Volume 68, Number 2, 2019

Pages 417-437

Tobore Onojighofia Tobore
On the Etiopathogenesis and Pathophysiology of Alzheimer’s Disease: A Comprehensive Theoretical Review
Abstract: Alzheimer's disease (AD) is the most common cause of dementia, with an estimated 5 million new cases occurring annually. Among the elderly, AD shortens life expectancy, results in disability, decreases quality of life, and ultimately, leads to institutionalization. Despite extensive research in the last few decades, its heterogeneous pathophysiology and etiopathogenesis have made it difficult to develop an effective treatment and prevention strategy. Aging is the biggest risk factor for AD and evidence suggest that the total number of older people in the population is going to increase astronomically in the next decades. Also, there is evidence that air pollution and increasing income inequality may result in higher incidence and prevalence of AD. This makes the need for a comprehensive understanding of the etiopathogenesis and pathophysiology of the disease extremely critical. In this paper, a quintuple framework of thyroid dysfunction, vitamin D deficiency, sex hormones, and mitochondria dysfunction and oxidative stress are used to provide a comprehensive description of AD etiopathogenesis and pathophysiology. The individual role of each factor, their synergistic and genetic interactions, as well as the limitations of the framework are discussed.

Pages 439-458

Nadia I. Bocai*, María S. Marcora*, Lautaro F. Belfiori-Carrasco, Laura Morelli, Eduardo M. Castaño (Handling Associate Editor: Khalid Iqbal) *These authors contributed equally to this work.
Endoplasmic Reticulum Stress in Tauopathies: Contrasting Human Brain Pathology with Cellular and Animal Models
Abstract: The accumulation and spreading of protein tau in the human brain are major features of neurodegenerative disorders known as tauopathies. In addition to several subcellular abnormalities, tau aggregation within neurons seems capable of triggering endoplasmic reticulum (ER) stress and the consequent unfolded protein response (UPR). In metazoans, full activation of a complex ER-UPR network may restore proteostasis and ER function or, if stress cannot be solved, commit cells to apoptosis. Due to these alternative outcomes (survival or death), the pharmacological manipulation of ER-UPR has become the focus of potential therapies in many human diseases, including tauopathies. Here we update and analyze the experimental data from human brain, cellular, and animal models linking tau accumulation and ER-UPR. We further discuss mechanistic aspects and put the ER-UPR into perspective as a possible therapeutic target in this group of diseases.

Pages 459-471

Alejandro R. Roda, Laia Montoliu-Gaya, Sandra Villegas
The Role of Apolipoprotein E Isoforms in Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD), the most common type of dementia worldwide, is characterized by high levels of amyloid-β (Aβ) peptide and hyperphosphorylated tau protein. Genetically, the ε4 allele of apolipoprotein E (ApoE) has been established as the major risk factor for developing late-onset AD (LOAD), the most common form of the disease. Although the role ApoE plays in AD is still not completely understood, a differential role of its isoforms has long been known. The current review compiles the involvement of ApoE isoforms in amyloid-β protein precursor transcription, Aβ aggregation and clearance, synaptic plasticity, neuroinflammation, lipid metabolism, mitochondrial function, and tau hyperphosphorylation. Due to the complexity of LOAD, an accurate description of the interdependence among all the related molecular mechanisms involved in the disease is needed for developing successful therapies.

Pages 473-481
Yoshiki Takamatsu, Gilbert Ho, Masaaki Waragai, Ryoko Wada, Shuei Sugama, Takato Takenouchi, Eliezer Masliah, Makoto Hashimoto
Transgenerational Interaction of Alzheimer’s Disease with Schizophrenia through Amyloid Evolvability
Abstract: Alzheimer’s disease (AD), the most common neurodegenerative dementia, leads to memory dysfunction due to widespread neuronal loss associated with aggregation of amyloidogenic proteins (APs), while schizophrenia (SCZ) represents a major psychiatric disorder characterized by delusions, hallucinations, and other cognitive abnormalities, the underlying mechanisms of which remain obscure. Although AD and SCZ partially overlap in terms of psychiatric symptoms and some aspects of cognitive impairment, the causal relationship between AD and SCZ is unclear. Based on the similarity of APs with yeast prion in terms of stress-induced protein aggregation, we recently proposed that evolvability of APs might be an epigenetic phenomenon to transmit stress information of parental brain to cope with the stressors in offspring. Although amyloid evolvability may be beneficial in evolution, AD might be manifested during parental aging as the mechanism of antagonistic pleiotropy phenomenon. Provided that accumulating evidence implicates stress as an important factor in SCZ, the main objective of this paper is to better understand the possible connection of AD and SCZ through amyloid evolvability. Hypothetically, the delivery of information of stress by APs may be less efficient under the decreased evolvability conditions such as disease-modifying treatment, leading to SCZ in offspring. Conversely, the increased evolvability conditions including gene mutations of APs are supposed to be beneficial for offspring, but might lead to AD in parents. Collectively, AD and SCZ might transgenerationally interfere with each other through amyloid evolvability, and this could explain why both AD and SCZ have not been selected out through evolution.

Pages 483-488

Björn Regland, Andrew McCaddon (Handling Associate Editor: Brett Garner)
Alzheimer’s Amyloidopathy: An Alternative Aspect
Abstract: The ‘amyloid hypothesis’ dominates Alzheimer’s disease (AD) research but has failed to deliver effective therapies. Amyloid precursor protein (APP) and presenilin-1 (PSEN1) genetic mutations are undoubtedly pathogenic, albeit by unclear mechanisms. Conversely, high dose B-vitamins convincingly slow brain atrophy in a pre-stage state of sporadic AD. Here we suggest a link between sporadic and genetic AD: 1) Increased serum homocysteine, a marker of B-vitamin deficiencies, is a significant risk factor for sporadic AD. It also correlates with elevated levels of antichymotrypsin, a serine protease inhibitor. 2) Family members with codon 717 APP mutations and dementia have low serum vitamin B12 values. Overexpression of the APP domain coding for a Kunitz type serine protease inhibitor might explain this. 3) PSEN1 mutations disrupt lysosomal function due to reduced proteolytic activity. They also trap cobalamin (B12) within lysosomes, leading to intracellular deficiency of the vitamin. In summary, APP and PSEN1 mutations both confer a risk for reduced protease activity and B12 bio-availability. Comparably, sporadic AD features a constellation of increased protease inhibition and B-vitamin deficiencies, the central part of which is believed to be B12. These concordant observations in three disparate AD etiologies suggest a common neuropathogenic pathway. This hypothesis is evaluable in laboratory and clinical trials.

Pages 489-492

Robert E. Becker, Nigel H Greig (Handling Associate Editor: Sultan Darvesh)
Can We Prevent Dementia and Not Prevent Neurons from Dying?
Abstract: Neuronal death is the final step in the progression of preclinical Alzheimer’s disease (AD) pathologies into clinically evident AD and its profound dementia. As such, a drug candidate proposed to be effective in AD must successfully prevent neuronal losses. The lack of preclinical demonstrated abilities to prevent neuronal programmed cell death may explain the recent failure of 300-400 AD drug candidates, identify a flaw in the Amyloid Hypothesis, and a risk for subsequent drug candidate interventions against AD. We propose that investigators use either animal models or small early translational clinical trials to test for AD drug candidates’ efficacy against clinically critical features of the disease, such as prevention of neuronal death. Such stringent testing would more effectively shelter AD patients from being recruited into clinical trials that are destined to fail in Phase II or III.

Pages 493-510

Giulia Paroni, Paola Bisceglia, Davide Seripa (Handling Associate Editor: Vincenzo Solfrizzi)
Understanding the Amyloid Hypothesis in Alzheimer’s Disease
The amyloid hypothesis (AH) is still the most accepted model to explain the pathogenesis of inherited Alzheimer’s disease (IAD). However, despite the complete neuropathological overlapping with the non-inherited form (NIAD), AH waver in explaining NIAD. Thus, 30 years after its first statement several questions are still open, mainly regarding the role of amyloid plaques (AP) and apolipoprotein E (APOE). Accordingly, a pathogenetic model including the role of AP and APOE unifying IAD and NIAD pathogenesis is still missing. In the present understanding of the AH, amyloid-β (Aβ) peptides production and AP formation are physiological aging processes resulting from a systemic age-related decrease in the efficiency of the proteins catabolism/clearance machinery. Aβ peptides also act as neurotoxic molecules, but only above a critical concentration [Aβ]c. A threshold mechanism triggers IAD/NIAD onset only when [Aβ]≥[Aβ]c. In this process, APOE modifies [Aβ]c threshold in an isoform-specific way. Consequently, all factors influencing Aβ anabolism, such as amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) gene mutations, and/or catabolism/clearance could contribute to overcoming [Aβ]c, being characteristic of each individual. In this model, AP formation does not depend on [Aβ]c. The present interpretation of the AH, unifying the pathogenetic theories for IAD and NIAD, will explain why AP and APOE4 may be observed in healthy aging and why they are not the cause of AD. It is clear that further studies are needed to confirm our pathogenetic model. Nevertheless, our suggestion may be useful to better understand the pathogenesis of AD.

Pages 511-516
Short Communication

Andrew Umstead, Irving E. Vega
Tau13 Antibody Preferentially Immunoprecipitates High Molecular Weight Tau Proteins
Abstract: The accumulation of tau protein aggregates is a pathological hallmark in Alzheimer’s disease (AD) and other neurodegenerative diseases. However, the identity of the toxic tau conformation that propagates and induces neurodegeneration is still unknown. Anti-tau antibodies are a common tool used to differentiate between normal and pathological-associated tau forms or as passive immunotherapy in the quest to interfere with tau-mediated neurodegeneration. Here, we show that Tau13, a tau N-terminal antibody, preferentially enriches high molecular weight tau species produced in a tauopathy mouse model and AD. The data suggest that Tau13 has higher affinity to specific tau conformation presence in higher molecular weight tau species.

Pages 517-521
Short Communication

Andreea M. Rawlings, A. Richey Sharrett, Thomas H. Mosley, Dean F. Wong, David S. Knopman, Rebecca F. Gottesman
Cognitive Reserve in Midlife is not associated with Amyloid-β Deposition in Late-Life
Abstract: We examined associations between cognitive reserve and late-life amyloid-β deposition using florbetapir positron emission tomography (PET). We used data from the Atherosclerosis Risk in Communities (ARIC) and ARIC-PET Study. 330 dementia-free participants underwent PET scans. Mean global cortical standardized uptake value ratio (SUVR)>1.2 was defined as elevated. Midlife cognition was significantly associated with late-life cognition, but not with late-life elevated SUVR; education was not associated with late-life SUVR, but was strongly associated with late-life cognition. Cognitive reserve may reduce dementia risk by mitigating the impact of Alzheimer’s disease pathology on the clinical expression of dementia, rather than by altering its pathogenesis.

Pages 523-529
Short Communication

Zachary A. Marcum, Sarah D. Hohl, Shelly L. Gray, Doug Barthold, Paul K. Crane, Eric B. Larson
Patient Perceptions of Antihypertensive Use as a Dementia Prevention Strategy: A Mixed-Method Analysis of a Web-Based Survey
Abstract: We administered a mixed-method survey to 1,661 patients in a large health system to assess preferences toward antihypertensive use for dementia prevention. If a specific antihypertensive medication was shown to prevent or delay dementia, the vast majority (>90%) of respondents currently taking an antihypertensive reported that they would be willing to take that specific antihypertensive starting as early as mid-life. Concerns reported were potential side effects, lack of evidence of effectiveness, blood pressure being normal or low, and medication cost. Analysis of free-text responses revealed themes of concerns regarding evidence of effectiveness and health priorities.

Pages 531-535

Pravat K. Mandal, Deepika Shukla, Manjari Tripathi, Lars Ersland
Cognitive Improvement with Glutathione Supplement in Alzheimer’s Disease: A Way Forward
Abstract: Alzheimer’s disease (AD) is a devastating neurodegenerative disorder affecting millions of people worldwide. The actual cause of AD is still unknown. Oxidative stress is believed to be important player in AD. Glutathione (GSH) is a major antioxidant, and it is already known that GSH is depleted significantly in the hippocampal regions in mild cognitive impairment and AD patients compared to healthy old subjects. Hence there is a serious discussion to improve the brain GSH level by supplementation. This editorial highlights the need for GSH supplementation for the cognitive enhancement in mild cognitive impairment and AD.

Pages 537-550
Priya Devanarayan, Viswanath Devanarayan, Daniel A. Llano, for the Alzheimer's Disease Neuroimaging Initiative
Identification of a Simple and Novel Cut-Point Based Cerebrospinal Fluid and MRI Signature for Predicting Alzheimer’s Disease Progression that Reinforces the 2018 NIA-AA Research Framework
Abstract: The 2018 NIA-AA research framework proposes a classification system with Amyloid-β deposition, pathologic Tau, and neurodegeneration (ATN) for diagnosis and staging of Alzheimer’s disease (AD). Data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database can be utilized to identify diagnostic signatures for predicting AD progression, and to determine the utility of this NIA-AA research framework. Profiles of 320 peptides from baseline cerebrospinal fluid (CSF) samples of 287 normal, mild cognitive impairment (MCI), and AD subjects followed over a 3-10-year period were measured via multiple reaction monitoring mass spectrometry. CSF Aβ42, total-Tau (tTau), phosphorylated-Tau (pTau-181), and hippocampal volume were also measured. From these candidate markers, optimal signatures with decision thresholds to separate AD and normal subjects were first identified via unbiased regression and tree-based algorithms. The best performing signature determined via cross-validation was then tested in an independent group of MCI subjects to predict future progression. This multivariate analysis yielded a simple diagnostic signature comprising CSF pTau-181 to Aβ42 ratio, MRI hippocampal volume, and low CSF levels of a novel PTPRN peptide, with a decision threshold on each marker. When applied to a separate MCI group at baseline, subjects meeting these signature criteria experience 4.3-fold faster progression to AD compared to a 2.2-fold faster progression using only conventional markers. This novel 4-marker signature represents an advance over the current diagnostics based on widely used markers, and is easier to use in practice than recently published complex signatures. This signature also reinforces the ATN construct from the 2018 NIA-AA research framework.

Pages 551-558
Jia Liu*, Qianqian Wang*, Donglai Jing, Ran Gao, Jing Zhang, Chunlei Cui, Hongwen Qiao, Zhigang Liang, Chaodong Wang, Pedro Rosa-Neto, Liyong Wu, Jianping Jia, Serge Gauthier *These authors contributed equally to this work.
Diagnostic Approach of Early-Onset Dementia with Negative Family History: Implications from Two Cases of Early-Onset Alzheimer’s Disease with de novo PSEN1 Mutation
Abstract: For early-onset Alzheimer's disease (EOAD) cases with unclear family history, most cases are sporadic. Some cases are positive in genetic findings, that is, either incomplete penetrance or de novo mutation. We aimed to focus on EOAD cases with de novo mutations. Case reports and literature review were performed. The implication for diagnostic approach of early-onset dementia with negative family history was developed. We reported two Chinese EOAD cases with de novo mutations. The genotype PSEN1 G206S appeared to correlate with the phenotype of EOAD with pure cognitive problems. The second case had a PSEN1 M233V mutation with an earlier age of onset of 25 with cognitive decline, parkinsonism, and epilepsy. Although EOAD due to de novo mutations is not common, it should be considered in patients with a phenotype of progressive cognitive decline and amyloid positivity on PET or CSF analysis.

Pages 559-569
Małgorzata Marjańska, J. Riley McCarten, James S. Hodges, Laura S. Hemmy, Melissa Terpstra (Handling Associate Editor: Marnie Shaw)
Distinctive Neurochemistry in Alzheimer’s Disease via 7 T In Vivo Magnetic Resonance Spectroscopy
Abstract: This study’s objective was to increase understanding of biological mechanisms underlying clinical Alzheimer’s disease (AD) by noninvasively measuring an expanded neurochemical profile and exploring how well this advanced technology distinguishes AD from cognitively normal controls. We measured concentrations of 14 neurochemicals using ultra-high field (7 T) ultra-short echo time (8 ms) magnetic resonance spectroscopy (MRS) in 16 participants with mild to moderate clinical AD and 33 age- and gender-matched control participants. MRS was localized to the posterior cingulate cortex (PCC), a region known to be impacted by AD, and the occipital cortex (OCC), a control region. Participants with AD were recruited from dementia specialty clinics. Concentration of the antioxidant ascorbate was higher (p < 0.0007) in both brain regions. Concentrations of the glial marker myo-inositol and the choline-containing compounds involved in membrane turnover were higher (p ≤ 0.0004) in PCC of participants with AD. Ascorbate and myo-inositol concentrations were strongly associated, especially in the PCC. Random forests, using the 14 neurochemicals in the two regions, distinguished participants with AD from controls: same-sample sensitivity and specificity were 88% and 97%, respectively, though out-of-sample-values would be lower. Ultra-high field ultra-short echo time MRS identified the co-occurrence of elevated ascorbate and myo-inositol in the PCC as markers that distinguish participants with mild to moderate AD from controls. While elevated myo-inositol may be a surrogate marker of neuroinflammation, the unexpected elevation of the antioxidant ascorbate may reflect infiltration of ascorbate-rich leukocytes.

Pages 571-582
Ann Tiiman, Vesna Jelić, Jüri Jarvet, Petter Järemo, Nenad Bogdanović, Rudolf Rigler, Lars Terenius, Astrid Gräslund, Vladana Vukojević
Amyloidogenic Nanoplaques in Blood Serum of Patients with Alzheimer’s Disease Revealed by Time-Resolved Thioflavin T Fluorescence Intensity Fluctuation Analysis
Abstract: Background: Biomarkers are central to current research on molecular mechanisms underlying Alzheimer’s disease (AD). Their further development is of paramount importance for understanding pathophysiological processes that eventually lead to disease onset. Biomarkers are also crucial for early disease detection, before clinical manifestation, and for development of new disease modifying therapies. Objective: The overall aim of this work is to develop a minimally invasive method for fast, ultra-sensitive and cost-effective detection of structurally modified peptide/protein self-assemblies in the peripheral blood and in other biological fluids. Specifically, we focus here on using this method to detect structured amyloidogenic oligomeric aggregates in the blood serum of apparently healthy individuals and patients in early AD stage, and measure their concentration and size. Methods: Time-resolved detection of Thioflavin T (ThT) fluorescence intensity fluctuations in a sub-femtoliter observation volume element was used to identify in blood serum ThT-active structured amyloidogenic oligomeric aggregates, hereafter called nanoplaques, and measure with single-particle sensitivity their concentration and size. Results: The concentration and size of structured amyloidogenic nanoplaques are significantly higher in the blood serum of individuals diagnosed with AD than in control subjects. Conclusion: A new method with the ultimate, single-particle sensitivity was successfully developed. The proposed approach neither relies on the use of immune-based probes, nor on the use of radiotracers, signal-amplification or protein separation techniques, and provides a minimally invasive test for fast and cost-effective early determination of structurally modified peptides/proteins in the peripheral blood, as shown here, but also in other biological fluids.

Pages 583-589
Josef Marksteiner, Herbert Oberacher, Christian Humpel
Acyl-Alkyl-Phosphatidlycholines Are Decreased in Saliva of Patients with Alzheimer’s Disease as Identified by Targeted Metabolomics
Abstract: Diagnosis of Alzheimer’s disease (AD) is still a challenge. Salivary analysis could produce an easily accessible and inexpensive possibility to study metabolic changes in AD. In the present pilot study, we show for the first time using targeted metabolomics that acyl-alkyl phosphatidylcholines (PCae C34:1-2; PCae C36:1-2-3; PCaeC38:1-3; PCae C40:2-3) are significantly reduced in saliva of AD patients (n=25) compared to healthy controls (n=25). Saliva levels of PCae C36:(1-2-3) were also decreased in patients with mild cognitive impairment (n=25). No changes were seen for saliva diacyl-phosphatidylcholines, lyso-acyl-phosphatidylcholines, and sphinogomyelins. These data suggest specific lipid changes in the saliva of AD patients, thus salivary measures could establish new biomarkers. However, these preliminary results have to be established in larger scale studies.

Pages 591-608
Benjamin L. Brett, Kristin Wilmoth, Peter Cummings, Gary S. Solomon, Michael A. McCrea, Scott L. Zuckerman
The Neuropathological and Clinical Diagnostic Criteria of Chronic Traumatic Encephalopathy: A Critical Examination in Relation to Other Neurodegenerative Diseases
Abstract: This work critically reviews chronic traumatic encephalopathy (CTE), with a specific focus on the single criterion necessary and sufficient for diagnosis. Herein, CTE is compared to other well-established neurodegenerative entities including Alzheimer’s disease and dementia with Lewy bodies. Each neurodegenerative disorder is reviewed in five pertinent areas: 1) historical perspective, 2) guideline formation process, 3) clinical diagnostic criteria, 4) pathological diagnostic criteria, and 5) validation of previously described diagnostic criteria (e.g., sensitivity and specificity). These comparisons indicate that CTE is a disease in the earliest stages of formation and has yet to undergo rigorous development and refinement similar to other neurodegenerative diseases. Suggested future revisions to the diagnostic criterion of CTE include establishing a lower threshold for accumulation of pathology, as well as accounting for the presence of concomitant neuropathology and comorbid neurodegenerative disorders. Currently, while initial efforts have been attempted, agreed upon antemortem clinical criteria do not exist. As has been the scientific standard with similar neurodegenerative disorders, antemortem diagnostic guidelines should first be refined through subcommittees of neuroscientists from diverse institutional backgrounds with a subclassification of levels of diagnostic certainty (possible, probably, and definite). Validation studies should then assess the predictive value and accuracy of proposed antemortem diagnostic criteria in relation to potential pathological criteria.

Pages 609-624
Kamar E. Ameen-Ali, Julie E. Simpson, Stephen B. Wharton, Paul R. Heath, Paul Sharp, Gaia Brezzo, Jason Berwick (Handling Associate Editor: Daniela Puzzo)
The Time Course of Recognition Memory Impairment and Glial Pathology in the hAPP-J20 Mouse Model of Alzheimer’s Disease
Abstract: The role of cellular changes in the neurovascular unit is increasingly being investigated to understand the pathogenesis of Alzheimer’s disease (AD). The aim of the current study was to determine the time course of recognition memory impairment in the J20 mouse model of AD, in relation to neuroinflammatory responses and the pathology of amyloid-β (Aβ). Male hAPP-J20 and wild-type mice were assessed at 3, 6, 9, and 12 months of age. The spontaneous object recognition (SOR) task provided a measure of memory, with assessment of both a short delay (1 min) and a long delay (4 h). Immunohistochemistry was used to characterize Aβ deposition, and quantify astrocyte and microglial responses. At all ages tested, J20 mice had impaired long-term, but preserved short-term, recognition memory. Wild-types demonstrated preserved long-term memory up to 9 months of age, and preserved short-term memory at all ages tested. Plaque pathology in the J20 mice was present from 6 months onwards, with co-localization of reactive microglia and activated astrocytes. Reactive microglia and astrocyte activation in the hippocampus were significantly greater in the J20 mice at 9 months, compared to wild-types. This study contributes to our understanding of the pathological and cognitive mechanisms at play in AD. J20 mice showed impairment in retaining information over longer periods from an early age, preceding the deposition of Aβ and glial activation. Defining early physiological changes in relation to cognitive decline could provide insight into new therapeutic targets early in the disease process, when intervention is most likely to effectively slow disease progression.

Pages 625-633
Erin L. Abner, Peter T. Nelson, Gregory A. Jicha, Gregory E. Cooper, David W. Fardo, Frederick A Schmitt, Richard J. Kryscio (Handling Associate Editor: André Karch)
Tobacco Smoking and Dementia in a Kentucky Cohort: A Competing Risk Analysis
Abstract: Tobacco smoking was examined as a risk for dementia and neuropathological burden in 531 initially cognitively normal older adults followed longitudinally at the University of Kentucky’s Alzheimer’s Disease Center. The cohort was followed for an average of 11.5 years; 111 (20.9%) participants were diagnosed with dementia, while 242 (45.6%) died without dementia. At baseline, 49 (9.2%) participants reported current smoking (median pack-years=47.3) and 231 (43.5%) former smoking (median pack-years=24.5). The hazard ratio (HR) for dementia for former smokers versus never smokers based on the Cox model was 1.64 (95% CI: 1.09, 2.46), while the HR for current smokers versus never smokers was 1.20 (0.50, 2.87). However, the Fine-Gray model, which accounts for the competing risk of death without dementia, yielded a subdistribution hazard ratio (sHR)=1.21 (0.81, 1.80) for former and 0.70 (0.30, 1.64) for current smokers. In contrast, current smoking increased incidence of death without dementia (sHR=2.38; 1.52, 3.72). All analyses were adjusted for baseline age, education, sex, diabetes, head injury, hypertension, overweight, APOE ε4, family history of dementia, and use of hormone replacement therapy. Once adjusted for the competing risk of death without dementia, smoking was not associated with incident dementia. This finding was supported by neuropathology on 302 of the participants.

Pages 635-646
Anika Kaczynski, Bernhard Michalowsky, Tilly Eichler, Jochen René Thyrian, Diana Wucherer, Ina Zwingmann, Wolfgang Hoffmann (Handling Associate Editor: Sophie Vandepitte)
Comorbidity in Dementia Diseases and Associated Health Care Resources Utilization and Cost
Abstract: Background: People with dementia (PwD) suffer from coexisting medical conditions, creating complex clinical challenges and increasing the risk of poor outcomes, which could be associated with high healthcare cost. Objective: To describe the prevalence of comorbidity in PwD and to analyze the association between comorbidity in dementia diseases and healthcare costs from a payer’s perspective. Methods: This cross-sectional analysis was based on n=362 PwD of the DelpHi-MV trial (Dementia: Life-and person-centered help in Mecklenburg-Western Pomerania). Comorbidity was assessed using the Charlson comorbidity index (CCI) and was categorized into low, high, and very high comorbidity. Healthcare resource utilization and unit costs were used to calculate costs. Multivariable regression models were applied to analyze the association between comorbidity and costs. Results: Comorbidity was highly prevalent in the sample. 47% of PwD had a very high, 37% a high, and 16% a low comorbidity in addition to dementia. The most prevalent co-existing comorbidity were diabetes mellitus (42%), peripheral vascular disease (28%) and cerebrovascular disease (25%). Total costs significantly increased by 528€ (SE=214, CI95=109-947, p=0.014) with each further comorbidity, especially due to higher cost for medication and medical aids. Compared with a low comorbidity, a very high comorbidity was significantly associated with 818€ (SE=168, CI95=489-1147, p<0.001) higher medication costs and 336€ (SE=161, CI95=20-652, p=0.037) higher cost for medical aids. There were no significant association between a higher comorbidity and cost for formal care services. Conclusions: Comorbidity in PwD represents a substantial financial burden on healthcare payers and is a challenge for patients, healthcare providers, and the health systems. Innovative approaches are needed to achieve a patient-oriented management of treatment and care in comorbid PwD to reduce long-term costs.

Pages 647-655
Cecilia S. Lee, Eric B. Larson, Laura E. Gibbons, Caitlin S. Latimer, Shannon E. Rose, Leanne L. Hellstern, C. Dirk Keene, Paul K. Crane for the Adult Changes in Thought (ACT) Study
Ophthalmology-Based Neuropathology Risk Factors: Diabetic Retinopathy Is Associated with Deep Microinfarcts in a Community-Based Autopsy Study
Abstract: Background: The aging eye offers unique opportunities to study and understand the aging brain, in particular related to Alzheimer’s disease (AD) and dementia. However, little is known about relationships between eye diseases and dementia-related neurodegeneration. Objective: To determine the potential association between three age-related eye diseases and AD and dementia-related neuropathology. Methods: We reviewed autopsy data from the prospective longitudinal Adult Changes in Thought (ACT) cohort. ICD-9 codes were used to identify diagnoses of diabetic retinopathy, glaucoma, and age-related macular degeneration. Multivariate regression models were used to determine odds ratios (OR) of neuropathology features associated with dementia, including Braak stage, Consortium to Establish a Registry for AD (CERAD score), Lewy bodies, hippocampal sclerosis, and microvascular brain injury, in addition to quantitative paired helical filament (PHF)-tau levels for people with and without each eye condition. We also evaluated interactions between eye conditions and dementia related neuropathologic findings were evaluated. Results: 676 autopsies were included. Diabetic retinopathy was significantly associated with increased risk of deep cerebral microinfarcts (OR=1.91 [95% confidence interval (CI) 1.11, 3.27], p=0.02). No other significant association or interaction between eye diseases and neuropathology was found. When PHF-tau quantity was evaluated in 124 decedents, the OR for the association between PHF-tau in the occipital cortex and glaucoma was 1.36 (95% CI 0.91, 2.03, p=0.13). No statistical correction was made for multiple comparisons. Conclusion: Increased risk of deep cerebral microinfarcts was found in participants diagnosed with diabetic retinopathy. Eye diseases such as glaucoma may increase susceptibility to neurofibrillary tangles in the occipital cortex.

Pages 657-668
Suzanne M. de la Monte, Ming Tong, Lori A. Daiello, Brian R. Ott
Early-Stage Alzheimer’s Disease Is Associated with Simultaneous Systemic and Central Nervous System Dysregulation of Insulin-Linked Metabolic Pathways
Abstract: Background: Brain insulin resistance is a well-recognized abnormality in Alzheimer’s disease (AD) and the likely mediator of impaired glucose utilization that emerges early and progresses with disease severity. Moreover, the rates of mild cognitive impairment (MCI) or AD are significantly greater in people with diabetes mellitus or obesity. Objective: This study was designed to determine whether systemic and central nervous system (CNS) insulin resistant disease states emerge together and thus may be integrally related. Methods: Insulin-related molecules were measured in paired human serum and cerebrospinal fluid (CSF) samples from 19 with MCI or early AD, and 21 controls using a multiplex ELISA platform. Results: In MCI/AD, both the CSF and serum samples had significantly elevated mean levels of C-peptide and an incretin, and reduced expression of Visfatin, whereas only CSF showed significant reductions in insulin and leptin and only serum had increased glucagon, PAI-1, and ghrelin. Although the overall CSF and serum responses reflected insulin resistance together with insulin deficiency, the specific alterations measured in CSF and serum were different. Conclusion: In MCI and early-stage AD, CNS and systemic insulin-related metabolic dysfunctions, including insulin resistance, occur simultaneously, suggesting that they are integrally related and possibly mediated similar pathogenic factors.

Pages 669-678
Paula Villela Nunes, Monise Caroline Schwarzer, Renata Elaine Paraizo Leite, Renata Eloah de Lucena Ferretti-Rebustini, Carlos Augusto Pasqualucci, Ricardo Nitrini, Roberta Diehl Rodriguez, Camila Fernandes Nascimento, Katia Cristina de Oliveiraa Lea Tenenholz Grinberg, Wilson Jacob-Filho, Beny Lafer, Claudia Kimie Suemoto (Handling Associate Editor: Paulo Caramelli)
Neuropsychiatric Inventory in Community-Dwelling Older Adults with Mild Cognitive Impairment and Dementia
Abstract: Background: Behavioral and psychological symptoms (BPSD) can be a prodrome of dementia, and the Neuropsychiatric Inventory (NPI) is widely used for BPSD evaluation. Objective: To compare the prevalence of BPSD according to cognitive status, and to determine NPI cutoffs that best discern individuals with mild cognitive impairment (MCI) and dementia from those without dementia. Methods: We included 1,565 participants (mean age=72.7±12.2 years, 48% male). BPSD and cognitive status were assessed with the NPI and the Clinical Dementia Rating (CDR). We used multivariable logistic regression models to investigate the association of BPSD with cognitive status. The area under the curve (AUC) was used to assess model discrimination, and to determine the best NPI cutoff for MCI and dementia. Results: Participants were cognitively normal (CDR=0; n=1,062), MCI (CDR=0.5; n=145), or dementia (CDR≥1.0, n=358). NPI symptoms were more frequent in dementia and MCI when compared to cognitively normal. Higher odds for delusions, hallucinations, disinhibition, and psychomotor alterations were found among participants with dementia and MCI than in those who were cognitively normal. The best NPI cutoff to discern participants with dementia from those cognitively normal was 11 (AUC=0.755). Poor discrimination (AUC=0.563) was found for the comparison of MCI and those cognitively normal. Conclusions: We found an increase in BPSD frequencies across the continuum of cognitive impairment. BPSD severity and frequency in MCI was more similar to individuals cognitively normal than with dementia. NPI scores ≥ to 11 in individuals with no diagnosis of dementia can support the decision for further investigation of dementia.

Pages 679-693
Maddaena Boccia*, Antonella Di Vita*, Sofia Diana, Roberta Margiotta, Letizia Imbriano, Lidia Rendace, Alessandra Campanelli, Fabrizia D’Antonio, Alessandro Trebbastoni, Carlo de Lena, Laura Piccardi, Cecilia Guariglia * These authors contributed equally to this work.
Is Losing One’s Way a Sign of Cognitive Decay? Topographical Memory Deficit as an Early Marker of Pathological Aging
Abstract: Spatial navigation tasks reveal small differences between normal and pathological aging and may thus disclose potential neuropsychological predictors of neurodegenerative diseases. The aim of our study was to investigate which navigational skills are compromised in the early phase of pathological aging as well as the extent to which they are compromised. We performed an extensive neuropsychological evaluation based on working memory and learning tasks (i.e., Corsi Block-Tapping Test and Walking Corsi Test) involving both reaching and navigational vista spaces. We also assessed spatial navigation skills in the real world by asking participants to perform route-learning and landmark-recognition tasks. We conducted a cross-sectional study on nineteen patients with a diagnosis of mild cognitive impairment (MCI) who displayed either an isolated memory deficit (single-domain amnestic MCI, MCIsd; N=3) or a memory deficit associated with deficits in other cognitive functions (multi-domain MCI, MCImd; N=16) as well as on nineteen healthy control participants. The groups’ performances were compared by means of mixed factorial ANOVA and two-sample t-tests. We found that patients with MCI performed worse than controls, especially when they were required to learn spatial positions within the navigational vista space. Route-learning within the real environment was also impaired whereas landmark-recognition was spared. The same pattern of results emerged in the MCImd subgroup. Moreover, single case analyses on MCIsd patients revealed a dissociation between learning of spatial positions within navigational vista space and within reaching space. These results suggest that topographical learning is compromised in the early phase of MCIsd and MCImd and that spatial navigation tasks may be used to better characterize topographical disorientation in MCI patients as well as for the early diagnosis of pathological aging.

Pages 695-710
Maximilian Strunz, Juliet T. Jarrell, David S. Cohen, Eric R. Rosin, Charles R. Vanderburg, Xudong Huang
Modulation of SPARC/Hevin Proteins in Alzheimer’s Disease Brain Injury
Abstract: Alzheimer’s disease (AD) is an age-related progressive form of dementia that features neuronal loss, intracellular tau, and extracellular amyloid-β (Aβ) protein deposition. Neurodegeneration is accompanied by neuroinflammation mainly involving microglia, the resident innate immune cell population of the brain. During AD progression, microglia shift their phenotype, and it has been suggested that they express matricellular proteins such as secreted protein acidic and rich in cysteine (SPARC) and Hevin protein, which facilitate the migration of other immune cells, such as blood-derived dendritic cells. We have detected both SPARC and Hevin in postmortem AD brain tissues and confirmed significant alterations in transcript expression using real-time qPCR. We suggest that an infiltration of myeloid-derived immune cells occurs in the areas of diseased tissue. SPARC is highly expressed in AD brain and collocates to Aβ protein deposits, thus contributing actively to cerebral inflammation and subsequent tissue repair, and Hevin may be downregulated in the diseased state. However, further research is needed to reveal the exact roles of SPARC and Hevin proteins and associated signaling pathways in AD-related neuroinflammation. Nevertheless, normalizing SPARC/Hevin protein expression such as interdicting heightened SPARC protein expression may confer a novel therapeutic opportunity for modulating AD progression.

Pages 711-722
Laure Ngabirano, Cecilia Samieri, Catherine Feart, Audrey Gabelle, Sylvaine Artero, Claire Duflos, Claudine Berr, Thibault Mura (Handling Associate Editor: Francesco Panza)
Intake of Meat, Fish, Fruits, and Vegetables and Long-Term Risk of Dementia and Alzheimer’s Disease
Abstract: Background: The links between diet and the risk of dementia have never been studied considering the possibility of protopathic bias (i.e., reverse causation). Objective: We aimed to examine the relationship between consumption frequency of meat, fish, fruits, and vegetables and long-term risk of dementia and Alzheimer’s disease (AD), by taking into account this possibility. Methods: We analyzed data of 5,934 volunteers aged 65 and over from the Three-city study who were followed every 2 to 4 years for 12 years. Dietary habits were assessed at inclusion using a brief food frequency questionnaire. The presence of symptoms of dementia was investigated at each follow-up visit. To limit the risk of protopathic bias, a 4-year lag window between exposure and disease assessment was implemented by excluding from the analyses all dementia cases that occurred during the first four years after inclusion. Analyses were performed using a Cox proportional hazard model and were adjusted for socio-demographic, lifestyle, and health factors. Results: The average follow-up time was 9.8 years. During this period, 662 cases of dementia, including 466 of AD, were identified. After adjustment, only low meat consumption (≤1 time/week) was associated with an increased risk of dementia and AD compared with regular consumption (≥4 times/week) (HR=1.58 95%CI=[1.17-2.14], HR=1.67 95%CI=[1.18-2.37], respectively). No association was found between the consumption of fish, raw fruits, or cooked fruits and vegetables and the risk of dementia or AD. Conclusion: These findings suggest very low meat consumption increases the long-term risk of dementia and AD, and that a protopathic bias could have impacted finding from previous studies.

Pages 723-733
Samir Abu-Rumeileh, Giulia Giannini, Barbara Polischi, Luca Albini-Riccioli, David Milletti, Federico Oppi, Michelangelo Stanzani-Maserati, Sabina Capellari, Paolo Mantovani, Giorgio Palandri, Pietro Cortelli, Sabina Cevoli, Piero Parchi
Revisiting the Cerebrospinal Fluid Biomarker Profile in Idiopathic Normal Pressure Hydrocephalus: The Bologna Pro-Hydro Study
Abstract: Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in idiopathic normal pressure hydrocephalus (iNPH) with the aim of a better differential diagnosis, but the pathophysiological mechanisms underlying CSF biomarker changes and the relationship between biomarker levels and clinical variables are still a matter of debate. We evaluated CSF amyloid-β (Aβ)42 and Aβ40, total(t)-tau, phosphorylated(p)-tau, total prion protein (t-PrP), and neurofilament light chain protein (NfL) in healthy controls (n=50) and subjects with iNPH (n=71), Alzheimer’s disease (AD) (n=60), and several other subtypes of dementia (n=145). Patients with iNPH showed significantly lower levels of Aβ42, Aβ40, t-tau, and p-tau compared to controls. Similarly, t-PrP values showed a trend toward lower levels in iNPH patients than in controls. At variance, NfL levels were increased in iNPH as in all other neurodegenerative dementias, with no significant difference between “pure” iNPH cases and those with vascular or AD comorbidities. The Aβ42/Aβ40 ratio showed higher diagnostic value than Aβ42 alone in the differential diagnosis between iNPH and AD. There were no clinically relevant associations between neuroimaging markers, scores at clinical and cognitive scales/tests, or rates of response at tap test and CSF biomarker results. In summary, the CSF biomarker signature in patients with iNPH is mainly characterized by reduced CSF concentrations of Aβ- and tau-related proteins. The assessment of CSF neurodegenerative biomarker profile in iNPH, including the Aβ42/Aβ40 ratio, contributes to the differential diagnosis with AD and other dementias but shows poor associations with clinical variables.

Pages 735-744
Madoka Nakajima, Nagato Kuriyama, Masakazu Miyajima, Ikuko Ogino, Chihiro Akiba, Kaito Kawamura, Michiko Kurosawa, Yoshiyuki Watanabe, Wakaba Fukushima, Etsuro Mori, Takeo Kato, Hidenori Sugano, Yuichi Tange, Kostadin Karagiozov, Hajime Arai
Background Risk Factors Associated with Shunt Intervention for Possible Idiopathic Normal Pressure Hydrocephalus: A Nationwide Hospital-Based Survey in Japan
Abstract: Background: Patients with idiopathic normal-pressure hydrocephalus (iNPH) are typically older adults with multiple comorbidities that are associated with a reduction in the efficacy of iNPH treatment via cerebrospinal fluid (CSF) shunt placement. Objective: The present study aimed to investigate the effectiveness of CSF shunt for iNPH using data from a nationwide epidemiological survey in Japan. Methods: We examined 1,423 patients (581 women) aged ≥60 years (median age [25%-75%]: 77 [73–80] years) who were diagnosed with iNPH following a hospital visit in 2012. Patients who experienced an improvement of at least one modified Rankin Scale (mRS) grade after the CSF shunt were classified as “improvement” while the remaining patients were classified as “non-improvement.” The efficacy of the shunt intervention (n = 842) was analyzed using a binomial logistic regression analysis. Results: An analysis of risk factors associated with shunt placement in patients with mRS grade 2 at study entry revealed an association between comorbid chronic ischemic lesions (odds ratio [OR], 2.28; 95% confidence interval [CI], 1.11–4.67; p = 0.025) and cervical spondylosis (OR, 3.62; 95% CI, 1.15–11.34; p = 0.027). Patients with mRS grade 3 at study entry had an association with comorbid Alzheimer’s disease (OR, 3.02; 95%CI, 1.44–6.31; p = 0.003). Conclusions: The results presented here showed that any age-related risk is minimal and should not be cause for rejection of surgical treatment options. Clinical decisions regarding CSF shunt should be individualized to each patient, with adequate consideration of the relative risks and benefits, including maximizing a healthy life expectancy.

Pages 745-755
Johanna Nordheim, Andreas Häusler, Sevil Yasar, Ralf Suhr, Adelheid Kuhlmey, Michael Rapp, Paul Gellert (Handling Associate Editor: Steffen Wolfsgruber)
Psychosocial Intervention in Couples Coping with Dementia Led by a Psychotherapist and Social Worker: The DYADEM Trial
Abstract: Background: Psychosocial interventions may improve the quality of life of both people with dementia (PWD) and their family caregivers. However, research is inconclusive and focused primarily on the quality of life of either the PWD or the caregiver, rather than on both. Objective: Our aim was to evaluate the effect of couple-based interdisciplinary psychosocial intervention in patients with mild-to-moderate dementia on quality of life of both partners. Methods: 108 community-dwelling PWD and their caregiving partners were enrolled in this pragmatic randomized controlled trial. The intervention consisted of 7 sessions at participants’ homes led by a psychotherapist and a social worker. Quality of life was evaluated at baseline, one, and six-month follow-up for patients and their partners. Mixed effects models have been applied. Results: Intervention allocation was not associated with an improvement in quality of life in either the patients or their partners. In subgroup analyses, intervention was negatively associated with caregiver performance. However, this was only present in those reporting poor relationship quality. Patients in the intervention group who reported good relationship quality were found to have decreased cognitive decline. Conclusion: A couple-based interdisciplinary intervention did not yield improvements in quality of life. This may be the result of a bias caused by an increased awareness due to the intervention. Relationship quality and support in the long-term should be considered when designing and implementing interventions for PWD and their partners.

Pages 757-766
Ya-Juan Wang, Yu Wan, Hui-Fu Wang, Chen-Chen Tan, Jie-Qiong Li, Jin-Tai Yu, Lan Tan, Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Yong Liu)
Effects of CD33 Variants on Neuroimaging Biomarkers in Non-Demented Elders
Abstract: Two CD33 common variants, rs3826656 and rs3865444, have been identified to be correlated with Alzheimer’s disease (AD). Our study examined the effects of the two AD-related CD33 common variants (rs3826656 and rs3865444) on the chosen AD-related brain regions (including hippocampus, amygdala, parahippocampus, middle temporal, entorhinal cortex, and total brain volume) in non-demented elders recruited from the Alzheimer’s Disease Neuroimaging Initiative database at baseline and during four-year follow-up. We further tested the effects in an Aβ-positive group (including preclinical and prodromal stage of AD) and an Aβ-negative group. In the total non-demented elderly population, no associations reached significant levels after FDR correction. In the Aβ-positive group, we found that rs3826656 was associated with hippocampal and amygdala volumes (Hippocampus-R: pc=0.0022; Amygdala-L: pc=0.0044; Amygdala-R: pc=0.0066), and rs3865444 was associated with right entorhinal volume (pc=0.0286). The associations of rs3826656 with hippocampal and amygdala volumes in the Aβ-positive group were successfully replicated in the prodromal AD group (Hippocampus-R: pc=0.0022; Amygdala-L: pc=0.0022; Amygdala-R: pc=0.0088). These changes became more obvious over time during four-year follow-up. No associations were found between the two CD33 variants and neuroimaging biomarkers in the Aβ-negative and preclinical AD groups after FDR correction. These results suggested that the two CD33 common variants (rs3826656 and rs3865444) influenced volumes and atrophy rates of AD-related brain regions in non-demented elders. Subgroup analyses showed the effects mainly existed in the Aβ-positive group instead of the Aβ-negative group, and the effects began in the prodromal AD stage.

Pages 767-775
Madeleine E. Hackney, Lauren E. McCullough, Allison A. Bay, Hayley A. Silverstein, Ariel R. Hart, Ryan J. Shin, Whitney Wharton
Rationale and Design of a Clinical Trial of Adapted Tango to Improve Negative Health Impacts in Middle Aged African-American Female Caregivers of Persons with Alzheimer’s Disease (ACT Trial)
Abstract: Alzheimer’s disease (AD) is a devastating progressive neurodegenerative disease resulting in memory loss and a severe reduction in ability to perform activities of daily living. The role of caring for someone with AD frequently falls to female family members, often daughters. The burden of caregiving can increase stress and anxiety and cause health decline in the caregiver. The combination of ethnicity-related genetic factors promoting the development of dementias among African-Americans (AA) and the increased risk among women for developing AD means that AA women who are caregivers of a parent with AD are at great risk for developing dementias including AD. The proposed study would compare the cognitive, motor, and psychosocial benefits of a well-established 12 week, 20-lesson adapted Argentine Tango intervention (N=30) to a no-contact control group (N=10) in middle-aged (45-65 years) AA women who are caregivers of a parent with AD in the metro Atlanta area.

Pages 777-788
Kenichiro Sato, Tatsuo Mano, Ryoko Ihara, Kazushi Suzuki, Naoki Tomita, Hiroyuki Arai, Kenji Ishii, Michio Senda, Kengo Ito, Takeshi Ikeuchi, Ryozo Kuwano, Hiroshi Matsuda, Takeshi Iwatsubo, Tatsushi Toda, Atsushi Iwata, Alzheimer's Disease Neuroimaging Initiative, and Japanese Alzheimer's Disease Neuroimaging Initiative
Lower Serum Calcium as a Potentially Associated Factor for Conversion of Mild Cognitive Impairment to Early Alzheimer’s Disease in the Japanese Alzheimer’s Disease Neuroimaging Initiative
Abstract: Background: Effect of serum calcium level to the incidence of mild cognitive impairment (MCI) conversion to early Alzheimer’s disease (AD) remains uncertain. Objective: To investigate association between baseline serum calcium and the MCI conversion in the Japanese Alzheimer’s Disease Neuroimaging Initiative (J-ADNI) study cohort. Methods: In this sub-analysis of J-ADNI study, we reviewed data from MCI participants at baseline regarding their conversion to early AD during the 3 years of observation period and assessed the associated factors including serum calcium level. In addition, we compared our results from the J-ADNI study with the corresponding results from the North American (NA)-ADNI. Results: Of 234 eligible MCI participants from the J-ADNI cohort, 121 (51.7%) converted to AD during the first 36 months of observation. Using univariate analysis, being female, having shorter years of education, and lower serum calcium level were correlated with increased risk of MCI-to-AD conversion exclusively in J-ADNI cohort. The lower corrected serum calcium level remained as one of conversion-associated factors in the J-ADNI cohort even after adjustment for multiple confounding variables, although this was not observed in the NA-ADNI cohort. Conclusion: Our findings suggest that lower serum calcium may be associated with an increased risk of MCI conversion to AD in Japanese cohorts. The reason for this correlation remains unclear and further external validation using other Asian cohorts is needed. It would be interesting for future AD studies to obtain serum calcium levels and other related factors, such as vitamin D levels, culture-specific dietary or medication information.

Pages 789-796
Anna Damulina, Lukas Pirpamer, Stephan Seiler, Thomas Benke, Peter Dal-Bianco, Gerhard Ransmayr, Walter Struhal, Edith Hofer, Christian Langkammer, Marco Duering, Franz Fazekas, Reinhold Schmidt
White Matter Hyperintensities in Alzheimer’s Disease: A Lesion Probability Mapping Study
Abstract: Background/Objective: Higher white matter hyperintensity (WMH) load has been reported in Alzheimer’s disease (AD) patients in different brain regions when compared to controls. We aimed to assess possible differences of WMH spatial distribution between AD patients and age-matched controls by means of lesion probability maps. Methods: The present study included MRI scans of 130 probable AD patients with a mean age of 73.4±8.2 years from the Prospective Dementia Registry Austria Study and 130 age-matched healthy controls (HC) from the Austrian Stroke Prevention Family Study. Risk factors such as hypertension, diabetes mellitus, hypercholesterolemia, coronary artery disease, and smoking were assessed. Manually segmented FLAIR WMH masks were non-linearly registered to a template and voxel-based probability mapping was performed. Results: There were no significant between group differences in cardiovascular risk factors and WMH volume. AD patients showed a significantly higher likelihood of having WMH in a bilateral periventricular distribution than controls before and after correcting for age, sex, cardiovascular risk factors, and ventricular volume (p≤0.05; threshold-free cluster enhancement corrected). There was no significant association between the periventricular WMH volume and cognitive decline of AD patients. Conclusion: In AD, WMH were preferentially found in a periventricular location but the volume of lesions was unrelated to cognitive decline in our study irrespective of lesion location.

Pages 797-808
Hiroo Kasahara, Masaki Ikeda, Kazuaki Nagashima, Yukio Fujita, Kouki Makioka, Setsuki Tsukagoshi, Tsuneo Yamazaki, Eriko Takai, Etsuko Sanada, Ayumi Kobayashi, Kazuhiro Kishi, Takayuki Suto, Tetsuya Higuchi, Yoshito Tsushima, Yoshio Ikeda
Deep White Matter Lesions Are Associated with Early Recognition of Dementia in Alzheimer’s Disease
Abstract: Neuroimages of cerebral amyloid-β (Aβ) accumulation and small vessel disease (SVD) were examined in patients with various types of cognitive disorders using 11C-labeled Pittsburgh Compound B-positron emission tomography (PiB-PET) and magnetic resonance imaging (MRI). The mean cortical standardized uptake value ratio (mcSUVR) was applied for a quantitative analysis of PiB-PET data. The severity of white matter lesions (WML) and enlarged perivascular spaces (EPVS) on MRI were assessed to evaluate complicating cerebral SVD using semiquantitative scales. In homozygous apolipoprotein E ε3/ε3 carriers, the incidence of more severe WML and EPVS was higher in PiB-positive than PiB-negative patients, indicating that WML and EPVS might be associated with enhanced Aβ accumulation. An association study between PiB-PET and MRI findings revealed that higher WML grades significantly correlate with lower mcSUVRs, especially in the frontal area, indicating that more severe ischemic MRI findings are associated with milder Aβ accumulation among patients with Alzheimer’s disease. In these patients SVD may accelerate the occurrence of cognitive decline and facilitate early recognition of dementia.

Pages 809-837
Chelsea M. Griffith, Lauren N. Macklin, Yan Cai, Andrew A. Sharp, Xiao-Xin Yan, Lawrence P. Reagan, April D. Strader, Gregory M. Rose, Peter R. Patrylo
Impaired Glucose Tolerance and Reduced Plasma Insulin Precede Decreased AKT Phosphorylation and GLUT3 Translocation in the Hippocampus of Old 3xTg-AD Mice
Abstract: Several studies have demonstrated that mouse models of Alzheimer’s disease (AD) can exhibit impaired peripheral glucose tolerance. Further, in the APP/PS1 mouse model, this is observed prior to the appearance of AD-related neuropathology (e.g., amyloid-β plaques; Aβ) or cognitive impairment. In the current study, we examined whether impaired glucose tolerance also preceded AD-like changes in the triple transgenic model of AD (3xTg-AD). Glucose tolerance testing (GTT), insulin ELISAs, and insulin tolerance testing (ITT) were performed at ages prior to (1-3 months and 6-8 months old) and post-pathology (16-18 months old). Additionally, we examined for altered insulin signaling in the hippocampus. Western blots were used to evaluate the two-primary insulin signaling pathways: PI3K/AKT and MAPK/ERK. Since the PI3K/AKT pathway affects several downstream targets associated with metabolism (e.g., GSK3, glucose transporters), western blots were used to examine possible alterations in the expression, translocation, or activation of these targets. We found that 3xTg-AD mice display impaired glucose tolerance as early as 1 month of age, concomitant with a decrease in plasma insulin levels well prior to the detection of plaques (~14 months old), aggregates of hyperphosphorylated tau (~18 months old), and cognitive decline (≥18 months old). These alterations in peripheral metabolism were seen at all time points examined. In comparison, PI3K/AKT, but not MAPK/ERK, signaling was altered in the hippocampus only in 18-20-month-old 3xTg-AD mice, a time point at which there was a reduction in GLUT3 translocation to the plasma membrane. Taken together, our results provide further evidence that disruptions in energy metabolism may represent a foundational step in the development of AD.