Volume 69, Number 4, 2019

Pages 897-904
Ethics Review

Julie M. Robillard, Julia M. Wu, Tanya L. Feng, Mallorie Tam
Prioritizing Benefits: A Content Analysis of the Ethics in Dementia Technology Policies
Abstract: Background: As the global prevalence of dementia rises, care costs impose a large burden on healthcare systems. Technology solutions in dementia care have the potential to ease this burden. While policies exist to guide and govern the use of dementia care technologies, little is known about how ethical considerations are incorporated into these documents. Objective: The goal of this study was to examine ethics-related content in dementia care technology policies. Methods: We used a two-step data mining approach to collect a sample of dementia technology policies. Policy documents were analyzed using emergent content analysis. Following the coding of the sample, thematic categories were organized using the principles of biomedical ethics as a framework. Results: A total of 23 policy documents from four Alzheimer associations in four countries were included in our analysis. General ethics considerations and themes related to beneficence were mentioned in 96% of the documents. Thematic categories related to justice were present in 74% of the sample, themes related to non-maleficence appeared in 52% of documents, and themes related to autonomy appeared in 43% of the sample. Conclusion: While ethical considerations are present in existing policies for dementia care technology, these considerations revolve primarily around the benefit of the technologies. Further efforts are needed to provide formal guidance that incorporates both benefits and potential harms.

Pages 905-919

Philippos Koulousakis, Pablo Andrade, Veerle Visser-Vandewalle, Thibaut Sesia
The Nucleus Basalis of Meynert and Its Role in Deep Brain Stimulation for Cognitive Disorders: A Historical Perspective
The nucleus basalis of Meynert (nbM) was first described at the end of the 19th century and named after its discoverer, Theodor Meynert. The nbM contains a large population of cholinergic neurons that project their axons to the entire cortical mantle, the olfactory tubercle, and the amygdala. It has been functionally associated with the control of attention and maintenance of arousal, both key functions for appropriate learning and memory formation. This structure is well-conserved across vertebrates, although its degree of organization varies between species. Since early in the investigation of its functional and pathological significance, its degeneration has been linked to various major neuropsychiatric disorders. For instance, Lewy bodies, a hallmark in the diagnosis of Parkinson’s disease, were originally described in the nbM. Since then, its involvement in other Lewy body and dementia-related disorders has been recognized. In the context of recent positive outcomes following nbM deep brain stimulation in subjects with dementia-associated disorders, we review the literature from an historical perspective focusing on how the nbM came into focus as a promising therapeutic option for patients with Alzheimer’s disease. Moreover, we will discuss what is needed to further develop and widely implement this approach as well as examine novel medical indications for which nbM deep brain stimulation may prove beneficial.

Pages 921-933

Anna Fischer, Jesus Landeira-Fernandez, Flavia Sollero de Campos, Daniel C. Mograbi
Empathy in Alzheimer’s Disease: Review of Findings and Proposed Model
Empathy is essential for social interaction and a crucial trait to understand the intentions and behaviors of others and to react accordingly. Alzheimer’s disease (AD) affects both cognitive and emotional processes and can lead to social dysfunction. Empathy results from the interaction of four components: shared neural representation, self-awareness, mental flexibility, and emotion regulation. This review discusses the abilities and deficits of patients with AD from the perspective of subcomponents of empathy and integrates these facets into a model of human empathy. The aim was to investigate the components that are affected by AD and the ways in which patients are still able to empathize with others in their social environment. It concludes that AD patients show a pattern of relatively preserved affective aspects and impairments in cognitive components of empathy and points out specific areas with the need for further research.

Pages 935-952

Ira R. Casson, David C. Viano
Long-Term Neurological Consequences Related to Boxing and American Football: A Review of the Literature
Abstract: The long-term effects of repetitive head trauma on the brain have often been studied in boxers and American football players. The medical literature on this topic was reviewed in order to compare the findings related to boxing with those related to football. The evidence gathered from this review indicates that there are significant differences between the clinical and neuropathological descriptions of the chronic brain damage reported in retired boxers compared to those reported in retired football players. Differing biomechanics of head impacts in the two sports may help explain the different clinical and neuropathological consequences of participation in boxing versus football.

Pages 953-961
Short Communication

Ece Bayram, Guogen Shan, Jeffrey L. Cummings
Associations between Comorbid TDP-43, Lewy Body Pathology, and Neuropsychiatric Symptoms in Alzheimer’s Disease
Abstract: More than half of the patients with Alzheimer’s disease (AD) have comorbidities including TDP-43 and Lewy bodies, which are also associated with frontotemporal lobar degeneration and dementia with Lewy bodies, respectively. These comorbidities may help explain the overlapping neuropsychiatric symptoms between AD and other dementias. Data on 221 AD patients with Neuropsychiatric Inventory-Questionnaire were obtained from the National Alzheimer's Coordinating Center. TDP-43 was associated with aberrant motor activity, whereas Lewy bodies were associated with anxiety, irritability, sleep behavior, and appetite problems. The associations between these comorbidities and neuropsychiatric symptoms were more significant for patients with sparse diffuse plaques.

Pages 963-967
Short Communication

Rachel H. Tan, Yue Yang, Heather McCann, Claire Shepherd, Glenda M. Halliday (Handling Associate Editor: Jennifer Whitwell)
Von Economo Neurons in Behavioral Variant Frontotemporal Dementia with Underlying Alzheimer’s Disease
Abstract: The selective loss of von Economo neurons has been linked to the behavioral deficits in behavioral variant frontotemporal dementia (bvFTD) but whether these neurons are affected in bvFTD patients with underlying Alzheimer’s disease (AD) has yet to be established. The present study assesses the von Economo neurons in pathological AD cases clinically diagnosed with either AD or bvFTD. Our results demonstrate no significant loss of von Economo neurons in all pathological AD cases, irrespective of clinical diagnosis or co-existing Lewy body pathology. These results suggest that the behavioral deficits in patients with clinical bvFTD and underlying pathological AD are not driven by the loss of von Economo neurons.

Pages 969-977
Short Communication

Virginia Torres-Lista, Lydia Giménez-Llort
Vibrating Tail, Digging, Body/Face Interaction, and Lack of Barbering: Sex-Dependent Behavioral Signatures of Social Dysfunction in 3xTg-AD Mice as Compared to Mice with Normal Aging
Abstract: Modeling of Alzheimer’s disease (AD), classically focused on the subject-environment interaction, foresees current social neuroscience efforts as improving the predictive validity of new strategies. Here we studied social functioning among congeners in 13-14-month-old mice with normal aging in naturalistic and experimental conditions and depicted behavioral signatures of dysfunction in age-matched 3xTg-AD mice. The most sensitive variables were vibrating tail, digging, body/face and self-grooming, that can be easily used in housing routines and the assessment of strategies. Sex-specific signatures (vibrating tail, digging, and grooming) defined female 3xTg-AD mice ethogram. All animals sleep huddled while barbering was only found in females with normal aging.

Pages 979-987
Jonathan A. Zegarra-Valdivia, Andrea Santi, Maria Estrella Fernández de Sevilla, Angel Nuñez, Ignacio Torres Aleman
Serum Insulin-Like Growth Factor I Deficiency Associates to Alzheimer’s Disease Co-Morbidities
Abstract: Increasing evidence supports the notion that Alzheimer’s disease (AD), a condition that presents heterogeneous pathological disturbances, is also associated to perturbed metabolic function affecting insulin and insulin-like growth factor I (IGF-I). While impaired insulin activity leading to insulin resistance has been associated to AD, whether altered IGF-I function affects the disease is not entirely clear. Despite the limitations of mouse models to mimic AD pathology, we took advantage that serum IGF-I deficient mice (LID mice) present many functional perturbations present in AD, most prominently cognitive loss, which is reversed by treatment with systemic IGF-I. We analyzed whether these mice display other pathological traits that are usual co-morbidities of AD. We found that LID mice not only display cognitive disturbances, but also show altered mood and sociability, increased susceptibility to epileptiform activity, and a disturbed sleep/wake cycle. Collectively, these data suggest that reduced IGF-I activity contributes to heterogeneous deficits commonly associated to AD. We suggest that impaired IGF-I activity needs to be taken into consideration when modeling this condition.

Pages 989-1001
Gaëtane Picard, Jean-Christophe Bier, Isabelle Capron, Peter Paul De Deyn, Olivier Deryck, Sebastiaan Engelborghs, Bernard Hanseeuw, Jean-Claude Lemper, Eric Mormont, Mirko Petrovic, Eric Salmon, Kurt Segers, Anne Sieben, Evert Thiery, Manfredi Ventura, Jan Versijpt, Adrian Ivanoiu
Dementia, End of Life, and Euthanasia: A Survey Among Dementia Specialists Organized by the Belgian Dementia Council
Abstract: Background: Palliative care and Advance Care Planning (ACP) are increasingly recommended for an optimal management of late-stage dementia. In Belgium, euthanasia has been decriminalized in 2002 for patients who are “mentally competent” (interpreted as non-demented). It has been suggested that advance directives for euthanasia (ADE) should be made possible for dementia patients. Objective: This study presents the results of an internet survey among Belgian dementia specialists. Methods: In 2013, the Belgian Dementia Council (BeDeCo) organized a debate on end of life decisions in dementia. Participants were medical doctors who are specialists in the dementia field. After the debate, an anonymous internet survey was organized. The participation rate was 55%. The sample was representative of the BeDeCo members. Results: The results showed consensus in favor of palliative care and ACP, although ACP is not systematically addressed in practice. Few patients with dementia have requested euthanasia, but for those who did the participants had agreed to implement it for some patients. A majority of participants (94%) believe that most patients and their families are poorly informed about euthanasia. Although most participants (77%) said they approved the Law on euthanasia, 65% said they were against an extension of the Law to allow ADE for dementia. Conclusion: Palliative care and ACP are clearly accepted by professionals, although a gap between recommendation and practice remain. Euthanasia is a much more debated issue, even if a majority of professionals are, in principle, in favor of the current Law and seem to disapprove with a Law change allowing ADE for dementia. A better education for both health professionals and the lay public will be a key element in the future.

Pages 1003-1018
Cheshire Hardcastle*, Hua Huang*, Sam Crowley, Jared Tanner, Carlos Hernaiz, Mark Rice, Hari Parvatanenic, Mingzhou Ding^, Catherine C. Price^ *These authors contributed equally to this work. ^Joint senior authors
Mild Cognitive Impairment and Decline in Resting State Functional Connectivity after Total Knee Arthroplasty with General Anesthesia
Abstract: Background: Research shows that older adults can have a decline in three key resting state networks (default mode network, central executive network, and salience network) after total knee arthroplasty and that patients’ pre-surgery brain and cognitive integrity predicts decline. Objectives: First, to assess resting state network connectivity decline from the perspective of nodal connectivity changes in a larger older adult surgery sample. Second, to compare pre-post functional connectivity changes in mild cognitive impairment (MCI) versus non-MCI. Methods: Surgery (n=69) and non-surgery (n=65) peers completed a comprehensive preoperative neuropsychological evaluation and pre- and acute (within 48 hours) post-surgery/pseudo-surgery functional brain magnetic resonance imaging scan. MCI was classified within both (MCI surgery, n=13; MCI non-surgery, n=10). Using standard coordinates, we defined default mode network, salience network, central executive network, and the visual network (serving as a control network). The functional connectivity of these networks and brain areas (nodes) that make up these networks were examined for pre-post-surgery changes through paired samples t-test and ANOVA. Results: There was a decline in RSN connectivity after surgery (p<0.05) only in the three cognitive networks (not the visual network). The default mode and salience network showed nodal connectivity changes (p<0.01). MCI surgery had greater functional connectivity decline in DMN and SN. Non-surgery participants showed no significant functional connectivity change. Conclusion: Surgery with general anesthesia selectively alters functional connectivity in major cognitive resting state networks particularly in DMN and SN. Participants with MCI appear more vulnerable to these functional changes.

Pages 1019-1030
Anselm B.M. Fuermaier*, Dafne Piersma*, Dick de Waard, Ragnhild J. Davidse, Jolieke de Groot, Michelle J.A. Doumen, Ruud A. Bredewoud, René Claesen, Afina W. Lemstra, Philip Scheltens, Annemiek Vermeeren, Rudolf Ponds, Frans Verhey, Peter Paul De Deyn, Wiebo H. Brouwer, Oliver Tucha (Handling Associate Editor: Nancy Pachana) *These authors contributed equally to this work.
Driving Difficulties Among Patients with Alzheimer’s Disease and Other Neurodegenerative Disorders
Abstract: Background/Objective: Neurodegenerative disorders impact fitness to drive of older drivers, but on-road driving studies investigating patients with different neurodegenerative disorders are scarce. A variety of driving errors have been reported in patients with Alzheimer’s disease (AD), but it is unclear which types of driving errors occur most frequently. Moreover, patients with other neurodegenerative disorders than AD typically present with different symptoms and impairments, therefore different driving errors may be expected. Methods: Patients with AD (n = 80), patients with other neurodegenerative disorders with cognitive decline (i.e., vascular dementia, frontotemporal dementia, dementia with Lewy bodies/Parkinson’s disease, n = 59), and healthy older drivers (n = 45) participated in a fitness-to-drive assessment study including on-road driving. Results: Patients with AD performed significantly worse than healthy older drivers on operational, tactical, visual, and global aspects of on-road driving. In patients with AD, on-road measures were significantly associated with ‘off-road’ measures. Patients with neurodegenerative disorders other than AD showed large overlap in the types of driving errors. Several driving errors were identified that appear to be characteristic for patients with particular neurodegenerative disorders. Conclusion: Patients from each group of neurodegenerative disorders commonly display tactical driving errors regarding lane positioning, slow driving, observation of the blind spot, and scanning behavior. Several other tactical and operational driving errors, including not communicating with cyclists and unsteady steering, were more frequently observed in patients with non-AD neurodegenerative disorders. These findings have implications for on-road and ‘off-road’ fitness-to-drive assessments for patients with neurodegenerative disorders with cognitive decline.

Pages 1031-1039
Shinji Matsunaga, Hiroshige Fujishiro, Hajime Takechi
Efficacy and Safety of Glycogen Synthase Kinase 3 Inhibitors for Alzheimer’s Disease: A Systematic Review and Meta-Analysis
Abstract: Background: The efficacy and safety of glycogen synthase kinase 3 (GSK-3) inhibitors in patients with Alzheimer’s disease (AD) is unknown. Objective: A systematic review and meta-analysis of randomized controlled trials (RCTs) to test GSK-3 inhibitors on AD patients. Methods: We included RCTs of GSK-3 inhibitors in AD patients and subjects with mild cognitive impairment (MCI), using cognitive function scores as a primary measure. Results: Five RCTs (three RCTs using lithium and two RCTs using tideglusib) with 568 patients were included. There was no significant difference in cognitive function scores between the GSK-3 inhibitors and placebo groups [standardized mean difference (SMD) = −0.25, p = 0.11, I2 = 55%]. However, significant heterogeneity remained. A sensitivity analysis revealed that the lithium subgroup was more effective on cognitive function scores than placebo for AD and MCI (lithium subgroup: SMD = −0.41, p = 0.04; tideglusib subgroup: SMD = −0.02, p = 0.89). Moreover, a meta-regression analysis showed that the effect size of GSK-3 inhibitors on cognitive function scores was associated with study duration (coefficient, −0.0116). For safety outcomes, tideglusib was associated with a higher incidence of increased aspartate aminotransferase than placebo. There were no significant differences in other secondary outcomes between treatments. Conclusion: Our results suggested that GSK-3 inhibitors were ineffective in treating AD and MCI; however, several studies included in the present meta-analysis were small, and future studies using a larger sample size are needed.

Pages 1041-1065
Sandra Suijkerbuijk, Henk Herman Nap, Lotte Cornelisse, Wijnand IJsselsteijn, Yvonne A.W. de Kort, Mirella M.N. Minkman (Handling Associate Editor: Francesca Baglio)
Active Involvement of People with Dementia: A Systematic Review of Studies Developing Supportive Technologies
Abstract: Although there are promising benefits of supportive technology in dementia care, use of these technologies is still limited. It is challenging for researchers and developers in this field to actively involve people with dementia in development. This review updates and builds on existing knowledge by including a contemporary and relevant perspective. This perspective was gained by including search words and search databases from the field of Human Computer Interaction (HCI) and Design, as these fields were expected to supply novel insights in the complex task of actively involving people with dementia in developing supportive technologies. A total of 49 out of 3456 studies were included which describe the development of a great variety of technologies. Often people with dementia were involved in the generative or evaluative phase of the development. Interviews and observations were most commonly used methods. In seven articles the people with dementia were co-designers. This literature review reflects that people with dementia can influence the development of technology in regards to content, design, and even the initial idea, although the impact on how they experience their own involvement remains largely unknown. There is a lack of specific knowledge on appropriate methods and materials for active involvement of people with dementia in supportive technology development, even when including articles from the field of HCI and Design. Future research is needed to further appreciate and improve the desired role of people with dementia in meaningful technology development.

Pages 1067-1075
Clare Clement*, Lucy E. Selman*, Patrick G. Kehoe, Beth Howden, J. Athene Lane, Jeremy Horwood *These authors contributed equally to this work.
Challenges to and Facilitators of Recruitment to an Alzheimer’s Disease Clinical Trial: A Qualitative Interview Study
Abstract: Background: Low participation in clinical trials is a major challenge to advancing clinical Alzheimer’s disease (AD) research and care. Factors influencing recruitment to AD trials are not fully understood. Objective: To identify barriers to, and facilitators of, recruitment in a UK multi-center, secondary care AD trial (Reducing pathology in Alzheimer’s Disease through Angiotensin TaRgeting (RADAR) trial) and implications for improving recruitment to AD trials. Methods: Semi-structured qualitative telephone interviews with a purposive sample of 17 trial site staff explored the RADAR trial recruitment pathway and views and experiences of recruitment. Interviews were analyzed thematically. Results: Diagnostic and care pathways hindered identifying patients with mild-moderate AD, with a lack of up-to-date patient records and data access problems affecting screening. Research is not routinely embedded in AD care but facilitated recruitment when it was. Clinicians’ and patients’ favorable view of the trial purpose facilitated recruitment, although the complexity of participant information sheets and requirement for study companion created challenges. Conclusion: These findings have important implications for the design of future AD trials and for planning how to best interface with clinical commitments to ensure sufficient and timely recruitment. Challenges to AD trial recruitment can occur at care pathway, clinician, and patient and companion levels. Recruitment can be facilitated by: improving diagnostic processes and systems for recording and sharing patient information, embedding research into routine patient care, collaborating with a range of services to identify and approach eligible patients, training and engaging trial staff, and providing patients with clear and concise study information.

Pages 1077-1087
Mengyu Liu, Luwen Wang, Ju Gao, Qing Dong, George Perry, Xuemei Ma, Xinglong Wang (Handling Editor: Jesus Avila)
Inhibition of Calpain Protects Against Tauopathy in Transgenic P301S Tau Mice
Abstract: Alzheimer’s disease (AD) and other tauopathies are characterized by intracellular accumulation of microtubule-associated tau protein leading to neurodegeneration. Calpastatin is the endogenous inhibitor of calpain, a calcium-dependent cysteine protease that has been increasingly implicated in tauopathies. In this study, we generated a neuron specific calpastatin overexpressing knock-in transgenic mouse model and crossed it with the PS19 tauopathy mouse model expressing human P301S mutant tau protein. The forced expression of calpastatin in neurons significantly alleviated tau hyperphosphorylation measured by immunocytochemistry and immunoblot. The genetic inhibition of calpain by calpastatin also greatly suppressed characteristic hippocampal neuron loss and widespread astrogliosis and microgliosis in PS19 mice. Consistently, PS19 mice with neuronal calpastatin overexpression exhibited remarkably alleviated cognitive deficits, muscle weakness, skeletal muscle atrophy, and neuromuscular denervation, together implying the neuroprotective effects of neuronal calpastatin in PS19 mice of tauopathy. In sum, this study provides additional evidence supporting the pathological role of calpain in neurodegenerative diseases associated with tau pathology, and suggests that targeting calpain is likely a promising therapeutic approach for these devastating diseases.

Pages 1089-1097
Toby Aarons, Steven Bradburn, Andrew Robinson, Antony Payton, Neil Pendleton, Chris Murgatroyd
Dysregulation of BDNF in Prefrontal Cortex in Alzheimer’s Disease
Abstract: Background: Brain-derived neurotrophic factor (BDNF) is essential for neurogenesis and has been implicated in Alzheimer’s disease (AD). However, few studies have investigated together the epigenetic, transcriptional, and translational regulation of this peptide in the brain in relation to AD. Objective: To investigate mechanisms underlying how BDNF is possibly dysregulated in the brain in relation to aging and AD neuropathology. Methods: Prefrontal cortex tissues were acquired from the Manchester Brain Bank (N = 67). BDNF exon I, and exon IV-containing transcripts and total long 3’ transcript gene expression were determined by quantitative PCR and bisulfite pyrosequencing was used to quantify DNA methylation within promoters I and IV. Protein concentrations were quantified via ELISA. Results: BDNF exon IV and total long 3’ isoform gene expression levels negatively associated with donor’s age at death (IV: r = -0.291, p = 0.020; total: r = -0.354, p = 0.004). Expression of BDNF exon I- containing isoform was significantly higher in Met-carriers of the rs6265 variant, compared to Val-homozygotes, when accounting for donor ages (F = 6.455, p = 0.014). BDNF total long 3’ transcript expression was significantly lower in those with early AD neuropathology, compared to those without any neuropathology (p = 0.021). There were no associations between BDNF promoter I and IV methylation or protein levels with ages, rs6265 genotype or AD neuropathology status. Conclusion: Prefrontal cortex BDNF gene expression is associated with aging, rs6265 carrier status, and AD neuropathology in a variant-specific manner that seems to be independent of DNA methylation influences.

Pages 1099-1108
Isabelle Rouch*, Jean-Michel Dorey*, Catherine Padovan, Béatrice Trombert-Paviot, Michel Benoit, Bernard Laurent, PACO group, Nawèle Boublay, Pierre Krolak-Salmon *These authors contributed equally to this work.
Does Personality Predict Behavioral and Psychological Symptoms of Dementia? Results from PACO Prospective Study
Abstract: Background: Premorbid personality could play a role in the onset of behavioral and psychological symptoms (BPS) in Alzheimer’s disease (AD) but prospective studies are lacking. Objective: The present study aimed at prospectively assessing the influence of premorbid personality traits on BPS evolution in a population of patients with prodromal or mild AD. Methods: We used a multicenter prospective cohort study of 237 patients followed-up for 18 months. The influence of personality traits on BPS evolution, measured with Neuropsychiatric Inventory (NPI), was assessed using linear mixed-effect models. Results: A principal components analysis of the 12 NPI behavioral domains yielded five factors labelled as psychotic symptoms, affective symptoms, behavioral dyscontrol, apathy/appetite symptoms, and sleep disorders. During the follow-up, higher neuroticism was significantly associated with a higher progression of affective symptoms (p<0.0001), apathy/appetite symptoms (p=0.002), sleep disorders (p=0.001) as well as global NPI scores (p<0.0001). Greater conscientiousness was related to a lower evolution of psychotic (p=0.002), affective (p=0.02) and apathy/appetite symptoms (p=0.02), and global NPI score (p<0.0001). Higher openness was associated with lower affective symptoms evolution (p=0.01). A significant relationship was found between higher extraversion, lower affective symptoms (p=0.02), and higher behavioral dyscontrol (p=0.04). Conclusion: The present analysis suggests that premorbid personality may influence the evolution of BPS in prodromal or mild AD. Given these results, it seems important to give more importance to personality assessment in early AD, in order to better identify and manage patients at risk of adverse behavioral changes.

Pages 1109-1136
Shea J. Andrews, G. Peggy McFall, Andrew Booth, Roger A. Dixon, Kaarin J. Anstey
Association of Alzheimer’s Disease Genetic Risk Loci with Cognitive Performance and Decline: A Systematic Review
Abstract: The association of Apolipoprotein E (APOE) with late-onset Alzheimer’s disease (LOAD) and cognitive endophenotypes of aging has been widely investigated. There is increasing interest in evaluating the association of other LOAD risk loci with cognitive performance and decline. The results of these studies have been inconsistent and inconclusive. We conducted a systematic review of studies investigating the association of non-APOE LOAD risk loci with cognitive performance in older adults. Studies published from January 2009 to April 2018 were identified through a PubMed database search using keywords and by scanning reference lists. Studies were included if they were either cross-sectional or longitudinal in design, included at least one genome-wide significant LOAD risk loci or a genetic risk score, and had one objective measure of cognition. Quality assessment of the studies was conducted using the quality of genetic studies (Q-Genie) tool. Of 2,466 studies reviewed, 49 met inclusion criteria. Fifteen percent of the associations between non-APOE LOAD risk loci and cognition were significant. However, these associations were not replicated across studies, and the majority were rendered non-significant when adjusting for multiple testing. One-third of the studies included genetic risk scores, and these were typically significant only when APOE was included. The findings of this systematic review do not support a consistent association between individual non-APOE LOAD risk and cognitive performance or decline. However, evidence suggests that aggregate LOAD genetic risk exerts deleterious effects on decline in episodic memory and global cognition.

Pages 1137-1151
Hailun Cui*, Rujing Ren*, Guozhen Lin, Yang Zou, Lijuan Jiang, Zhengde Wei, Chunbo Li, Gang Wang (Handling Associate Editor: Jin-Tai Yu) *These authors contributed equally to this work.
Repetitive Transcranial Magnetic Stimulation Induced Hypoconnectivity Within the Default Mode Network Yields Cognitive Improvements in Amnestic Mild Cognitive Impairment: A Randomized Controlled Study
Abstract: Background: Repetitive transcranial magnetic stimulation (rTMS) is thought to be effective in alleviating cognitive symptoms in patients with amnestic mild cognitive impairment (aMCI), but the mechanisms related to network modification are poorly understood. Objective: Here we tested rTMS efficacy and explored the effect of rTMS-induced changes in the default mode network (DMN) and their predictive value for treatment response. Methods: Twenty-one subjects clinically diagnosed with aMCI were recruited to complete a 10-session randomized and sham-controlled rTMS treatment targeting the right dorsolateral prefrontal cortex. Resting-state functional magnetic resonance imaging in tandem with neuropsychological assessments were administered before and after the intervention. Changes in functional connectivity of the DMN and relevant brain regions, as well as the correlations between baseline functional connectivity and clinical rating scales were calculated in order to elucidate the mechanism of treatment response to rTMS therapy. Results: Compared to the sham group, the rTMS group achieved improvement of neuropsychological performance and significant functional connectivity changes within the DMN. Group x Time interactions were found between posterior cingulate gyrus and right fusiform gyrus (F(1,19)=17.154, p=0.001), and also left anterior cingulate gyrus (F(1,19)=3.908, p=0.063), showing an rTMS-induced deactivation of functional connectivity within the DMN. Baseline functional connectivity analysis of seeds within the DMN in the rTMS group revealed negative correlation with AVLT-Recognition score changes. Conclusion: rTMS-induced hypoconnectivity within DMN is associated with clinical cognitive improvements in patients with aMCI. Further, pre-rTMS baseline activity of the DMN at rest may be a predictor for favorable rTMS treatment response.

Pages 1153-1160
Karen Stanley, Tim Whitfield, Karoline Kuchenbaecker, Oliver Sanders, Tim Stevens, Zuzana Walker
Rate of Cognitive Decline in Alzheimer's Disease Stratified by Age
Abstract: Background: There is only limited information available about the effect of age on course of cognitive decline in patients with onset of Alzheimer's disease (AD) over the age of 64 years. Objective: We compared the rate of, and factors affecting, cognitive decline in patients with AD aged <65 years (young-onset AD), 65-74 years (middle-onset AD), and ≥75 years (late-onset AD). Method: The study used longitudinal data from the Essex Memory Clinic which included a total of 305 participants; 56 had YOAD, 73 had MOAD, and 176 had LOAD. The rate of cognitive decline was measured using scores from the Mini-Mental State Examination (MMSE), and the data were examined using multilevel models analysis. Results: There was evidence of a difference in cognitive decline across the age groups with the YOAD group declining 2.8 MMSE points per year, those with MOAD declined 2.0 MMSE points per year, and the LOAD group declined 1.4 MMSE points per year. Conclusions: Patients with LOAD have a better prognosis than YOAD and MOAD. However, even between the MOAD and LOAD groups, age is a significant predictor of cognitive decline, with older patients having a more benign course.

Pages 1161-1169
Xiwu Wang, Wenjun Zhou, Teng Ye, Xiaodong Lin, Jie Zhang, for Alzheimer’s Disease Neuroimaging Initiative
Sex Difference in the Association of APOE4 with Memory Decline in Mild Cognitive Impairment
Abstract: Our aim was to examine whether the influence of apolipoprotein E4 (APOE4) genotype on cognitive decline differs in male and female across the Alzheimer’s disease (AD) continuum. Among individuals with normal cognition (NC; n = 415), mild cognitive impairment (MCI; n = 870), and AD (n = 334), we investigated the longitudinal associations of APOE4 genotype and sex with cognitive decline over 13 years. Our cognitive outcomes were Rey Auditory Verbal Learning Test (RAVLT) total learning score and delayed recall and Mini-Mental State Examination (MMSE) score. There were significant effects of the APOE4 × sex interaction on change in verbal memory in the MCI group, but not the NC or AD group. Specifically, among individuals with MCI, female APOE4 carriers had a steeper decline in RAVLT total learning score, but not delayed recall or MMSE score compared to all other groups (APOE4+/Male, APOE4-/Female, APOE4-/Male). In conclusion, female APOE4 carriers have faster rates of memory decline than their male counterparts among MCI individuals.

Pages 1171-1182
Daniel A. Nation, Jean K. Ho, Shubir Dutt, S. Duke Han, Hok Choi Lai; for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Mark Bondi)
Neuropsychological Decline Improves Prediction of Dementia Beyond Alzheimer’s Disease Biomarker and Mild Cognitive Impairment Diagnoses
Abstract: Background: A clinical diagnosis of cognitive impairment is traditionally based on a single cognitive exam, but serial cognitive testing can be sensitive to subtle cognitive changes in asymptomatic individuals and inform cognitive trajectory. Objective: We evaluated the prognostic utility of identifying longitudinal neuropsychological decline along with single cognitive exam and Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers in predicting dementia. We also examined brain volumetric differences based on decline trajectories. Method: Regression models quantified 12-month neuropsychological decline relative to normative expectations among non-demented older adults (N=1,074). Progression to dementia over follow-up (18-120 months) was diagnosed using independent modes of assessment. Results: In Cox regression models controlling for age, sex, education, apolipoprotein E4, and baseline cognitive diagnosis, neuropsychological decline predicted increased dementia risk, χ2=69.861, p<0.001, odds ratio=2.841, even after correction for CSF biomarkers (amyloid-β, phosphorylated tau, total tau), χ2=26.365, p<0.001, odds ratio=2.283. Voxel-based morphometry analysis indicated smaller hippocampal and medial temporal volume in participants with neuropsychological decline. Conclusions: Longitudinal diagnosis of neuropsychological decline improved prognostic accuracy beyond single cognitive exam diagnoses and AD CSF biomarkers, even in asymptomatic older adults. Older adults with a trajectory of neuropsychological decline exhibit smaller medial temporal and hippocampal brain volume. Longitudinal diagnostic approaches may benefit selection and randomization procedures for AD clinical trials in asymptomatic individuals.

Pages 1183-1193
Alexandra König, Nicklas Linz, Radia Zeghari, Xenia Klinge, Johannes Tröger, Jan Alexandersson, Philippe Robert
Detecting Apathy in Older Adults with Cognitive Disorders Using Automatic Speech Analysis
Abstract: Background: Apathy is present in several psychiatric and neurological conditions and has been found to have a severe negative effect on disease progression. In older people, it can be a predictor of increased dementia risk. Current assessment methods lack objectivity and sensitivity, thus new diagnostic tools and broad-scale screening technologies are needed. Objective: This study is the first of its kind aiming to investigate whether automatic speech analysis could be used for characterization and detection of apathy. Methods: A group of apathetic and non-apathetic patients (n = 60) with mild to moderate neurocognitive disorder were recorded while performing two short narrative speech tasks. Paralinguistic markers relating to prosodic, formant, source, and temporal qualities of speech were automatically extracted, examined between the groups and compared to baseline assessments. Machine learning experiments were carried out to validate the diagnostic power of extracted markers. Results: Correlations between apathy sub-scales and features revealed a relation between temporal aspects of speech and the subdomains of reduction in interest and initiative, as well as between prosody features and the affective domain. Group differences were found to vary for males and females, depending on the task. Differences in temporal aspects of speech were found to be the most consistent difference between apathetic and non-apathetic patients. Machine learning models trained on speech features achieved top performances of AUC = 0.88 for males and AUC = 0.77 for females. Conclusions: These findings reinforce the usability of speech as a reliable biomarker in the detection and assessment of apathy.

Pages 1195-1211
Oh Hoon Kwon, Yoon Young Cho, Tae-Wan Kim, Sungkwon Chung (Handling Associate Editor: Sally Hunter)
O-GlcNAcylation of Amyloid-β Protein Precursor by Insulin Signaling Reduces Amyloid-β Production
Abstract: Alzheimer’s disease (AD) is caused by the accumulation of neurotoxic amyloid-β (Aβ) peptides. Aβ is derived from amyloid-β protein precursor (AβPP). In the non-amyloidogenic pathway, AβPP is cleaved by α-secretase and γ-secretase at the plasma membrane, excluding Aβ production. Alternatively, AβPP in the plasma membrane is internalized via endocytosis, and delivered to early endosomes and lysosomes, where it is cleaved by β-secretase and γ-secretase. Recent studies have shown that insulin in the periphery crosses the blood-brain barrier, and plays important roles in the brain. Furthermore, impaired insulin signaling has been linked to the progression of AD, and intranasal insulin administration improves memory impairments and cognition. However, the underlying molecular mechanisms of insulin treatment remain largely unknown. To investigate the effects of insulin on AβPP processing, we tested the effects of insulin on neuroblastoma SH-SY5Y cells overexpressing AβPP, and cultured rat cortical neurons. We found that insulin increased the level of cell surface AβPP, decreasing the endocytosis rate of AβPP. Insulin reduced Aβ generation through upregulation of AβPP O-GlcNAcylation via Akt insulin signaling. Our present data suggest that insulin affects Aβ production by regulating AβPP processing through AβPP O-GlcNAcylation. These results provide mechanistic insight into the beneficial effects of insulin, and a possible link between insulin deficient diabetes and cerebral amyloidosis in the pathogenesis of AD

Pages 1213-1220
Karolina Minta, Erik Portelius, Shorena Janelidze, Oskar Hansson, Henrik Zetterberg, Kaj Blennow, Ulf Andreasson (Handling Associate Editor: Jagan Pillau)
Cerebrospinal Fluid Concentrations of Extracellular Matrix Proteins in Alzheimer’s Disease
Abstract: Background: Brevican, neurocan, tenascin-C, and tenascin-R are extracellular matrix (ECM) proteins that are mainly expressed in the brain. They play important roles in proliferation and migration of neurons and other cell types in the brain. These ECM proteins may also be involved in various pathologies, including reactive gliosis. Objective: The aim of the study was to investigate if ECM protein concentrations in cerebrospinal fluid (CSF) are linked to the neurodegenerative process in Alzheimer’s disease (AD). Methods: Lumbar CSF samples from a non-AD control group (n=50) and a clinically diagnosed AD group (n=42), matched for age and gender, were analyzed using commercially available ELISAs detecting ECM proteins. Mann-Whitney U test was used to examine group differences, while Spearman’s rho test was used for correlations. Results: Brevican, neurocan, tenascin-R, and tenascin-C concentrations in AD patients did not differ compared to healthy controls or when the groups were dichotomized based on the Aβ42/40 cut-off. CSF tenascin-C and tenascin-R concentrations were significantly higher in women than in men in the AD group (p=0.02). Conclusion: ECM proteins do not reflect AD-pathology in CSF. CSF tenascin-C and tenascin-R upregulation in women possibly reveal sexual dimorphism in the central nervous system immunity during AD.