therefore, we investigated the serum levels of vitamin B1, vitamin B6, folate, and vitamin B12 in 97 patients with mild cognitive impairment (MCI) or different forms of dementia and 54 elderly control persons without dementia. Results: Compared to aged non-demented people, vitamins B1, B6, B12, and folate were decreased in serum of patients with AD, and patients with Lewy body dementia had reduced vitamin B12 level. Vitamin B6 was diminished in VaD. Patients with frontotemporal dementia showed no alterations in vitamin levels. Age was identified as an important factor contributing to the concentrations of vitamin B1 and B6 in serum, but not vitamin B12 and folate. Increased levels of total homocysteine were detected especially in MCI and AD. Homocysteine correlated negatively with levels of vitamins B6, B12, and folate and positively with Q Albumin. Conclusion: Our data suggest that despite increased homocysteine already present in MCI, vitamin levels are decreased only in dementia. We propose to determine the vitamin levels in patients with cognitive decline, but also elderly people in general, and recommend supplementing these nutrients if needed.