Volume 83, Number 1, IN PRESS

Obituary
Gunnar K. Gouras
M. Flint Beal

Editorial
Nikolaos K. Robakis
On the Nomenclature of the Alzheimer’s Disease Amyloid and Its Precursor

Review
Rebecca Beardmore, Ruihua Hou, Angela Darekar, Clive Holmes, Delphine Boche (Handling Associate Editor: Sergio Ferreira)
The Locus Coeruleus in Aging and Alzheimer's Disease: A Postmortem and Brain Imaging Review
Abstract: The locus coeruleus (LC), a tiny nucleus in the brainstem and the principal site of noradrenaline synthesis, has a major role in regulating autonomic function, arousal, attention, and neuroinflammation. LC dysfunction has been linked to a range of disorders; however particular interest is given to the role it plays in Alzheimer’s disease (AD). The LC undergoes significant neuronal loss in AD, thought to occur early in the disease process. While neuronal loss in the LC has also been suggested to occur in aging, this relationship is less clear as the findings have been contradictory. LC density has been suggested to be indicative of cognitive reserve and the evidence for these claims will be discussed. Recent imaging techniques allowing visualization of the LC in vivo using neuromelanin-sensitive MRI are developing our understanding of the role of LC in aging and AD. Tau pathology within the LC is evident at an early age in most individuals; however, the relationship between tau accumulation and neuronal loss and why some individuals then develop AD is not understood. Neuromelanin pigment accumulates within LC cells with age and is proposed to be toxic and inflammatory when released into the extracellular environment. This review will explore our current knowledge of the LC changes in both aging and AD from postmortem, imaging, and experimental studies. We will discuss the reasons behind the susceptibility of the LC to neuronal loss, with a focus on the role of extracellular neuromelanin and neuroinflammation caused by the dysfunction of the LC-noradrenaline pathway.

Hypothesis
Rosanna Squitti, Faller Peter, Christelle Hureau, Alberto Granzotto, Anthony R. White, Kasper P. Kepp
Copper Imbalance in Alzheimer's Disease and Its Link with the Amyloid Hypothesis: Towards a Combined Clinical, Chemical, and Genetic Etiology
Abstract: The cause of Alzheimer's disease (AD) is incompletely defined. To date, no mono-causal treatment has so far reached its primary clinical endpoints, probably due to the complexity and diverse neuropathology contributing to the neurodegenerative process. In the present paper, we describe the plausible etiological role of copper (Cu) imbalance in the disease. Cu imbalance is strongly associated with neurodegeneration in dementia, but a complete biochemical etiology consistent with the clinical, chemical, and genetic data is required to support a causative association, rather than just correlation with disease. We hypothesize that a Cu imbalance in the aging human brain evolves as a gradual shift from bound metal ion pools, associated with both loss of energy production and antioxidant function, to pools of loosely bound metal ions, involved in gain-of-function oxidative stress, a shift that may be aggravated by chemical aging. We explain how this may cause mitochondrial deficits, energy depletion of high-energy demanding neurons, and aggravated protein misfolding/oligomerization to produce different clinical consequences shaped by the severity of risk factors, additional comorbidities, and combinations with other types of pathology. Cu imbalance should be viewed and integrated with concomitant genetic risk factors, aging, metabolic abnormalities, energetic deficits, neuroinflammation, and the relation to tau, prion proteins, α-synuclein, TAR DNA binding protein-43 (TDP-43) as well as systemic comorbidity. Specifically, the Amyloid Hypothesis is strongly intertwined with Cu imbalance because amyloid-β protein precursor (AβPP)/Aβ are probable Cu/Zn binding proteins with a potential role as natural Cu/Zn buffering proteins (loss of function), and via the plausible pathogenic role of Cu-Aβ.

Short Communication
Giulia Remoli*, Marco Canevelli*, Umberto Maria Robertazzo, Filippo Nuti, Ilaria Bacigalupo, Emanuela Salvi, Martina Valletta, Marco Toccaceli Blasi, Matteo Cesari, Nicola Vanacore, Giuseppe Bruno (Handling Associate Editor: Carlo Abbate)*These authors contributed equally to the work.
Supporting and Protecting People with Dementia in the COVID-19 Pandemic
Abstract:
We aimed to explore the awareness and preparedness of dementia caregivers and people with mild cognitive deficits on how to prevent COVID-19 infection and cope with the indirect consequences of the pandemic. A total of 139 patient-caregiver dyads received a telephone survey and 109 completed the survey. The majority of respondents reported having a moderate-to-good knowledge of the typical manifestations of COVID-19. Conversely, only few of them were informed of the atypical presentations and on how to recognize emergency warning signs. Filling the knowledge gaps on COVID-19 in the most vulnerable people may represent a significant resource to tackle the pandemic.

Short Communication
Rachana Tank, Joey Ward, Carlos Celis-Morales, Daniel J. Smith, Kristin E. Flegal, Donald M. Lyall
Testing for Interactions Between APOE and Klotho Genotypes on Cognitive, Dementia, and Brain Imaging Metrics in UK Biobank
Abstract: Recent research suggests genetic variation in the Klotho locus may modify the association between APOE ε4 and cognitive impairment. We tested for associations and interactions between these genotypes versus risk of dementia, cognitive abilities, and brain structure in older UK Biobank participants. Klotho status was indexed with rs9536314 heterozygosity (versus not), in unrelated people with versus without APOE ε4 genotype, corrected for various confounders. APOE ε4 associated with increased risk of dementia, worse cognitive abilities, and brain structure. Klotho was associated with better reasoning. There were no interactions; potentially suggesting an age- and pathology-dependent Klotho effect.

Koh Tadokoro, Toru Yamashita, Satoko Kawano, Junko Sato, Yoshio Omote, Mami Takemoto, Ryuta Morihara, Koichiro Nishiura, Natsuki Sagawa, Tomiko Tani, Koji Abe (Handling Associate Editor: Mikio Shoji)
Immediate Beneficial Effect of Makeup Therapy on Behavioral and Psychological Symptoms of Dementia and Facial Appearance Analyzed by Artificial Intelligence Software
Abstract: Background: Possible benefits of makeup therapy, in terms of immediate and late effects on cognitive and affective functions, have not been fully proved for dementia patients. Objective: To evaluate the immediate effect of makeup therapy on dementia patients. Methods: Female nursing home residents with dementia received either only skin care treatment (control group, n = 17) or skin care plus makeup therapy treatment (makeup therapy group, n = 19). Cognitive, affective, and activity of daily living (ADL) scores were evaluated before and just after treatments. Apparent age and emotion were also evaluated with artificial intelligence (AI) software. Results: Makeup therapy significantly improved Abe’s behavioral and psychological symptoms of dementia (BPSD) score (ABS, *p < 0.05). AI software judged that makeup therapy significantly made the apparent age younger (*p < 0.05). In particular, patients with moderate ADL scores had a significantly higher happiness score in makeup therapy (*p < 0.05), with a modest correlation to the Mini-Mental State Examination (MMSE, r = 0.42, *p < 0.05). The severe baseline MMSE group reported a greater feeling of satisfaction following makeup therapy (*p < 0.05). Conclusion: The present makeup therapy is a promising non-pharmacological approach to immediately alleviate BPSD in female dementia patients, and the present AI software quickly and quantitatively evaluated the beneficial effects of makeup therapy on facial appearance.

Isabel J. Sible, Katherine J. Bangen, Anna E. Blanken, Jean K. Ho, Daniel A. Nation (Handling Associate Editor: Whitney Wharton)
Antemortem Visit-To-Visit Blood Pressure Variability Predicts Cerebrovascular Lesion Burden in Autopsy-Confirmed Alzheimer’s Disease
Abstract: Background: Blood pressure variability is linked to Alzheimer’s disease (AD) risk and MRI-based markers of cerebrovascular disease. Less is known about the role of blood pressure variability in postmortem evaluation of cerebrovascular disease and AD. Objective: To determine whether antemortem blood pressure variability predicts cerebrovascular and AD pathology and follow-up cognitive change in autopsy-confirmed AD. Methods: National Alzheimer’s Coordinating Center participants (n = 513) underwent 3-4 approximately annual blood pressure measurements and were confirmed to have AD at postmortem evaluation. A subset (n = 493) underwent neuropsychological evaluation at follow-up. Regression models examined relationships between blood pressure variability and cerebrovascular and AD pathological features and follow-up cognitive change. Results: Elevated blood pressure variability predicted increased postmortem cerebrovascular lesion burden (ß = 0.26 [0.10, 0.42]; p = 0.001; R2 = 0.12). Increased blood pressure variability predicted specific cerebrovascular lesion severity, including atherosclerosis in the Circle of Willis (OR = 1.22 [1.03, 1.44]; p = 0.02) and cerebral arteriolosclerosis (OR = 1.32 [1.04, 1.69]; p = 0.03). No significant relationships were observed between blood pressure variability and AD pathological findings, including Braak & Braak stage, neuritic plaques or diffuse plaques, or cerebral amyloid angiopathy, or follow-up cognitive decline. Conclusion: Findings suggest that elevated blood pressure variability is related to postmortem cerebrovascular lesion burden in autopsy-confirmed AD, independent of average blood pressure and AD neuropathology. Blood pressure fluctuation may selectively promote atherosclerotic and arteriolosclerotic brain lesions with potential implications for cognitive impairment and dementia.

Bernhard Michalowsky, Wolfgang Hoffmann, Feng Xie
Psychometric Properties of EQ-5D-3L and EQ-5D-5L in Cognitively Impaired Patients Living with Dementia
Abstract: Background: Assessing health-related quality of life in dementia poses challenges due to patients’ cognitive impairment. It is unknown if the newly introduced EQ-5D five-level version (EQ-5D-5L) is superior to the 3-level version (EQ-5D-3L) in this cognitively impaired population group. Objective: To assess the psychometric properties of the EQ-5D-5L in comparison to the EQ-5D-3L in patients living with dementia (PwD). Methods: The EQ-5D-3L and EQ-5D-5L were assessed via interviews with n=78 PwD at baseline and three and six months after, resulting in 131 assessments. The EQ-5D-3L and EQ-5D-5L were evaluated in terms of acceptability, agreement, ceiling effects, redistribution properties and inconsistency, informativity as well as convergent and discriminative validity. Results: Mean index scores were higher for the EQ-5D-5L than the EQ-5D-3L (0.70 versus 0.64). Missing values occurred more frequently in the EQ-5D-5L than the EQ-5D-3L (8% versus 3%). Agreement between both measures was acceptable but poor in PwD with moderate to severe cognitive impairment. The index value's relative ceiling effect decreased from EQ-5D-3L to EQ-5D-5L by 17%. Inconsistency was moderate to high (13%). Absolute and relative informativity increased in the EQ-5D-5L compared to the 3L. The EQ-5D-5L demonstrated a lower discriminative ability and convergent validity, especially in PwD with moderate to severe cognitive deficits. Conclusion: The EQ-5D-5L was inferior as a self-rating instrument due to low acceptability and discriminative ability and a high inconsistency, especially in moderate to severe dementia. The EQ-5D-3L had better psychometric properties and should preferably be used as a self-rating instrument in economic evaluations in dementia.

Eddie Jones, Myrlene Sanon Aigbogun, James Pike, Mia Berry, Christy R. Houle, Joseph Husbands
Agitation in Dementia: Real-World Impact and Burden on Patients and the Healthcare System
Abstract: Background: At least 90% of patients with dementia experience behavioral or neuropsychiatric symptoms including agitation, psychotic symptoms, apathy, depression, and sleep disturbances. Agitation has been reported to be experienced by 60% of patients with mild cognitive impairment and 76% of patients with Alzheimer’s disease. Objective: We aimed to assess the impact of agitation in patients with dementia on healthcare resource utilization (HCRU) and healthcare costs. Methods: This was a retrospective analysis of physician-reported patient data from a point-in-time survey. Patients included were aged ≥50 years, with early cognitive impairment or dementia. Agitated and non-agitated patients were compared. Regression analyses assessed the relationship of agitation score (calculated from number/severity of agitation symptoms) with outcomes, with covariates including age and Mini-Mental State Examination score. Sensitivity analyses compared patients with 0 and ≥2 agitation symptoms following propensity score matching on the base-case covariates. Results: Data were included for 1,349 patients (agitated, n=693; non-agitated, n=656). Based on regression analyses, agitation score was correlated with proportion of patients with professional caregivers (p<0.01), institutionalized (p<0.01), hospitalized in a psychiatric ward (p<0.05), and receiving an antipsychotic/antidepressant (both p<0.001); number of consultations with a healthcare professional (HCP), psychiatrist, or psycho-geriatrician; number and cost of hospitalizations (p<0.01); cost of HCP consultations (p<0.001); and total direct healthcare costs (p<0.001). Sensitivity analyses generally supported the base-case analysis. Conclusion: Agitation in dementia is associated with increased HCRU and healthcare costs. Effective therapies are needed to address agitation in dementia, with the potential to alleviate patient impact, HCRU, and healthcare costs.

Perla Werner, Sarang Kim (Handling Associate Editor: Sid O'Bryant)
A Cross-National Study of Dementia Stigma Among the General Public in Israel and Australia
Abstract: Background: Despite the increasing amount of research on dementia stigma, there is a dearth of cross-national studies conducted on this subject. This is surprising since the experience of stigma is closely associated to socio-cultural aspects. Objective: The present study intended to expand knowledge about the impact of culture on dementia stigma by comparing the level and correlates of stigmatic beliefs about dementia among the general public in Israel and Australia. Methods: A cross-sectional study using an online survey was conducted with two age-matched samples: 447 adults in Israel and 290 adults in Australia. Results: Overall, dementia stigma was moderate in both countries. However, the level of dementia stigma was significantly higher in Australia than in Israel. Lower levels of subjective knowledge and higher levels of ageism were associated with increased levels of stigmatic beliefs in both countries. Gender was a significant correlate of dementia stigma, with male participants reporting higher levels of public stigma than women, although this gender difference was mainly driven by the Australian sample. Conclusion: Our findings indicate that providing knowledge and decreasing ageist attitudes should be key considerations in dementia awareness and stigma reduction campaigns despite the cultural context. In addition, developing gender-specific messages should be considered as a way of improving the effects of such campaigns.

Shanshan Chen*, Yu Song*, Wenwen Xu, Guanjie Hu, Honglin Ge, Chen Xue, Ju Gao, Wenzhang Qi, Xingjian Lin, Jiu Chen and the Alzheimer’s Disease Neuroimaging Initiative *These authors contributed equally to this work.
Impaired Memory Awareness and Loss Integration in Self-Referential Network Across the Progression of Alzheimer’s Disease Spectrum
Abstract: Background: Anosognosia, or unawareness of memory deficits, is a common manifestation of Alzheimer’s disease (AD), but greatly variable in subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) subjects. Self-referential network (SRN) is responsible for self-referential processing and considered to be related to AD progression. Objective: Our aim is to explore connectivity changes of SRN and its interaction with memory-related network and primary sensorimotor network (SMN) in the AD spectrum. Methods: About 444 Alzheimer’s Disease Neuroimaging Initiative subjects (86 cognitively normal [CN]; 156 SCD; 146 aMCI; 56 AD) were enrolled in our study. The independent component analysis (ICA) method was used to extract the SRN, SMN, and memory-related network from all subjects. The alteration of functional connectivity (FC) within SRN and its connectivity with memory-related network/SMN were compared among four groups and further correlation analysis between altered FC and awareness index as well as episodic memory score were performed. Results: Compared with CN group, individuals with SCD exhibited hyperconnectivity within SRN, while aMCI and AD patients showed hypoconnectivity. Furthermore, aMCI patients and AD patients both showed the interruption of the FC between the SRN and memory-related network compared to CN group. Pearson correlation analysis showed that disruptive FC within SRN and its interaction with memory-related network were related to memory awareness and episodic memory scores. Conclusion: In conclusion, impaired memory awareness and episodic memory in the AD spectrum are correlated to the disconnection within SRN and its interaction with memory-related network.

Justinas Narbutas, Maxime Van Egroo, Daphne Chylinski, Mohamed Ali Bahri, Ekaterina Koshmanova, Puneet Talwar, Gabriel Besson, Vincenzo Muto, Christina Schmidt, André Luxen, Evelyne Balteau, Christophe Phillips, Pierre Maquet, Eric Salmon, Christine Bastin, Gilles Vandewalle, Fabienne Collette
Associations Between Cognitive Complaints, Memory Performance, Mood, and Amyloid-β Accumulation in Healthy Amyloid Negative Late-Midlife Individuals
Abstract: Background: Cognitive complaints are gaining more attention as they may represent an early marker of increased risk for AD in individuals without objective decline at standard neuropsychological examination. Objective: Our aim was to assess whether cognitive complaints in late middle-aged individuals not seeking medical help are related to objective cognitive outcomes known as early markers for AD risk, concomitant affective state, and amyloid-β (Aβ) burden. Methods: Eighty-seven community-based cognitively normal individuals aged 50-69 years underwent neuropsychological assessment for global cognition, using Preclinical Alzheimer’s Cognitive Composite 5 (PACC5) score, and a more specific episodic memory measure. Affective state was based on self-assessment questionnaires for depression and anxiety. Aβ PET burden was assessed via [18F]Flutemetamol (N=84) and [18F]Florbetapir (N=3) uptake. Cognitive complaints were evaluated using Cognitive Difficulties Scale. Results: Higher cognitive complaints were significantly associated with lower episodic memory performance and worse affective state. Moreover, higher level of cognitive complaints was related to higher (but still sub-clinical) global Aβ accumulation (at uncorrected significance level). Importantly, all three aspects remained significant when taken together in the same statistical model, indicating that they explained distinct parts of variance. Conclusion: In healthy Aβ negative late middle-aged individuals, a higher degree of cognitive complaints is associated with lower episodic memory efficiency, more anxiety and depression, as well as, potentially, with higher Aβ burden, suggesting that complaints might signal subtle decline. Future studies should untangle how cognitive complaints in healthy aging populations are related to longitudinal changes in objective cognition and AD biomarker correlates.

Caroline Bitencourt Soares, Leticia Rossi Daré, Karine Ramires Lima, Luiza Freitas Lopes, Alexandre Garcia dos Santos, Helen Lidiane Schimidt, Felipe Pivetta Carpes, Ana Lloret, Jose Viña, Pâmela Billig Mello-Carpes
Multicomponent Training Prevents Memory Deficit Related to Amyloid-β Protein-Induced Neurotoxicity
Abstract: Background: Alzheimer's disease (AD) is characterized by the accumulation of the amyloid-β peptide in the brain, leading to early oxidative stress and neurotoxicity. It has been suggested that physical exercise could be beneficial in preventing AD, but studies with multicomponent training are scanty. Objective: Verify the effects of multicomponent exercise training to prevent deficits in recognition memory related to Aβ neurotoxicity. Methods: We subjected Wistar rats to multicomponent training (including aerobic and anaerobic physical exercise and cognitive exercise) and then infused amyloid-β peptide into their hippocampus. Results: We show that long-term multicomponent training prevents the amyloid-β-associated neurotoxicity in the hippocampus. It reduces hippocampal lipid peroxidation, restores antioxidant capacity, and increases glutathione levels, finally preventing recognition memory deficits. Conclusion: Multicomponent training avoids memory deficits related to amyloid-β neurotoxicity on an animal model.

Paul Theo Zebhauser, Achim Berthele, Marie-Sophie Franz, Oliver Goldhardt, Janine Diehl-Schmid, Josef Priller, Marion Ortner*, Timo Grimmer* (Handling Associate Editor: Robert Rissmann) *These authors contributed equally to this work.
Age-Dependency of Total Tau in the Cerebrospinal Fluid Is Corrected by Amyloid-β 1-40: A Correlational Study in Healthy Adults
Abstract: Background: Tau proteins are established biomarkers of neuroaxonal damage in a wide range of neurodegenerative conditions. Although measurement of total-Tau in the cerebrospinal fluid is widely used in research and clinical settings, the relationship between age and total-Tau in the cerebrospinal fluid is yet to be fully understood. While past studies reported a correlation between age and total-Tau in the cerebrospinal fluid of healthy adults, in clinical practice the same cut-off value is used independently of patient’s age. Objective: To further explore the relationship between age and total-Tau and to disentangle neurodegenerative from drainage-dependent effects. Methods: We analyzed cerebrospinal fluid samples of 76 carefully selected cognitively healthy adults and included amyloid-β 1-40 as a potential marker of drainage from the brain’s interstitial system. Results: We found a significant correlation of total-Tau and age, which was no longer present when correcting total-Tau for amyloid-β 1-40 concentrations. These findings were replicated under varied inclusion criteria. Conclusion: Results call into question the association of age and total-Tau in the cerebrospinal fluid. Furthermore, they suggest diagnostic utility of amyloid-β 1-40 as a possible proxy for drainage-mechanisms into the cerebrospinal fluid when interpreting biomarker concentrations for neurodegenerative diseases.

Fang Wang, Chun-shuang Xu, Wei-hua Chen, Shi-wei Duan, Shu-jun Xu, Jun-jie Dai, Qin-wen Wang (Handling Associate Editor: Ling-Qiang Zhu)
Identification of Blood-Based Glycolysis Gene Associated with Alzheimer’s Disease by Integrated Bioinformatics Analysis
Abstract: Background: Alzheimer's disease (AD) is one of many common neurodegenerative diseases without ideal treatment, but early detection and intervention can prevent the disease progression. Objective: This study aimed to identify AD-related glycolysis gene for AD diagnosis and further investigation by integrated bioinformatics analysis. Methods: 122 subjects were recruited from the affiliated hospitals of Ningbo University between 1 October 2015 and 31 December 2016. Their clinical information and methylation levels of 8 glycolysis genes were assessed. Machine learning algorithms were used to establish an AD prediction model. Receiver operating characteristic curve (AUC) and decision curve analysis (DCA) were used to assess the model. An AD risk factor model was developed by SHapley Additive exPlanations (SHAP) to extract features that had important impacts on AD. Finally, gene expression of AD-related glycolysis genes were validated by AlzData. Results: An AD prediction model was developed using random forest algorithm with the best average ROC_AUC (0.969544). The threshold probability of the model was positive in the range of 0~0.9875 by DCA. Eight glycolysis genes (GAPDHS, PKLR, PFKFB3, LDHC, DLD, ALDOC, LDHB, HK3) were identified by SHAP. Five of these genes (PFKFB3, DLD, ALDOC, LDHB, LDHC) have significant differences in gene expression between AD and control groups by Alzdata, while three of the genes (HK3, ALDOC, PKLR) are related to the pathogenesis of AD. GAPDHS is involved in the regulatory network of AD risk genes. Conclusion: We identified 8 AD-related glycolysis genes (GAPDHS, PFKFB3, LDHC, HK3, ALDOC, LDHB, PKLR, DLD) as promising candidate biomarkers for early diagnosis of AD by integrated bioinformatics analysis. Machine learning has the advantage in identifying genes.

Kaito Kawamura, Masakazu Miyajima, Madoka Nakajima, Mitsuyasu Kanai, Yumiko Motoi, Shuko Nojiri, Chihiro Akiba, Ikuko Ogino, Hanbing Xu, Chihiro Kamohara, Shinya Yamada, Kostadin Karagiozov, Takeshi Ikeuchi, Akihide Kondo, Hajime Arai
Cerebrospinal Fluid Amyloid-β Oligomer Levels in Patients with Idiopathic Normal Pressure Hydrocephalus
Abstract: Background: The amyloid-β oligomers, consisting of 10-20 monomers (AβO10-20), have strong neurotoxicity and are associated with cognitive impairment in Alzheimer’s disease (AD). However, their role in patients with idiopathic normal pressure hydrocephalus (iNPH) is poorly understood. Objective: We hypothesized that cerebrospinal fluid (CSF) AβO10-20 accumulates in patients with iNPH, and its clearance after CSF shunting contributes to neurological improvement. We measured CSF AβO10-20 levels before and after CSF shunting in iNPH patients evaluating their diagnostic and prognostic role. Methods: We evaluated two iNPH cohorts: “evaluation” (cohort-1) with 32 patients and “validation” (cohort-2) with 13 patients. Comparison cohorts included: 27 neurologically healthy controls (HCs), and 16 AD, 15 Parkinson’s disease (PD), and 14 progressive supranuclear palsy (PSP) patients. We assessed for all cohorts CSF AβO10-20 levels and their comprehensive clinical data. iNPH cohort-1 pre-shunting data were compared with those of comparison cohorts, using cohort-2 for validation. Next, we compared cohort-1’s clinical and CSF data: 1) before and after CSF shunting, and 2) increased versus decreased AβO10-20 levels at baseline, 1 and 3 years after shunting. Results: Cohort-1 had higher CSF AβO10-20 levels than the HCs, PD, and PSP cohorts. This result was validated with data from cohort-2. CSF AβO10-20 levels differentiated cohort-1 from the PD and PSP groups, with an area under receiver operating characteristic curve of 0.94. AβO10-20 levels in cohort-1 decreased after CSF shunting. Patients with AβO10-20 decrease showed better cognitive outcome than those without. Conclusion: AβO10-20 accumulates in patients with iNPH and is eliminated by CSF shunting. AβO10-20 can be an applicable diagnostic and prognostic biomarker.

Stavros I. Dimitriadis, Christos Lyssoudis, Anthoula C. Tsolaki, Eftychia Lazarou, Mahi Kozori, Magda Tsolaki
Greek High Phenolic Early Harvest Extra Virgin Olive Oil Reduces the Over-Excitation of Information-Flow Based on Dominant Coupling Mode Model in Patients with Mild Cognitive Impairment: An EEG Resting-State Validation Approach
Abstract: Background: Extra virgin olive oil (EVOO) constitutes a natural compound with high protection over cognitive function that could positively alter brain dynamics and the mixture of within and between-frequency connectivity. Objective: The balance of cross-frequency coupling over within-frequency coupling can build a nonlinearity index (NI) that encapsulates the over-excitation of information flow between brain areas and across experimental time. The present study investigated for the very first time how the Greek High Phenolic Early Harvest Extra Virgin Olive Oil (HP-EH-EVOO) versus Moderate Phenolic (MP-EVOO) and Mediterranean Diet (MeDi) intervention in people with mild cognitive impairment (MCI) could affect their spontaneous EEG dynamic connectivity. Methods: Forty-three subjects (14 in MeDi, 16 in MP-EVOO, and 13 in HP-EH-EVOO) followed an EEG resting-state recording session (eyes-open and closed) before and after the treatment. Following our dominant coupling mode model, we built a dynamic integrated dynamic functional connectivity graph that tabulates the functional strength and the dominant coupling mode model of every pair of brain areas. Results: Signal spectrum within 1-13 Hz and theta/beta ratio have decreased in the HP-EH-EVOO group in the eyes-open condition. The intervention improved the F1DoCM across groups and conditions but was more prominent in the HP-EH-EVOO group (p < 0.001). Finally, we revealed a significant higher post-intervention reduction of NI (ΔΝΙTotal and α) for the HP-EH-EVOO compared to the MP-EVOO and MeDi groups (p < 0.0001). Conclusion: Long-term intervention with HP-EH-EVOO reduced the over-excitation of information flow in spontaneous brain activity and altered the signal spectrum of EEG rhythms.

Lucy Beishon, Victoria Haunton, Hari Subramaniam, Elizabeta B. Mukaetova-Ladinska, Ronney B. Panerai, Thompson Robinson, Rachel Evley
Qualitative Analysis of the Cognition and Flow (CoGFlowS) Study: An Individualized Approach to Cognitive Training for Dementia Is Needed
Abstract: Background: Cognitive training (CT) may have benefits for both healthy older adults (HC) and those with early cognitive disorders [mild cognitive impairment (MCI) and dementia]. However, few studies have qualitatively evaluated home-based, computerized CT programs. Objective: We present the qualitative arm of a feasibility randomized controlled trial evaluating a CT program for HC and people living with MCI or dementia. Methods: Participants underwent semi-structured interviews after 12 weeks of CT. Where possible, participants were interviewed with their carers. The interview schedule and analysis were underpinned by the health belief model. Interviews were audio-recorded, transcribed, open-coded, and categorized into themes. The analytical framework was developed, and themes were condensed under five major categories: benefits, barriers, threat, self-efficacy, and cues to action. Results: 37 participants underwent interviews. CT was feasible and acceptable to participants. Benefits included: enjoyment, improved awareness, benchmarking cognitive function, reassurance of abilities and giving back control. Barriers were more prevalent among those with dementia: problems with technology, frustration, conflict between patients and carers, apathy and lack of insight, anxiety or low mood, and lack of portability. HC and MCI perceived the severity of dementia risk as high, partially mitigated by CT. Participants living with dementia valued a more individualized approach to training, accounting for baseline characteristics. Conclusion: CT was a feasible intervention for HC and people living with dementia and MCI. Benefits were present, but the identified barriers need to be addressed for CT to be implemented successfully.

Agustín Ibañez*, Sol Fittipaldi*, Catalina Trujillo, Tania Jaramillo, Alejandra Torres, Juan F. Cardona, Rodrigo Rivera, Andrea Slachevsky, Adolfo García, Maxime Bertoux, Sandra Baez *These authors contributed equally to this work.
Predicting and Characterizing Neurodegenerative Subtypes with Multimodal Neurocognitive Signatures of Social and Cognitive Processes
Abstract: Background: Social cognition is critically compromised across neurodegenerative diseases, including the behavioral variant frontotemporal dementia (bvFTD), Alzheimer’s disease (AD), and Parkinson’s disease (PD). However, no previous study has used social cognition and other cognitive tasks to predict diagnoses of these conditions, let alone reporting the brain correlates of prediction outcomes. Objective: We performed a diagnostic classification analysis using social cognition, cognitive screening (CS), and executive function (EF) measures, and explored which anatomical and functional networks were associated with main predictors. Methods: Multiple group discriminant function analyses (MDAs) and ROC analyses of social cognition (facial emotional recognition, theory of mind), CS, and EF were implemented in 223 participants (bvFTD, AD, PD, controls). Gray matter volume and functional connectivity correlates of top discriminant scores were investigated. Results: Although all patient groups revealed deficits in social cognition, CS, and EF, our classification approach provided robust discriminatory characterizations. Regarding controls, probabilistic social cognition outcomes provided the best characterization for bvFTD (together with CS) and PD, but not AD (for which CS alone was the best predictor). Within patient groups, the best MDA probabilities scores yielded high classification rates for bvFTD versus PD (98.3%, social cognition), AD versus PD (98.6%, social cognition + CS), and bvFTD versus AD (71.7%, social cognition + CS). Top MDA scores were associated with specific patterns of atrophy and functional networks across neurodegenerative conditions. Conclusion: Standardized validated measures of social cognition, in combination with cognitive screening, can provide a dimensional classification with specific pathophysiological markers of neurodegeneration diagnoses.

Angelina R. Sutin, Damaris Aschwanden, Martina Luchetti, Yannick Stephan, Antonio Terracciano (Handling Associate Editor: Isabelle Rouch)
Sense of Purpose in Life Is Associated with Lower Risk of Incident Dementia: A Meta-Analysis
Abstract: Background: A sense of purpose in life has been associated with healthier cognitive outcomes across adulthood, including risk of dementia. The robustness and replicability of this association, however, has yet to be evaluated systematically. Objective: To test whether a greater sense of purpose in life is associated with lower risk of dementia in four population-based cohorts and combined with the published literature. Methods: Random-effect meta-analysis of prospective studies (individual participant data and from the published literature identified through a systematic review) that examined sense of purpose and risk of incident dementia. Results: In six samples followed up to 17 years (four primary data and two published; total N=53,499; n=5,862 incident dementia), greater sense of purpose in life was associated with lower dementia risk (HR=0.77, 95% CI=0.73-0.81, p<0.001). The association was generally consistent across cohorts (I2=47%), remained significant controlling for clinical (e.g., depression) and behavioral (e.g., physical inactivity) risk factors, and was not moderated by age, gender, or education. Conclusion: Sense of purpose is a replicable and robust predictor of lower risk of incident dementia and is a promising target of intervention for cognitive health outcomes.

Panagiotis Alexopoulos*, Maria Skondra*, Evagellia Kontogianni, Aikaterini Vratsista, Maria Frounta, Georgia Konstantopoulou, Suzana Ιoanna Aligianni, Marina Charalampopoulou, Iliana Lentzari, Philippos Gourzis, Matthias Kliegel, Polychronis Εconomou, Antonios Politis *These authors contributed equally to this work.
Validation of the Cognitive Telephone Screening Instruments COGTEL and COGTEL+ in Identifying Clinically Diagnosed Neurocognitive Disorder Due to Alzheimer’s Disease in a Naturalistic Clinical Setting
Abstract: Background: Telephone-based neurocognitive instruments embody valuable tools in identifying cognitive impairment in research settings and lately also in clinical contexts due to the pandemic crisis. The accuracy of the Cognitive Telephone Screening Instrument (COGTEL) in detecting mild- (MiND) and major (MaND) neurocognitive disorder has not been studied yet. Objective: Comparison of the utility of COGTEL and COGTEL+, which is enriched with orientation items, with the modified Mini-Mental State Examination (3MS) in detecting MiND and MaND due to Alzheimer’s disease (AD) and assessment of the impact of COGTEL face-to-face- versus telephone administration on individual performance. Methods: The study included 197 cognitively intact individuals (CI), being at least 45 years old, 95 and 65 patients with MiND and MaND due to AD, respectively. In 20 individuals COGTEL was administered both in face-to-face and telephone sessions. Statistical analyses included proportional odds logistic regression models, stratified repeated random subsampling used to recursive partitioning to training and validation set (70/30 ratio), and an appropriate F-test. Results: All studied instruments were significant predictors of diagnostic outcome, but COGTEL+ and 3MS explained more variance relative to the original COGTEL. Except for the validation regression models including COGTEL in which the average misclassification error slightly exceeded 15%, in all other cases the average misclassification errors (%) were lower than 15%. COGTEL administration modality was not related to systematic over- or underestimation of performance on COGTEL. Conclusions: COGTEL+ is a valuable instrument in detecting MiND and MaND and can be administered in face-to-face or telephone sessions.

Sven J. van der Lee*, Inger van Steenoven*, Marleen van de Beek, Niccolo Tési, Iris E. Jansen, Natasja M. van Schoor, Marcel J.T. Reinders, Martijn Huisman, Philip Scheltens, Charlotte E. Teunissen, Henne Holstege, Wiesje M. van der Flier, Afina W. Lemstra *These authors contributed equally to this work.
Genetics Contributes to Concomitant Pathology and Clinical Presentation in Dementia with Lewy Bodies
Abstract: Background: Dementia with Lewy bodies (DLB) is a complex, progressive neurodegenerative disease with considerable phenotypic, pathological, and genetic heterogeneity. Objective: We tested if genetic variants in part explain the heterogeneity in DLB. Methods: We tested the effects of variants previously associated with DLB (near APOE, GBA, and SNCA) and polygenic risk scores for Alzheimer’s disease (AD-PRS) and Parkinson’s disease (PD-PRS). We studied 190 probable DLB patients from the Alzheimer’s dementia Cohort and compared them to 2,552 control subjects. The p-tau/Aβ1-42 ratio in cerebrospinal fluid was used as in vivo proxy to separate DLB cases into DLB with concomitant AD pathology (DLB-AD) or DLB without AD (DLB-pure). We studied the clinical measures age, Mini-Mental State Examination (MMSE), and the presence of core symptoms at diagnosis and disease duration. Results: We found that all studied genetic factors significantly associated with DLB risk (all-DLB). Second, we stratified the DLB patients by the presence of concomitant AD pathology and found that APOE ɛ4 and the AD-PRS associated specifically with DLB-AD, but less with DLB-pure. In addition, the GBA p.E365K variant showed strong associated with DLB-pure and less with DLB-AD. Last, we studied the clinical measures and found that APOE ɛ4 associated with reduced MMSE, higher odds to have fluctuations and a shorter disease duration. In addition, the GBA p.E365K variant reduced the age at onset by 5.7 years, but the other variants and the PRS did not associate with clinical features. Conclusion: These finding increase our understanding of the pathological and clinical heterogeneity in DLB.

Hidemasa Takao, Shiori Amemiya, Osamu Abe, for the Alzheimer’s Disease Neuroimaging Initiative
Reproducibility of Brain Volume Changes in Longitudinal Voxel-Based Morphometry Between Non-Accelerated and Accelerated Magnetic Resonance Imaging
Abstract: Background: Scan acceleration techniques, such as parallel imaging, can reduce scan times, but reliability is essential to implement these techniques in neuroimaging. Objective: To evaluate the reproducibility of the longitudinal changes in brain morphology determined by longitudinal voxel-based morphometry (VBM) between non-accelerated and accelerated magnetic resonance images (MRI) in normal aging, mild cognitive impairment (MCI), and Alzheimer’s disease (AD). Methods: Using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) 2 database, comprising subjects who underwent non-accelerated and accelerated structural T1-weighted MRI at screening and at a 2-year follow-up on 3.0 T Philips scanners, we examined the reproducibility of longitudinal gray matter volume changes determined by longitudinal VBM processing between non-accelerated and accelerated imaging in 50 healthy elderly subjects, 54 MCI patients, and eight AD patients. Results: The intraclass correlation coefficient (ICC) maps differed among the three groups. The mean ICC was 0.72 overall (healthy elderly, 0.63; MCI, 0.75; AD, 0.63), and the ICC was good to excellent (0.6–1.0) for 81.4% of voxels (healthy elderly, 64.8%; MCI, 85.0%; AD, 65.0%). The differences in image quality (head motion) were not significant (Kruskal–Wallis test, p = 0.18) and the within-subject standard deviations of longitudinal gray matter volume changes were similar among the groups. Conclusion: The results indicate that the reproducibility of longitudinal gray matter volume changes determined by VBM between non-accelerated and accelerated MRI is good to excellent for many regions but may vary between diseases and regions.

Daniel E. Gustavson, Amy J. Jak, Jeremy A. Elman, Matthew S. Panizzon, Carol E. Franz, Katherine A. Gifford, Chandra A. Reynolds, Rosemary Toomey, Michael J. Lyons, William S. Kremen (Handling Associate Editor: Jessica Peter)
How Well Does Subjective Cognitive Decline Correspond to Objectively Measured Cognitive Decline? Assessment of 10-12 Year Change
Abstract: Background: Although not strongly correlated with current objective cognitive ability, subjective cognitive decline (SCD) is a risk factor for Alzheimer’s disease. Most studies focus on SCD in relation to future decline rather than objective prior decline that it purportedly measures. Objective: We evaluated whether self-report of cognitive decline—as a continuous measure—corresponds to objectively-assessed episodic memory and executive function decline across the same period. Methods: 1,170 men completed the Everyday Cognition Questionnaire (ECog) at mean age 68 assessing subjective changes in cognitive ability relative to 10 years prior. A subset had mild cognitive impairment (MCI), but MCI was diagnosed without regard to subjective decline. Participants completed up to 3 objective assessments of memory and executive function (M=56, 62, and 68 years). Informant-reported ECogs were completed for 1,045 individuals. Analyses controlled for depression and anxiety symptoms assessed at mean age 68. Results: Participant-reported ECog scores were modestly associated with objective decline for memory (β=-0.23, 95% CI [-0.37, -0.10]) and executive function (β=-0.19, 95% CI [-0.33, -0.05]) over the same time period. However, these associations were nonsignificant after excluding MCI cases. Results were similar for informant ratings. Participant-rated ECog scores were more strongly associated with concurrent depression and anxiety symptoms, (β=0.44, 95% CI [0.36, 0.53]). Conclusion: Continuous SCD scores are correlated with prior objective cognitive changes in non-demented individuals, though this association appears driven by individuals with current MCI. However, participants’ current depression and anxiety ratings tend to be strongly associated with their SCD ratings. Thus, what primarily drives SCD ratings remains unclear.

Anshika Goel*, Saurav Roy*, Khushboo Punjabi*, Ritwick Mishra, Manjari Tripathi, Deepika Shukla, Pravat K. Mandal *These authors contributed equally to this work.
PRATEEK: Integration of Multimodal Neuroimaging Data to Facilitate Advanced Brain Research
Abstract: Background: In vivo neuroimaging modalities such as magnetic resonance imaging (MRI), functional MRI (fMRI), magnetoencephalography (MEG), magnetic resonance spectroscopy (MRS), and quantitative susceptibility mapping (QSM) are useful techniques to understand brain anatomical structure, functional activity, source localization, neurochemical profiling, and tissue susceptibility respectively. Integrating unique and distinct information from these neuroimaging modalities will further help to enhance the understanding of complex neurological disease. Objective: To develop a processing scheme for multimodal data integration in seamless manner on healthy young population, thus establishing a generalized framework for various clinical conditions (e.g., Alzheimer’s disease). Methods: A multimodal data integration scheme has been developed to integrate the outcomes from multiple neuroimaging data (fMRI, MEG, MRS, and QSM) spatially. Furthermore, the entire scheme has been incorporated into a user-friendly toolbox- “PRATEEK”. Results: The proposed methodology and toolbox has been tested for viability among fourteen healthy young participants for bilateral occipital cortices as the region of interest. This scheme can also be extended to other anatomical regions of interest. Overlap percentage from each combination of two modalities (fMRI-MRS, MEG-MRS, fMRI-QSM, and fMRI-MEG) has been computed and also been qualitatively assessed for combinations of the three (MEG-MRS-QSM) and four (fMRI-MEG-MRS-QSM) modalities. Conclusion: This user-friendly toolbox minimizes the need of an expertise in handling different neuroimaging tools for processing and analyzing multimodal data. The proposed scheme will be beneficial for clinical studies where geometric information plays a crucial role in advance brain research.

Erin L. Richard, Linda K. McEvoy, Eyal Oren, John E. Alcaraz, Gail A. Laughlin, Andrea Z. LaCroix, Rany M. Salem (Handling Associate Editor: Barbara Bendlin)
Markers of Kidney Function and Longitudinal Cognitive Ability Among Older Community-Dwelling Adults: The Rancho Bernardo Study
Abstract: Background: Reduced kidney function has been associated with cognitive decline. Most studies have examined a single marker of kidney function and have limited duration of follow-up. Objective: This study evaluated associations between markers of kidney function (urine albumin, estimated glomerular filtration rate [eGFR], and hyperuricemia) with cognitive performance over time. Methods: This is a longitudinal study of 1,634 community-dwelling adults (mean age=71.7 years), with kidney function markers and cognitive ability measured at baseline (1992-1996) and at up to five additional time points with a maximum of 23.4 years (mean=8.1 years) of follow-up. Associations between kidney function and cognitive performance were assessed using linear mixed effects models. Testing for interaction by sex was conducted. Results: Albuminuria (urine albumin-to-creatinine ratio [ACR] ≥30 mg/g) was associated with steeper annual declines in global cognitive function (MMSE, β=-0.12, p=0.003), executive function (Trails B, β=4.50, p<0.0001) and episodic memory (Buschke total recall, β=-0.62, p=0.02) scores in men. Results were similar when cognitive test scores were regressed on latent trajectory classes of ACR. In men, hyperuricemia (serum uric acid [SUA] ≥6.8 mg/dl for men and SUA ≥6.0 mg/dl for women) was associated with lower baseline MMSE (β=-0.70, p=0.009) scores but not with MMSE change over time. No such associations were detected in women. There were no significant associations between eGFR and cognitive performance for either sex. Conclusion: In older men, albuminuria is an independent predictor of subsequent cognitive decline. More investigations are needed to explain the observed sex differences and the potential relationship between hyperuricemia and poorer global cognition.

Nadine Sontheimer, Alexander Konnopka*, Hans-Helmut König* *These authors share last authorship.
The Excess Costs of Dementia: A Systematic Review and Meta-Analysis
Abstract: Background: Dementia is one of the costliest diseases for health care systems with growing importance for policy makers. Objective: The aim of this study is to systematically review the current literature of excess cost studies for dementia and to analyze excess costs in a meta-analysis. Methods: A systematic literature search was conducted in PubMed, EconLit, NHS-EED, and Cochrane Library. 22 studies were included and assigned to one of three subgroups according to the time period that they analyzed during disease progression: the time of diagnosis, the time between diagnosis and death, and the time prior to death. Excess costs were analyzed using the ratio of means (ROM) and meta-analysis was performed by pooling ROMs in a random effects model. Results: Total costs were significantly higher for demented persons compared to non-demented persons at the time of diagnosis (ROM: 2.08 [1.71, 2.54], p < 0.00001, I2 = 98%) and in the time period between diagnosis and death (ROM: 2.19 [1.97, 2.44], p < 0.00001, I2= 100%). The ROM was highest for professional home care (ROM: 4.96 [2.62, 9.40], p < 0.0001, I2= 88%) and for nursing facilities (ROM: 4.02 [2.53, 6.40], p < 0.00001, I2= 100%) for the time period between diagnosis and death. Conclusion: This meta-analysis is the first to assess excess costs of dementia by the ROM method on a global scale. We conclude that our findings demonstrate that costs of dementia constitute a substantial economic burden.

Una Smailovic, Ingemar Kåreholt, Thomas Koenig, Nicholas J. Ashton, Bengt Winblad, Kina Höglund, Per Nilsson, Henrik Zetterberg, Kaj Blennow, Vesna Jelic (Handling Associate Editor: Laura Bonanni)
Synaptic Molecular and Neurophysiological Markers Are Independent Predictors of Progression in Alzheimer’s Disease
Abstract: Background: Cerebrospinal fluid (CSF) neurogranin and quantitative electroencephalography (qEEG) are potential molecular and functional markers of synaptic pathology in Alzheimer’s disease (AD). Synaptic markers have emerged as candidate prognostic indicators of AD since synaptic degeneration was shown to be an early event and the best correlate of cognitive deficits in patients along the disease continuum. Objective: The present study investigated the association between CSF neurogranin and qEEG measures as well as their potential to predict clinical deterioration in mild cognitive impairment (MCI) patients. Methods: Patients diagnosed with MCI (n = 99) underwent CSF conventional AD biomarkers and neurogranin analysis and resting-state EEG recordings. The study population was further stratified into stable (n = 41) and progressive MCI (n = 31), based on the progression to AD dementia during two years follow-up. qEEG analysis included computation of global field power and global field synchronization in four conventional frequency bands. Results: CSF neurogranin levels were associated with theta power and synchronization in the progressive MCI group. CSF neurogranin and qEEG measures were significant predictors of progression to AD dementia, independent of baseline amyloid status in MCI patients. A combination of CSF neurogranin with global EEG power in theta and global EEG synchronization in beta band exhibited the highest classification accuracy as compared to either of these markers alone. Conclusion: qEEG and CSF neurogranin are independent predictors of progression to AD dementia in MCI patients. Molecular and neurophysiological synaptic markers may have additive value in a multimodal diagnostic and prognostic approach to dementia.

Min Zhu, Longfei Jia, Jianping Jia
Inhibition of miR-96-5p May Reduce Aβ42/Aβ40 Ratio via Regulating ATP-Binding Cassette A1
Abstract: Background: Imbalance between amyloid-β (Aβ) production and clearance results in Aβ accumulation. Regulating Aβ levels is still a hot point in the research of Alzheimer’s disease (AD). Objective: To identify the differential expression of ATP-binding cassette A1 (ABCA1) and its upstream microRNA (miRNA) in AD models, and to explore their relationships with Aβ levels. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were performed to determine the expression of ABCA1 in 5xFAD mice, SH-SY5Y cells treated with Aβ oligomers and SH-SY5YAβPP695 cells (AD models). TargetScan was used to predict the upstream miRNAs for ABCA1. Dual-luciferase assay was conducted to identify the regulation of the miRNA on ABCA1. qRT-PCR was used to measure the expression of miRNA in AD models. Finally, enzyme-linked immunosorbent assays were performed to detect Aβ42 and Aβ40 levels. Results: The expression of ABCA1 was significantly downregulated in AD models at both mRNA and protein levels. Dual-luciferase assay showed that miR-96-5p could regulate the expression of ABCA1 through binding to the 3’ untranslated region of ABCA1. The level of miR-96-5p was significantly elevated in AD models. The expression of ABCA1 was enhanced while Aβ42 levels and Aβ42/Aβ40 ratios were reduced in SH-SY5YAβPP695 cells after treated with miR-96-5p inhibitor. Conclusion: The current study found that miR-96-5p is the upstream miRNA for ABCA1. Suppression of miR-96-5p in AD models could reduce Aβ42/Aβ40 ratios via upregulating the expression of ABCA1, indicating that miR-96-5p plays an important role in regulating the content of Aβ.

Donna J. Cross, Bertrand R. Huber, Michael A. Silverman, Marcella M. Cline, Trevor B. Gill, Chloe G. Cross, David G. Cook, Satoshi Minoshima
Intranasal Paclitaxel Alters Alzheimer’s Disease Phenotypic Features in 3xTg-AD Mice
Abstract: Background: Microtubule stabilizing drugs, commonly used as anti-cancer therapeutics, have been proposed for treatment of Alzheimer’s disease (AD); however, many do not cross the blood-brain barrier. Objective: This research investigated if paclitaxel (PTX) delivered via the intranasal (IN) route could alter the phenotypic progression of AD in 3xTg-AD mice. Methods: We administered intranasal PTX in 3XTg-AD mice (3xTg-AD n=15, 10 weeks and n=10, 44 weeks, PTX: 0.6 mg/kg or 0.9% saline (SAL)) at 2-week intervals. After treatment, 3XTg-AD mice underwent manganese-enhanced magnetic resonance imaging to measure in vivo axonal transport. In a separate 3XTg-AD cohort, PTX-treated mice were tested in a radial water tread maze at 52 weeks of age after four treatments, and at 72 weeks of age, anxiety was assessed by an elevated-plus maze after 14 total treatments. Results: PTX increased axonal transport rates in treated 3XTg-AD compared to controls (p≤0.003). Further investigation using an in vitro neuron model of Aβ-induced axonal transport disruption confirmed PTX prevented axonal transport deficits. Confocal microscopy after treatment found fewer phospho-tau containing neurons (5.25±3.8 versus 8.33±2.5, p<0.04) in the CA1, altered microglia, and reduced reactive astrocytes. PTX improved performance of 3xTg-AD on the water tread maze compared to controls and not significantly different from WT (Day 5, 143.8±43 versus 91.5±77s and Day 12, 138.3±52 versus 107.7±75s for SAL versus PTX). Elevated plus maze revealed that PTX-treated 3xTg-AD mice spent more time exploring open arms (Open arm 129.1±80 versus 20.9±31s for PTX versus SAL, p≤0.05). Conclusion: Taken collectively, these findings indicate that intranasal-administered microtubule-stabilizing drugs may offer a potential therapeutic option for treating AD.

Rosa Romero-Moreno, María Márquez-González, Samara Barrera-Caballero, Carlos Vara-García, Javier Olazarán, María del Sequeros Pedroso-Chaparro, Lucía Jiménez-Gonzalo, Andrés Losada-Baltar
Depressive and Anxious Comorbidity and Treatment Response in Family Caregivers of People with Dementia
Abstract: Background: While most intervention studies conducted with dementia family caregivers have focused on depressive symptoms as the main outcome, no study has analyzed the effects of an intervention on comorbid clinical presentations of depressive and anxious symptomatology. Objective: The aim of this study was to examine the association between clinical depressive and anxious symptomatology at baseline and treatment responses of dementia family caregivers using samples from two randomized intervention trials with the same pre-post design. Methods: Specifically, the effects on depressive and anxious comorbidity of three intervention conditions (Cognitive Behavioral Therapy (CBT), Acceptance and Commitment Therapy (ACT), and a control group (CG)) were analyzed. Participants were 130 dementia family caregivers. In addition to sociodemographic variables, depressive and anxious symptomatology were measured. Results: Caregivers with clinical depressive and anxiety comorbid symptoms at baseline recovered less well from depressive symptoms after CBT (45.45%) and ACT (47.72%) interventions than caregivers with non-comorbidity (100% recovery in both treatments). No significant association between comorbidity and treatment responses on depression was found for the control group. Regarding anxiety, among participants with comorbidity at baseline, 36.36% of caregivers in CBT and 30.9 % in the ACT group recovered from anxiety symptoms after treatment, compared to 6.45% in the control group. Similar results were obtained regarding those who recovered both from clinical depressive and anxiety symptoms and showed comorbidity at baseline. Conclusion: Caregivers that show comorbid depressive and anxiety symptoms at baseline may benefit less from interventions than caregivers who do not show comorbidity.

Seyed Hani Hojjati, Farnia Feiz, Sindy Ozoria, Qolamreza R. Razlighi; Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Babak Ardekani)
Topographical Overlapping of the Amyloid-β and Tau Pathologies in the Default Mode Network Predicts Alzheimer's Disease with Higher Specificity
Abstract: Background: While amyloid-β (Aβ) plaques and tau tangles are the well-recognized pathologies of Alzheimer’s disease (AD), they are more often observed in healthy individuals than in AD patients. This discrepancy makes it extremely challenging to utilize these two proteinopathies as reliable biomarkers for the early detection as well as later diagnosis of AD. Objective: We hypothesize and provide preliminary evidence that topographically overlapping Aβ and tau within the default mode network (DMN) play more critical roles in the underlying pathophysiology of AD than each of the tau and/or Aβ pathologies alone. Methods: We used our newly developed quantification methods and publicly available neuroimaging data from 303 individuals to provide preliminary evidence of our hypothesis. Results: We first showed that the probability of observing overlapping Aβ and tau is significantly higher within than outside the DMN. We then showed evidence that using Aβ and tau overlap can increase the reliability of the prediction of healthy individuals converting to mild cognitive impairment (MCI) and to a lesser degree converting from MCI to AD. Finally, we provided evidence that while the initial accumulations of Aβ and tau seems to be started independently in the healthy participants, the accumulations of the two pathologies interact in the MCI and AD groups. Conclusion: These findings shed some light on the complex pathophysiology of AD and suggest that overlapping Aβ and tau pathologies within the DMN might be a more reliable biomarker of AD for early detection and later diagnosis of the disease.

Lucas M. Walden, Song Hu, Anant Madabhushi, Jeffrey W. Prescott, for the Alzheimer’s Disease Neuroimaging Initiative
Amyloid Deposition Is Greater in Cerebral Gyri than in Cerebral Sulci with Worsening Clinical Diagnosis Across the Alzheimer's Disease Spectrum
Abstract: Background: Histopathologic studies have demonstrated differential amyloid-β (Aβ) burden between cortical sulci and gyri in Alzheimer’s disease (AD), with sulci having a greater Aβ burden. Objective: To characterize Aβ deposition in the sulci and gyri of the cerebral cortex in vivo among subjects with normal cognition (NC), mild cognitive impairment (MCI), and AD, and to evaluate if these differences could improve discrimination between diagnostic groups. Methods: T1-weighted 3T MR and florbetapir (amyloid) positron emission tomography (PET) data were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). T1 images were segmented and the cortex was separated into sulci/gyri based on pial surface curvature measurements. T1 images were registered to PET images and regional standardized uptake value ratios (SUVr) were calculated. A linear mixed effects model was used to analyze the relationship between clinical variables and amyloid PET SUVr measurements in the sulci/gyri. Receiver operating characteristic (ROC) analysis was performed to define amyloid positivity. Logistic models were used to evaluate predictive performance of clinical diagnosis using amyloid PET SUVr measurements in sulci/gyri. Results: 719 subjects were included: 272 NC, 315 MCI, and 132 AD. Gyral and sulcal Aβ increased with worsening cognition, however there was a greater increase in gyral Aβ. Females had a greater gyral and sulcal Aβ burden. Focusing on sulcal and gyral Aβ did not improve predictive power for diagnostic groups. Conclusion: While there were significant differences in Aβ deposition in cerebral sulci and gyri across the AD spectrum, these differences did not translate into improved prediction of diagnosis. Females were found to have greater gyral and sulcal Aβ burden.

Yassin Watson, Brenae Nelson, Jamie Hernandez Kluesner, Caroline Tanzy, Shreya Ramesh, Zoey Patel, Kaci Hernandez Kluesner, Anita Singh, Vibha Murthy, Cassie S. Mitchell
Aggregate Trends of Apolipoprotein E on Cognition in Transgenic Alzheimer’s Disease Mice
Abstract: Background: Apolipoprotein E (APOE) genotypes typically increase risk of amyloid-β deposition and onset of clinical Alzheimer’s disease (AD). However, cognitive assessments in APOE transgenic AD mice have resulted in discord. Objective: Analysis of 31 peer-reviewed AD APOE mouse publications (n=3,045 mice) uncovered aggregate trends between age, APOE genotype, gender, modulatory treatments, and cognition. Methods: T-tests with Bonferroni correction (significance = p<0.002) compared age-normalized Morris water maze (MWM) escape latencies in wild type (WT), APOE2 knock-in (KI2), APOE3 knock-in (KI3), APOE4 knock-in (KI4), and APOE knock-out (KO) mice. Positive treatments (t+) to favorably modulate APOE to improve cognition, negative treatments (t-) to perturb etiology and diminish cognition, and untreated (t0) mice were compared. Machine learning with random forest modeling predicted MWM escape latency performance based on 12 features: mouse genotype (WT, KI2, KI3, KI4, KO), modulatory treatment (t+, t-, t0), mouse age, and mouse gender (male=g_m; female=g_f, mixed gender=g_mi). Results: KI3 mice performed significantly better in MWM, but KI4 and KO performed significantly worse than WT. KI2 performed similarly to WT. KI4 performed significantly worse compared to every other genotype. Positive treatments significantly improved cognition in WT, KI4, and KO compared to untreated. Interestingly, negative treatments in KI4 also significantly improved mean MWM escape latency. Random forest modeling resulted in the following feature importance for predicting superior MWM performance: [KI3, age, g_m, KI4, t0, t+, KO, WT, g_mi, t-, g_f, KI2] = [0.270, 0.094, 0.092, 0.088, 0.077, 0.074, 0.069, 0.061, 0.058, 0.054, 0.038, 0.023]. Conclusion: APOE3, age, and male gender was most important for predicting superior mouse cognitive performance.

Heather Yemm, Dame Louise Robinson, Stella-Maria Paddick, Catherine Dotchin, Michaela Louise Goodson, Alla Narytnyk, Marie Poole, Ríona Mc Ardle
Instrumental Activities of Daily Living Scales to Detect Cognitive Impairment and Dementia in Low- and Middle-Income Countries: A Systematic Review
Abstract: Background: The largest proportion of people with dementia worldwide live in low- and middle- income countries (LMICs), with dementia prevalence continuing to rise. Assessment and diagnosis of dementia involves identifying the impact of cognitive decline on function, usually measured by instrumental activities of daily living (IADLs). Objective: This review aimed to identify IADL measures which are specifically developed, validated, or adapted for use in LMICs to guide selection of such tools. Methods: A systematic search was conducted (fourteen databases) up to April 2020. Only studies reporting on development, validation, or adaptation of IADL measures for dementia or cognitive impairment among older adults (aged over 50) in LMICs were included. The QUADAS 2 was used to assess quality of diagnostic accuracy studies. Results: 22 papers met inclusion criteria; identifying 19 discrete IADL tools across 11 LMICs. These were either translated from IADL measures used in high-income countries (n=6), translated and adapted for cultural differences (n=6), or newly developed for target LMIC populations (n=7). Seven measures were investigated in multiple studies; overall quality of diagnostic accuracy was moderate to good. Conclusion: Reliability, validity, and accuracy of IADL measures for supporting dementia diagnosis within LMICs was reported. Key components to consider when selecting an IADL tool for such settings were highlighted, including choosing culturally appropriate, time-efficient tools that account for gender- and literacy-bias, and can be conducted by any volunteer with appropriate training. There is a need for greater technical and external validation of IADL tools across different regions, countries, populations, and cultures.

Alexandra Martini Oliveira, Marcia Radanovic, Patricia Cotting Homem de Mello, Patricia Cardoso Buchain, Adriana Dias Barbosa Vizzotto, Janaína Harder, Florindo Stella, Laura N. Gitlin, Catherine Verrier Piersol, Leandro L.C. Valiengo, Orestes Vicente Forlenza
Adjunctive Therapy to Manage Neuropsychiatric Symptoms in Moderate and Severe Dementia: Randomized Clinical Trial Using an Outpatient Version of Tailored Activity Program
Abstract: Background: Neuropsychiatric symptoms (NPS) such as aggression, apathy, agitation, and wandering may occur in up to 90% of dementia cases. International guidelines have suggested that non‐pharmacological interventions are as effective as pharmacological treatments, however without the side effects and risks of medications. An occupational therapy method, called Tailored Activity Program (TAP), was developed with the objective to treat NPS in the elderly with dementia and has been shown to be effective. Objective: Evaluate the efficacy of the TAP method (outpatient version) in the treatment of NPS in individuals with dementia and in the burden reduction of their caregivers. Methods: This is a randomized, double‐blind, controlled clinical trial for the treatment of NPS in dementia. Outcome measures consisted of assessing the NPS of individuals with dementia, through the Neuropsychiatric Inventory‐Clinician rating scale (NPI‐C), and assessing the burden on their caregivers, using the Zarit Scale. All the participants were evaluated pre-and post‐intervention. Results: 54 individuals with dementia and caregivers were allocated to the experimental (n=28) and control (n=26) groups. There was improvement of the following NPS in the experimental group: delusions, agitation, aggressiveness, depression, anxiety, euphoria, apathy, disinhibition, irritability, motor disturbance, and aberrant vocalization. No improvement was observed in hallucinations, sleep disturbances, and appetite disorders. The TAP method for outpatient settings was also clinically effective in reducing burden between caregivers of the experimental group. Conclusion: The use of personalized prescribed activities, coupled with the caregiver training, may be a clinically effective approach to reduce NPS and caregiver burden of individuals with dementia.