Pages 487-498
Ethics Review
Richard Milne, Eline Bunnik, Ana Diaz, Edo Richard, Shirlene Badger, Dianne Gove, Jean Georges, Karine Fauria, Jose-Luis Molinuevo, Katie Wells, Craig Ritchie, Carol Brayne (Handling Associate Editor: Joshua Grill; Ethics Editor: Allyson Rosen)
Perspectives on Communicating Biomarker-Based Assessments of Alzheimer’s Disease to Cognitively Healthy Individuals
Abstract: In clinical trials which target pathophysiological mechanisms associated with Alzheimer’s disease, research participants who are recruited based on biomarker test results should be informed about their increased risk of developing Alzheimer’s dementia. This paper presents the results of a qualitative focus group study of attitudes and concerns toward learning information about biomarker-based risk status among healthy research participants in the United Kingdom and Spain and people with dementia and their supporters/caregivers from countries represented in the European Working Group of People with Dementia of Alzheimer Europe. The study identified expectations related to learning risk status and preferences related to the content, quality, and follow-up of the disclosure process. The latter emphasize distinctions between risk and diagnoses, the importance of clear information about risk, and suggestions for risk reduction, as well as expectations for follow up and support. The implications of these preferences for practice are discussed. Providing details of research participants’ experience and views may serve as a guide for the development of processes for the responsible disclosure of Alzheimer’s disease biomarkers.
Pages 499-502
Ethics Response
Shana D. Stites
Cognitively Healthy Individuals Want to Know Their Risk for Alzheimer’s Disease: What Should We Do?
Abstract: Richard Milne and colleagues (2018) present the results of a study to discover what cognitively unimpaired research participants hope to gain by learning AD biomarker results and the associated risk for AD dementia. These results are useful to develop procedures to safely disclose these results in prevention trials. They also foreshadow the ethical and pragmatic challenges of using AD biomarkers in routine clinical practice. What is currently known is largely from studies of cognitively unimpaired or mildly impaired individuals who learned they had genetic markers of AD. Little is known about learning biomarker results. Milne and colleagues found that participants expect they will routinely learn risk reduction strategies and have access to follow up care. Can we meet these expectations? Mixed evidence supports effective therapies for delaying symptoms of AD and virtually nonexistent evidence for prevention of AD. Healthcare resources, including follow up, are designed to manage patients who have clinical symptoms—not the potentially large numbers of unimpaired individuals. To meet these needs, researchers who disclose AD biomarker results to cognitively unimpaired research participants may have an obligation to develop effective interventions and provide follow up care.
Pages 503-522
Review
Marine L. Croze, Luc Zimmer (Handling Associate Editor: Hyoung-gon Lee)
Ozone Atmospheric Pollution and Alzheimer’s Disease: From Epidemiological Facts to Molecular Mechanisms
Abstract: Atmospheric pollution is a well-known environmental hazard, especially in developing countries where millions of people are exposed to airborne pollutant levels above safety standards. Accordingly, several epidemiological and animal studies confirmed its role in respiratory and cardiovascular pathologies and identified a strong link between ambient air pollution exposure and adverse health outcomes such as hospitalization and mortality. More recently, the potential deleterious effect of air pollution inhalation on the central nervous system was also investigated and mounting evidence supports a link between air pollution exposure and neurodegenerative pathologies, especially Alzheimer’s disease (AD). The focus of this review is to highlight the possible link between ozone air pollution exposure and AD incidence. This review’s approach will go from observational and epidemiological facts to the proposal of molecular mechanisms. First, epidemiological and postmortem human study data concerning residents of ozone-severely polluted megacities will be presented and discussed. Then, the more particular role of ozone air pollution in AD pathology will be described and evidenced by toxicological studies in rat or mouse with ozone pollution exposure only. The experimental paradigms used to reproduce in rodent the human exposure to ozone air pollution will be described. Finally, current insights into the molecular mechanisms through which ozone inhalation can affect the brain and play a role in AD development or progression will be recapitulated.
Pages 523-547
Review
Dénes Zádori, Gábor Veres, Levente Szalárdy, Péter Klivényi, László Vécsei
Alzheimer’s Disease: Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines
Abstract: The pathomechanism of Alzheimer’s disease (AD) certainly involves mitochondrial disturbances, glutamate excitotoxicity, and neuroinflammation. The three main aspects of mitochondrial dysfunction in AD, i.e., the defects in dynamics, altered bioenergetics, and the deficient transport, act synergistically. In addition, glutamatergic neurotransmission is affected in several ways. The balance between synaptic and extrasynaptic glutamatergic transmission is shifted toward the extrasynaptic site contributing to glutamate excitotoxicity, a phenomenon augmented by increased glutamate release and decreased glutamate uptake. Neuroinflammation in AD is predominantly linked to central players of the innate immune system, with central nervous system (CNS)-resident microglia, astroglia, and perivascular macrophages having been implicated at the cellular level. Several abnormalities have been described regarding the activation of certain steps of the kynurenine (KYN) pathway of tryptophan metabolism in AD. First of all, the activation of indolamine 2,3-dioxygenase, the first and rate-limiting step of the pathway, is well-demonstrated. 3-Hydroxy-L-KYN and its metabolite, 3-hydroxy-anthranilic acid have pro-oxidant, antioxidant, and potent immunomodulatory features, giving relevance to their alterations in AD. Another metabolite, quinolinic acid, has been demonstrated to be neurotoxic, promoting glutamate excitotoxicity, reactive oxygen species production, lipid peroxidation, and microglial neuroinflammation, and its abundant presence in AD pathologies has been demonstrated. Finally, the neuroprotective metabolite, kynurenic acid, has been associated with antagonistic effects at glutamate receptors, free radical scavenging, and immunomodulation, giving rise to potential therapeutic implications. This review presents the multiple connections of KYN pathway-related alterations to three main domains of AD pathomechanism, such as mitochondrial dysfunction, excitotoxicity, and neuroinflammation, implicating possible therapeutic options.
Pages 549-560
Review
Leszek Szablewski
Human Gut Microbiota in Health and Alzheimer’s Disease
Abstract: Gut microbiota plays a crucial role in human health and disease. The alterations in the composition of gut microbiota may cause the onset of certain human pathologies. One of these is Alzheimer’s disease (AD). High-fat diets, administration of antibiotics, lack of probiotics and/or prebiotics in diet increase the risk of AD. On the other hand, modulation of the composition of gut microbiota may decrease the risk of AD and be able to slow down the progression of AD.
Pages 561-570
Editorial
A. David Smith, Helga Refsum, Teodoro Bottiglieri, Michael Fenech, Babak Hooshmand, Andrew McCaddon, Joshua W. Miller, Irwin H. Rosenberg, Rima Obeid
Homocysteine and Dementia: An International Consensus Statement
Abstract: Identification of modifiable risk factors provides a crucial approach to the prevention of dementia. Nutritional or nutrient-dependent risk factors are especially important because dietary modifications or use of dietary supplements may lower the risk factor level. One such risk factor is a raised concentration of the biomarker plasma total homocysteine, which reflects the functional status of three B vitamins (folate, vitamins B12, B6). A group of experts reviewed literature evidence from the last 20 years. We here present a Consensus Statement, based on the Bradford Hill criteria, and conclude that elevated plasma total homocysteine is a modifiable risk factor for development of cognitive decline, dementia, and Alzheimer’s disease in older persons. In a variety of clinical studies, the relative risk of dementia in elderly people for moderately raised homocysteine (within the normal range) ranges from 1.15 to 2.5, and the Population Attributable risk ranges from 4.3 to 31%. Intervention trials in elderly with cognitive impairment show that homocysteine-lowering treatment with B vitamins markedly slows the rate of whole and regional brain atrophy and also slows cognitive decline. The findings are consistent with moderately raised plasma total homocysteine (>11 µmol/L), which is common in the elderly, being one of the causes of age-related cognitive decline and dementia. Thus, the public health significance of raised tHcy in the elderly should not be underestimated, since it is easy, inexpensive, and safe to treat with B vitamins. Further trials are needed to see whether B vitamin treatment will slow, or prevent, conversion to dementia in people at risk of cognitive decline or dementia.
Pages 571-578
Short Communication
Daniel C.S. Tan, Sherilyn Yao, Arne Ittner, Josefine Bertz, Yazi D. Ke, Lars M. Ittner, Fabien Delerue
Generation of a New Tau Knockout (tau∆ex1) Line Using CRISPR/Cas9 Genome Editing in Mice
Abstract: Alzheimer’s disease and other dementias present with tau pathology. Several mouse lines with knockout of the tau-encoding Mapt gene have been reported, yet findings often differed between lines and sites. Here, we report a new tau knockout strain (tau∆ex1), generated by CRISPR/Cas9-mediated genome editing of intron -1/exon 1 of Mapt in C57Bl/6J mice. Tau∆ex1 mice had no overt phenotype, but, in line with previous models, they showed a significantly reduced susceptibility to excitotoxic seizures, with normal memory formation in young mice. This new in vivo resource will be made freely available to the research community.
Pages 579-581
Short Communication
Marit L. Sanders, Tim Stuckenschneider, Kate E. Devenney, Brian Lawlor, Stefan Schneider, Marcel G.M. Olde Rikkert, on behalf of the NeuroExercise Study Group
Real World Recruiting of Older Subjects with Mild Cognitive Impairment for Exercise Trials: Community Readiness is Pivotal
Abstract: Prevention trials in subjects with mild cognitive impairment (MCI), especially lifestyle interventions, can be difficult to carry out, particularly the recruitment and retention of subjects. We experienced these challenges in our multi-site one-year exercise trial in MCI, NeuroExercise. Trial recruitment rates differed significantly across sites; the non-medical sport university site, providing free access to a range of group exercise in a sports environment, proved far more successful than memory clinics linked to hospitals. This suggests that non-medical settings and a non-medical research community facilitating physical activities may be important factors in recruitment of subjects with MCI for large prevention trials.
Pages 583-589
Short Communication
Courtney Alexander*, Dagmar Zeithamova*, Ging-Yuek R. Hsiung, Ian R. Mackenzie, Claudia Jacova *These authors contributed equally to this work.
Decreased Prefrontal Activation during Matrix Reasoning in Predementia Progranulin Mutation Carriers
Abstract: We tested the potential of task-based functional neuroimaging as a biomarker of emerging prefrontal brain changes in progranulin (GRN) mutations carriers. Five GRN mutation carriers free of frontotemporal dementia (FTD) and 11 non-carriers from families with FTD-GRN underwent functional MRI while solving matrix-reasoning problems. Mutation carriers displayed slower responses for more difficult problems and lower lateral prefrontal activation across all problems. Overall task-evoked posterior ventrolateral prefrontal activation predicted mutation status with 100% sensitivity and 91% specificity. Volumetric differences did not account for activation differences. Prefrontal activation may have utility as a biomarker in GRN mutation.
Pages 591-596
Short Communication
Jillian L. King, Aimee A. Wong, Richard E. Brown (Handling Associate Editor: Dirk Montag)
Age-Related Changes in the Spatial Frequency Threshold of Male and Female 3xTg-AD Mice Using OptoMotry
Abstract: Visual impairments and retinal abnormalities occur in patients with Alzheimer’s disease (AD) and in mouse models of AD. It is important to know the visual ability of mouse models of AD to ensure that age-related cognitive deficits are not confounded by visual impairments. Using OptoMotry, the spatial frequency thresholds of male and female 3xTg-AD mice did not differ from their B6129SF2 wildtype controls between 1-18 months of age, but females had higher spatial frequency thresholds than males. However, the differences were quite small, and the visual ability of all mice was comparable to that of C57BL/6 mice.
Pages 597-609
Qiushan Tao, Haihao Zhu, Xi Chen, Robert A. Stern, Neil Kowall, Rhoda Au, Jan Krzysztof Blusztajn, Wei Qiao Qiu; for the Alzheimer’s Disease Metabolomics Consortium (Handling Associate Editor: Weiming Xia)
Pramlintide: The Effects of a Single Drug Injection on Blood Phosphatidylcholine Profile for Alzheimer’s Disease
Abstract: Studies suggest that a single injection of pramlintide, an amylin analog, induces changes in Alzheimer’s disease (AD) biomarkers in the blood of AD mouse models and AD patients. The aim of this study was to examine whether a pramlintide challenge combined with a phosphatidylcholine (PC) profile diagnoses of AD and mild cognitive impairment (MCI) better than PC alone. Non-diabetic subjects with cognitive status were administered a single subcutaneous injection of 60 mcg of pramlintide under fasting condition. A total of 71 PCs, amyloid-β peptide (Aβ), and total tau (t-tau) in plasma at different time points were measured and treated as individual variables. A single injection of pramlintide altered the levels of 7 PCs in the blood, while a pramlintide injection plus food modulated the levels of 10 PCs in the blood (p < 0.05). The levels of 2 PCs in MCI and 12 PCs in AD in the pramlintide challenge were significantly lower than the ones in controls. We found that while some PCs were associated with only Aβ levels, other PCs were associated with both Aβ and t-tau levels. A receiver operating characteristic analysis of the PCs was combined with the Aβ and t-tau data to produce an area under the curve predictive value of 0.9799 between MCI subjects and controls, 0.9794 between AD subjects and controls, and 0.9490 between AD and MCI subjects. A combination of AD biomarkers and a group of PCs post a pramlintide challenge may provide a valuable diagnostic and prognostic test for AD and MCI.
Pages 611-619
Montserrat Alegret, Mar Peretó, Alba Pérez, Sergi Valero, Ana Espinosa, Gemma Ortega, Isabel Hernández, Ana Mauleón, Maitée Rosende-Roca, Liliana Vargas, Octavio Rodríguez-Gómez, Carla Abdelnour, Marcelo L. Berthier, Thomas H. Bak, Agustín Ruíz, Lluís Tárraga, Mercè Boada
The Role of Verb Fluency in the Detection of Early Cognitive Impairment in Alzheimer’s Disease
Abstract: Background: Verb fluency (VF) is the less commonly used fluency test, despite several studies suggesting its potential as a neuropsychological assessment tool. Objective: To investigate the presence of VF deficits in mild cognitive impairment (MCI) and mild Alzheimer’s disease (AD) dementia; to assess the usefulness of VF in the detection of cognitively healthy (CH) people who will convert to MCI, and from MCI to dementia; and to establish the VF cut-offs useful in the cognitive assessment of Spanish population. Methods: 568 CH, 885 MCI, and 367 mild AD dementia individuals were administered the VF test and a complete neuropsychological battery. Longitudinal analyses were performed in 231 CH and 667 MCI subjects to search for VF predictors of diagnosis conversion. Results: A worsening on VF performance from CH, MCI to AD dementia groups was found. Lower performances on VF were significantly related to conversion from CH to MCI/MCI to dementia. When the effect of time to conversion was analyzed, a significant effect of VF was found on the faster conversion from CH to MCI, but not from MCI to dementia. Moreover, VF cut-off scores and sensitivity/specificity values were calculated for 6 conditions (3 age ranges by 2 educational levels). Conclusion: The VF test may be a useful tool for the differential diagnosis of cognitive failure in the elderly. Since VF deficits seem to take place in early stages of the disease, it is a suitable neuropsychological tool for the detection not only of CH people who will convert to MCI, but also from MCI to dementia.
Pages 621-633
Douglas W. Scharre, Emily Weichart, Dylan Nielson, Jun Zhang, Punit Agrawal, Per B. Sederberg, Michael V. Knopp, Ali R. Rezai, for the Alzheimer’s Disease Neuroimaging Initiative
Deep Brain Stimulation of Frontal Lobe Networks to Treat Alzheimer’s Disease
Abstract: The study objective was to evaluate the safety and efficacy of deep brain stimulation (DBS) at the ventral capsule/ventral striatum (VC/VS) region to specifically modulate frontal lobe behavioral and cognitive networks as a novel treatment approach for Alzheimer’s disease (AD) patients. This is a non-randomized phase I prospective open label interventional trial of three subjects with matched comparison groups. AD participants given DBS for at least 18 months at the VC/VS target were compared on the Clinical Dementia Rating–Sum of Boxes (CDR-SB), our primary outcome clinical measure, to matched groups without DBS from the AD Neuroimaging Initiative (ADNI) cohort. Serial 2-Deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET) images of AD participants were also compared longitudinally over time. Three AD DBS participants were matched to subjects from the ADNI cohort. All participants tolerated DBS well without significant adverse events. All three AD DBS participants had less performance decline and two of them meaningfully less decline over time on our primary outcome measure, CDR-SB, relative to matched comparison groups from the ADNI using score trajectory slopes. Minimal changes or increased metabolism on FDG-PET were seen in frontal cortical regions after chronic DBS at the VC/VS target. The first use of DBS in AD at a frontal lobe behavior regulation target (VC/VS) was well-tolerated and revealed less performance decline in CDR-SB. Frontal network modulation to improve executive and behavioral deficits should be furthered studied in AD.
Pages 635-648
Laura L. Ekblad, Sini Toppala, Jouni K. Johansson, Seppo Koskinen, Jouko Sundvall, Juha O. Rinne, Pauli Puukka, Matti Viitanen, Antti Jula
Albuminuria and Microalbuminuria as Predictors of Cognitive Performance in a General Population: An 11-Year Follow-Up Study
Abstract: Microalbuminuria, defined as urine albumin-to-creatinine ratio (UACR) > 3.0 mg/mmol and ≤ 30 mg/mmol, is an early marker of endothelial damage of the renal glomeruli. Recent research suggests an association among microalbuminuria, albuminuria (UACR > 3.0 mg/mmol), and cognitive impairment. Previous studies on microalbuminuria, albuminuria, and cognition in the middle-aged have not provided repeated cognitive testing at different time-points. We hypothesized that albuminuria (micro- plus macroalbuminuria) and microalbuminuria would predict cognitive decline independently of previously reported risk factors for cognitive decline, including cardiovascular risk factors. In addition, we hypothesized that UACR levels even below the cut-off for microalbuminuria might be associated with cognitive functioning. These hypotheses were tested in the Finnish nationwide, population-based Health 2000 Survey (n=5,921, mean age 52.6, 55.0% women), and its follow-up, Health 2011 (n=3,687, mean age at baseline 49.3, 55.6% women). Linear regression analysis was used to determine the associations between measures of albuminuria and cognitive performance. Cognitive functions were assessed with verbal fluency, word-list learning, word-list delayed recall (at baseline and at follow-up), and with simple and visual choice reaction time tests (at baseline only). Here, we show that micro- plus macroalbuminuria associated with poorer word-list learning and a slower reaction time at baseline, with poorer word-list learning at follow-up, and with a steeper decline in word-list learning during 11 years after multivariate adjustments. Also, higher continuous UACR consistently associated with poorer verbal fluency at levels below microalbuminuria. These results suggest that UACR might have value in evaluating the risk for cognitive decline.
Pages 649-663
Mariagnese Barbera, Francesca Mangialasche, Susan Jongstra, Juliette Guillemont, Tiia Ngandu, Cathrien Beishuizen, Nicola Coley, Carol Brayne, Sandrine Andrieu, Edo Richard, Hilkka Soininen, Miia Kivipelto, for the HATICE study group (Handling Associate Editor: Patrizia Mecocci)
Designing an Internet-Based Multidomain Intervention for the Prevention of Cardiovascular Disease and Cognitive Impairment in Older Adults: The HATICE Trial
Abstract: Background: Many dementia and cardiovascular disease (CVD) cases in older adults are attributable to modifiable vascular and lifestyle-related risk factors, providing opportunities for prevention. In the Healthy Aging Through Internet Counselling in the Elderly (HATICE) randomized controlled trial, an internet-based multidomain intervention is being tested to improve the cardiovascular risk (CVR) profile of older adults. Objective: To design a multidomain intervention to improve CVR, based on the guidelines for CVR management, and administered through a coach-supported, interactive, platform to over 2500 community-dwellers aged 65+ in three European countries. Methods: A comparative analysis of national and European guidelines for primary and secondary CVD prevention was performed. Results were used to define the content of the intervention. Results: The intervention design focused on promoting awareness and self-management of hypertension, dyslipidemia, diabetes mellitus, and overweight, and supporting smoking cessation, physical activity, and healthy diet. Overall, available guidelines lacked specific recommendations for CVR management in older adults. The comparative analysis of the guidelines showed general consistency for lifestyle-related recommendations. Key differences, identified mostly in methods used to assess the overall CVR, did not hamper the intervention design. Minor country-specific adaptations were implemented to maximize the intervention feasibility in each country. Conclusion: Despite differences in CVR management within the countries considered, it was possible to design and implement the HATICE multidomain intervention. The study can help define preventative strategies for dementia and CVD that are applicable internationally.
Pages 665-673
Xue-Ying He, Charles Isaacs, Song-Yu Yang
Roles of Mitochondrial 17β-Hydroxysteroid Dehydrogenase Type 10 in Alzheimer’s Disease
Abstract: 17β-Hydroxysteroid dehydrogenase type 10 is a multifunctional, homotetrameric, mitochondrial protein encoded by the HSD17B10 gene at Xp 11.2. This protein, 17β-HSD10, is overexpressed in brain cells of Alzheimer’s disease (AD) patients. It was reported to be involved in AD pathogenesis as the endoplasmic reticulum-associated amyloid-β binding protein (ERAB) and as amyloid-β binding alcohol dehydrogenase (ABAD). However, the exaggerated catalytic efficiencies for ERAB/ABAD in these reports necessitated the re-characterization of the catalytic functions of this brain enzyme. In addition to isoleucine metabolism, 17β-HSD10 is also responsible for the mitochondrial metabolism of neurosteroids such as 5α-androstane-3α,17β-diol and 17β-estradiol. These neurosteroids are inactivated by the oxidation catalyzed by 17β-HSD10. Since neurosteroid homeostasis is presumably essential for cognitive function, analysis of the impact of 17β-HSD10 and its inhibitor, amyloid-β peptide (Aβ), on the metabolism of neuroactive steroids offers a new approach to AD pathogenesis.
Pages 675-686
Tau Ming Liew, Junhong Yu, Rathi Mahendran, Tze-Pin Ng, Ee-Heok Kua, Lei Feng (Handling Associate Editor: Jin-Tai Yu)
Neuropsychiatric and Cognitive Subtypes among Community-Dwelling Older Persons and the Association with DSM-5 Mild Neurocognitive Disorder: Latent Class Analysis
Abstract: Background: Neuropsychiatric symptoms (NPS) have been shown to increase the risk of neurocognitive disorders (NCD), leading to the recently-published criteria of mild behavioral impairment (MBI) to identify pre-dementia using NPS alone. However, MBI drew concerns about over-diagnosing subclinical psychiatric disorders. Objective: We hypothesized that the specificity of NPS in predicting NCD may be improved by considering NPS together with various domains of cognitive deficits. We tested this hypothesis by identifying subtypes based on the combination of NPS and cognitive deficits among community-dwelling older persons, and evaluating how the identified subtypes were associated with mild NCD. Methods: Our participants were from a community-based cohort study. They completed assessments such as Geriatric Depression Scale (GDS), Geriatric Anxiety Inventory (GAI), and Montreal Cognitive Assessment (MoCA). Those with possible cognitive impairment underwent further evaluations for mild NCD. Latent class analysis was conducted using GDS, GAI, and MoCA domains. Logistic regression was performed to investigate the association between the latent-classes and mild NCD. Results: We included 825 participants, and identified four distinct subtypes: Subtype 1 (no NPS or cognitive deficits), Subtype 2 (NPS alone), Subtype 3 (cognitive deficits alone), and Subtype 4 (both NPS and cognitive deficits). Subtype 1 and 2 had low risk of prevalent mild NCD (OR 0.92–1.00), while Subtype 3 conferred a moderate risk (OR 4.47–4.85) and Subtype 4 had the highest risk (OR 7.95–8.63). Conclusion: We demonstrated the benefits of combining NPS and cognitive deficits to predict those at highest risk of prevalent mild NCD. Our findings highlighted the relevance of subclinical psychiatric symptoms in predicting NCD, and indirectly supported the need for longer durations of NPS to improve its specificity.
Pages 687-697
Maria Pia Giannoccaro, Anna Bartoletti-Stella, Silvia Piras, Alfonsina Casalena, Federico Oppi, Giovanni Ambrosetto, Pasquale Montagna, Rocco Liguori, Piero Parchi, Sabina Capellari
The First Historically Reported Italian Family with FTD/ALS Teaches a Lesson on C9orf72 RE: Clinical Heterogeneity and Oligogenic Inheritance
Abstract: Background. In 1969, Dazzi and Finizio reported the second observation of frontotemporal dementia (FTD) - amyotrophic lateral sclerosis (ALS) association in a large Italian kindred affected by an autosomal dominant form of ALS with high penetrance, frequent bulbar onset, and frequent cognitive decline. Objective. To expand the original characterization of this family and report the link with the C9orf72 repeat expansion (RE). Methods. We followed or reviewed the medical records of thirteen patients belonging to the original family and performed genetic analyses in four individuals. Results. Eight patients presented with ALS, four with FTD, and one with schizophrenia. The C9orf72 RE was found in three patients but not in the healthy survivor. Additionally, we found a novel possible pathogenic variant in the ITM2B gene in one patient with a complex phenotype, associating movement disorders, psychiatric and cognitive features, deafness, and optic atrophy. The neuropathological examination of this patient did not show the classical features of ITM2B mutation related dementias suggesting that the putative pathogenic mechanism does not involve cellular mislocalization of the protein or the formation of amyloid plaques. Conclusion. We showed that the original Italian pedigree described with FTD/ALS carries the C9orf72 RE. Moreover, the finding of an additional mutation in another dementia causing gene in a patient with a more complex phenotype suggests a possible role of genetic modifiers in the disease. Together with other reports showing the coexistence of mutations in multiple ALS/FTD causative genes in the same family, our study supports an oligogenic etiology of ALS/FTD.
Pages 699-711
Grazia D’Onofrio, Francesco Panza, Daniele Sancarlo, Filomena Addante, Vincenzo Solfrizzi, Chiara Cantarini, Antonio Mangiacotti, Michele Lauriola, Leandro Cascavilla, Francesco Paris, Madia Lozupone, Antonio Daniele, Antonio Greco, Davide Seripa
Executive Dysfunction Detected with the Frontal Assessment Battery in Alzheimer’s Disease Versus Vascular Dementia
Abstract: Alzheimer’s disease (AD) and vascular dementia (VaD) lead to progressive decline in executive function. We estimated the prevalence of executive dysfunction in AD and VaD patients, investigating cognitive, functional, and clinical correlates and also using a multidimensional approach based on a standardized comprehensive geriatric assessment (CGA). We included 215 patients (115 AD patients and 100 VaD patients) consecutively evaluated with a complete cognitive and affective assessment, a CGA, and the Frontal Assessment Battery (FAB) with six subtests investigating conceptualization, mental flexibility, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy. The prevalence of dysexecutive syndrome screened with a FAB score < 12 points was high in both AD (97 patients) and VaD (77 patients) (84.3% versus 77.0%, p=0.171). AD patients were significantly younger, with higher grade of cognitive impairment and less severe comorbidity and polypharmacy than VaD patients. AD patients showed a significantly higher impairment in FAB total score and five FAB subtests (conceptualization, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy) than VaD patients. These findings were largely confirmed in a sub-analysis conducted subdividing the sample in mild and moderate-to-severe demented patients and suggesting that in moderate-to-severe AD there was higher impairment in FAB total score and four FAB subtests (conceptualization, sensitivity to interference, inhibitory control, and environmental autonomy). Executive dysfunction could be greater in AD patients with moderate-to-severe dementia compared to VaD patients, although our groups were also not matched for age, comorbidity or polypharmacy, which could also exert an effect.
Pages 713-725
Lorenzo Falsetti, Giovanna Viticchi, Laura Buratti, Francesco Grigioni, Alessandro Capucci, Mauro Silvestrini (Handling Associate Editor: Lucilla Parnetti)
Interactions between Atrial Fibrillation, Cardiovascular Risk Factors, and ApoE Genotype in Promoting Cognitive Decline in Patients with Alzheimer’s Disease: A Prospective Cohort Study
Abstract: Background: An association between non-valvular atrial fibrillation (NVAF) and cognitive impairment has been hypothesized. Objective: We sought to evaluate whether and how permanent NVAF (pNVAF) is associated with progression of cognitive impairment in patients with Alzheimer’s disease (AD) in the presence of vascular or genetic risk factors. Methods: 310 consecutive patients affected by mild-moderate AD were included and followed for a 24–month period. At the end of the follow-up, based on the results of the neuropsychological evaluation patients were classified as stable or deteriorated to severe AD. Clinical history, therapy, time in therapeutic range for anticoagulation, Framingham cardiovascular risk profile (FCRP), CHA2DS2-VASc score, Mini-Mental State Examination (MMSE), ApoE genotype, brain CT-scan, carotid ultrasound, and ECG were collected. Binary logistic and path analysis were adopted to assess relationships between pNVAF, ApoE, and cognitive outcome. Results: Despite anticoagulant therapy, pNVAF was associated with lower entry MMSE, higher mean intima-media thickness (mIMT) and higher FCRP. Among patients carrying ApoE ε4 allele and affected by pNVAF, the lowest MMSE (14.90±7.62) and the highest mIMT (1.16±0.17 mm) and FCRP (26.24±3.96) values were detected. In this group, the risk of cognitive deterioration reached the highest probability. pNVAF was associated with an increased cognitive deterioration in subjects with high FCRP, CHA2DS2-VASc, or mIMT. Conclusions: pNVAF seems to identify AD patients with a significant atherosclerotic burden and reduced cognitive performances. The interaction between pNVAF and ApoE ε4 genotype, especially with aggregated risk factors and an advanced stage of vascular damage is associated with higher risk of fast cognitive deterioration.
Pages 727-735
Tessa van Middelaar, Jan W. van Dalen, Willem A. van Gool, Bert-Jan H. van den Born, Lonneke A. van Vught, Eric P. Moll van Charante, Edo Richard (Handling Associate Editor: Ronan O'Caoimh)
Visit-To-Visit Blood Pressure Variability and the Risk of Dementia in Older People
Abstract: Background: High visit-to-visit variability (VVV) in blood pressure (BP) is associated with cerebrovascular lesions on neuroimaging. Objective: Our primary objective was to investigate whether VVV is associated with incident all-cause dementia. As a secondary objective, we studied the association of VVV with cognitive decline and cardiovascular disease (CVD). Methods: We included community-dwelling people (age 70-78 year) from the ‘Prevention of Dementia by Intensive Vascular Care’ (preDIVA) trial with three to five 2-yearly BP measurements during 6-8 years follow-up. VVV was defined using coefficient of variation (CV; SD/mean × 100). Cognitive decline was assessed using the Mini-Mental State Examination (MMSE). Incident CVD was defined as myocardial infarction or stroke. We used a Cox proportional hazard regression and mixed-effects model adjusted for sociodemographic factors and cardiovascular risk factors. Results: In 2,305 participants (aged 74.2±2.5), mean systolic BP over all available visits was 150.1 mmHg (SD 13.6), yielding a CV of 9.0. After 6.4 years (SD 0.8) follow-up, 110 (4.8%) participants developed dementia and 140 (6.1%) CVD. Higher VVV was not associated with increased risk of dementia (hazard ratio [HR] 1.00 per point CV increase; 95% confidence interval [CI] 0.96-1.05), although the highest quartile of VVV was associated with stronger decline in MMSE (β -0.09, 95% CI -0.17 to -0.01). Higher VVV was associated with incident CVD (HR 1.07; 95% CI 1.04-1.11). Conclusion: In our study among older people, high VVV is not associated with incident all-cause dementia. It is associated with decline in MMSE and incident CVD.
Pages 737-744
Ziyi Liu, Naoko Kameshima, Toshifumi Nanjo, Akihiko Shiino, Tomoko Kato, Shino Shimizu, Takeshi Shimizu, Sachiko Tanaka, Katsuyuki Miura, Ikuo Tooyama
Development of a High-Sensitivity Method for the Measurement of Human Nasal Aβ42, Tau, and Phosphorylated Tau
Abstract: Cost-effective and feasible methods for early diagnosis of Alzheimer’s disease (AD) are needed. We present two methods to measure AD-related biomarkers simultaneously from one nasal smear for the purpose of diagnosing AD. Japanese men and women aged 63–85 years old were recruited in 2015–2016 for this case–control study. A total of 25 AD cases and 25 controls (22 men and 28 women) participated in this research. Nasal smears were collected from the common nasal meatus, inferior concha, middle nasal meatus, and olfactory cleft, and the proteins in the samples were analyzed by two methods, which we named PGD (Pre-treatment with guanidine- n-Dodecyl-beta-D-maltoside solution) method 1 (PGD-I) and 2 (PGD-II). The PGD-I method measured total tau and amyloid-β (Aβ)42, but no differences in median levels of total tau and Aβ42 between AD cases and controls were found in any of the nasal locations. The PGD-II method measured Aβ42, total tau, and phosphorylated tau, but levels of Aβ40 in all nasal locations of both groups were near zero. Median levels of phosphorylated tau to total tau (p-tau/t-tau) ratios in the middle nasal meatus and in the olfactory cleft were significantly higher in AD cases than in controls, and could significantly predict AD. To assess diagnostic reliability, areas under the ROC curve were 0.74 (95% CL =0.52–0.95, p = 0.030) for the middle nasal meatus and 0.72 (95% CL =0.52–0.92, p = 0.029) for the olfactory cleft. Thus, PGD-I and PGD-II can detect AD-related biomarkers in nasal smears and PGD-II may be a useful tool for diagnosing AD.
Pages 745-756
Jorge L. Del-Aguila, Maria Victoria Fernández, Suzanne Schindler, Laura Ibanez, Yuetiva Deming, Shengmei Ma, Ben Saef, Kathleen Black, John Budde, Joanne Norton, Rachel Chasse, Alzheimer’s Disease Neuroimaging Initiative (ADNI), Oscar Harari, Alison Goate, Chengjie Xiong, John C. Morris, Carlos Cruchaga (Handling Associate Editor: Pau Pastor)
Assessment of the Genetic Architecture of Alzheimer’s Disease Risk in Rate of Memory Decline
Abstract: Many genetic studies for Alzheimer’s disease (AD) have been focused on the identification of common genetic variants associated with AD risk and not on other aspects of the disease, such as age at onset or rate of dementia progression. There are multiple approaches to untangling the genetic architecture of these phenotypes. We hypothesized that the genetic architecture of rate of progression is different than the risk for developing AD dementia. To test this hypothesis, we used longitudinal clinical data from ADNI and the Knight-ADRC at Washington University, and we calculated PRS (polygenic risk score) based on the IGAP study to compare the genetic architecture of AD risk and dementia progression. Dementia progression was measured by the change of Clinical Dementia Rating Sum of Boxes (CDR)-SB per year. Out of the 21 loci for AD risk, no association with the rate of dementia progression was found. The PRS rate was significantly associated with the rate of dementia progression (β=0.146, p=0.03). In the case of rare variants, TREM2 (β=0.309, p=0.02) was also associated with the rate of dementia progression. TREM2 variant carriers showed a 23% faster rate of dementia compared with non-variant carriers. In conclusion, our results indicate that the recently identified common and rare variants for AD susceptibility have a limited impact on the rate of dementia progression in AD patients.
Pages 757-771
Paula Squarzoni, Fabio Luis Souza Duran, Geraldo F. Busatto, Tania Correa Toledo de Ferraz Alves (Handling Associate Editor: Jack de la Torre)
Reduced Gray Matter Volume of the Thalamus and Hippocampal Region in Elderly Healthy Adults with no Impact of APOE ε4: A Longitudinal Voxel-Based Morphometry Study
Abstract: Background: Many cross-sectional voxel-based morphometry (VBM) investigations have shown significant inverse correlations between chronological age and gray matter (GM) volume in several brain regions in healthy humans. However, few VBM studies have documented GM decrements in the healthy elderly with repeated MRI measurements obtained in the same subjects. Also, the extent to which the APOE ε4 allele influences longitudinal findings of GM reduction in the healthy elderly is unclear. Objective: Verify whether regional GM changes are associated with significant decrements in cognitive performance taking in account the presence of the APOE ε4 allele. Methods: Using structural MRI datasets acquired in 55 cognitively intact elderly subjects at two time-points separated by approximately three years, we searched for voxels showing significant GM reductions taking into account differences in APOE genotype. Results: We found global GM reductions as well as regional GM decrements in the right thalamus and left parahippocampal gyrus (p<0.05, family-wise error corrected for multiple comparisons over the whole brain). These findings were not affected by APOE ε4. Conclusions: Irrespective of APOE ε4, longitudinal VBM analyses show that the hippocampal region and thalamus are critical sites where GM shrinkage is greater than the degree of global volume reduction in healthy elderly subjects.
Pages 773-787
Alfonsina D’Iorio, Federica Garramone, Fausta Piscopo, Chiara Baiano, Simona Raimo, Gabriella Santangelo
Meta-Analysis of Personality Traits in Alzheimer’s Disease: A Comparison with Healthy Subjects
Abstract: Background: The role of specific personality traits as factor risks of Alzheimer’s disease (AD) has been consistently found, whereas personality traits specifically related to AD (after the diagnosis) have not been outlined yet. Objective: A meta-analysis of published studies was performed to determine whether AD patients have a distinctive personality trait profile compared to healthy subjects (HC), similar to or different from a premorbid personality profile consistently reported in previous studies. Methods: A systematic literature search was performed using PsycInfo (PROQUEST), PubMed, and Scopus. The meta-analysis pooled results from primary studies using Hedges’ g unbiased approach. Results: The meta-analysis included 10 primary studies and revealed that, when the personality was evaluated by informant-rated measures, AD patients had significantly higher levels of Neuroticism, lower levels of Openness, Agreeableness, Conscientiousness, and Extraversion than HCs. When the personality was evaluated by self-rated measures, the results obtained from informants were confirmed for Neuroticism, Openness, and Extraversion but not for Agreeableness and Conscientiousness where AD patients and HCs achieved similar scores. Conclusions: The meta-analysis revealed that high Neuroticism and low Openness and Extraversion are distinctive personality traits significantly associated with a diagnosis of AD when evaluated both self-rated and informant-rated measures. This personality trait profile is similar to premorbid one, which contributes to development of AD over time. Therefore, our findings indirectly support the idea of specific premorbid personality traits as harbingers of AD.
Pages 789-794
Kasper Katisko, Annakaisa Haapasalo, Anne Koivisto, Johanna Krüger, Päivi Hartikainen, Ville Korhonen, Seppo Helisalmi, Sanna-Kaisa Herukka, Anne M. Remes, Eino Solje (Handling Associate Editor: Luisa Benussi)
Low Prevalence of Cancer in Patients with Frontotemporal Lobar Degeneration
Abstract: Several studies have reported reduced risk of cancer in patients with Alzheimer’s disease (AD) or Parkinson’s disease. The relationship between cancer and frontotemporal lobar degeneration (FTLD) has not been previously reported. Here, our aim was to evaluate the occurrence of cancer in Finnish FTLD patients with a high proportion of C9ORF72 repeat expansion carriers in comparison to age- and sex-matched group of AD patients and control subjects classified as not cognitively impaired (NCI). The prevalence of cancer was 9.7% in FTLD, 18.7% in AD, and 17.4% in NCI (FTLD versus AD p=0.012, FTLD versus NCI p=0.029) groups. No differences were observed between C9ORF72 repeat expansion carriers and non-carriers inside the FTLD group. To our knowledge, this is the first study showing significantly lower prevalence of cancer in FTLD patients compared to patients with AD or NCI subjects. Our data suggest an inverse association between neurodegeneration and cancer and that FTLD-specific mechanisms may underlie the especially strong inverse association observed in this study.
Pages 795-806
Sarah C. McEwen*, Prabha Siddarth*, Berna Abedelsater, Yena Kim, Wenli Mui, Pauline Wu, Natacha D. Emerson, Jacob Lee, Shayna Greenberg, Tiffany Shelton, Scott Kaiser, Gary W. Small, David A. Merrill (Handling Associate Editor: Cyrus Raji) *These authors contributed equally to this work.
Simultaneous Aerobic Exercise and Memory Training Program in Older Adults with Subjective Memory Impairments
Abstract: Background: Several modifiable lifestyle factors have been shown to have potential beneficial effects in slowing cognitive decline. Two such factors that may affect cognitive performance and slow the progression of memory loss into dementia in older adults are cognitive training and physical activity. There are currently no effective treatments for dementia; therefore, preventative strategies to delay or prevent the onset of dementia are of critical importance. Objective: The aim of this study was to determine the relative effectiveness of simultaneous performance of memory training and aerobic exercise to a sequential performance intervention on memory functioning in older adults. Methods: 55 older adults (aged 60-75) with subjective memory impairments (non-demented and non-MCI) completed the intervention that consisted of 90-minute small group classes held twice weekly. Participants were randomized to either 4-weeks of supervised strategy-based memory training done simultaneously while stationary cycling (SIM) or sequentially after the stationary cycling (SEQ). Standardized neurocognitive measures of memory, executive functioning, speed of processing, attention, and cognitive flexibility were assessed at baseline and post-intervention. Results: The SIM group, but not the SEQ group, had a significant improvement on composite memory following the intervention (t(51)=2.7, p=0.01, effect size (ES)=0.42) and transfer to non-trained reasoning abilities (t(51)=6.0, ES=0.49) and complex attention (t(51)=3.1, p=0.003, ES=0.70). Conversely, the SEQ group, but not the SIM, showed significant improvement in executive functioning (t(51)=5.0, p=0.0001, ES=0.96). Conclusion: These findings indicate that a 4-week simultaneous memory training and aerobic exercise program is sufficient to improve memory, attention, and reasoning abilities in older adults.
Pages 807-819
Wei Zhang*, Yi Guo*, Bo Li, Qi Zhang, Jian-hui Liu, Guo-jun Gu, Jin-hong Wang, Rui-kang Bao, Yu-jie Chen, Jian-rong Xu *These authors contributed equally to this work.
GDF11 Rejuvenates Cerebrovascular Structure and Function in an Animal Model of Alzheimer’s Disease
Abstract: Cerebral amyloid angiopathy (CAA) is present in up to 90% of patients with Alzheimer´s disease (AD), and may interact with classical neuropathology to exacerbate cognitive decline. Since growth differentiation factor 11 (GDF11) can activate vascular remodeling, we tested its effects on cognitive function and neuroinflammatory changes of AD model mice. We intravenously administered GDF11 or vehicle daily to 12-month-old transgenic mice overexpressing the amyloid-β protein precursor (AβPP)/PS1). Cognitive function was monitored using the Morris water maze, and after conclusion of the treatment, we assessed the morphology and presence of inflammatory markers in the cerebral vasculature. Subchronic treatment of adult AβPP/PS1 mice with GDF11 rescued cognitive function and ameliorated cerebrovascular function. In particular, the de novo genesis of small blood vessels and the expression of vascular-related proteins were significantly higher than in the vehicle-treated AβPP/PS1 mice, whereas the expressions of the inflammatory markers Iba-1 and GFAP significantly decreased in proportion to the lower ratio of two forms of amyloid-β (Aβ40/42). Daily intravenous treatment with GDF11-injection can rejuvenate respects of cognition and cerebrovascular changes in AD mice.
Pages 821-831
Kilan Le Guennec, Hélène Tubeuf, Didier Hannequin, David Wallon, Olivier Quenez, Stéphane Rousseau, Anne-Claire Richard, Jean-François Deleuze, Anne Boland, Thierry Frebourg, Pascaline Gaildrat, Dominique Campion, Alexandra Martins, Gaël Nicolas (Handling Associate Editor: Amalia Bruni)
Biallelic Loss of Function of SORL1 in an Early Onset Alzheimer’s Disease Patient
Abstract: Heterozygous SORL1 protein truncating variants (PTV) are a strong risk factor for early-onset Alzheimer’s disease (EOAD). In case control studies performed at the genome-wide level, PTV definition is usually straightforward. Regarding splice site variants, only those affecting canonical sites are typically included. Some other variants, not annotated as PTV, could, however, affect splicing and hence result in a loss of SORL1 function. We took advantage of the whole exome sequencing data from the 9/484 patients with a previously reported SORL1 PTV in the French EOAD series and searched for a second variant which may affect splicing and eventually result in more than 50% loss of function overall. We found that one patient, known to carry a variant predicted to disrupt the canonical 5’ splice site of exon 8, also carried a second novel intronic variant predicted to affect SORL1 splicing of exon 29. Segregation analysis showed that the second variant was located in trans from the known PTV. We performed ex vivo minigene splicing assays and showed that both variants led to the generation of transcripts containing a premature stop codon. This is therefore the first evidence of a human carrying biallelic SORL1 PTV. This patient had a family history of dementia in both maternal and paternal lineages with later ages of onset than the proband himself. However, his 55 years age at onset was in the same ranges as previously published SORL1 heterozygous PTV carriers. This suggests that biallelic loss of SORL1 function is an extremely rare event that was not associated with a dramatically earlier age at onset than heterozygous SORL1 loss-of-function variant carriers, in this single patient.
Pages 833-840
Christine M. Burns, Alfred W. Kaszniak, Kewei Chen, Wendy Lee, Daniel J. Bandy, Richard J. Caselli, Eric M. Reiman (Handling Associate Editor: Jeff Burns)
Longitudinal Changes in Serum Glucose Levels are Associated with Metabolic Changes in Alzheimer’s Disease Related Brain Regions
Abstract: Background: The association between longitudinal changes in serum glucose level and longitudinal changes in [18F] Fluorodeoxyglucose-PET (FDG PET) measurements of Alzheimer’s disease (AD) risk are unknown. Objective: To investigate whether variation in serum glucose levels across time are associated with changes in FDG PET measurements of cerebral metabolic rate for glucose (rCMRgl) in brain regions preferentially affected by Alzheimer’s disease (AD). Methods: Participants are a subset of a prospective cohort study investigating FDG PET, apolipoprotein E (APOE) ε4, and risk for AD which includes data from baseline, interim, and follow up visits over 4.4 ± 1.0-years. An automated brain-mapping algorithm was utilized to characterize and compare associations between longitudinal changes in serum glucose levels and longitudinal changes in rCMRgl. Results: This study included 80 adults aged 61.5 ± 5 years, including 38 carriers and 42 non-carriers of the APOE ε4 allele. Longitudinal increases in serum glucose levels were associated with longitudinal CMRgl decline in the vicinity of parietotemporal, precuneus/posterior cingulate, and prefrontal brain regions preferentially affected by AD (p<0.05, corrected for multiple comparisons). Findings remained significant when controlled for APOE ε4 status and baseline and advancing age. Conclusions: Additional studies are needed to clarify and confirm the relationship between longitudinal changes in peripheral glucose and FDG PET measurements of AD risk. Future findings will set the stage on the use of FDG PET in the evaluation of possible interventions that target risk factors for the development of AD.
Pages 841-854
Fabian Dorninger, Ann B. Moser, Jianqiu Kou, Christoph Wiesinger, Sonja Forss-Petter, Andreas Gleiss, Margareta Hinterberger, Susanne Jungwirth, Peter Fischer, Johannes Berger
Alterations in the Plasma Levels of Specific Choline Phospholipids in Alzheimer’s Disease Mimic Accelerated Aging
Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disease and of continuously rising prevalence. The identification of easy-to-measure biomarkers capable to assist in the prediction and early diagnosis of AD is currently a main research goal. Lipid metabolites in peripheral blood of human patients have recently gained major attention in this respect. Here, we analyzed plasma of 174 participants (not demented at baseline; mean age: 75.70±0.44 years) of the Vienna Transdanube Aging (VITA) study, a longitudinal, population-based birth cohort study, at baseline and after 90 months or at diagnosis of probable AD. We determined the levels of specific choline phospholipids, some of which have been suggested as potential biomarkers for the prediction of AD. Our results show that during normal aging the levels of lysophosphatidylcholine, choline plasmalogen, and lyso-platelet activating factor increase significantly. Notably, we observed similar but more pronounced changes in the group that developed probable AD. Thus, our results imply that, in terms of choline-containing plasma phospholipids, the conversion to AD mimics an accelerated aging process. We conclude that age, even in the comparatively short time frame between 75 and 82.5 years, is a crucial factor in the quest for plasma lipid biomarkers for AD that must be carefully considered in future studies and trials.
Pages 855-865
Dai Wang, Tim Schultz, Gerald P. Novak, Susan Baker, David A. Bennett, Vaibhav A. Narayan (Handling Associate Editor: Peter Whitehouse)
Longitudinal Modeling of Functional Decline Associated with Pathologic Alzheimer’s Disease in Older Persons without Cognitive Impairment
Abstract: Background: Therapeutic research on Alzheimer’s disease (AD) has moved to intercepting the disease at the preclinical phase. Most drugs in late development have focused on the amyloid hypothesis. Objective: To understand the magnitude of amyloid-related functional decline and to identify the functional domains sensitive to decline in a preclinical AD population. Methods: Data were from the Religious Orders Study and the Rush Memory and Aging Project. Cognitive decline was measured by a modified version of the Alzheimer’s Disease Cooperative Study Preclinical Alzheimer Cognitive Composite. The trajectories of functional decline, as measured by the instrumental and basic activities of daily living, were longitudinally modeled in 484 participants without cognitive impairment at baseline and having both a final clinical and a postmortem neuropathology assessment of AD. Results: Individuals with different final clinical diagnoses had different trajectories of cognitive and functional decline. Individuals with AD dementia, minor cognitive impairment, and no cognitive impairment had the most, intermediate, and least declines. While individuals with pathologic AD had significantly more cognitive decline over time than those without, the magnitude of difference in functional decline between these two groups was small. Functional domains such as handling finance and handling medications were more sensitive to decline. Conclusion: Demonstrating the functional benefit of an amyloid-targeting drug represents a significant challenge as elderly people experience functional decline due to a wide range of reasons with limited manifestation attributable to AD neuropathology. More sensitive functional scales focusing on the functional domains sensitive to decline in preclinical AD are needed.
Pages 867-876
Julia F.-M. Gilmartin-Thomas, John McNeil, Anne Powell, Daniel T. Malone, Rory Wolfe, Ian C. Larson, Claire L. O’Reilly, Carl M. Kirkpatrick, Eva Kipen, Tanya Petrovich, J. Simon Bell
Impact of a Virtual Dementia Experience on Medical and Pharmacy Students’ Knowledge and Attitudes Toward People with Dementia: A Controlled Study
Abstract: Background: Clinical practice guidelines for dementia highlight the importance of providing patient-centered care. This can be achieved by improving health professionals’ attitudes and knowledge toward people with dementia. Objective: Quantitatively evaluate the impact of a virtual dementia experience on medical and pharmacy students’ knowledge and attitudes toward people with dementia. Methods: A non-randomized controlled study from September-October 2016. The intervention group received a 1.5-hour multisensory, virtual simulation of light, sound, color, and visual content to experience the cognitive and perceptual difficulties faced by people with dementia. Controls participated in the standard curriculum only. All students were invited to complete the 20-item Dementia Attitudes Scale (DAS) pre- and post-intervention. Results: A total of 278 students (n=64 medical, n=214 pharmacy) were analyzed (n=80 intervention, n=198 control). The majority of students were female (n=184, 66.2%), with an average age of 22.5 years. The intervention improved the DAS total score and subdomains of comfort and knowledge (p<0.001). Conclusion: The intervention had a positive impact on medical and pharmacy students’ knowledge and attitudes toward people with dementia.
Pages 877-885
Bryce Tan, Narayanaswamy Venketasubramanian, Henri Vrooman, Ching-Yu Cheng, Tien Yin Wong, Mohammad Kamran Ikram, Christopher Chen, Saima Hilal (Handling Associate Editor: Barbara Bendlin)
Homocysteine and Cerebral Atrophy: The Epidemiology of Dementia In Singapore Study
Abstract: Background: Plasma homocysteine levels are increasingly studied as a potential risk factor for dementia. Elevated homocysteine levels have been linked with gray and white matter volume reduction among individuals with mild cognitive impairment and Alzheimer’s disease. However, the effects of homocysteine on brain changes in preclinical stages of dementia remain unexplored. Objective: To examine the association of elevated homocysteine levels with markers of neurodegeneration, i.e., white and gray matter volume in an elderly population. Methods: The study included 768 participants (mean age: 69.6 ± 6.5 years, 51.3% women) from the Epidemiology of Dementia In Singapore study. Participants underwent a brain MRI scan and blood tests. Serum homocysteine was measured using competitive immunoassay. Cortical thickness and subcortical structural volume were quantified using FreeSurfer whereas white matter volume was quantified using a previous validated method. Results: Higher homocysteine levels were significantly associated with decreased global white matter volume [mean difference (β) in volume (ml) per micromole per liter (µmol/l) increase in homocysteine levels: -0.555, 95% Confidence Interval (CI): -0.873; -0.237], decreased parietal cortical thickness [β in thickness (µm) per µmol/l increase in homocysteine levels : -1.429, 95%CI: -2.781; -0.077], and smaller volumes of the thalamus [β: -0.017, 95%CI: -0.026; -0.008], brainstem [β: -0.037, 95%CI: -0.058; -0.016], and accumbens [β: -0.004, 95%CI: -0.006; -0.002]. Conclusion: Higher homocysteine levels were associated with cerebral atrophy. Further studies are required to assess whether lowering plasma homocysteine levels may prevent neurodegenerative changes or delay progression of clinical symptoms before the development of dementia.
Pages 887-900
Shraddha Sapkota, Roger A. Dixon
A Network of Genetic Effects on Non-Demented Cognitive Aging: Alzheimer’s Genetic Risk (CLU + CR1 + PICALM) Intensifies Cognitive Aging Genetic Risk (COMT + BDNF) Selectively for APOE ε4 Carriers
Abstract: Background: Trajectories of complex neurocognitive phenotypes in preclinical aging may be produced differentially through selective and interactive combinations of genetic risk. Objective: We organize three possible combinations into a “network” of genetic risk indices derived from polymorphisms associated with normal and impaired cognitive aging, as well as Alzheimer’s disease (AD). Specifically, we assemble and examine three genetic clusters relevant to non-demented cognitive trajectories: 1) Apolipoprotein E (APOE), 2) a Cognitive Aging Genetic Risk Score (CA-GRS; Catechol-O-methyltransferase + Brain-derived neurotrophic factor), and 3) an AD-Genetic Risk Score (AD-GRS; Clusterin + Complement receptor 1 + Phosphatidylinositol-binding clathrin assembly protein). Method: We use an accelerated longitudinal design (n = 634; age range = 55-95 years) to test whether AD-GRS (low versus high) moderates the effect of increasing CA-GRS risk on executive function (EF) performance and change as stratified by APOE status (ε4+ versus ε4-). Results: APOE ε4 carriers with high AD-GRS had poorer EF performance at the centering age (75 years) and steeper 9-year decline with increasing CA-GRS but this association was not present in APOE ε4 carriers with low AD-GRS. Conclusions: APOE ε4 carriers with high AD-GRS are at elevated risk of cognitive decline when they also possess higher CA-GRS risk. Genetic risk from both common cognitive aging and AD-related indices may interact in intensification networks to differential predict (1) level and trajectories of EF decline and (2) potential selective vulnerability for transitions into impairment and dementia.
