Volume 78, Number 2, IN PRESS

Review
Zizhen Si, Xidi Wang (Handling Associate Editor: Wolff Kirsch)
The Neuroprotective and Neurodegeneration Effects of Heme Oxygenase-1 in Alzheimer's Disease
Abstract: Alzheimer's disease (AD) is a neurodegenerative disease characterized by complex pathological and biological features. Notably, extracellular amyloid-β deposits as senile plaques and intracellular aggregation of hyperphosphorylated tau as neurofibrillary tangles remain the primary premortem criterion for the diagnosis of AD. Currently, there exist no disease-modifying therapies for AD, and many clinical trials have failed to show its benefits for patients. Heme oxygenase 1 (HO-1) is a 32 kDa enzyme, which catalyzes the degradation of cellular heme to free ferrous iron, biliverdin, and carbon monoxide under stressful conditions. Several studies highlight the crucial pathological roles of HO-1 in the molecular processes of AD. The beneficial roles of HO-1 overexpression in AD brains are widely accepted due to its ability to convert pro-oxidant heme to biliverdin and bilirubin (antioxidants), which promote restoration of a suitable tissue redox microenvironment. However, the intracellular oxidative stress might be amplified by metabolites of HO-1 and exacerbate the progression of AD under certain circumstances. Several lines of evidence have demonstrated that upregulated HO-1 is linked to tauopathies, neuronal damage, and synapse aberrations in AD. Here, we review the aspects of the molecular mechanisms by which HO-1 regulates AD and the latest information on the pathobiology of AD. We further highlight the neuroprotective and neurodystrophic actions of HO-1 and the feasibility of HO-1 as a therapeutic target for AD.

Review
Lilian Calderón-Garcidueñas, Ricardo Torres-Jardón, Maricela Franco-Lira, Randy Kulesza, Angélica González-Maciel, Rafael Reynoso-Robles, Rafael Brito-Aguilar, Berenice García-Arreola, Paula Revueltas-Ficachi, Juana Adriana Barrera-Velázquez, Griselda García-Alonso, Edgar García-Rojas, Partha S. Mukherjee, Ricardo Delgado-Chávez
Environmental Nanoparticles, SARS-CoV-2 Brain Involvement, and Potential Acceleration of Alzheimer’s and Parkinson’s Diseases in Young Urbanites Exposed to Air Pollution
Abstract: Alzheimer’s and Parkinson’s diseases (AD, PD) have a pediatric and young adult onset in Metropolitan Mexico City (MMC). The SARS-CoV-2 neurotropic RNA virus is triggering neurological complications and deep concern regarding acceleration of neuroinflammatory and neurodegenerative processes already in progress. This review, based on our MMC experience, will discuss two major issues: 1) why residents chronically exposed to air pollution are likely to be more susceptible to SARS-CoV-2 systemic and brain effects and 2) why young people with AD and PD already in progress will accelerate neurodegenerative processes. Secondary mental consequences of social distancing and isolation, fear, financial insecurity, violence, poor health support, and lack of understanding of the complex crisis are expected in MMC residents infected or free of SARS-CoV-2. MMC residents with pre-SARS-CoV-2 accumulation of misfolded proteins diagnostic of AD and PD and metal-rich, magnetic nanoparticles damaging key neural organelles are an ideal host for neurotrophic SARS-CoV-2 RNA virus invading the body through the same portals damaged by nanoparticles: nasal olfactory epithelium, the gastrointestinal tract, and the alveolar-capillary portal. We urgently need MMC multicenter retrospective-prospective neurological and psychiatric population follow-up and intervention strategies in place in case of acceleration of neurodegenerative processes, increased risk of suicide, and mental disease worsening. Identification of vulnerable populations and continuous effort to lower air pollution ought to be critical steps.

Review
Zhenting Huang*, Qian Yan*, Yangyang Wang, Qian Zou, Jing Li, Zhou Liu, Zhiyou Cai *These authors contributed equally to this work.
Role of Mitochondrial Dysfunction in the Pathology of Amyloid-β
Abstract: Mitochondrial dysfunction has been widely reported in several neurodegenerative disorders, including in the brains of patients with Alzheimer’s disease (AD), Parkinson’s disease, and Huntington disease. An increasing number of studies have implicated altered glucose and energy metabolism in patients with AD. There is compelling evidence of abnormalities in some of the key mitochondrial enzymes involved in glucose metabolism, including the pyruvate dehydrogenase and α-ketoglutarate dehydrogenase complexes, which play a great significance role in the pathogenesis of AD. Changes in some of the enzyme activities of the mitochondria found in AD have been linked with the pathology of amyloid-β (Aβ). This review highlights the role of mitochondrial function in the production and clearance of Aβ and how the pathology of Aβ leads to a decrease in energy metabolism by affecting mitochondrial function.

Review
Eric R. Rosin*, Drew Blasco*, Alexander R. Pilozzi, Lawrence H. Yang**, Xudong Huang** *These authors contributed equally to this work. **Co-senior authors
A Narrative Review of Alzheimer's Disease Stigma
Abstract: As the most common form of senile dementia, Alzheimer’s disease (AD) is accompanied by a great deal of uncertainty which can lead to fear and stigma for those identified with this devastating disease. As the AD definition evolves from a syndromal to a biological construct, and early diagnoses becomes more commonplace, more confusion and stigma may result. We conducted a narrative review of the literature on AD stigma to consolidate information on this body of research. From the perspective of several stigma theories, we identified relevant studies to inform our understanding of the way in which implementation of the new framework for a biological based AD diagnosis may have resulted in new and emerging stigma. Herein, we discuss the emergence of new AD stigma as our understanding of the definition of the disease changes. We further propose recommendations for future research to reduce the stigma associated with AD.

Short Communication
Marlena Walter, Jens Wiltfang, Jonathan Vogelgsang
Pre-Analytical Sampling and Storage Conditions of Amyloid-β Peptides in Venous and Capillary Blood
Abstract: Previous studies on blood-based biomarkers for Alzheimer’s disease suggest a less invasive blood test might be a valuable screening tool for Alzheimer-specific pathology. Pre-analytical sample storage conditions seem to play an important role on amyloid-β (Aβ) stability, impacting reliability and reproducibility. This study shows that Aβ40, Aβ42, and Aβ42/40 levels significantly and early decrease during storage at room temperature in whole blood or plasma. Storing blood samples at 4°C leads to stable Aβ peptide concentrations up to 72 h. In addition, Aβ peptides can be measured in capillary blood with a stable Aβ42/40 ratio up to 72 h at 4°C.

Short Communication
Jordi A Matias-Guiu, Vanesa Pytel, Jorge Matías-Guiu
Death Rate Due to COVID-19 in Alzheimer’s Disease and Frontotemporal Dementia
Abstract: We aimed to evaluate the frequency and mortality of COVID-19 in patients with Alzheimer’s disease (AD) and frontotemporal dementia (FTD). We conducted an observational case series. We enrolled 204 patients, 15.2% of whom were diagnosed with COVID-19, and 41.9% of patients with the infection died. Patients with AD were older than patients with FTD (80.36±8.77 versus 72.00±8.35 years old) and had a higher prevalence of arterial hypertension (55.8% versus 26.3%). COVID-19 occurred in 7.3% of patients living at home, but 72.0% of those living at care homes. Living in care facilities and diagnosis of AD were independently associated with a higher probability of death. We found that living in care homes is the most relevant factor for an increased risk of COVID-19 infection and death, with AD patients exhibiting a higher risk than those with FTD.

María Encarnación Andreu-Reinón, José María Huerta, Diana Gavrila, Pilar Amiano, Javier Mar, Mikel Tainta, Eva Ardanaz, Rosa Larumbe, Carmen Navarro, Sandra M. Colorado-Yohar, Fernando Navarro-Mateu, María Dolores Chirlaque (Handling Associate Editor: Anne Fink)
Incidence of Dementia and Associated Factors in the EPIC-Spain Dementia Cohort
Abstract: Background: Dementia has become a public health priority as the number of cases continues to grow worldwide. Objective: To assess dementia incidence and determinants in the EPIC-Spain Dementia Cohort. Methods: 25,015 participants (57% women) were recruited from three Spanish regions between 1992-1996 and followed-up for over 20 years. Incident cases were ascertained through individual revision of medical records of potential cases. Crude and age-adjusted incidence rates (IR) of dementia and sub-types (Alzheimer’s disease (AD), and non-AD) were calculated by sex. Neelson-Aalen cumulative incidence estimates at 10, 15, and 20 years were obtained for each sex and age group. Multivariate Royston-Parmar models were used to assess independent determinants. Results: Global IR were higher in women for dementia and AD, and similar by sex for non-AD. IR ranged from 0.09 cases of dementia (95% confidence interval: 0.06-0.13) and 0.05 [0.03-0.09] of AD per 1000 person-years (py) in participants below 60 years, to 23.2 (15.9-33.8) cases of dementia and 14.6 (9.1-33.5) of AD (per 1000 py) in those ≥85 years. Adjusted IR were consistently higher in women than men for overall dementia and AD. Up to 12.5% of women and 9.1% of men 60–65 years-old developed dementia within 20 years. Low education, diabetes, and hyperlipidemia were the main independent predictors of dementia risk, whereas alcohol showed an inverse association. Conclusion: Dementia incidence increased with age and was higher among women, but showed no geographical pattern. Dementia risk was higher among subjects with lower education, not drinking alcohol, and presenting cardiovascular risk factors.

Klaus Hauer, Michael Schwenk, Stefan Englert, G.A. Rixt Zijlstra, Sabine Tuerner, Ilona Dutzi (Handling Associate Editor: Manuel Montero-Odasso)
Mismatch of Subjective and Objective Risk of Falling in Patients with Dementia
Abstract: Background: Match or mismatch of objective physiological and subjectively perceived fall risk may have serious consequences in patients with dementia (PwD) while research is lacking. Objective: To analyze mismatch of objective and subjective fall risk and associated factors in PwD. Method: Cohort study in a geriatric rehabilitation center. Objective and subjective risk of falling were operationalized by Tinetti’s Performance Oriented Mobility Assessment and the Falls Efficacy Scale-International. Four sub-groups according to objective and subjective fall risk were classified. Subgroups were compared for differences in clinical, cognitive, psychological, and behavioral variables. Results: In geriatric rehab patients with mild to moderate dementia (n=173), two-thirds showed a mismatch of subjective versus objective risk of falling, independently associated with previous falls. Underestimation of objective fall risk (37.6%) was determined by lower activity avoidance (OR 0.39), less concerns about falling due to previous falls (OR 0.25), and higher quality of life (OR 1.10), while overestimation (28.9%) was determined by higher rate of support seeking strategies (OR 50.3), activity avoidance (OR 15.2), better executive (OR 21.0) and memory functions (OR 21.5), and lower quality of life (OR .75) in multivariate logistic regression. Conclusion: The majority of patients showed a mismatch between objective and subjective falls risk. Underestimation as well as overestimation of fall risk was associated with specific profiles based on cognitive- and psychological status, falls and fall-related behavioral consequences which should be included in the comprehensive assessment of fall risk, and planning of individualized fall prevention programs for this population.

Hyemin Jang*, Hee Jin Kim, Yeong Sim Choe, Soo-Jong Kim, Seongbeom Park, Yeshin Kim, Ko Woon Kim, Chul Hyoung Lyoo, Hanna Cho, Young Hoon Ryu, Jae Yong Choi, Charles DeCarli, Duk L. Na, Sang Won Seo* *These authors contributed equally to this work.
The Impact of Amyloid-β or Tau on Cognitive Change in the Presence of Severe Cerebrovascular Disease
Abstract: Background: As Alzheimer’s disease (AD) and cerebral small vessel disease (CSVD) commonly coexist, the interaction between two has been of the considerable interest. Objective: We determined whether the association of Aβ and tau with cognitive decline differs by the presence of significant CSVD. Methods: We included 60 subcortical vascular cognitive impairment (SVCI) from Samsung Medical Center and 82 Alzheimer’s disease-related cognitive impairment (ADCI) from ADNI, who underwent Aβ (florbetaben or florbetapir) and tau (flortaucipir, FTP) PET imaging. They were retrospectively assessed for 5.0 ± 3.9 and 5.6 ±1.9 years with Clinical Dementia Rating-sum of boxes (CDR-SB)/Mini-Mental State Examination (MMSE). Mixed effects models were used to investigate the interaction between Aβ/tau and group on CDR-SB/MMSE changes. Results: The frequency of Aβ positivity (45% versus 54.9%, p=0.556) and mean global FTP SUVR (1.17±0.21 versus 1.16±0.17, p=0.702) were not different between the two groups. We found a significant interaction effect of Aβ positivity and SVCI group on CDR-SB increase/MMSE decrease (p=0.013/p<0.001) change, and a significant interaction effect of global FTP uptake and SVCI group on CDR-SB increase/MMSE decrease (p<0.001 and p=0.030) change. Finally, the interaction effects of regional tau and group were prominent in the Braak III/IV (p=0.001) and V/VI (p=0.003) not in Braak I/II region (p=0.398). Conclusion: The association between Aβ/tau and cognitive decline is stronger in SVCI than in ADCI. Therefore, our findings suggested that Aβ positivity or tau burden (particularly in the Braak III/IV or V/VI regions) and CSVD might synergistically affect cognitive decline.

Remy Cardoso, Carolina Lemos, Bárbara Oliveiros, Maria Rosário Almeida, Inês Baldeiras, Cláudia Fragão Pereira, Ana Santos, Diana Duro, Daniela Vieira, Isabel Santana, Catarina Resende Oliveira
APOE ε4-TOMM40L Haplotype Increases the Risk of Mild Cognitive Impairment Conversion to Alzheimer’s Disease
Abstract: Background: Mild cognitive impairment (MCI) has been considered as a pre-dementia stage, although the factors leading to Alzheimer’s disease (AD) conversion remain controversial. Objective: Evaluate whether TOMM40 poly-T (TOMM40’ 523) polymorphism is associated with the risk and conversion time from MCI to AD and secondly with AD cerebrospinal fluid (CSF) biomarkers, disentangling the APOE genotype. Methods: 147 AD patients, 102 MCI patients, and 105 cognitively normal controls were genotyped for poly-T polymorphism. MCI patients were subdivided into two groups, the group of patients that converted to AD (MCI-AD) and the group of those that remained stable (MCI-S). Results: TOMM40’ 523 L allele was significantly more frequent in the MCI-AD group and having at least one L allele significantly increased the risk of conversion from MCI to AD (OR = 8.346, p<0.001, 95%CI: 2.830 to 24.617). However, when adjusted for the presence of APOE ε4 allele, both the L allele and ε4 allele lost significance in the model (p>0.05). We then analyzed the APOE ε4-TOMM40’ 523 haplotype and observed that patients carrying this haplotype had significantly higher risk (OR=5.83; 95% CI=2.30-14.83) and mean lower times of conversion to AD (p=0.003). This haplotype was also significantly associated with a biomarker profile compatible with AD (p=0.007). Conclusion: This study shows that the APOE ε4-TOMM40’ 523 haplotype is associated with a higher risk and shorter times of conversion from MCI to AD, possibly driven by CSF biomarkers and mitochondrial dysfunction.

Kimberly Ashby-Mitchell, Douladel Willie-Tyndale, Denise Eldemire-Shearer
Proportion of Dementia Explained by Five Key Factors in Jamaica
Abstract: Background: Dementia has no known cure and age is its strongest predictor. Given that populations in the Caribbean are aging, a focus on policies and programs that reduce the risk of dementia and its risk factors is required. Objective: To estimate the proportion of dementia in the Jamaican setting attributable to key factors. Methods: We analyzed the contribution of five modifiable risk factors to dementia prevalence in Jamaica using a modified Levin's Attributable Risk formula (low educational attainment, diabetes, smoking status, depression, and physical inactivity). Four sources of data were used: risk factor prevalence was obtained from the Jamaica Health and Lifestyle Survey, 2008, relative risk data were sourced from published meta-analyses, shared variance among risk factors was determined using cross-sectional data from the Health and Social Status of Older Persons in Jamaica Study. Estimated future prevalence of dementia in Jamaica was sourced from a published ADI/BUPA report which focused on dementia in the Americas. We computed the number of dementia cases attributable to each risk factor and estimated the effect of a reduction in these risk factors on future dementia prevalence. Results: Accounting for the overlapping of risk factors, 34.46% of dementia cases in Jamaica (6548 cases) were attributable to the five risk factors under study. We determined that if each risk factor were to be reduced by 5%-10% per decade from 2010–2050, dementia prevalence could be reduced by up to 14.0%. Conclusion: As the risk factors for dementia are shared with several of the main causes of death in Jamaica, a reduction in risk factors by even 5% can result in considerable public health benefit.

Melinda L. Jackson, Marina Cavuoto, Rachel Schembri, Vincent Doré, Victor L. Villemagne, Maree Barnes, Fergal J. O’Donoghue, Christopher C. Rowe, Stephen R. Robinson
Severe Obstructive Sleep Apnea Is Associated with Higher Brain Amyloid Burden: A Preliminary PET Imaging Study
Abstract: Background: Obstructive sleep apnea (OSA) has been linked to an increase risk of dementia. Few studies have cross-sectionally examined whether clinically-confirmed OSA is associated with a higher brain amyloid burden. Objective: The aim of this study was to compare brain amyloid burden in individuals with untreated OSA and healthy controls, and explore associations between amyloid burden and polysomnographic and subjective measures of sleep, demographics, and mood. Methods: Thirty-four individuals with OSA (mean age 57.5±4.1 y; 19 males) and 12 controls (mean age 58.5±4.2 y; 6 males) underwent a clinical polysomnogram and a 11C-PiB positron emission tomography (PET) scan to quantify amyloid burden. Results: Amyloid burden was elevated in the OSA group relative to controls, and was significantly higher in those with severe OSA relative to mild/moderate OSA. Correlation analyses indicated that higher amyloid burden was associated with a higher Non-REM apnea hypopnea index, poorer sleep efficiency, and less time spent in stage N3 sleep, when controlling for age. Conclusion: Severe OSA is associated with a modest elevation of brain amyloid, the significance of which should be further investigated to explore the implications for dementia risk.

Noel Torres-Acosta, James H. O’Keefe, Evan L. O’Keefe, Richard Isaacson, Gary Small (Handling Associate Editor: Dharma Singh Khalsa)
Therapeutic Potential of TNF-α Inhibition for Alzheimer’s Disease Prevention
Abstract: Background: Alzheimer’s disease (AD) is increasingly prevalent and over 99% of drugs developed for AD have failed in clinical trials. A growing body of literature suggests that potent inhibitors of tumor necrosis factor-α (TNF-α) have potential to improve cognitive performance. Objective: In this review, we summarize the evidence regarding the potential for TNF-α inhibition to prevent AD and improve cognitive function in people at risk for dementia. Methods: We conducted a literature review in PubMed, screening all articles published before July 7, 2019 related to TNF blocking agents and curcumin (another TNF-α inhibitor) in the context of AD pathology. The keywords in the search included: AD, dementia, memory, cognition, TNF-α, TNF inhibitors, etanercept, infliximab, adalimumab, golimumab, and curcumin. Results: Three large epidemiology studies reported etanercept treated patients had 60 to 70% lower odds ratio (OR) of developing AD. Two small-randomized control trials (RCTs) demonstrated an improvement in cognitive performance for AD patients treated with etanercept. Studies using animal models of dementia also reported similar findings with TNF blocking agents (etanercept, infliximab, adalimumab, Theracurmin), which appeared to improve cognition. A small human RCT using Theracurmin, a well-absorbed form of curcumin that lowers TNF-α, showed enhanced cognitive performance and decreased brain levels of amyloid-β plaque and tau tangles. Conclusion: TNF-α targeted therapy is a biologically plausible approach to the preservation of cognition, and warrants larger prospective RCTs to further investigate potential benefits in populations at risk of developing AD.

Paula Duarte-Guterman, Arianne Y. Albert, Amy M. Inkster, Cindy K. Barha, Liisa A.M. Galea, on behalf of the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Beatrice Arosio)
Inflammation in Alzheimer’s Disease: Do Sex and APOE Matter?
Abstract: Background: Alzheimer’s disease (AD) disproportionately affects females with steeper cognitive decline and more neuropathology compared to males, which is exacerbated in females carrying the APOE ε4 allele. The risk of developing AD is also higher in female APOE ε4 carriers in earlier age groups (aged 65-75), and the progression from cognitively normal to mild cognitive impairment (MCI) and to AD may be influenced by sex. Inflammation is observed in AD and is related to aging, stress, and neuroplasticity, and although studies are scarce, sex differences are noted in inflammation. Objective: The objective of this study was to investigate underlying physiological inflammatory mechanisms that may help explain why there are sex differences in AD and APOE ε4 carriers. Methods: We investigated, using the ADNI database, the effect of sex and APOE genotype (non-carriers or carriers of 1 and 2 APOE ε4 alleles) and sex and diagnosis (cognitively normal (CN), MCI, AD) on CSF (N= 279) and plasma (N= 527) markers of stress and inflammation. Results: We found CSF IL-16 and IL-8 levels were significantly lower in female non-carriers of APOE ε4 alleles compared to males, whereas levels were similar between the sexes among carriers of APOE ε4 alleles. Furthermore, females had on average higher levels of plasma CRP and ICAM1 but lower levels of CSF ICAM1, IL-8, IL-16, and IgA than males. Carrying APOE ε4 alleles and diagnosis (MCI and AD) decreased plasma CRP in both sexes. Conclusion: Sex differences in inflammatory biomarkers support that the underlying physiological changes during aging differ by sex and tissue origin.

Gregory S. Day, Allison Long, John C. Morris
Assessing the Reliability of Reported Medical History in Older Adults
Abstract: Background: Age-associated increases in medical complexity, frailty, and cognitive impairment may compromise reliable reporting of medical history. Objective: To evaluate the influence of increasing age and cognitive impairment on concordance between reported history of stroke and cerebral infarction, and reported history of diabetes and elevated hemoglobinA1c in community-dwelling older adults. Methods: The association between participant-specific factors and accurate reporting of cerebral infarction or diabetes was evaluated using multivariable logistic regression in 1,401 participants enrolled in longitudinal studies of memory and aging, including 425 participants with dementia (30.3%). Stroke and diabetes were selected as index variables as gold standard measures of both were obtained in all participants: magnetic resonance neuroimaging for cerebral infarcts and hemoglobinA1c (≥6.5%) for diabetes. Results: Concordance between reported history of stroke and imaging-confirmed cerebral infarction was low (sensitivity: 17.4%, 8/46; specificity: 97.9%, 799/816). Small infarcts were strongly associated with inaccurate reporting (OR=265.8; 95%CI: 86.2, 819.4), suggesting that occult/silent infarcts contributed to discordant reporting. Reporting accuracy was higher concerning diabetes (sensitivity: 83.5%, 147/176; specificity: 96.2%, 1100/1143). A history of hypertension (OR=2.3; 95%CI: 1.3, 4.2), higher hemoglobinA1c (OR=1.9; 95%CI: 1.5, 2.4), and hemoglobinA1c compatible with impaired glucose tolerance (OR=3.1; 95%CI 1.8, 5.3) associated with increased odds of discordant reporting. Cognitive impairment and increased age were not independently associated with reliable reporting. Conclusion: Factors beyond advancing age and cognitive impairment appear to drive discordance in reported medical history in older participants. Objective testing for cerebral infarcts or diabetes should be performed when relevant to diagnostic or therapeutic decisions in clinical and research settings.

Yuval Gavriel, Inna Rabinovich-Nikitin, Assaf Ezra, Becki Barbiro, Beka Solomon
Subcutaneous Administration of AMD3100 into Mice Models of Alzheimer’s Disease Ameliorated Cognitive Impairment, Reduced Neuroinflammation, and Improved Pathophysiological Markers
Abstract: Background: Alzheimer’s disease (AD), the prevalent dementia in the elderly, involves many related and interdependent pathologies that manifest simultaneously, leading to cognitive impairment and death. Amyloid-β (Aβ) accumulation in the brain triggers the onset of AD, accompanied by neuroinflammatory response and pathological changes. The CXCR4/CXCL12 (SDF1) axis is one of the major signal transduction cascades involved in the inflammation process and regulation of homing of hematopoietic stem cells (HSCs) within the bone marrow niche. Inhibition of the axis with AMD3100, a reversible antagonist of CXCR4 mobilizes endogenous HSCs from the bone marrow into the periphery, facilitating the recruitment of bone marrow-derived microglia-like cells into the brain, attenuates the neuroinflammation process that involves release of excitotoxic markers such as TNFα, intracellular Ca2+, and glutamate and upregulates monocarboxylate transporter 1, the major L-lactate transporter in the brain. Objective: Herein, we investigate if administration of a combination of AMD3100 and L-lactate may have beneficial effects in the treatment of AD. Methods: We tested the feasibility of the combined treatment for short- and long-term efficacy for inducing endogenous stem cells’ mobilization and attenuation of neuroinflammation in two distinct amyloid-β-induced AD mouse models. Results: The combined treatment did not demonstrate any adverse effects on the mice, and resulted in a significant improvement in cognitive/memory functions, attenuated neuroinflammation, and alleviated AD pathologies compared to each treatment alone. Conclusion: This study showed AMD3100’s beneficial effect in ameliorating AD pathogenesis, suggesting an alternative to the multistep procedures of transplantation of stem cells in the treatment of AD.

Jianjun Wang*, Hanqing Lyu*, Jianxiang Chen, Songjun Lin, Haotao Zheng, Jinfang Li, Fanxin Kong, Jinyun Gao, Haibo Yu, Yuanming Hu, Zhouke Guo (Handling Associate Editor: Cyrus Raji)*These authors contributed equally to this work.
Cortical Alterations Are Associated with Depression in Subcortical Vascular Mild Cognitive Impairment Revealed by Surface-Based Morphometry
Abstract: Background: Late-life depression often coexists with vascular cognitive impairment and affects the quality of life for elders. However, little is known about cortical morphometric interactions between subcortical vascular mild cognitive impairment (svMCI) and concomitant mild depressive symptoms at the early stage. Objective: We aimed to investigate cortical alterations of svMCI with and without depressive symptoms and determine whether these parameters are associated with depression symptoms and/or cognitive impairments. Methods: Surface based morphometry was performed on 18 svMCI patients with depressive symptoms (svMCI+D), 16 svMCI patients without depressive symptoms (svMCI-D), and 23 normal controls (NC). Results: Compared to NC, both svMCI+D and svMCI-D patients exhibited significantly decreased surface area (SA) in many cortical areas. Interestingly, svMCI+D patients showed significantly increased rather than decreased SA in right lateral occipital gyrus (LOG.R), and a consistent trend of increased SA in these areas compared to svMCI-D. In addition, the svMCI+D showed increased gray matter volume of left pericalcarine (periCAL.L) than svMCI_D, whereas svMCI_D showed decreased gray matter volume of periCAL.L than NC. Further correlation analyses revealed that the SA of left superior temporal gyrus (STG.L) and right lateral orbital part of frontal gyrus (lorbFG.R) were significantly correlated with Hamilton depression rating scale of svMCI+D. Conclusion: In conclusion, these results extend our insight into svMCI and add weight to reevaluation of concomitant early stage depressive symptoms. Moreover, we suggest that LOG.R\periCAL.L\STG.L\lorbFG.R might serve as sensitive and trait-dependent biomarkers to detect concomitant depressive symptoms in svMCI patients.

Moira Marizzoni*, Annamaria Cattaneo*, Peppino Mirabelli, Cristina Festari, Nicola Lopizzo, Valentina Nicolosi, Elisa Mombelli, Monica Mazzelli, Delia Luongo, Daniele Naviglio, Luigi Coppola, Marco Salvatore, Giovanni B. Frisoni (Handling Associate Editor: Vincenzo Solfrizzi) *These authors contributed equally to this work.
Short-Chain Fatty Acids and Lipopolysaccharide as Mediators Between Gut Dysbiosis and Amyloid Pathology in Alzheimer’s Disease
Abstract: Background: Metagenomic data support an association between certain bacterial strains and Alzheimer’s disease (AD), but their functional dynamics remain elusive. Objective: To investigate the association between amyloid pathology, bacterial products such as lipopolysaccharide (LPS) and short chain fatty acids (SCFAs: acetate, valerate, butyrate), inflammatory mediators, and markers of endothelial dysfunction in AD. Methods: Eighty-nine older persons with cognitive performance from normal to dementia underwent florbetapir amyloid PET and blood collection. Brain amyloidosis was measured with standardized uptake value ratio versus cerebellum. Blood levels of LPS was measured by ELISA, SCFAs by mass spectrometry, cytokines by using real-time PCR, and biomarkers of endothelial dysfunction by flow cytometry. We investigated the association between the variables listed above with Spearman’s rank test. Results: Amyloid SUVR uptake was positively associated with blood LPS (rho≥0.32, p≤0.006), acetate and valerate (rho≥0.45, p<0.001), pro-inflammatory cytokines (rho≥0.25, p≤0.012), and biomarkers of endothelial dysfunction (rho≥0.25, p≤0.042). In contrast, it was negatively correlated with butyrate (rho≤-0.42, p≤0.020) and the anti-inflammatory cytokine IL10 (rho≤-0.26, p≤0.009). Endothelial dysfunction was positively associated with pro-inflammatory cytokines, acetate and valerate (rho≥0.25, p≤0.045) and negatively with butyrate and IL10 levels (rho≤-0.25, p≤0.038). Conclusion: We report a novel association between gut microbiota-related products and systemic inflammation with brain amyloidosis via endothelial dysfunction, suggesting that SCFAs and LPS represent candidate pathophysiologic links between the gut microbiota and AD pathology.

Ling Gao*, Jin Wang*, Yu Jiang, Shan Wei, Suhang Shang, Chen Chen, Liangjun Dang, Kang Huo, Meiying Deng, Jingyi Wang, Qiumin Qu *These authors contributed equally to this work.
Relationship Between Peripheral Transport Proteins and Plasma Amyloid-β in Patients with Alzheimer’s Disease Were Different from Cognitively Normal Controls: A Propensity Score Matching Analysis
Abstract: Background: Transport proteins, soluble LRP1 (sLRP1) and soluble RAGE (sRAGE), play a pivotal role in the peripheral clearance of plasma amyloid-β (Aβ). However, their relationship is seldom discussed, especially in Alzheimer’s disease (AD). Objective: To explore whether their relationship in patients with AD varied from those in cognitively normal (CN) controls. Methods: We initially recruited 70 patients with AD and 725 CN controls, then applied propensity score matching (PSM) analysis to balance the differences between two groups. Plasma levels of sLRP1, sRAGE, and Aβ were measured using commercial ELISA kits and log transformed when skewed distributed. The relationship between sLRP1/sRAGE and plasma Aβ were analyzed using Pearson’s correlation analysis followed by multiple linear regression separately in the original population and matched participants. Results: After PSM, 70 patients with AD and 140 matched controls were included for further analysis. Log sLRP1 was positively correlated with plasma Aβ40 in matched CN controls (r=0.222, p=0.008) but not in patients with AD (r=0.137, p=0.260). After multivariable adjustment, Log sLRP1 remained significantly associated with plasma Aβ40 in the CN group (β=7.347, p=0.014) but not in the AD group (β=10.409, p=0.105). In contrast, Log sLRP1 was not correlated with plasma Aβ42 in patients with AD or CN controls, and Log sRAGE was consistently not associated with plasma Aβ40 or Aβ42 in either group. Conclusion: The significant correlation between sLRP1 and plasma Aβ40 present in CN controls was not found in patients with AD, suggesting that their relationship was different in AD. However, the specific mechanisms and its influence on cerebral amyloid burden require further validation.

Kuo-Hsuan Chang, Ching-Chang Huang, Chiung-Mei Chen, Hsiu-Chuan Wu, Hung-Chou Kuo
Differences in Clinical Presentation of Behavioral and Psychological Symptoms of Dementia in Alzheimer’s Disease According to Sex and Education Level
Abstract: Background: The behavioral and psychological symptoms of dementia (BPSD) seriously affect the quality of life of patients with Alzheimer’s disease (AD) and their caregivers. Objective: We aimed to identify associations between demographic/genetic factors and clinical presentations of BPSD. Methods: In a cohort of 463 AD patients with BPSD, we retrospectively analyzed sex, education level, AD severity (assessed using the Clinical Dementia Rating and Mini-Mental Status Examination), and BPSD severity (assessed using the Neuropsychiatry Inventory, NPI). Severe BPSD was defined as NPI≥10 for 3 consecutive years. Results: Among patients with severe BPSD (NPI ≥10), we observed more female patients (62.96%) and a lower level of education (6.03±4.77 years) as compared to those with mild BPSD (NPI<10) (female: 51.09%, p = 0.007; education years: 7.91±4.93, p < 0.001). Females had a lower level of education (5.72±4.50 years) and higher scores for depression/dysphoria (1.22±2.05) compared with males (education: 8.96±4.89 years, p < 0.001; depression/dysphoria: 0.78±1.42, p = 0.047). Patients with a high level of education (defined as ≥12 years) had higher scores for appetite/eating (0.90±2.02) than did those without (0.69±1.79; p = 0.001). Genetic analysis showed similar total and subscale NPI scores between patients with and without APOE4 and with and without the GRN rs5848 genotype. Conclusion: Our findings indicate potential contributions of sex and education to the presentation of BPSD. Further study is warranted to provide models for tailoring therapeutic programs to individual AD patients according to these factors.

Cynthia M. Stonnington, Stefanie N. Velgos, Yinghua Chen, Sameena Syed, Matt Huentelman, Pradeep Thiyyagura, Wendy Lee, Ryan Richholt, Richard J. Caselli, Dona E.C. Locke, Bai Lu, Eric M. Reiman, Yi Su, Kewei Chen (Handling Associate Editor: Jing Zhang)
Interaction Between BDNF Val66Met and APOE4 on Biomarkers of Alzheimer’s Disease and Cognitive Decline
Abstract: Background: Whether brain-derived neurotrophic factor (BDNF) Met carriage impacts the risk or progression of Alzheimer’s disease (AD) is unknown. Objective: To evaluate the interaction of BDNF Met and APOE4 carriage on cerebral metabolic rate for glucose (CMRgl), amyloid burden, hippocampus volume, and cognitive decline among cognitively unimpaired (CU) adults enrolled in the Arizona APOE cohort study. Methods: 114 CU adults (mean age 56.85 years, 38% male) with longitudinal FDG PET, magnetic resonance imaging, and cognitive measures were BDNF and APOE genotyped. A subgroup of 58 individuals also had Pittsburgh B (PiB) PET imaging. We examined baseline CMRgl, PiB PET amyloid burden, CMRgl, and hippocampus volume change over time, and rate of change in cognition over an average of 15 years. Results: Among APOE4 carriers, BDNF Met carriers had significantly increased amyloid deposition and accelerated CMRgl decline in regions typically affected by AD, but without accompanying acceleration of cognitive decline or hippocampal volume changes and with higher baseline frontal CMRgl and slower frontal decline relative to the Val/Val group. The BDNF effects were not found among APOE4 non-carriers. Conclusion: Our preliminary studies suggest that there is a weak interaction between BDNF Met and APOE4 on amyloid-β plaque burden and longitudinal PET measurements of AD-related CMRgl decline in cognitively unimpaired late-middle-aged and older adults, but with no apparent effect upon rate of cognitive decline. We suggest that cognitive effects of BDNF variants may be mitigated by compensatory increases in frontal brain activity—findings that would need to be confirmed in larger studies.

Zhongzhi Xu, Jiannan Yang, Kui Kai Lau, Paul S.F. Yip, Ian C.K. Wong, Qingpeng Zhang (Handling Associate Editor: Tommaso Cassano)
Understanding the Association Between Antidepressants and the Risk of Being Diagnosed with Dementia in Older People: A Self-Controlled Case Series Study
Abstract: Background: Given concerns about adverse outcomes for older people taking antidepressants in the literature, we investigated whether taking antidepressants elevates the risk of dementia. Objective: This study aims to investigate the putative association of antidepressants with the risk of dementia. Methods: We conducted a population-based self-controlled case series analysis of older people with dementia and taking antidepressants, using territory-wide medical records of 194,507 older patients collected by the Hospital Authority of Hong Kong, to investigate the association between antidepressant treatment and the risk of developing dementia in older people. Results: There was a significantly higher risk of being diagnosed with dementia during the pre-drug-exposed period (incidence rate ratio (IRR) 20.42 (95% CI: 18.66-22.34)) compared to the non-drug-exposed baseline period. The IRR remained high during the drug-exposed period (IRR 8.86 (7.80-10.06)) before returning to a baseline level after washout (IRR 1.12 (0.77-1.36)). Conclusion: The higher risk of dementia before antidepressant treatment may be related to emerging psychiatric symptoms co-occurring with dementia, which trigger medical consultations that result in a decision to begin antidepressants. Our findings do not support a causal relationship between antidepressant treatment and the risk of dementia.

Jun Ho Lee, Min Soo Byun, Dahyun Yi, Kang Ko, So Yeon Jeon, Bo Kyung Sohn, Jun-Young Lee, Younghwa Lee, Haejung Joung, Dong Young Lee, for the KBASE Research Group
Long-Term Exposure to PM10 and in vivo Alzheimer’s Disease Pathologies
Abstract: Background: Previous studies indicated an association between Alzheimer's disease (AD) dementia and air particulate matter (PM) with aerodynamic diameter <10 μm (PM10), as well as smaller PM. Limited information, however, is available for the neuropathological links underlying such association. Objective: This study aimed to investigate the relationship between long-term PM10 exposure and in vivo pathologies of AD using multimodal neuroimaging. Methods: The study population consisted of 309 older adults without dementia (191 cognitively normal and 118 mild cognitive impairment individuals), who lived in Republic of Korea. Participants underwent comprehensive clinical assessments, 11C-Pittsburg compound B (PiB) positron emission tomography (PET), and magnetic resonance imaging scans. A subset of 78 participants also underwent 18F-AV-1451 tau PET evaluation. The mean concentration of PM with aerodynamic diameter <10 μm over the past 5 years (PM10mean) collected from air pollution surveillance stations were matched to each participant’s residence. Results: In this non-demented study population, of which 62% were cognitively normal and 38% were in mild cognitive impairment state, exposure to the highest tertile of PM10mean was associated with increased risk of amyloid-β (Aβ) positivity (odds ratio 2.19, 95% confidence interval 1.13 to 4.26) even after controlling all potential confounders. In contrast, there was no significant associations between PM10mean exposure and tau accumulation. AD signature cortical thickness and white matter hyperintensity volume were also not associated with PM10mean exposure. Conclusion: The findings suggest that long-term exposure to PM10 may contribute to pathological Aβ deposition.

Taylor M. Snowden*, Anthony K. Hinde*, Hannah M.O. Reid, Brian R. Christie *These authors contributed equally to this work.
Does Mild Traumatic Brain Injury Increase the Risk for Dementia? A Systematic Review and Meta-Analysis
Abstract: Background: Mild traumatic brain injury (mTBI) is a putative risk factor for dementia; however, despite having apparent face validity, the evidence supporting this hypothesis remains inconclusive. Understanding the role of mTBI as a risk factor is becoming increasingly important given the high prevalence of mTBI, and the increasing societal burden of dementia. Objective: Our objective was to use the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) format to determine if an association exists between mTBI and dementia and related factors, and to quantify the degree of risk. Methods: In this format, two authors conducted independent database searches of PubMed, PsycInfo, and CINAHL using three search blocks to find relevant papers published between 2000 and 2020. Relevant studies were selected using pre-defined inclusion/exclusion criteria, and bias scoring was performed independently by the two authors before a subset of studies was selected for meta-analysis. Twenty-one studies met the inclusion criteria for this systematic review. Results: The meta-analysis yielded a pooled odds ratio of 1.96 (95% CI 1.698-2.263), meaning individuals were 1.96 times more likely to be diagnosed with dementia if they had a prior mTBI. Most studies examining neuropsychiatric and neuroimaging correlates of dementia found subtle, persistent changes after mTBI. Conclusion: These results indicate that mTBI is a risk factor for the development of dementia and causes subtle changes in performance on neuropsychiatric testing and brain structure in some patients.

Ramit Ravona-Springer, Inbal Sharvit-Ginon, Ithamar Ganmore, Lior Greenbaum, Barbara B. Bendlin, Shelley A. Sternberg, Abigail Livny, Liran Domachevsky, Israel Sandler, Simona Ben Haim, Sapir Golan, Liat Ben-Ami, Orit Lesman-Segev, Sigalit Manzali, Anthony Heymann, Michal Schnaider Beeri
The Israel Registry for Alzheimer’s Prevention (IRAP) Study: Design and Baseline Characteristics
Abstract: Background: Family history of Alzheimer’s disease (AD) is associated with increased dementia-risk. Objective: The Israel Registry for Alzheimer’s Prevention (IRAP) is a prospective longitudinal study of asymptomatic middle-aged offspring of AD patients (family history positive; FH+) and controls (whose parents have aged without dementia; FH-) aimed to unravel the contribution of midlife factors to future cognitive decline and dementia. Here we present the study design, methods, and baseline characteristics. Methods: Participants are members of the Maccabi Health Services, 40-65 years of age, with exquisitely detailed laboratory, medical diagnoses and medication data available in the Maccabi electronic medical records since 1998. Data collected through IRAP include genetic, sociodemographic, cognitive, brain imaging, lifestyle, and health-related characteristics at baseline and every three years thereafter. Results: Currently IRAP has 483 participants [mean age 54.95 (SD=6.68) and 64.8% (n=313) women], 379 (78.5%) FH+, and 104 (21.5%) FH-. Compared to FH-, FH+ participants were younger (p=0.011), more often males (p=0.003) and with a higher prevalence of the APOE E4 allele (32.8% FH+, 22% FH-; p=0.040). Adjusting for age, sex, and education, FH+ performed worse than FH- in global cognition (p=0.027) and episodic memory (p=0.022). Conclusion: Lower cognitive scores and higher rates of the APOE E4 allele among the FH+ group suggest that FH ascertainment is good. The combination of long-term historical health-related data available through Maccabi with the multifactorial information collected through IRAP will potentially enable development of dementia-prevention strategies already in midlife, a critical period in terms of risk factor exposure and initiation of AD-neuropathology.

Elizabeth Crocco, Rosie E. Curiel-Cid, Marcela Kitaigorodsky, Christian J. González-Jiménez, Diane Zheng, Ranjan Duara, David A. Loewenstein
A Brief Version of the LASSI-L Detects Prodromal Alzheimer’s Disease States
Abstract: Background: The Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L) is an increasingly utilized cognitive stress test designed to identify early cognitive changes associated with incipient neurodegenerative disease. Objective: To examine previously derived cut-points for cognitively unimpaired older adults that were suggestive of performance impairment on multiple subscales of the LASSI-L. These cut-points were applied to a new sample of older adults who were cognitive healthy controls (HC: n=26) and those on the Alzheimer’s disease (AD) continuum from early stage mild cognitive impairment (E-MCI: n=28), late stage MCI (L-MCI: n-18) to mild AD (AD: n=27). Methods: All participants were administered the LASSI-L. All cognitively impaired participants were PET amyloid positive which likely reflects underlying AD neuropathology, while cognitively normal counterparts were deemed to have amyloid negative scans. Results: There was a monotonic relationship between the number of deficits on LASSI-L subscales and independent classification of study groups with greater severity of cognitive impairment. Importantly, taken together, impairment on maximum learning ability and measures of proactive semantic interference (both reflected by cued recall and intrusion errors) correctly classified 74.1% of EMCI, 94.4% of LMCI, and 96.3% of AD. Only 7.7% of HC were incorrectly classified as having impairments. Conclusion: A modest number of LASSI-L subscales taking approximately 8 minutes to administer, had excellent discriminative ability using established cut-offs among individuals with presumptive stages of AD. This has potential implications for both clinical practice and clinical research settings targeting AD during early prodromal stages.

Magda Tsolak, Eftychia Lazarou, Mahi Kozori, Niki Petridou, Irene Tabakis, Ioulietta Lazarou, Maria Karakota, Iordanis Saoulidis, Eleni Melliou, Prokopios Magiatis
A Randomized Clinical Trial of Greek High Phenolic Early Harvest Extra Virgin Olive Oil in Mild Cognitive Impairment: The MICOIL Pilot Study
Abstract: Background: Extra virgin olive oil (EVOO) constitutes a natural compound with high protection over cognitive function. Objective: To investigate for the first time the effect of Greek High Phenolic Early Harvest Extra Virgin Olive Oil (HP-EH-EVOO) versus Moderate Phenolic (MP-EVOO) and Mediterranean Diet (MeDi) in people with mild cognitive impairment (MCI). Methods: We conducted a randomized prospective study so as to examine the HP-EH-EVOO and MP-EVOO versus MeDi in MCI. Genetic predisposition (APOE ε4) to Alzheimer’s disease (AD) was tested and an extensive neuropsychological battery was administered at baseline and after 12 months. Each participant was randomized and assigned one of three groups: 1) Group 1 received the HP-EH-EVOO (50 mL/day); 2) Group 2 received the MP-EVOO (50 mL/day), and 3) Group 3 received only the MeDi instructions. Results: Better follow-up performance was found in Group 1 compared to Group 2 and Group 3 in the almost all cognitive domains. Moreover, Group 2 showed also significant improvement compared to Group 3 in ADAS-cog (p=0.001) and MMSE (p=0.05), whereas Group 3 exhibited worse or similar to baseline performance in almost all domains. In particular, Group 1 and Group 2 had better outcomes with regards to ADAS-cog (p=0.003), Digit Span (p=0.006), and Letter fluency (p=0.003). Moreover, there was a significant difference (p=0.001) in the presence of APOΕ ε4 between the Groups 1 and 2 versus Group 3. Conclusion: Long-term intervention with HP-EH-EVOO or MP-EVOO was associated with significant improvement in cognitive function compared to MeDi, independent of the presence of APOE ε4.

Felix Menne, Carola Gertrud Schipke, Arne Klostermann, Manuel Fuentes-Casañ, Silka Dawn Freiesleben, Chris Bauer, Oliver Peters (Handling Associate Editor: Yuping Ning)
Value of Neuropsychological Tests to Identify Patients with Depressive Symptoms on the Alzheimer’s Disease Continuum
Abstract: Background: Depressive symptoms often co-occur with Alzheimer's disease (AD) and can impact neuropsychological test results. In early stages of AD, disentangling cognitive impairments due to depression from those due to neurodegeneration often poses a challenge. Objective: We aimed to identify neuropsychological tests able to detect AD-typical pathology while taking into account varying degrees of depressive symptoms. Methods: A battery of neuropsychological tests (CERAD-NP) and the Geriatric Depression Scale (GDS) were assessed, and cerebrospinal fluid (CSF) biomarkers were obtained. After stratifying patients into CSF positive or negative and into low, moderate, or high GDS score groups, sensitivity and specificity and area under the curve (AUC) were calculated for each subtest. Results: 497 participants were included in the analyses. In patients with low GDS scores (≤10), the highest AUC (0.72) was achieved by Mini-Mental State Examination, followed by Constructional Praxis Recall and Wordlist Total Recall (AUC=0.714, both). In patients with moderate (11-20) and high (≥21) GDS scores, Trail Making Test-B (TMT-B) revealed the highest AUCs with 0.77 and 0.82, respectively. Conclusion: Neuropsychological tests showing AD-typical pathology in participants with low GDS scores are in-line with previous results. In patients with higher GDS scores, TMT-B showed the best discrimination. This indicates the need to focus on executive function rather than on memory task results in depressed patients to explore a risk for AD.

Emily A. Hu, Aozhou Wu, Jennifer L. Dearborn, Rebecca F. Gottesman, A. Richey Sharrett, Lyn M. Steffen, Josef Coresh, Casey M. Rebholz (Handling Associate Editor: William Grant)
Adherence to Dietary Patterns and Risk of Incident Dementia: Findings from the Atherosclerosis Risk in Communities Study
Abstract: Background: Previous studies have suggested that adherence to healthy dietary patterns during late life may be associated with improved cognition. However, few studies have examined the association between healthy dietary patterns during midlife and incident dementia. Objective: Our study aimed to determine the association between adherence to healthy dietary patterns at midlife and incident dementia. Methods: We included 13,630 adults from the Atherosclerosis Risk in Communities (ARIC) Study in our prospective analysis. We used food frequency questionnaire responses to calculate four dietary scores: Healthy Eating Index-2015 (HEI-2015), Alternative Healthy Eating Index-2010 (AHEI-2010), alternate Mediterranean (aMed) diet, and Dietary Approaches to Stop Hypertension (DASH). Participants were followed until the end of 2017 for incident dementia. Cox regression models adjusted for covariates were used to estimate risk of incident dementia by quintile of dietary scores. Results: Over a median of 27 years, there were 2,352 cases of incident dementia documented. Compared with participants in quintile 1 of HEI-2015, participants in quintile 5 (healthiest) had a 14% lower risk of incident dementia (hazard ratio, HR: 0.86, 95% confidence interval, CI: 0.74-0.99). There were no significant associations of incident dementia with the AHEI-2010, aMed, or DASH scores. There were no significant interactions by sex, age, race, education, physical activity, hypertension, or obesity. Conclusion: Adherence to the HEI-2015, but not the other dietary scores, during midlife was associated with lower risk of incident dementia. Further research is needed to elucidate whether timing of a healthy diet may influence dementia risk.

Eman M. Khedr, Asmaa M.S. Gomaa, Omyma G. Ahmed, Hanaa M.M. Sayed, Ayman Gamea
Cognitive Impairment, P300, and Transforming Growth Factor β1 in Different Forms of Dementia
Abstract: Background: There are currently few biomarkers to assist in early diagnosis of dementias. Objective: To distinguish between different dementias: Alzheimer’s disease (AD), vascular dementia (VaD), and Parkinson’s disease dementia (PDD) using simple neurophysiologic (P300) and laboratory markers (transforming growth factor β1 “TGF-β1”). Methods: The study included 15 patients for each type of dementia and 25 age- and sex-matched control subjects. Dementia patients were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition-revised (DSM-IV-R). Modified Mini-Mental State Examination (3MS), Memory Assessment Scale (MAS), P300, and TGF-β1 were examined for each participant. Results: There were no significant differences between groups as regard to age, sex, and education, social, and economic levels. Significant differences between groups were observed in registration and naming variables of the 3MS. Compared with the control group, P300 latency was prolonged in all groups, although to a greater extent in AD and PDD than in VaD. A serum level of TGF-β1 was significantly elevated in all groups but was significantly higher in AD and VaD than in PDD. 3MS tended to correlate with P300 more than TGF-β1, and to be stronger in AD than the other groups. Conclusion: Measurements of P300 latency and serum levels of TGF-β1 can help distinguish AD, PDD, and VaD. P300 was more prolonged in AD and PDD than VaD whereas TGF-β1 was significantly higher in AD and VaD than PDD. Thus P300 and TGF-β1 may be useful biomarkers for detection and evaluation of the extent of cognitive dysfunction.

Mohamad El Haj, Philippe Allain, Cédric Annweiler, Claire Boutoleau-Bretonnière, Guillaume Chapelet, Karim Gallouj, Dimitrios Kapogiannis, Jean Roche, Abdel Halim Boudoukha
Burnout of Healthcare Workers in Acute Care Geriatric Facilities During the COVID-19 Crisis: An Online-Based Study
Abstract: Background/Objective: The COVID-19 crisis has been increasing the burden of healthcare workers in acute care geriatric facilities. These workers have been dealing with drastic changes in the care they provide to their residents including cancelation of group activities and communal dining and even restrictions of activities outside rooms. Healthcare workers have also been devoting more time and energy to perform COVID-related medical duties. Geriatric facilities have been facing shortages in equipment and supplies, as well as staffing shortages. Finally, healthcare workers have been facing challenges regarding their personal safety and that of their families. Consequently, we hypothesized the presence of high levels of burnout among healthcare workers during the COVID-19 crisis. Methods: To evaluate burnout in healthcare workers in French acute care geriatric facilities, we used an online survey based on the Oldenburg Burnout Inventory. Eighty-four healthcare workers answered the survey, during April of 2020. Results: Analysis demonstrated that they were experiencing medium levels of burnout, exhaustion, and disengagement. Conclusion: This level of burnout reflected their fatigue, loss of energy, and/or feelings of being overextended and exhausted. Considering the expected cumulative impact of various stressors, the medium level of burnout observed has come as a surprise to us and might actually be considered as relatively good news. Nevertheless, no level of burnout is negligible and has wide ranging negative consequences.

Book Review
The End of Alzheimer’s Protocol: The First Protocol to Enhance Cognition and Reverse Decline at Any Age by Dale Bredesen, Avery, 2020, 352 pp. Reviewed by Dharma Singh Khalsa, MD