Pages 865-880
Review
Viola Luca Nemeth, Anita Must, Szatmar Horvath, Andras Király, Zsigmond Tamas Kincses, Laszlo Vecsei
Gender-Specific Degeneration of Dementia-Related Subcortical Structures Throughout the Lifespan
Abstract: Age-related changes in brain structure are a question of interest to a broad field of research. Structural decline has been consistently, but not unambiguously, linked to functional consequences, including cognitive impairment and dementia. One of the areas considered of crucial importance throughout this process is the medial temporal lobe, and primarily the hippocampal region. Gender also has a considerable effect on volume deterioration of subcortical grey matter (GM) structures, such as the hippocampus. The influence of age x gender interaction on disproportionate GM volume changes might be mediated by hormonal effects on the brain. Hippocampal volume loss appears to become accelerated in the postmenopausal period. This decline might have significant influences on neuroplasticity in the CA1 region of the hippocampus highly vulnerable to pathological influences. Additionally, menopause has been associated with critical pathobiochemical changes involved in neurodegeneration. The micro- and macrostructural alterations and consequent functional deterioration of critical hippocampal regions might result in clinical cognitive impairment—especially if there already is a decline in the cognitive reserve capacity. Several lines of potential vulnerability factors appear to interact in the menopausal period eventually leading to cognitive decline, mild cognitive impairment, or Alzheimer’s disease. This focused review aims to delineate the influence of unmodifiable risk factors of neurodegenerative processes, i.e., age and gender, on critical subcortical GM structures in the light of brain derived estrogen effects. The menopausal period appears to be of key importance for the risk of cognitive decline representing a time of special vulnerability for molecular, structural, and functional influences and offering only a narrow window for potential protective effects.
Pages 881-892
Hypothesis
Silvia Serino, Giuseppe Riva
The Proactive Self in Space: How Egocentric and Allocentric Spatial Impairments Contribute to Anosognosia in Alzheimer’s Disease
Abstract: In addition to impairments in episodic and spatial memory, anosognosia (i.e., loss of awareness of the deficient aspect of own cognitive functioning) may be considered an important cognitive marker of Alzheimer's disease (AD). However, although a growing body of interesting models have been proposed to explain this early symptom, what is still missing is a unifying framework of all the characteristic signs occurring in patients with AD that may guide the search for its causal neuropathological process and, ultimately, the etiological process. This contribution will first show how anosognosia may be related to the above-mentioned episodic and spatial memory impairment through a unifying framework of all these characteristic signs, i.e., the continuous interaction between different spatial representations. Second, we hypothesize that a break in the interaction between different spatial representations, as we suggest occurs in AD, may contribute significantly both to the early impairments in spatial and episodic memory, and to a deficient self-awareness since it may interfere with the capacity of the brain to detect predictive errors.
Pages 893-897
Short Communication
Frank J. Wolters*, Daniel Bos*, Meike W. Vernooij, Oscar H. Franco, The Heart-Brain Connection collaborative research group, Albert Hofman, Peter J. Koudstaal, Aad van der Lugt, M. Arfan Ikram *These authors contributed equally to this manuscript.
Aortic Valve Calcification and the Risk of dementia: A Population-Based Study
Abstract: The association of aortic valve calcification (AVC) with dementia remains unknown. In 2,428 non-demented participants from the population-based Rotterdam Study, we investigated the association of CT-assessed AVC with risk of dementia and cognitive decline. AVC was present in 33.1% of the population. During a median follow-up of 9.3 years, 160 participants developed dementia. We found no association between presence of AVC and risk of all-cause dementia [hazard ratio (HR): 0.89 (95% confidence interval (CI):0.63;1.26)]. Presence of AVC was not associated with cognitive decline on any of the cognitive tests, nor with a measure of global cognition.
Pages 899-903
Short Communication
Jose Enrique de la Rubia Ortí, Sandra Sancho Castillo, Maria Benlloch, Mariano Julián Rochina, Silvia Corchón Arreche, María Pilar García Pardo
Impact of the Relationship of Stress and the Immune System in the Appearance of Alzheimer’s Disease
Abstract: The understanding of how the immune system works, as well as its relationship with the stress level, seems to be important at the start of Alzheimer’s disease (AD). To analyze this, immunoglobulin A (IgA) and cortisol in saliva were measured using ELISA in patients with mild AD and healthy volunteers, and the production of both biomarkers was compared and correlated. In participants without AD, IgA was higher when cortisol was lower, and the opposite happened in participants with AD, with the quantification in saliva being a suitable method to determine it.
Pages 905-913
Moeko Noguchi-Shinohara, Junji Komatsu, Miharu Samuraki, Ichiro Matsunari, Tokuhei Ikeda, Kenji Sakai, Tsuyoshi Hamaguchi, Kenjiro Ono, Hiroyuki Nakamura, Masahito Yamada (Handling Associate Editor: Robert Friedland)
Cerebral Amyloid Angiopathy-Related Microbleeds and Cerebrospinal Fluid Biomarkers in Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) commonly accompanies cerebral amyloid angiopathy (CAA). Objective: We aimed to reveal associations between CAA-related brain microbleeds and cerebrospinal fluid (CSF) markers in AD patients. Methods: Patients with probable AD (n = 88) from consecutive patients in our memory clinic were evaluated for patient demographics, vascular risk factors, neuropsychological tests, apolipoprotein E phenotype, MRI including T2*-weighted image and fluid attenuated inversion recovery sequence, and CSF amyloid and tau markers. Results: The 88 patients with AD included 15 with microbleeds only in cortical/subcortical regions (cortical microbleeds) that could be CAA-related, 16 with microbleeds only in deep locations (deep microbleeds), 3 with microbleeds in both cortical and deep locations (mixed microbleeds), and 54 without microbleeds. The CSF levels of amyloid β-protein 1-40 (Aβ40) and amyloid β-protein 1-42 (Aβ42) were significantly lower in patients with cortical microbleeds than in those without microbleeds (p = 0.001 and p = 0.027, respectively). The result remained unchanged after adjustment for age, sex, apolipoprotein E E4 presence, and leukoaraiosis. Conclusions: CAA-related cortical microbleeds would be associated with lower CSF levels of Aβ40 and Aβ42 in AD, reflecting the deposition of both Aβ40 and Aβ42 in the cerebrovasculature.
Pages 915-932
Isaura V.A. Martins, Jack Rivers-Auty, Stuart M. Allan, Catherine B. Lawrence (Handling Associate Editor: Paula Moreira)
Mitochondrial Abnormalities and Synaptic Loss Underlie Memory Deficits Seen in Mouse Models of Obesity and Alzheimer’s Disease
Abstract: Obesity is associated with impaired memory in humans, and obesity induced by high-fat diets leads to cognitive deficits in rodents and in mouse models of Alzheimer’s disease (AD). However, it remains unclear how high-fat diets contribute to memory impairment. Therefore, we tested the effect of a high-fat diet on memory in male and female control non-transgenic (Non-Tg) and triple-transgenic AD (3xTgAD) mice and determined if a high-fat diet caused similar ultrastructural abnormalities to those observed in AD. Behavior was assessed in mice on control or high-fat diet at 4, 8, or 14 months of age and ultrastructural analysis at 8 months of age. A high-fat diet increased body weight, fat weight, and insulin levels with some differences in these metabolic responses observed between Non-Tg and 3xTgAD mice. In both sexes, high-fat feeding caused memory impairments in Non-Tg mice and accelerated memory deficits in 3xTgAD mice. In 3xTgAD mice, changes in hippocampal mitochondrial morphology were observed in capillaries and brain neuropil that were accompanied by a reduction in synapse number. A high-fat diet also caused mitochondria abnormalities and a reduction in synapse number in Non-Tg mice, but did not exacerbate the changes seen in 3xTgAD mice. Our data demonstrate that a high-fat diet affected memory in Non-Tg mice and produced similar impairments in mitochondrial morphology and synapse number comparable to those seen in AD mice, suggesting that the detrimental effects of a high-fat diet on memory might be due to changes in mitochondrial morphology leading to a reduction in synaptic number.
Pages 933-949
Hannah L. Golden*, Camilla N. Clark*, Jennifer M. Nicholas, Miriam H. Cohen, Catherine F. Slattery, Ross W. Paterson, Alexander J.M. Foulkes, Jonathan M. Schott, Catherine J. Mummery, Sebastian J. Crutch, Jason D. Warren (Handling Associate Editor: Teppo Särkämö) *These authors contributed equally to this work.
Music Perception in Dementia
Abstract: Despite much recent interest in music and dementia, music perception has not been widely studied across dementia syndromes using an information processing approach. Here we addressed this issue in a cohort of 30 patients representing major dementia syndromes of typical Alzheimer’s disease (AD, n=16), logopenic aphasia (LPA, an Alzheimer variant syndrome; n=5), and progressive nonfluent aphasia (PNFA; n=9) in relation to 19 healthy age-matched individuals. We designed a novel neuropsychological battery to assess perception of musical patterns in the dimensions of pitch and temporal information (requiring detection of notes that deviated from the established pattern based on local or global sequence features) and musical scene analysis (requiring detection of a familiar tune within polyphonic harmony). Performance on these tests was referenced to generic auditory (timbral) deviance detection and recognition of familiar tunes and adjusted for general auditory working memory performance. Relative to healthy controls, patients with AD and LPA had group-level deficits of global pitch (melody contour) processing while patients with PNFA as a group had deficits of local (interval) as well as global pitch processing. There was substantial individual variation within syndromic groups. No specific deficits of musical temporal processing, timbre processing, musical scene analysis, or tune recognition were identified. The findings suggest that particular aspects of music perception such as pitch pattern analysis may open a window on the processing of information streams in major dementia syndromes. The potential selectivity of musical deficits for particular dementia syndromes and particular dimensions of processing warrants further systematic investigation.
Pages 951-964
Martina Pařízková, Ross Andel, Ondřej Lerch, Hana Marková, Ivana Gažová, Martin Vyhnálek, Jakub Hort, Jan Laczó (Handling Associate Editor: Thomas Benke)
Homocysteine and Real-Space Navigation Performance among Non-Demented Older Adults
Abstract: Background: High plasma homocysteine (Hcy) level is related to higher risk of Alzheimer’s disease (AD) and lower cognitive performance in older adults. Objective: To assess the association between plasma Hcy level and real-space navigation performance and the role of vascular risk and protective factors, APOE status, and white matter lesions (WML) on this association. Methods: Ninety-two non-demented older adults (29 with amnestic mild cognitive impairment, 46 with subjective cognitive decline, and 17 cognitively normal older adults) underwent spatial navigation testing of egocentric, allocentric, and mixed navigation in a real-space analogue of the Morris water maze, neuropsychological examination, blood collection, and MRI brain scan with evaluation of WML. Results: In the regression analyses controlling for age, gender, education, and depressive symptoms, higher plasma Hcy level was related to worse mixed and egocentric (β=0.31; p=0.003 and β=0.23; p=0.017) but not allocentric (p>0.05) navigation performance. Additional controlling for vascular risk and protective factors, WML, and APOE status did not modify the results. High total cholesterol and low vitamin B12 and folate levels increased the adverse effect of Hcy on egocentric and mixed navigation. WML did not explain the association between plasma Hcy level and navigation performance. Conclusion: Elevated plasma Hcy level may affect real-space navigation performance above and beyond vascular brain changes. This association may be magnified in the presence of high total cholesterol and low folate or vitamin B12 levels. Attention to the level of plasma Hcy may be a viable intervention strategy to prevent decline in spatial navigation in non-demented older adults.
Pages 965-971
Olivier Beauchet, Cyrille P. Launay, Julia. Chabot, Elise J. Levinoff, Gilles Allali (Handling Associate Editor: Miguel Gago)
Subjective Memory Impairment and Gait Variability in Cognitively Healthy Individuals: Results from a Cross-Sectional Pilot Study
Abstract: Background. Increased stride time variability has been associated with memory impairment in mild cognitive impairment. Subjective memory impairment (SMI) is considered the earliest clinical stage of Alzheimer’s disease (AD). The association between increased stride time variability and SMI has not been reported. Objective. This study aims to examine the association of stride time variability while performing single and dual tasking with SMI in cognitively healthy individuals (CHI). Methods. A total of 126 CHI (15 without SMI, 69 with SMI expressed by participants, 10 with SMI expressed by participant’s relative, and 32 with SMI expressed by both participants and their relatives) were included in this cross-sectional study. The coefficient of variation (CoV) of stride time and walking speed were recorded under usual condition and while counting backwards. Age, gender, body mass index, number of drugs taken daily, use of psychoactive drugs, fear of falling, history of previous falls, and walking speed were used as covariates. Results. The multiple linear regression models showed that CoV of stride time while counting backwards, but not while single tasking, was associated with a participant’s relative SMI (p=0.038). Conclusion. This study found a specific association between SMI expressed by a participant’s relative and a greater CoV of stride time (i.e., worse performance) while dual tasking, suggesting that the association between gait variability and memory may be present in the earliest stages of memory impairment. Thus, gait variability under dual-task in individuals with SMI expressed by their relatives can be a potential biomarker of AD.
Pages 973-979
Apostolos Papazacharias*, Madia Lozupone*, Maria Rosaria Barulli, Rosa Capozzo, Bruno P. Imbimbo, Federica Veneziani, Roberto De Blasi, Marcello Nardini, Davide Seripa, Francesco Panza, Giancarlo Logroscino (Handling Associate Editor: M. Cristina Polidori) *These authors contributed equally to this work.
Bipolar Disorder and Frontotemporal Dementia: An Intriguing Association
Abstract: Bipolar disorder (BD) could represent a prodromal state of frontotemporal dementia (FTD). Two patients affected by lifelong BD with a progressive decline of cognitive functions, behavioral, and neurological signs, reached the early diagnosis of FTD before the age of 60. They were diagnosed as affected by primary progressive aphasia and FTD with parkinsonism, respectively. A diagnosis of FTD should therefore be taken into account, in case of unexpected cognitive and behavioral decline in patients with a long history of BD. Follow-up studies with genetic, neuropsychological, and neuroimaging markers of these BD/FTD patients could further explore some of the underlying association, opening new viable therapeutic options.
Pages 981-993
Jennifer Andreotti, Thomas Dierks, Lars-Olof Wahlund, Matthias Grieder (Handling Associate Editor: Claudio Babiloni)
Diverging Progression of Network Disruption and Atrophy in Alzheimer’s Disease and Semantic Dementia
Abstract: The progression of cognitive deficits in Alzheimer’s disease and semantic dementia is accompanied by grey matter atrophy and white matter deterioration. The impact of neuronal loss on the structural network connectivity in these dementia subtypes is, however, not well understood. In order to gain a more refined knowledge of the topological organization of white matter alterations in dementia, we used a network-based approach to analyze the brain’s structural connectivity network. Diffusion-weighted and anatomical MRI images of groups with eighteen Alzheimer’s disease and six semantic dementia patients, as well as twenty-one healthy controls were recorded to reconstruct individual connectivity networks. Additionally, voxel-based morphometry, using grey and white matter volume, served to relate atrophy to altered structural connectivity. The analyses showed that Alzheimer’s disease is characterized by decreased connectivity strength in various cortical regions. An overlap with grey matter loss was found only in the inferior frontal and superior temporal areas. In semantic dementia, significantly reduced network strength was found in the temporal lobes, which converged with grey and white matter atrophy. Therefore, this study demonstrated that the structural disconnection in early Alzheimer’s disease goes beyond grey matter atrophy and is independent of white matter volume loss, an observation that was not found in semantic dementia.
Pages 995-1003
Tiina Laiterä*, Jussi Paananen*, Seppo Helisalmi, Timo Sarajärvi, Joel Huovinen, Marjo Laitinen, Tuomas Rauramaa, Irina Alafuzoff, Anne M. Remes, Hilkka Soininen, Annakaisa Haapasalo, Juha E. Jääskeläinen, Ville Leinonen*, Mikko Hiltunen* *These authors contributed equally to this work.
Effects of Alzheimer’s Disease-Associated Risk Loci on Amyloid-β Accumulation in the Brain of Idiopathic Normal Pressure Hydrocephalus Patients
Abstract: Background: Idiopathic normal pressure hydrocephalus (iNPH) is a dementing condition featuring characteristic symptoms, ventriculomegaly, and normal or slightly elevated cerebrospinal fluid pressure. In Alzheimer’s disease (AD) patients, diffuse aggregates of amyloid-β (Aβ) and neurofibrillary hyperphosphorylated tau are detected in the neocortex of the brain, while similar accumulation of Aβ is also detected in iNPH. Recent genome-wide association studies have identified several novel risk loci for AD, potentially affecting Aβ-related cellular processes. Apart from the apolipoprotein E ε4 allele (APOE4), the risk effect of single loci is low, emphasizing the importance of the polygenic risk score approach when assessing the combined effects. Objective: To study the effects of AD-associated individual and polygenic risk score of single nucleotide polymorphisms (SNPs) on the accumulation of Aβ in the brain samples of iNPH patients. Methods: A sample set of frontal cortex biopsies from 188 iNPH patients were divided into two groups according to the Aβ pathology. After the genotyping of the AD-associated risk loci, polygenic risk score was calculated for each iNPH patient and subsequently analyzed in relation to Aβ deposition. Results: Apart from the APOE4, none of the SNPs revealed a statistically significant effect on the accumulation of Aβ in iNPH. Also, the non-APOE4 polygenic risk score did not associate with Aβ deposition. Conclusion: Novel AD-associated risk genes have no significant effect on Aβ accumulation in the brain of iNPH patients. However, APOE4 affects the Aβ deposition in the brain of iNPH and AD patients in a similar manner.
Pages 1005-1017
Lucia Crispoltoni, Anna Maria Stabile, Alessandra Pistilli, Massimo Venturelli, Giuliano Cerulli, Cristina Fonte, Nicola Smania, Federico Schena, Mario Rende (Handling Associate Editor: Elliott Mufson)
Changes in Plasma β-NGF and Its Receptors Expression on Peripheral Blood Monocytes During Alzheimer’s Disease Progression
Abstract: Alzheimer’s disease (AD), the most common cause of dementia, is characterized by the deposition of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles, and by neuroinflammation. During the pathogenesis of AD, monocyte-macrophage lineage cells become increasingly ineffective in clearing Aβ deposits, less able to differentiate, and shift toward pro-inflammatory processes. Beta-nerve growth factor (β-NGF) and its receptors, TrKA and p75NTR, produce several biological responses, including cell apoptosis and survival, and inflammation. In the central nervous system, the involvement of these receptors in several critical hallmarks of AD is well known, but their role in circulating monocytes during the progression of dementia is unclear. We investigated the relationship between plasma β-NGF concentration and TrkA/p75NTR receptor expression in monocytes of patients with mild cognitive impairment (MCI), mild AD, and severe AD. We observed that plasma β-NGF concentration was increased with a higher expression of TrKA, but not of p75NTR, in monocytes from patients with MCI and mild AD, whereas β-NGF concentration and TrKA expression were decreased and p75NTR expression was increased, associated with caspase 3-mediated apoptosis, in patients with severe AD. In our study, we show evidence of variation in plasmatic β-NGF and monocytic TrkA/p75NTR receptor expression during the progression of dementia. These novel findings add evidence to support the hypothesis for the involvement of β-NGF and its receptors on monocytes during AD progression.
Pages 1019-1029
Kamini Krishnan, Mary M. Machulda, Jennifer L. Whitwell, Alissa M. Butts, Joseph R. Duffy, Edythe A. Strand, Matthew L. Senjem, Anthony J. Spychalla, Clifford R. Jack Jr., Val J. Lowe, Keith A. Josephs (Handling Associate Editor: Cristian Leyton)
Varying Degrees of Temporoparietal Hypometabolism on FDG-PET Reveal Amyloid-Positive Logopenic Primary Progressive Aphasia is not a Homogeneous Clinical Entity
Abstract: Background: The logopenic variant of primary progressive aphasia (lvPPA) manifests due to a breakdown of the language network with prominent hypometabolism of the left temporoparietal region. LvPPA is strongly associated with amyloid deposition, yet there is question as to whether it is a homogeneous clinical entity. Objective: This study investigated whether differences in temporoparietal metabolic patterns on 18F fludeoxyglucose positron emission tomography (FDG-PET) could elucidate brain regions preferentially affected in lvPPA. Method: We used differences in FDG-PET metabolic z-scores relative to controls for means of left lateral temporal, inferior parietal, and superior parietal regions to classify 53 amyloid-positive lvPPA patients into temporal, parietal, or temporoparietal predominate groups. Clinical features and FDG-PET regions of hypometabolism outside of the temporoparietal region were then compared across the three groups; the latter using statistical parametric mapping. Results: Of the 53 lvPPA patients, 15 were classified as temporal, 14 as temporoparietal, and 22 as parietal predominate. There were no significant differences between the groups on demographic measures, language evaluation, or apolipoprotein E genotype. Compared to the other two groups, individuals with the parietal predominate pattern had extensive hypometabolism in left frontal lobe and the precuneus. Furthermore, this group had greater behavioral dyscontrol and deficits in executive function, visuospatial skills, visual memory retention, working memory, and cognitive flexibility (Bonferroni p < 0.05). Conclusions: This study demonstrates that there is clinical heterogeneity within amyloid-positive lvPPA. Patients with lvPPA with predominant parietal hypometabolism, unlike those with temporal or temporoparietal predominant hypometabolism, demonstrated widespread cognitive and behavioral changes.
Pages 1031-1038
Zhiqian Tong*, Weishan Wang*, Wenhong Luo*, Jihui Lv*, Hui Li, Hongjun Luo, Jianping Jia, Rongqiao He (Handling Associate Editor: Jing Zhang) *These authors contributed equally to this work.
Urine Formaldehyde Predicts Cognitive Impairment in Post-Stroke Dementia and Alzheimer’s Disease
Abstract: Although Alzheimer’s disease (AD) was first described over 100 years ago, there is still no suitable biomarker for diagnosing AD in easily collectable samples (e.g., blood plasma, saliva, and urine). Here, we investigated the relationship between morning urine formaldehyde concentration and cognitive impairment in patients with post-stroke dementia (PSD) or AD in this cross-sectional survey for 7 years. Cognitive abilities of the study participants (n = 577, four groups: 231 controls, 61 stroke, 65 PSD, and 220 AD) were assessed by Mini-Mental State Examination (MMSE). Morning urine formaldehyde concentrations were measured by high performance liquid chromatography (HPLC). Gender- and age-matched participants were selected from the four groups (n = 42 in each group). Both semicarbazide-sensitive amine oxidase (SSAO, a formaldehyde-generating enzyme) and formaldehyde levels in the blood and urine were analyzed by using an enzyme-linked immunosorbent assay (ELISA) and HPLC, respectively. We found that morning urine formaldehyde levels were inversely correlated with MMSE scores. The threshold value (the best Cut-Off value) of formaldehyde concentration for predicting cognitive impairment was 0.0418 mM in patients with PSD (Sensitivity: 92.3%; Specificity: 77.1%), and 0.0449 mM in patients with AD (Sensitivity: 94.1%; Specificity: 81.8%), respectively. The results of biochemical analysis revealed that the observed increase in urine formaldehyde resulted from an overexpression of SSAO in the blood. The findings suggest that measuring the concentration of formaldehyde in overnight fasting urine could be used as a potentially noninvasive method for evaluating the likelihood of ensuing cognitive impairment or dementia.
Pages 1039-1053
Gvido Cebers, Robert C. Alexander, Samantha Budd Haeberlein, David Han, Ronald Goldwater, Larry Ereshefsky, Tina Olsson, Naidong Ye, Laura Rosen, Muir Russell, Justine Maltby, Susanna Eketjäll, Alan R. Kugler
AZD3293: Pharmacokinetic and Pharmacodynamic Effects in Healthy Subjects and Patients with Alzheimer’s Disease
Abstract: AZD3293 (LY3314814) is a promising new potentially disease-modifying BACE1 (β-secretase) inhibitor in Phase III clinical development for the treatment of Alzheimer’s disease. Reported here are the first two Phase I studies: (1) a single ascending dose study evaluating doses of 1-750 mg with a food-effect component (n=72), and (2) a 2-week multiple ascending dose study evaluating doses of 15 or 50 mg once daily (QD) or 70 mg once weekly (QW) in elderly subjects (Part 1, n=31), and 15, 50, or 150 mg QD in patients with mild to moderate Alzheimer’s disease (Part 2, n=16). AZD3293 was generally well tolerated up to the highest doses given. No notable food effects were observed. PK following multiple doses (Part 2) were tmax of 1 to 3 h and mean t1/2 of 16 to 21 h across the 15 to 150 mg dose range. For single doses of ≥5 mg, a ≥70% reduction was observed in mean plasma Aβ40 and Aβ42 concentrations, with prolonged suppression for up to 3 weeks at the highest dose level studied. Following multiple doses, robust reductions in plasma (≥64% at 15 mg and ≥78% at ≥50 mg) and cerebrospinal fluid (≥51% at 15 mg and ≥76% at ≥50 mg) Aβ peptides were seen, including prolonged suppression even with a QW dosing regimen. AZD3293 is the only BACE1 inhibitor for which prolonged suppression of plasma Aβ with a QW dosing schedule has been reported. Two Phase III studies of AZD3293 (AMARANTH, NCT02245737; and DAYBREAK-ALZ, NCT02783573) are now ongoing.
Pages 1055-1067
Timo Pekkala, Anette Hall, Jyrki Lötjönen, Jussi Mattila, Hilkka Soininen, Tiia Ngandu, Tiina Laatikainen, Miia Kivipelto, Alina Solomon
Development of a Late-Life Dementia Prediction Index with Supervised Machine Learning in the Population-Based CAIDE Study
Abstract: Background and objective: This study aimed to develop a late-life dementia prediction model using a novel validated supervised machine learning method, the Disease State Index (DSI), in the Finnish population-based CAIDE study. Methods: The CAIDE study was based on previous population-based midlife surveys. CAIDE participants were re-examined twice in late-life, and the first late-life re-examination was used as baseline for the present study. The main study population included 709 cognitively normal subjects at first re-examination who returned to the second re-examination up to 10 years later (incident dementia n=39). An extended population (n=1009, incident dementia 151) included non-participants/non-survivors (national registers data). DSI was used to develop a dementia index based on first re-examination assessments. Performance in predicting dementia was assessed as area under the ROC curve (AUC). Results: AUCs for DSI were 0.79 and 0.75 for main and extended populations. Included predictors were cognition, vascular factors, age, subjective memory complaints, and APOE genotype. Conclusion: The supervised machine learning method performed well in identifying comprehensive profiles for predicting dementia development up to 10 years later. DSI could thus be useful for identifying individuals who are most at risk and may benefit from dementia prevention interventions.
Pages 1069-1082
Prashanthi Vemuri, David S. Knopman, Clifford R. Jack Jr., Emily S. Lundt, Stephen D. Weigand, Samantha M. Zuk, Kaely B. Thostenson, Robert I. Reid, Kejal Kantarci, Yelena Slinin, Kamakshi Lakshminarayan, Cynthia S. Davey, Anne M. Murray
Association of Kidney Function Biomarkers with Brain MRI Findings: The BRINK Study
Abstract: Background: Chronic kidney disease (CKD) studies have reported variable prevalence of brain pathologies, in part due to low inclusion of participants with moderate to severe CKD. Objective: To measure the association between kidney function biomarkers and brain MRI findings in CKD. Methods: In the BRINK (BRain IN Kidney Disease) study, MRI was used to measure gray matter volumes, cerebrovascular pathologies (white matter hyperintensity (WMH), infarctions, microhemorrhages), and microstructural changes using diffusion tensor imaging (DTI). We performed regression analyses with estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR) as primary predictors, and joint models that included both predictors, adjusted for vascular risk factors. Results: We obtained 240 baseline MRI scans (150 CKD with eGFR < 45 in ml/min/1.73 m2; 16 mild CKD: eGFR 45-59; 74 controls: eGFR ≥ 60). Lower eGFR was associated with greater WMH burden, increased odds of cortical infarctions, and worsening diffusion changes throughout the brain. In eGFR models adjusted for UACR, only cortical infarction associations persisted. However, after adjusting for eGFR, higher UACR provided additional information related to temporal lobe atrophy, increased WMH, and whole brain microstructural changes as measured by increased DTI mean diffusivity. Conclusions: Biomarkers of kidney disease (eGFR and UACR) were associated with MRI brain changes, even after accounting for vascular risk factors. UACR adds unique additional information to eGFR regarding brain structural and diffusion biomarkers. There was a greater impact of kidney function biomarkers on cerebrovascular pathologies and microstructural brain changes, suggesting that cerebrovascular etiology may be the primary driver of cognitive impairment in CKD.
Pages 1083-1099
Ashley N. Nilson*, Kelsey C. English*, Julia E. Gerson, T. Barton Whittle, C. Nicolas Crain, Judy Xue, Urmi Sengupta, Diana L. Castillo-Carranza, Wenbo Zhang, Praveena Gupta, Rakez Kayed *These authors contributed equally to this work.
Tau Oligomers Associate with Inflammation in the Brain and Retina of Tauopathy Mice and in Neurodegenerative Diseases
Abstract: It is well-established that inflammation plays an important role in Alzheimer’s disease (AD) and frontotemporal lobar dementia (FTLD). Inflammation and synapse loss occur in disease prior to the formation of larger aggregates, but the contribution of tau to inflammation has not yet been thoroughly investigated. Tau pathologically aggregates to form large fibrillar structures known as tangles. However, evidence suggests that smaller soluble aggregates, called oligomers, are the most toxic species and form prior to tangles. Furthermore, tau oligomers can spread to neighboring cells and between anatomically connected brain regions. In addition, recent evidence suggests that inspecting the retina may be a window to brain pathology. We hypothesized that there is a relationship between tau oligomers and inflammation, which are hallmarks of early disease. We conducted immunofluorescence and biochemical analyses on tauopathy mice, FTLD, and AD subjects. We showed that oligomers co-localize with astrocytes, microglia, and HMGB1, a pro-inflammatory cytokine. Additionally, we show that tau oligomers are present in the retina and are associated with inflammatory cells suggesting that the retina may be a valid non-invasive biomarker for brain pathology. These results suggest that there may be a toxic relationship between tau oligomers and inflammation. Therefore, the ability of tau oligomers to spread may initiate a feed-forward cycle in which tau oligomers induce inflammation, leading to neuronal damage, and thus more inflammation. Further mechanistic studies are warranted in order to understand this relationship, which may have critical implications for improving the treatment of tauopathies.
Pages 1101-1108
Xianbo Zhuang, Yanxiu Chen, Xianpeng Zhuang, Tao Xing, Tuanzhi Chen, Guisheng Jiang, Xiafeng Yang
Impaired Center-Surround Suppression in Patients with Alzheimer’s Disease
Abstract: Alzheimer's disease (AD) is often associated with declined visual processing abilities. Here we tested whether the functions of center-surround suppression—a hallmark property in the visual system—are altered by AD. To this end, we recruited three groups of participants (AD, elderly, and young) in a motion direction discrimination task, in which we measured the temporal duration threshold of a drifting Gabor with varying stimulus sizes. We first replicated the phenomena of center-surround suppression that the required duration for discriminating a high contrast grating decreases with increasing stimulus size. We then showed that the magnitudes of suppression varied among the three groups. There was progressive reduction of suppression in the elderly and AD groups compared with the young group. Interestingly, we found that the levels of suppression can predict the severity of dementia in the AD group. Our results suggest that AD is associated with impaired center-surround functions in the visual motion processing pathway.
Pages 1109-1121
Maria Anderson, Feng Xu, Ming-Hsuan Ou-Yang, Judianne Davis, William E. Van Nostrand, John K. Robinson
Intensive ‘Brain Training’ Intervention Fails to Reduce Amyloid Pathologies or Cognitive Deficits in Transgenic Mouse Models of Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is the leading cause of dementia in the elderly. Amyloid-β protein (Aβ) depositions in both the brain parenchyma and the cerebral vasculature are recognized as important pathological components that contribute to the cognitive impairments found in individuals with AD. Because pharmacological options have been minimally effective in treating cognitive impairment to date, interest in the development of preventative lifestyle intervention strategies has increased in the field. One controversial strategy, cognitive-specific stimulation, has been studied previously in human participants and has been widely commercialized in the form of ‘brain-training games.’ In the present study, we developed a highly controlled, isolated cognitive training intervention program for mice. Two transgenic mouse lines, one that develops Aβ deposition largely in brain parenchyma, and another in the cerebral microvasculature, progressed through a series of domain-specific tasks for an average of 4 months. Despite the high intensity and duration of the intervention, we found little evidence of positive benefits for AD amyloid pathologies and post-training cognitive testing in these two models. Taken together, these results support the current evidence in human studies that cognitive-specific stimulation does not lead to a measurable reduction in AD pathology or an improvement in general brain health.
Pages 1123-1130
Katherine Amy Lin, Colin Rundel, P. Murali Doraiswamy, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Pankaj Mehta)
Serum SHBG Levels are not Associated with Longitudinal Cognitive Decline in Mild Cognitive Impairment
Abstract: Background: Prior studies have noted gender differences in cognition, imaging, and pathological markers in mild cognitive impairment (MCI) subjects. Sex hormone-binding globulin (SHBG), a major controlling factor in the proportion of bioavailable versus bound testosterone and estrogen, has been proposed to contribute to links between hormones and dementia, but has not yet been investigated fully in a prospective biomarker trial. Objective: This study examined whether, among subjects with MCI, SHBG levels predict future rate of cognitive decline. Methods: We examine the effect of gender on cognitive decline and factors modulating potential gender differences in 378 MCI subjects (134 females, 244 males) in the Alzheimer's Disease Neuroimaging Initiative-1 (ADNI-1), followed for up to 8 years (mean + SE, 4.0 ± 0.1 years). Cognition was assessed using the ADAS-Cog-11. Multivariate models examined the effect of gender covarying for age, ApoE4, baseline cognition, years of education, and SHBG levels. Results: MCI women declined significantly faster than men in cognition over follow up period. Baseline SHBG levels differed significantly between men and women (p < 0.0001), and by age in men, but not by ApoE4 status. In the multivariate models, SHBG levels were not a significant predictor of cognitive decline in men or women but ApoE4 status, baseline cognition, years of education, and female gender were. Conclusion: SHBG levels did not influence the rate of cognitive decline in MCI. Further studies to confirm these findings and uncover other potential mechanisms of gender differences in the risk for AD may be warranted.
Pages 1131-1139
Jeffrey Cummings, Philip Scheltens, Ian McKeith, Rafael Blesa, John E. Harrison, Paulo H.F. Bertolucci, Kenneth Rockwood, David Wilkinson, Wouter Wijker, David A. Bennett, Raj C. Shah
Effect Size Analyses of Souvenaid in Patients with Alzheimer’s Disease
Abstract: Background: Souvenaid® (uridine monophosphate, docosahexaenoic acid, eicosapentaenoic acid, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium), was developed to support the formation and function of neuronal membranes. Objective: To determine effect sizes observed in clinical trials of Souvenaid and to calculate the number needed to treat to show benefit or harm. Methods: Data from all three reported randomized controlled trials of Souvenaid in Alzheimer’s disease (AD) dementia (Souvenir I, Souvenir II, and S-Connect) and an open-label extension study were included in analyses of effect size for cognitive, functional, and behavioral outcomes. Effect size was determined by calculating Cohen’s d statistic (or Cramér’s V method for nominal data), number needed to treat and number needed to harm. Statistical calculations were performed for the intent-to-treat populations. Results: In patients with mild AD, effect sizes were 0.21 (95% confidence intervals: ‒0.06, 0.49) for the primary outcome in Souvenir II (neuropsychological test battery memory z-score) and 0.20 (0.10, 0.34) for the co-primary outcome of Souvenir I (Wechsler memory scale delayed recall). No effect was shown on cognition in patients with mild-to-moderate AD (S-Connect). The number needed to treat (6 and 21 for Souvenir I and II, respectively) and high number needed to harm values indicate a favorable harm:benefit ratio for Souvenaid versus control in patients with mild AD. Conclusions: The favorable safety profile and impact on outcome measures converge to corroborate the putative mode of action and demonstrate that Souvenaid can achieve clinically detectable effects in patients with early AD.
Pages 1141-1154
Marion T. Turnbull, Elizabeth J. Coulson (Handling Associate Editor: Antonino Cattaneo)
Cholinergic Basal Forebrain Lesion Decreases Neurotrophin Signaling without Affecting Tau Hyperphosphorylation in Genetically Susceptible Mice
Abstract: Alzheimer’s disease (AD) is a progressive, irreversible neurodegenerative disease that destroys memory and cognitive function. Aggregates of hyperphosphorylated tau protein are a prominent feature in the brain of patients with AD, and are a major contributor to neuronal toxicity and disease progression. However, the factors that initiate the toxic cascade that results in tau hyperphosphorylation in sporadic AD are unknown. Here we investigated whether degeneration of basal forebrain cholinergic neurons (BFCNs) and/or a resultant decrease in neurotrophin signaling cause aberrant tau hyperphosphorylation. Our results reveal that the loss of BFCNs in pre-symptomatic pR5 (P301L) tau transgenic mice results in a decrease in hippocampal brain-derived neurotrophic factor levels and reduced TrkB receptor activation. However, there was no exacerbation of the levels of phosphorylated tau or its aggregation in the hippocampus of susceptible mice. Furthermore the animals’ performance in a hippocampal-dependent learning and memory task was unaltered, and no changes in hippocampal synaptic markers were observed. This suggests that tau pathology is likely to be regulated independently of BFCN degeneration and the corresponding decrease in hippocampal neurotrophin levels, although these features may still contribute to disease etiology.
Pages 1155-1166
Stephen Beesley, James Olcese, Charles Saunders, Ewa A. Bienkiewicz (Handling Associate Editor: Whitney Wharton)
Combinatorial Treatment Effects in a Cell Culture Model of Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is the leading cause of dementia, and as its prevalence increases, so does its detrimental impact on society. The currently available therapies have limited efficacy, leaving AD patients on an irrevocably fatal path of this disease. Objective: The purpose of this study was to test efficacy of a novel combinatorial treatment approach to alleviate AD-like pathology. Methods: We selected four naturally occurring compounds and used them in different combinations to test their effect on AD-like pathology. Employing a well-established cell culture AD model system, we evaluated levels of several diverse biomarkers associated with a number of cellular pathways associated with AD. The readouts included: amyloid-β peptides, anti-inflammatory and anti-apoptotic proteins, oxidative enzymes, and reactive oxygen species. Results: Using this approach, we demonstrated that the compounds delivered in combination had higher efficacy than individual treatments. Specifically, we observed significant reduction in levels of the amyloid-β peptides, as well as pro-inflammatory proteins and reactive oxygen species. Similarly, delivery of compounds in combination resulted in an increased expression of anti-apoptotic proteins and anti-oxidative enzymes. Collectively, these modifications in AD pathology biomarkers reflect a promising therapeutic and preventive strategy to combat this disease. Conclusion: The above findings support a novel therapeutic approach to address a currently unmet medical need, which would benefit not only AD patients and their caregivers, but also society as a whole.
Pages 1167-1174
Liina Kuuluvainen, Minna Pöyhönen, Petra Pasanen, Maija Siitonen, Jaana Rummukainen, Pentti J. Tienari, Anders Paetau, Liisa Myllykangas
A Novel Loss-Of-Function GRN Mutation p.(Tyr229*): Clinical and Neuropathological Features
Abstract: Mutations in the progranulin (GRN) gene represent about 5-10% of frontotemporal lobar degeneration (FTLD). We describe a proband with a novel GRN mutation c.687T>A, p.(Tyr229*), presenting with dyspraxia, dysgraphia, and dysphasia at the age of 60 and a very severe FTLD neuropathological phenotype with TDP43 inclusions. The nephew of the proband had signs of dementia and personality changes at the age of 60 and showed similar but milder FTLD pathology. Three other family members had had early-onset dementia. Gene expression studies showed decreased GRN gene expression in mutation carriers’ blood samples. In conclusion, we describe a novel GRN, p.(Tyr229*) mutation, resulting in haploinsufficiency of GRN and a severe neuropathologic FTLD phenotype.
Pages 1175-1182
Moonhee Lee, Jian-Ping Guo, Krista Kennedy, Edith G. McGeer, Patrick L. McGeer
A Method for Diagnosing Alzheimer’s Disease Based on Salivary Amyloid-β Protein 42 Levels
Abstract: We have developed a non-invasive method of diagnosing Alzheimer’s disease (AD), which can also predict the risk of its future onset. It is based on measuring salivary levels of amyloid-β protein terminating at position 42 (Aβ42). Brain deposits of this peptide are characteristic of AD. Biomarker studies indicate that such brain deposits commence a decade or more prior to clinical onset of the disease. We report here that Aβ42 is produced in all peripheral organs tested, thus establishing the generality of its production. We used this information to develop simple and sensitive tests to determine salivary Aβ42 levels. The levels were first stabilized by adding thioflavin S as an anti-aggregation agent and sodium azide as an anti-bacterial agent. We then quantitated the Aβ42 in a series of samples with ELISA type tests. Control cases showed almost identical levels of salivary Aβ42 regardless of sex or age. All AD cases secreted levels of Aβ42 more than double those of controls. Individuals at elevated risk of developing AD secreted levels comparable to the AD cases. The results establish that salivary Aβ42 levels can be used to diagnose AD as well as to predict the risk of its future onset.
Pages 1183-1193
Jennifer A. Yates, Linda Clare, Robert T. Woods in collaboration with The Cognitive Function and Ageing Study: Wales
What is the Relationship between Health, Mood, and Mild Cognitive Impairment?
Abstract: Mild cognitive impairment (MCI) often co-exists with mood problems, and both cognitive functioning and mood are known to be linked with health. This study aims to investigate how health, mood, and cognitive impairment interact. Health is often assessed using a single proxy measure, but the use of a range of measures can provide a more informative picture and allows for combination into a comprehensive measure of health. We report an analysis of data from the Cognitive Function and Ageing Study Wales (CFAS Wales, N=3,173), in which structured interviews with older people captured measures of cognition, mood, and health. Each measure of health was assessed independently in relation to cognition and mood, and then all measures were combined to form a latent health variable and tested using structural equation modeling (SEM). SEM confirmed the association between health and cognition, with depression acting as a mediator. All measures of health were individually associated with levels of anxiety and depression. Participants reporting mood problems were less likely to engage in physical activity and more likely to report poor or fair health, have more comorbid health conditions, use more services, and experience difficulties with instrumental activities of daily living. Perceived health was associated with cognitive status; participants with MCI were more likely to report fair or poor health than participants who were cognitively unimpaired. Careful intervention and encouragement to maintain healthy lifestyles as people age could help to reduce the risk of both mood problems and cognitive decline.
Pages 1195-1205
John Fredy Ochoa, Joan Francesc Alonso, Jon Edinson Duque, Carlos Andrés Tobón, Miguel Angel Mañanas, Francisco Lopera, Alher Mauricio Hernández (Handling Associate Editor: Claudio Babiloni)
Successful Scene Encoding Induces Increased Directed Connectivity in Presymptomatic Early-Onset Alzheimer’s Disease Abstract: Background: Recent studies report increases in neural activity in brain regions critical to episodic memory at preclinical stages of Alzheimer’s disease (AD). Although electroencephalography (EEG) is widely used in AD studies, given its non-invasiveness and low cost, there is a need to translate the findings in other neuroimaging methods to EEG. Objective: To examine how the previous findings using functional magnetic resonance imaging (fMRI) at preclinical stage in presenilin-1 E280A mutation carriers could be assessed and extended, using EEG and a connectivity approach. Methods: EEG signals were acquired during resting and encoding in 30 normal cognitive young subjects, from an autosomal dominant early-onset AD kindred from Antioquia, Colombia. Regions of the brain previously reported as hyperactive were used for connectivity analysis. Results: Mutation carriers exhibited increasing connectivity at analyzed regions. Among them, the right precuneus exhibited the highest changes in connectivity. Conclusion: Increased connectivity in hyperactive cerebral regions is seen in individuals, genetically-determined to develop AD, at preclinical stage. The use of a connectivity approach and a widely available neuroimaging technique opens the possibility to increase the use of EEG in early detection of preclinical AD.
Pages 1207-1221
Irit Cohen-Manheim, Glen M. Doniger, Ronit Sinnreich, Ely S. Simon, Havi Murad, Ronit Pinchas-Mizrachi, Jeremy D. Kark
Body Mass Index, Height, and Socioeconomic Position in Adolescence, Their Trajectories into Adulthood, and Cognitive Function in Midlife
Abstract: Background: Whether life course anthropometric indices relate to cognitive function in midlife remains insufficiently explored. Rarely was socioeconomic position (SEP) adequately accounted for. Objective: To examine the association of the cumulative life course burden of high-ranked body mass index (BMI), its trajectory, and stature with cognitive function in midlife. Methods: Weight and height were measured from age 17 across a 33-year follow-up. 507 individuals completed a NeuroTrax computerized cognitive assessment at ages 48-52. Life course SEP was assessed by multiple methods. Using mixed models we calculated the area under the curve (AUC), representing both the life-course burden of BMI (total AUC) and trends in BMI (incremental AUC) from age 17 to midlife. The associations of BMI and height with global cognition and its five component domains were assessed by multiple regression. Results: Higher BMI in late adolescence and total AUC over the life course were associated with poorer global cognition (Standardized beta (Beta)= -0.111, p=0.005 and Beta= -0.105, p=0.018, respectively), adjusted for childhood and adulthood SEP, and demographic characteristics. The associations with higher adolescent and midlife BMI were both restricted to those with low childhood SEP (p<0.05 for interaction). Short adolescent stature was related to poorer cognition (Beta=0.084, p=0.044), whereas late final growth in women was associated with better cognition (Beta=0.213, p=0.007). Conclusion: An adverse association of higher BMI with cognitive function began in adolescence and was restricted to low childhood SEP. Taller stature in both sexes and late growth in women were associated with better midlife cognitive performance.
Pages 1223-1233
Theresa A. Lusardi*, Jay I. Phillips*, Jack T. Wiedrick*, Christina A. Harrington, Babett Lind, Jodi A. Lapidus, Joseph F. Quinn, Julie A. Saugstad (Handling Associate Editor: Robert Rissman) *These authors contributed equally to this work.
MicroRNAs in Human Cerebrospinal Fluid as Biomarkers for Alzheimer's Disease
Abstract: Background: Currently available biomarkers of Alzheimer's disease (AD) include cerebrospinal fluid (CSF) protein analysis and amyloid PET imaging, each of which has limitations. The discovery of extracellular microRNAs (miRNAs) in CSF raises the possibility that miRNA may serve as novel biomarkers of AD. Objective: Investigate miRNAs in CSF obtained from living donors as biomarkers for AD. Methods: We profiled miRNAs in CSF from 50 AD patients and 49 controls using TaqMan® arrays. Replicate studies performed on a subset of 32 of the original CSF samples verified 20 high confidence miRNAs. Stringent data analysis using a four-step statistical selection process including log-rank and receiver operating characteristic (ROC) tests, followed by random forest tests, identified 16 additional miRNAs that discriminate AD from controls. Multimarker modeling evaluated linear combinations of these miRNAs via best-subsets logistic regression, and computed area under the ROC (AUC) curve ascertained classification performance. The influence of ApoE genotype on miRNA biomarker performance was also evaluated. Results: We discovered 36 miRNAs that discriminate AD from control CSF. 20 of these retested in replicate studies verified differential expression between AD and controls. Stringent statistical analysis also identified these 20 miRNAs, and 16 additional miRNA candidates. Top-performing linear combinations of 3 and 4 miRNAs have AUC of 0.80–0.82. Addition of ApoE genotype to the model improved performance, i.e., AUC of 3 miRNA plus ApoE4 improves to 0.84. Conclusions: CSF miRNAs can discriminate AD from controls. Combining miRNAs improves sensitivity and specificity of biomarker performance, and adding ApoE genotype improves classification.
Pages 1235-1247
Naotoshi Iwahara, Shin Hisahara, Jun Kawamata, Akihiro Matsumura, Kazuki Yokokawa, Taro Saito, Mai Fujikura, Tatsuo Manabe, Hiromi Suzuki, Takashi Matsushita, Syuuichirou Suzuki, Shun Shimohama
Role of Suppressor of Cytokine Signaling 3 (SOCS3) in Altering Activated Microglia Phenotype in APPswe/PS1dE9 Mice
Abstract: In response to changes of the central nervous system environment, microglia are capable of acquiring diverse phenotypes for cytotoxic or immune regulation and resolution of injury. Alzheimer’s disease (AD) pathology also induces several microglial activations, resulting in production of pro-inflammatory cytokines and reactive oxygen species or clearance of amyloid-β (Aβ) through phagocytosis. We previously demonstrated that microglial activation and increase in oxidative stress started from the middle age in APPswe/PS1dE9 mice, and hypothesized that M1 activation occurs in middle-aged AD mice by Aβ stimulation. In the present study, we analyzed in vivo expressions of pro-inflammatory cytokines (M1 microglial markers), M2 microglial markers, and suppressor of cytokine signaling (SOCS) family, and examined the microglial phenotypic profile in APPswe/PS1dE9 mice. Then we compared the in vitro gene expression patterns of Aβ- and lipopolysaccharide (LPS)-stimulated primary-cultured microglia. Microglia in APPswe/PS1dE9 mice exhibited an M1-like phenotype, expressing tumor necrosis factor α (TNFα) but not interleukin 6 (IL6). Aβ-stimulated primary-cultured microglia also expressed TNFα but not IL6, whereas LPS-stimulated primary-cultured microglia expressed both pro-inflammatory cytokines. Furthermore, both microglia in APPswe/PS1dE9 mice and Aβ-stimulated primary-cultured microglia expressed SOCS3. Reduction of SOCS3 expression in Aβ-challenged primary-cultured microglia resulted in upregulation of IL6 expression. Our findings indicate that SOCS3 suppresses complete polarization to M1 phenotype through blocking IL6 production, and Aβ-challenged primary-cultured microglia replicate the in vivo gene expression pattern of microglia in APPswe/PS1dE9 mice. Aβ may induce the M1-like phenotype through blocking of IL6 by SOCS3.
Pages 1249-1259
Chiara Cupidi*, Francesca Frangipane*, Maura Gallo*, Alessandra Clodomiro, Rosanna Colao, Livia Bernardi, Maria Anfossi, Maria Elena Conidi, Franca Vasso, Sabrina Anna Maria Curcio, Maria Mirabelli, Nicoletta Smirne, Giusi Torchia, Maria Gabriella Muraca, Gianfranco Puccio, Raffaele Di Lorenzo, Stefania Zampieri, Milena Romanello, Andrea Dardis, Raffaele Giovanni Maletta, Amalia Cecilia Bruni *These authors contributed equally to this work.
Role of Niemann-Pick Type C Disease Mutations in Dementia
Abstract: Background. Several neurological and systemic diseases can cause dementia, beyond Alzheimer’s disease. Rare genetic causes are often responsible for dementia with atypical features. Recently, mutations causative for Niemann-Pick type C disease (NPC) have also been implicated in neurodegenerative diseases. NPC is an autosomal recessive lipid storage disorder caused by mutations in NPC1 and NPC2 genes. In adults, clinical presentation mimicking other neurodegenerative diseases makes diagnosis difficult. Recent evidence suggests that heterozygous mutations in NPC genes may take on etiological significance. Objective. To investigate the presence of NPC1 and NPC2 mutations in adults affected by neurodegenerative dementia plus. Methods. We performed a genetic screening on 50 patients using a wide clinical and biochemical approach to characterize the phenotype of mutated patients. Results. Sequencing analysis revealed four different and known heterozygous mutations in NPC1 and NPC2 genes. Patient 1 carried the p. F284LfsX26 in NPC1 and was affected by progressive supranuclear palsy-like syndrome. The remaining three patients showed a corticobasal syndrome and harbored the c.441+1G>A variant of NPC2 (patient 2), the missense p.N222S mutation associated with the c.1947+8G>C variant in the splice region of intron 12 in NPC1 (patient 3), and the p.V30M mutation in NPC2 (patient 4), respectively. Filipin staining was abnormal in patients 1 and 2. mRNA analysis revealed an altered splicing of the NPC2 gene in patient 2. Conclusions. Heterozygous mutations of NPC1 and NPC2 genes could contribute to dementia plus, at least in a subset of patients. We highlight the occurrence of NPC1 and NPC2 heterozygous variants in dementia-plus as pathological event.
Pages 1261-1272
Mariateresa Buongiorno*, Francesca Antonelli*, Yaroslau Compta*, Yolanda Fernandez, Javier Pavia, Francisco Lomeña, José Ríos, Isabel Ramírez, José Ramón García, Marina Soler, Ana Cámara, Manel Fernández, Misericòrdia Basora, Fàtima Salazar, Gerard Sanchez-Etayo, Francesc Valldeoriola, Jorge Raúl Barrio, Maria Jose Marti *These authors equally contributed to this work.
Cross-Sectional and Longitudinal Cognitive Correlates of FDDNP PET and CSF Amyloid-β and Tau in Parkinson’s Disease
Abstract: Tau and amyloid-β (Aβ) aggregates have been suggested to play a role in the development of dementia in Parkinson’s disease (PD). Positron emission tomography (PET) with [18F]FDDNP and the determination of cerebrospinal fluid (CSF) levels of these proteins constitute a means to visualize in vivo Aβ and tau brain accumulation. Information about longitudinal changes of these CSF and PET biomarkers in PD with regard to progression to dementia is lacking. We assessed the cross-sectional and longitudinal associations of CSF and PET biomarkers of tau and Aβ with PD-related cognitive dysfunction in 6 healthy-controls (HC), 16 patients with PD without dementia (PDND), and 8 PD with dementia (PDD). All subjects underwent comprehensive neuropsychological testing, [18F]FDDNP PET, and CSF Aβ-tau determination. After 18 months, the PDND group was re-assessed clinically and by neuropsychological, PET, and CSF determinations. Cross-sectionally, PDD had higher [18F]FDDNP binding in lateral temporal regions and lower levels of CSF Aβ levels compared to PDND, with a congruent correlation between the [18F]FDDNP binding and CSF Aβ levels. Longitudinally, higher baseline lateral temporal [18F]FDDNP binding was associated to longitudinal worsening in cognitive performances and progression to dementia among subjects classified as PDND at baseline, who additionally disclosed at follow-up an increase in lateral-temporal FDDNP binding, as well as a reduction in CSF Aβ and an increase in CSF tau levels. These results confirm the relevance of these CSF and PET biomarkers to PDD, being specifically the first to show [18F]FDDNP PET as a dementia risk biomarker in PD, along with longitudinal CSF and PET changes over time.
Pages 1273-1283
Jesus Mendiola-Precoma, Karla Padilla, Alfredo Rodríguez-Cruz, Laura C. Berumen, Ricardo Miledi, Guadalupe García-Alcocer (Handling Associate Editor: Israel Ampuero Sánchez)
Theobromine-Induced Changes in A1 Purinergic Receptor Gene Expression and Distribution in a Rat Brain Alzheimer’s Disease Model
Abstract: Dementia caused by Alzheimer’s disease (AD) is mainly characterized by accumulation in the brain of extra- and intraneuronal amyloid-β (Aβ) and tau proteins, respectively, which selectively affect specific regions, particularly the neocortex and the hippocampus. Sporadic AD is mainly caused by an increase in apolipoprotein E, a component of chylomicrons, which are cholesterol transporters in the brain. Recent studies have shown that high lipid levels, especially cholesterol, are linked to AD. Adenosine is an atypical neurotransmitter that regulates a wide range of physiological functions by activating four P1 receptors (A1, A2A, A2B, and A3) and P2 purinergic receptors that are G protein-coupled. A1 receptors are involved in the inhibition of neurotransmitter release, which could be related to AD. The aim of the present work was to study the effects of a lard-enriched diet (LED) on cognitive and memory processes in adult rats (6 months of age) as well as the effect of theobromine on these processes. The results indicated that the fat-enriched diet resulted in a long-term deterioration in cognitive and memory functions. Increased levels of Aβ protein and IL-1β were also observed in the rats fed with a high-cholesterol diet, which were used to validate the AD animal model. In addition, the results of qPCR and immunohistochemistry indicated a decrease in gene expression and distribution of A1 purinegic receptor, respectively, in the hippocampus of LED-fed rats. Interestingly, theobromine, at both concentrations tested, restored A1 receptor levels and improved cognitive functions and Aβ levels for a dose of 30 mg/L drinking water.
Pages 1285-1294
Donald E. Moss, Ruth G. Perez, Haruo Kobayashi (Handling Associate Editor: Taher Darreh-Shori)
Cholinesterase Inhibitor Therapy in Alzheimer’s Disease: The Limits and Tolerability of Irreversible CNS-Selective Acetylcholinesterase Inhibition in Primates
Abstract: Irreversible acetylcholinesterase (AChE) inhibition accumulates to high levels in the central nervous system (CNS) because AChE turnover in the brain is much slower than in peripheral tissues. As expected from this CNS selectivity, the irreversible AChE inhibitor methanesulfonyl fluoride (MSF) produces significant cognitive improvement in Alzheimer’s disease patients without the gastrointestinal toxicity that plagues other AChE inhibitors. However, without dose-limiting gastrointestinal toxicity, one shortcoming of the prior human studies of MSF is that the upper limits of CNS AChE inhibition that might be tolerated could not be tested. Therefore, in this study, monkeys were treated with escalating intramuscular (IM) doses of MSF that culminated with several weeks of 1.5 mg/kg dosing, more than eight times the prior human clinical dose, still without signs of toxicity. Brain biopsies showed that ~80% AChE inhibition had been produced and that the new synthesis of cortical AChE had a half-time (t1/2) of ~12 days. A single IM dose of 1.5 mg/kg MSF produced ~59% inhibition in cerebrospinal fluid (CSF) AChE as measured one day later. This corresponds to a peak of ~80% inhibition in CSF AChE at the time of the injection, recovering with a t1/2 of 2.4 days. Computational analyses suggest that MSF at clinically relevant doses could theoretically produce a steady-state AChE inhibition between 65% and 85% in the CNS. These data suggest that the full therapeutic advantage of AChE inhibition therapy can be realized without interference from dose-limiting gastrointestinal toxicity if an irreversible inhibitor is employed.
