Page 725
Editorial
George Perry
Two Hundred Treasured Issues!
Pages 727-728
Editorial
Carl R. Merril, Hossein A. Ghanbari
Two Hundred Issues Later: The Dream Comes True
Pages 729-744
Review
Tapan K. Khan, Daniel L. Alkon
Peripheral Biomarkers of Alzheimer’s Disease
Abstract: Currently available diagnostic tests have moved the field closer to early diagnosis of Alzheimer’s disease (AD); however, a definitive diagnosis is made only with the development of clinical dementia and the presence of amyloid plaques and neurofibrillary tangles at autopsy. An ideal antemortem AD biomarker should satisfy the following criteria: the ability to diagnose AD with high sensitivity and specificity as confirmed by the gold standard of autopsy validation; the ability to detect early-stage disease and track the progression of AD; and monitor therapeutic efficacy. Several AD biomarker technologies are currently under development, including in vivo brain imaging with PET and MRI (i.e., imaging of amyloid plaques) and biochemical assays of various factors in cerebrospinal fluid (CSF) and peripheral tissues. CSF biomarkers have received increased attention in the past decade. However, it is unclear whether these biomarkers are capable of early diagnosis of AD, prior to Aβ accumulation, or whether they can differentiate between AD and non-AD dementias. In addition, CSF biomarkers may not lend themselves to diagnostic screening of elderly patients, given the invasiveness of the required lumbar puncture procedure, inter-laboratory variability in techniques and sample handling, and the circadian fluctuation of CSF components. Although commonly viewed as an abnormality of the brain, AD is a systemic disease with associated dysfunction in metabolic, oxidative, inflammatory, and biochemical pathways in peripheral tissues, such as the skin and blood cells. This has led researchers to investigate and develop assays of peripheral AD biomarkers that require minimally invasive skin or blood samples.
Pages 745-754
Review
Yves Ingenbleek, Larry H. Bernstein
Downsizing of Lean Body Mass is a Key Determinant of Alzheimer’s Disease
Abstract: Lean body mass (LBM) encompasses all metabolically active organs distributed into visceral and structural tissue compartments and collecting the bulk of N and K stores of the human body. Transthyretin (TTR) is a plasma protein mainly secreted by the liver within a trimolecular TTR-RBP-retinol complex revealing from birth to old age strikingly similar evolutionary patterns with LBM in health and disease. TTR is also synthesized by the choroid plexus along distinct regulatory pathways. Chronic dietary methionine (Met) deprivation or cytokine-induced inflammatory disorders generates LBM downsizing following differentiated physiopathological processes. Met-restricted regimens downregulate the transsulfuration cascade causing upstream elevation of homocysteine (Hcy) safeguarding Met homeostasis and downstream drop of hydrogen sulfide (H2S) impairing anti-oxidative capacities. Elderly persons constitute a vulnerable population group exposed to increasing Hcy burden and declining H2S protection, notably in plant-eating communities or in the course of inflammatory illnesses. Appropriate correction of defective protein status and eradication of inflammatory processes may restore an appropriate LBM size allowing the hepatic production of the retinol circulating complex to resume, in contrast with the refractory choroidal TTR secretory process. As a result of improved health status, augmented concentrations of plasma-derived TTR and retinol may reach the cerebrospinal fluid and dismantle senile amyloid plaques, contributing to the prevention or the delay of the onset of neurodegenerative events in elderly subjects at risk of Alzheimer’s disease.
Pages 755-770
Hypothesis
Natalie L. Marchant, Robert J. Howard (Handling Associate Editor: Mark Bondi)
Cognitive Debt and Alzheimer’s Disease
Abstract: We propose the concept of Cognitive Debt to characterize thoughts and behaviors that increase vulnerability to symptomatic Alzheimer’s disease (AD). Evidence indicates that depression, anxiety, sleep disorder, neuroticism, life stress, and post-traumatic stress disorder increase risk for AD, and we suggest they do so by increasing Cognitive Debt. Repetitive negative thinking (RNT), a behaviorally measurable process common to these factors, may drive Cognitive Debt acquisition. RNT transcends disorder-specific definition, encompasses rumination and worry, and is defined by perseverative, negative thought tendencies. Evidence of dysregulated stress responses supports the concept of Cognitive Debt, of RNT as its causal mechanism, and of an interaction with the APOE-ε4 genotype to increase vulnerability to clinical AD, independent from traditional AD pathology. Defining a more specific behavioral profile of risk would enable interventions to be targeted earlier and more precisely at individuals most vulnerable to developing AD. Additionally, modulating RNT could potentially reduce risk of clinical AD. Interventions to reduce RNT are discussed, as are suggestions for future research. For these reasons we submit that the Cognitive Debt model may aid understanding of the psychological mechanisms that potentially increase predisposition to AD.
Pages 771-776
Short Communication
Kevin N. Hascup, Erin R. Hascup
Altered Neurotransmission Prior to Cognitive Decline in AβPP/PS1 Mice, a Model of Alzheimer’s Disease
Abstract: Indirect evidence supports altered glutamate signaling with Alzheimer’s disease, however, it is not known if glutamate neurotransmission is impacted prior to cognitive decline. We examined cognition and glutamate neurotransmission in 2-4 month AβPP/PS1, an Alzheimer’s disease model, and age-matched control mice. There were no differences in learning and memory as assessed by Morris water maze. However, in vivo electrochemical measures of potassium-evoked glutamate release in the CA1, but not the CA3 or dentate, was significantly elevated in AβPP/PS1 mice. These data support changes in the glutamatergic system that precedes cognitive decline in a mouse model of Alzheimer’s disease.
Pages 777-786
Nozomi Okamoto, Masayuki Morikawa, Kimiko Tomioka, Motokazu Yanagi, Nobuko Amano, Norio Kurumatani
Association between Tooth Loss and the Development of Mild Memory Impairment in the Elderly: The Fujiwara-kyo Study
Abstract: Background: Tooth loss may be a modifiable risk factor for memory disorders, but the causal relationship has not been evaluated sufficiently. Objective: This 5-year prospective cohort study investigated the effect of tooth loss on the development of mild memory impairment (MMI) among the elderly. Methods: Data are from the baseline and follow-up examinations of 2,335 community residents who were cognitively intact at baseline. The number of remaining teeth at baseline was classified as zero, 1–8, 9–16, 17–24, and 25–32. The main outcome for the analysis was the development of MMI at follow-up. Results: After adjustment for potential confounding factors in multivariable logistic regression analysis, the odds ratio of per 1 tooth loss at baseline was 1.02 (95% confidence interval, 1.00–1.03). The odds ratio of edentulism for MMI was 2.39 (1.48–3.86) compared to 25–32 teeth. The odds ratio of becoming edentulous compared to retaining 1–8 teeth in the 1–8 teeth group at baseline was 4.68 (1.50–14.58). Conclusion: Tooth loss predicts the development of MMI among the elderly.
Pages 787-795
Avery M. Foley, Zeena M. Ammar, Robert H. Lee, Cassie S. Mitchell
Systematic Review of the Relationship between Amyloid-β Levels and Measures of Transgenic Mouse Cognitive Deficit in Alzheimer’s Disease
Abstract: Amyloid-β (Aβ) is believed to directly affect memory and learning in Alzheimer’s disease (AD). It is widely suggested that there is a relationship between Aβ40 and Aβ42 levels and cognitive performance. In order to explore the validity of this relationship, we performed a meta-analysis of 40 peer-reviewed, published AD transgenic mouse studies that quantitatively measured Aβ levels in brain tissue after assessing cognitive performance. We examined the relationship between Aβ levels (Aβ40, Aβ42, or the ratio of Aβ42 to Aβ40) and cognitive function as measured by escape latency times in the Morris water maze or exploratory preference percentage in the novel object recognition test. Our systematic review examined five mouse models (Tg2576, APP, PS1, 3xTg, APP(OSK)-Tg), gender, and age. The overall result revealed no statistically significant correlation between quantified Aβ levels and experimental measures of cognitive function. However, enough of the trends were of the same sign to suggest that there probably is a very weak qualitative trend visible only across many orders of magnitude. In summary, the results of the systematic review revealed that mice bred to show elevated levels of Aβ do not perform significantly worse in cognitive tests than mice that do not have elevated Aβ levels. Our results suggest two lines of inquiry: 1) Aβ is a biochemical “side effect” of the AD pathology; or 2) learning and memory deficits in AD are tied to the presence of qualitatively “high” levels of Aβ but are not quantitatively sensitive to the levels themselves.
Pages 797-808
Srikant Rangaraju, Marla Gearing, Lee-Way Jin, Allan Levey
Potassium Channel Kv1.3 Is Highly Expressed by Microglia in Human Alzheimer’s Disease
Abstract: Recent genetic studies suggest a central role for innate immunity in Alzheimer’s disease (AD) pathogenesis, wherein microglia orchestrate neuroinflammation. Kv1.3, a voltage-gated potassium channel of therapeutic relevance in autoimmunity, is upregulated by activated microglia and mediates amyloid-mediated microglial priming and reactive oxygen species production in vitro. We hypothesized that Kv1.3 channel expression is increased in human AD brain tissue. In a blinded postmortem immunohistochemical semi-quantitative analysis performed on ten AD patients and ten non-disease controls, we observed a significantly higher Kv1.3 staining intensity (p=0.03) and Kv1.3-positive cell density (p=0.03) in the frontal cortex of AD brains, compared to controls. This paralleled an increased number of Iba1-positive microglia in AD brains. Kv1.3-positive cells had microglial morphology and were associated with amyloid-β plaques. In immunofluorescence studies, Kv1.3 channels co-localized primarily with Iba1 but not with astrocyte marker GFAP, confirming that elevated Kv1.3 expression is limited to microglia. Higher Kv1.3 expression in AD brains was also confirmed by western blot analysis. Our findings support that Kv1.3 channels are biologically relevant and microglia-specific targets in human AD.
Pages 809-813
Charlotte E. Teunissen, Wiesje M. van der Flier, Philip Scheltens, Anneli Duits, Nienke Wijnstok, Giel Nijpels, Jacqueline M. Dekker, Rien M.A. Blankenstein, Annemieke C. Heijboer
Serum Leptin is not Altered nor Related to Cognitive Decline in Alzheimer’s Disease
Abstract: Background: Low plasma leptin levels can be a risk factor for Alzheimer’s disease (AD) but the relation of leptin with disease progression in clinical AD is unknown. Objective: The aim of this study was to investigate the relation between serum leptin concentrations and disease progression in clinical AD. Methods: Serum leptin levels were analyzed in 295 non-obese subjects including healthy controls (n=65), patients with subjective memory complaints (n=99), patients with AD (n=100), and patients with vascular dementia (n=31). Leptin levels were related to hippocampal atrophy, baseline Mini-Mental State Examination (MMSE) scores and annual decline in MMSE measured over 2 years (range 0.4-4.5 years). Results: Serum leptin levels were similar in AD patients compared to healthy controls and patients with subjective memory complaints. No correlation was observed between leptin concentrations and MMSE, annual change in MMSE during follow-up or atrophy. Conclusion: Serum leptin levels are not altered in this population of relatively young AD or vascular dementia patients (mean ~60) compared to healthy and clinical control groups. These results suggest that peripheral leptin levels do not play a role in evolution of AD pathology.
Pages 815-826
Silvia Morbelli, Andrea Brugnolo, Irene Bossert, Ambra Buschiazzo, Giovanni B. Frisoni, Samantha Galluzzi, Bart N.M. van Berckel, Rik Ossenkoppele, Robert Perneczky, Alexander Drzezga, Mira Didic, Eric Guedj, Gianmario Sambuceti, Gianluca Bottoni, Dario Arnaldi, Agnese Picco, Fabrizio De Carli, Marco Pagani, Flavio Nobili
Visual versus Semi-Quantitative Analysis of 18F-FDG-PET in Amnestic MCI: An European Alzheimer’s Disease Consortium (EADC) Project
Abstract: We aimed to investigate the accuracy of FDG-PET to detect the Alzheimer’s disease (AD) brain glucose hypometabolic pattern in 142 patients with amnestic mild cognitive impairment (aMCI) and 109 healthy controls. aMCI patients were followed for at least two years or until conversion to dementia. Images were evaluated by means of visual read by either moderately-skilled or expert readers, and by means of a summary metric of AD-like hypometabolism (PALZ score). Seventy-seven patients converted to AD-dementia after 28.6±19.3 months of follow-up. Expert reading was the most accurate tool to detect these MCI converters from healthy controls (sensitivity 89.6%, specificity 89.0%, accuracy 89.2%) while two moderately-skilled readers were less (p<0.05) specific (sensitivity 85.7%, specificity 79.8%, accuracy 82.3%) and PALZ score was less (p<0.001) sensitive (sensitivity 62.3%, specificity 91.7%, accuracy 79.6%). Among the remaining 67 aMCI patients, 50 were confirmed as aMCI after an average of 42.3 months, 12 developed other dementia, and 3 reverted to normalcy. In 30/50 persistent MCI patients, the expert recognized the AD hypometabolic pattern. In 13/50 aMCI, both the expert and PALZ score were negative while in 7/50, only the PALZ score was positive due to sparse hypometabolic clusters mainly in frontal lobes. Visual FDG-PET reads by an expert is the most accurate method but an automated, validated system may be particularly helpful to moderately-skilled readers because of high specificity, and should be mandatory when even a moderately-skilled reader is unavailable.
Pages 827-838
George K. Acquaah-Mensah, Nnenna Agu, Tayyiba Khan, Alice Gardner
A Regulatory Role for the Insulin- and BDNF-Linked RORa in the Hippocampus: Implications for Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is the leading cause of dementia. The etiology of AD remains, in large part, unresolved. In this study, gene expression (microarray) data from postmortem brains in normal aged as well as AD-affected brains in conjunction with transcriptional regulatory networks were explored for etiological insights. The focus was on the hippocampus, a brain region key to memory and learning. The transcriptional regulatory networks were inferred using a trees-based (random forests or extra-trees) as well as a mutual information-based algorithm applied to compendia of adult mouse whole brain and hippocampus microarray data. Network nodes representing human orthologs of the mouse networks were used in the subsequent analysis. Among the potential transcriptional regulators tied to insulin or brain-derived neurotrophic factor (INS1, INS2, BDNF), whose peptide products have been linked to AD, is the Retinoic Acid Receptor-Related Orphan Receptor (RORA). RORA is a nuclear receptor transcription factor whose expression is distinctly upregulated in the AD hippocampus. A notable cross-section of genes differentially expressed in the AD hippocampus was found to be linked to RORA in the networks. Furthermore, several genes associated with RORA in the networks, such as APP, DNM1L, and TIA1 have been implicated in AD. Computationally-derived clusters and modules within the networks indicated strong ties between RORA and genes involved in the AD etiology. In addition, a functional mapping scheme using activity and interaction data affirmed the same network links to RORA. Thus, RORA emerges as a gene with a probable central role in the AD pathology/etiology.
Pages 839-850
Chunxia Huang, Yuen-Shan Ho, Olivia Tsz-Wa Ng, Michael G. Irwin, Raymond Chuen-Chung Chang, Gordon Tin-Chun Wong (Handling Associate Editor: Fei Liu)
Dexmedetomidine Directly Increases Tau Phosphorylation
Abstract: Exposure to anesthetic agents has been linked to abnormal tau protein phosphorylation, an antecedent to the development of neurofibrillary tangles. This study evaluates the direct and indirect effects of dexmedetomidine. Primary culture of cortical neurons established from Sprague-Dawley (SD) rat embryos were exposed to dexmedetomidine for 1 or 6 hours, and the degree of tau phosphorylation at the AT8, AT180, and S396 sites was assessed by western blot analysis. To assess and compare their relative in vivo effects, the same agent was administered intravenously to 8 to 10 week old male SD rats and titrated to the loss of the righting reflex for 2 hours. After 1 hour of recovery, the rats were sacrificed and samples taken from the cortex and hippocampus were subjected to western blot and immunohistochemical analysis. The in vitro studies reviewed significant hyperphosphorylation only at the S396 site, and these changes have largely disappeared at 6 hours. With temperature maintenance, dexmedetomidine induced significant changes in hyperphosphorylation at the AT8 site in the cortex and hippocampus and at the AT180 in the hippocampus. The direct effect of anesthetic agents on fully differentiated cortical neurons is epitope-specific and short-lived. The in vivo effects are comparatively more complicated and depend not only on the phosphorylation site but the regions of the brain examined. These findings suggest that dexmedetomidine increases tau phosphorylation both in vitro and in vivo under normothermic conditions, and further studies are warranted to determine the long-term impact of this anesthetic on the tau pathology and even cognitive function.
Pages 851-857
Stewart F. Graham, Muhammad Bin Nasarauddin, Manus Carey, Bernadette McGuinness, Christian Holscher, Patrick G. Kehoe, Seth Love, Anthony P. Passmore, Christopher T. Elliott1, Andrew Meharg, Brian D. Green
Quantitative Measurement of [Na+] and [K+] in Postmortem Human Brain Tissue Indicates Disturbances in Subjects with Alzheimer’s Disease and Dementia with Lewy Bodies
Abstract: Alzheimer’s disease (AD) is associated with significant disturbances in the homeostasis of Na+ and K+ ions as well as reduced levels of Na+/K+ ATPase in the brain. This study used ICP-MS to accurately quantify Na+ and K+ concentrations in human postmortem brain tissue. We analyzed parietal cortex (Brodmann area 7) from 28 cognitively normal age-matched controls, 15 cases of moderate AD, 30 severe AD, and 15 dementia with Lewy bodies (DLB). Associations were investigated between [Na+] and [K+] and a number of variables including diagnosis, age, gender, Braak tangle stage, amyloid-β (Aβ) plaque load, tau load, frontal tissue pH, and APOE genotype. Brains from patients with severe AD had significantly higher (26%; p<0.001) [Na+] (mean 65.43 ± standard error 2.91 mmol/kg) than controls, but the concentration was not significantly altered in moderate AD or DLB. [Na+] correlated positively with Braak stage (r=0.45; p<0.0001), indicating association with disease severity. [K+] in tissue was 10% lower (p<0.05) in moderate AD than controls. However, [K+] in severe AD and DLB (40.97±1.31 mmol/kg) was not significantly different from controls. There was a significant positive correlation between [K+] and Aβ plaque load (r=0.46; p=0.035), and frontal tissue pH (r=0.35; p=0.008). [Na+] was not associated with [K+] across the groups, and neither ion was associated with tau load or APOE genotype. We have demonstrated disturbances of both [Na+] and [K+] in relation to the severity of AD and markers of AD pathology, although it is possible that these relate to late-stage secondary manifestations of the disease pathology.
Pages 859-865
Eman Al-khateeb, Arwa Althaher, Mohammed Al-khateeb, Hanan Al-Musawi, Ola Azzouqah, Samir Al-Shweiki, Yanal Shafagoj
Relation between Uric Acid and Alzheimer’s Disease in Elderly Jordanians
Abstract: Background: It has been suggested that oxidative injuries have a role in the pathogenesis of Alzheimer’s disease (AD). Uric acid (UA) has a contradictory effect on cognitive function and several lines of evidence suggest that UA may modulate outcome in neurological diseases. Objectives: Many studies investigated serum UA levels in AD patients, but to date, results from these observational studies are conflicting. In this study, we assess whether serum UA levels would be altered in the AD Jordanian patients compared to those of the healthy controls. Methods: Serum UA and lipid profile levels were measured in 41 AD patients and 40 healthy controls. Results were statistically evaluated at p < 0.05 level of significance. The Arabic version of the Mini-Mental State Examination (MMSE-A) was used to evaluate the cognitive functions of all participants. Results: Demographic variables indicate that individuals that are illiterate demonstrate a 7.5 fold (p=0.033) increase in risk of developing AD. The AD group shows 12.6% lower serum UA level than control subjects and the difference between groups is statistically significant (p=0.033). No significant differences could be found between the two groups in lipid profile levels. Pearson correlation coefficients and Multivarient linear regression show no significant correlation between MMSE and continuous variables in AD patients except for age. Conclusion: The results suggest that serum UA levels are significantly lower in AD patients in comparison to control subjects. UA may have a protective role against AD; however this role needs further investigations.
Pages 867-878
Kara M. Hawkins, Aman I. Goyal, Lauren E. Sergio
Diffusion Tensor Imaging Correlates of Cognitive-Motor Decline in Normal Aging and Increased Alzheimer’s Disease Risk
Abstract: Alzheimer’s disease (AD) is typically associated with impairments in memory and other aspects of cognition, while deficits in complex movements are commonly observed later in the course of the disease. Recent studies, however, have indicated that subtle deteriorations in visuomotor control under cognitively demanding conditions may in fact be an early identifying feature of AD. Our previous work has shown that the ability to perform visuomotor tasks that rely on visual-spatial and rule-based transformations is disrupted in prodromal and preclinical AD. Here, in a sample of 30 female participants (10 young: mean age = 26.6 ± 2.7, 10 low AD risk: mean age = 58.7 ± 5.6, and 10 high AD risk: mean age = 58.5 ± 6.9), we test the hypothesis that these cognitive-motor impairments are associated with early AD-related brain alterations. Using diffusion-weighted magnetic resonance imaging, we examined changes in white matter (WM) integrity associated with normal aging and increased AD risk, and assessed the relationship between these underlying WM alterations and cognitive-motor performance. Our whole-brain analysis revealed significant age-related declines in WM integrity, which were more widespread in high relative to low AD risk participants. Furthermore, analysis of mean diffusivity measures within isolated WM clusters revealed a stepwise decline in WM integrity across young, low AD risk, and high AD risk groups. In support of our hypothesis, we also observed that lower WM integrity was associated with poorer cognitive-motor performance. These results are the first to demonstrate a relationship between AD-related WM alterations and impaired cognitive-motor control. The application of these findings may provide a novel clinical strategy for the early detection of individuals at increased AD risk.
Pages 879-896
Jana Renziehausen, Christof Hiebel, Heike Nagel, Arpita Kundu, Stefan Kins, Donat Kögel, Christian Behl*, Parvana Hajieva* (Handling Associate Editor: Jürgen Götz) *These authors contributed equally to this work.
The Cleavage Product of Amyloid-β Protein Precursor sAβPPα Modulates BAG3-Dependent Aggresome Formation and Enhances Cellular Proteasomal Activity
Abstract: Alzheimer’s disease (AD) is the major age-associated form of dementia characterized by gradual cognitive decline. Aberrant cleavage of the amyloid-β protein precursor (AβPP) is thought to play an important role in the pathology of this disease. Two principal AβPP processing pathways exist: amyloidogenic cleavage of AβPP resulting in production of the soluble N-terminal fragment sAβPPβ, amyloid-β (Aβ), which accumulates in AD brain, and the AβPP intracellular domain (AICD) sAβPPα, p3 and AICD are generated in the non-amyloidogenic pathway. Prevalence of amyloidogenic versus non-amylodogenic processing leads to depletion of sAβPPα and an increase in Aβ. Although sAβPPα is a well-accepted neurotrophic protein molecular effects of this fragment remains unknown. Different studies reported impaired protein degradation pathways in AD brain, pointing to a role of disturbed proteasomal activity in the pathogenesis of this disease. Here we studied the possible role of sAβPPα in Bag3-mediated selective macroautophagy and proteasomal degradation. Employing human IMR90 cells, HEK 293 cells, and primary neurons, we demonstrate that sAβPPα prevents the proteotoxic stress-induced increase of Bag3 at the protein and at the mRNA level indicating a transcriptional regulation. Intriguingly, p62 and LC3, two other key players of autophagy, were not affected. Moreover, the formation and the accumulation of disease-related protein aggregates were significantly reduced by sAβPPα. Interestingly, there was a significant increase of proteasomal activity by sAβPPα as demonstrated by using various proteasome substrates. Our findings demonstrate that sAβPPα modulates Bag3 expression, aggresome formation, and proteasomal activity, thereby providing first evidence for a function of sAβPPα in the regulation of proteostasis.
Pages 897-906
Amy Claxton, Laura D. Baker, Angela Hanson, Emily H. Trittschuh, Brenna Cholerton, Amy Morgan, Maureen Callaghan, Matthew Arbuckle, Colin Behl, Suzanne Craft
Long-Acting Intranasal Insulin Detemir Improves Cognition for Adults with Mild Cognitive Impairment or Early-Stage Alzheimer’s Disease Dementia
Abstract: Previous trials have shown promising effects of intranasally administered insulin for adults with Alzheimer’s disease dementia (AD) or amnestic mild cognitive impairment (MCI). These trials used regular insulin, which has a shorter half-life compared to long-lasting insulin analogues such as insulin detemir. The current trial examined whether intranasal insulin detemir improves cognition or daily functioning for adults with MCI or AD. Sixty adults diagnosed with MCI or mild to moderate AD received placebo (n = 20), 20 IU of insulin detemir (n = 21), or 40 IU of insulin detemir (n = 19) for 21 days, administered with a nasal drug delivery device. Results revealed a treatment effect for the memory composite for the 40 IU group compared with placebo (p<0.05). This effect was moderated by APOE status (p<0.05), reflecting improvement for APOE-ε4 carriers (p<0.02), and worsening for non-carriers (p<0.02). Higher insulin resistance at baseline predicted greater improvement with the 40 IU dose (r=0.54, p<0.02). Significant treatment effects were also apparent for verbal working memory (p<0.03) and visuospatial working memory (p<0.04), reflecting improvement for subjects who received the high dose of intranasal insulin detemir. No significant differences were found for daily functioning or executive functioning. In conclusion, daily treatment with 40 IU insulin detemir modulated cognition for adults with AD or MCI, with APOE-related differences in treatment response for the primary memory composite. Future research is needed to examine the mechanistic basis of APOE-related treatment differences, and to further assess the efficacy and safety of insulin detemir.
Pages 907-916
Virginie Dauphinot, Floriane Delphin-Combe, Christelle Mouchoux, Aline Dorey, Anthony Bathsavanis, Zaza Makaroff, Isabelle Rouch, Pierre Krolak-Salmon
Risk Factors of Caregiver Burden Among Patients with Alzheimer’s Disease or Related Disease: A Cross-Sectional Study
Abstract: Background: Caregivers play a major role in the care of patients with dementia and are themselves at higher risk of disease. Objectives: We investigate which factors are associated with caregivers burden of outpatients visiting a memory clinic and how functional autonomy and behavioral and psychological symptoms can influence caregiver burden. Methods: The study population was chosen from outpatients with progressive cognitive complaint. The caregiver burden was with the short version of the Zarit Burden Interview (ZBI). The relationship was assessed between the ZBI and the patients characteristics, including Neuropsychiatric Inventory (NPI), Instrumental Activities of Daily Living scale (IADL), the Mini-Mental State Examination (MMSE), etiology, and stage of the cognitive impairment. Results: In a population of 548 patients, IADL, NPI, antidepressant drugs, and MMSE were found to be related to ZBI, while diagnosed etiology and disease stage were not significant: ZBI decreased by 0.34 point for every unit of IADL, and by 0.03 point for every unit of MMSE; ZBI increased by 0.03 point for every unit of NPI. From the IADL scale, the ability to handle finances, food preparation, responsibility to take own medications, mode of transportation, and ability to use the telephone increased the ZBI. Five areas of the NPI increased the ZBI: apathy, agitation, aberrant motor behavior, appetite disorders (p<0.001), and irritability (p=0.03). Conclusion: Caregivers experience a higher burden due to disease symptoms such as impairment of functional autonomy and behavioral and cognitive impairment, whatever the etiology of the cognitive decline.
Pages 917-925
Alan Rembach, Francesco C. Stingo, Christine Peterson, Marina Vannucci, Kim-Anh Do, William J. Wilson, S. Lance Macaulay, Timothy M. Ryan, Ralph N. Martins, David Ames, Colin L. Masters, James D. Doecke and the AIBL Research Group
Bayesian Graphical Network Analyses Reveal Complex Biological Interactions Specific to Alzheimer’s Disease
Abstract: With different approaches to finding prognostic or diagnostic biomarkers for Alzheimer’s disease (AD), many studies pursue only brief lists of biomarkers or disease specific pathways, potentially dismissing information from groups of correlated biomarkers. Using a novel Bayesian graphical network method, with data from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, the aim of this study was to assess the biological connectivity between AD associated blood-based proteins. Briefly, three groups of protein markers (18, 37, and 48 proteins, respectively) were assessed for the posterior probability of biological connection both within and between clinical classifications. Clinical classification was defined in four groups: high performance healthy controls (hpHC), healthy controls (HC), participants with mild cognitive impairment (MCI), and participants with AD. Using the smaller group of proteins, posterior probabilities of network similarity between clinical classifications were very high, indicating no difference in biological connections between groups. Increasing the number of proteins increased the capacity to separate both hpHC and HC apart from the AD group (0 for complete separation, 1 for complete similarity), with posterior probabilities shifting from 0.89 for the 18 protein group, through to 0.54 for the 37 protein group, and finally 0.28 for the 48 protein group. Using this approach, we identified beta-2 microglobulin (β2M) as a potential master regulator of multiple proteins across all classifications, demonstrating that this approach can be used across many data sets to identify novel insights into diseases like AD.
Pages 927-935
Rebecca K. West, Ramit Ravona-Springer, Anthony Heymann, James Schmeidler, Derek Leroith, Keren Koifman, Elizabeth Guerrero-Berroa, Rachel Preiss, Hadas Hoffman, Jeremy M. Silverman, Michal Schnaider Beeri
Shorter Adult Height is Associated with Poorer Cognitive Performance in Elderly Men with Type II Diabetes
Abstract: We studied the relationship of adult body height with five cognitive outcomes (executive functioning, semantic categorization, attention/working memory, episodic memory, and an overall cognition measure) in 897 cognitively normal elderly with type 2 diabetes. Regression analyses controlling for sociodemographic, cardiovascular, and diabetes-related risk factors and depression demonstrated that in males, shorter stature was associated with poorer executive functioning (p=0.001), attention/working memory (p=0.007), and overall cognition (p=0.016), but not with episodic memory (p=0.715) or semantic categorization (p=0.948). No relationship between height and cognition was found for females. In cognitively normal type 2 diabetes male subjects, shorter stature, a surrogate for early-life stress and poor nutrition, was associated with cognitive functions.
Pages 937-947
Laiq-Jan Saidi, Manuela Polydoro, Kevin R. Kay, Laura Sanchez, Eva-Maria Mandelkow, Bradley T. Hyman, Tara L. Spires-Jones (Handling Associate Editor: Alexis Stranahan)
Carboxy Terminus Heat Shock Protein 70 Interacting Protein Reduces Tau-Associated Degenerative Changes
Abstract: One of the hallmarks of Alzheimer’s disease is the formation of neurofibrillary tangles, intracellular aggregates of hyperphosphorylated, mislocalized tau protein, which are associated with neuronal loss. Changes in tau are known to impair cellular transport (including that of mitochondria) and are associated with cell death in cell culture and mouse models of tauopathy. Thus clearing pathological forms of tau from cells is a key therapeutic strategy. One critical modulator in the degradation and clearance of misfolded proteins is the co-chaperone CHIP (Carboxy terminus Hsp70 interacting Protein), which is known to play a role in refolding and clearance of hyperphosphorylated tau. Here, we tested the hypothesis that CHIP could ameliorate pathological changes associated with tau. We find that co-expressing CHIP with full-length tau, tau truncated at D421 mimicking caspase cleavage, or the short tauRDΔK280 tau construct containing only the tau repeat domain with a tauopathy mutation, decreases tau protein levels in human H4 neuroglioma cells in a manner dependent on the Hsp70-binding TPR domain of CHIP. The observed reduction in tau levels by CHIP is associated with a decrease of tau phosphorylation and reduced levels of cleaved Caspase 3 indicating that CHIP plays an important role in preventing tau-induced pathological changes. Furthermore, tau-associated mitochondrial transport deficits are rescued by CHIP co-expression in H4 cells. Together, these data suggest that the co-chaperone CHIP can rescue the pathological effects of tau, and indicate that other diseases of protein misfolding and accumulation may also benefit from CHIP upregulation.
Pages 949-962
James P. Barrett, Aedín M. Minogue, Raasay S. Jones, Catia Ribeiro, Ronan J. Kelly, Marina A. Lynch
Bone Marrow-Derived Macrophages from AβPP/PS1 Mice are Sensitized to the Effects of Inflammatory Stimuli
Abstract: Macrophages are key cells in tissue defense in the periphery and, under certain circumstances, infiltrate the central nervous system, where they may play a similar role in the brain, perhaps supporting the function of microglia. Macrophages have been shown to adopt different activation states in response to various stimuli. Specifically, when exposed to inflammatory stimuli such as interferon (IFN)γ, the cells adopt the M1 phenotype, whereas when exposed to anti-inflammatory cytokines such as interleukin (IL)-4 or IL-13, the M2 phenotype is adopted. While M1 macrophages are associated with tissue defense and destruction of invading pathogens, M2 macrophages are involved in tissue repair and in terminating inflammation. It is well known that an inflammatory microenvironment exists in the brain of aged animals and also in the brain of mice that overexpress amyloid-β protein precursor (AβPP) and presenilin 1 (PS1; AβPP/PS1 mice), a commonly-used model of Alzheimer's disease (AD). Recent studies have revealed that immune cells, including macrophages, infiltrate the brain in both circumstances raising the possibility that these cells adopt the M1 activation state and contribute to the already-existing neuroinflammation. We set out to examine the responses of bone marrow-derived macrophages prepared from wildtype and AβPP/PS1 mice and demonstrate that cells from AβPP/PS1 mice, even after several days in culture, respond more profoundly to IFNγ than those from wildtype mice. We suggest that this propensity to respond to M1-polarizing stimuli, together with the described changes in the brain of AβPP/PS1 mice, contribute to the development of chronic neuroinflammation.
Pages 963-975
Hee Jin Kim, Kiho Im, Hunki Kwon, Jong Min Lee, Byoung Seok Ye, Yeo Jin Kim, Hanna Cho, Yearn Seong Choe, Kyung Han Lee, Sung Tae Kim, Jae Seung Kim, Jae Hong Lee, Duk L. Na, Sang Won Seo (Handling Associate Editor: YongSoo Shim)
Effects of Amyloid and Small Vessel Disease on White Matter Network Disruption
Abstract: There is growing evidence that the human brain is a large scale complex network. The structural network is reported to be disrupted in cognitively impaired patients. However, there have been few studies evaluating the effects of amyloid and small vessel disease (SVD) markers, the common causes of cognitive impairment, on structural networks. Thus, we evaluated the association between amyloid and SVD burdens and structural networks using diffusion tensor imaging (DTI). Furthermore, we determined if network parameters predict cognitive impairments. Graph theoretical analysis was applied to DTI data from 232 cognitively impaired patients with varying degrees of amyloid and SVD burdens. All patients underwent Pittsburgh compound-B (PiB) PET to detect amyloid burden, MRI to detect markers of SVD, including the volume of white matter hyperintensities and the number of lacunes, and detailed neuropsychological testing. The whole-brain network was assessed by network parameters of integration (shortest path length, global efficiency) and segregation (clustering coefficient, transitivity, modularity). A greater PiB retention ratio was not associated with any white matter network parameters. Greater white matter hyperintensity volumes or lacunae numbers were significantly associated with decreased network integration (increased shortest path length, decreased global efficiency) and increased network segregation (increased clustering coefficient, increased transitivity, increased modularity). Decreased network integration or increased network segregation were associated with poor performances in attention, language, visuospatial, memory, and frontal-executive functions. Our results suggest that amyloid burden disrupts white matter network integration, while SVD alters white matter network integration and segregation, which further predicts cognitive dysfunction.
Pages 977-987
Crystal E. Humphries, Martin A. Kohli, Lubov Nathanson, Patrice Whitehead, Gary Beecham, Eden Martin, Deborah C. Mash, Margaret A. Pericak-Vance, John Gilbert
Integrated Whole Transcriptome and DNA Methylation Analysis Identifies Gene Networks Specific to Late-Onset Alzheimer’s Disease
Abstract: Previous transcriptome studies observed disrupted cellular processes in late-onset Alzheimer’s disease (LOAD), yet it is unclear whether these changes are specific to LOAD, or are common to general neurodegeneration. In this study, we address this question by examining transcription in LOAD and comparing it to cognitively normal controls and a cohort of “disease controls.” Differential transcription was examined using RNA-seq, which allows for the examination of protein coding genes, non-coding RNAs, and splicing. Significant transcription differences specific to LOAD were observed in five genes: C10orf105, DIO2, a lincRNA, RARRES3, and WIF1. These findings were replicated in two independent publicly available microarray data sets. Network analyses, performed on 2,504 genes with moderate transcription differences in LOAD, reveal that these genes aggregate into seven networks. Two networks involved in myelination and innate immune response specifically correlated to LOAD. FRMD4B and ST18, hub genes within the myelination network, were previously implicated in LOAD. Of the five significant genes, WIF1 and RARRES3 are directly implicated in the myelination process; the other three genes are located within the network. LOAD specific changes in DNA methylation were located throughout the genome and substantial changes in methylation were identified within the myelination network. Splicing differences specific to LOAD were observed across the genome and were decreased in all seven networks. DNA methylation had reduced influence on transcription within LOAD in the myelination network when compared to both controls. These results hint at the molecular underpinnings of LOAD and indicate several key processes, genes, and networks specific to the disease.
Pages 989-994
Mamoonah Chaudhry, Xingbin Wang, Mikhil N. Bamne, Shahida Hasnain, F. Yesim Demirci, Oscar L. Lopez, M. Ilyas
Genetic Variation in Imprinted Genes is Associated with Risk of Late-Onset Alzheimer’s Disease
Abstract: Epigenetic changes including genomic imprinting may affect risk of late-onset Alzheimer’s disease (LOAD). There are >100 known imprinted genes and most of them are expressed in human brain. In this study, we examined the association of single nucleotide polymorphisms (SNPs) in 93 imprinted genes with LOAD risk in 1291 LOAD cases and 958 cognitively normal controls. We performed single-site, gene-based, and haplotype analyses. Single-site analysis showed 14 significant associations at p<0.01. The most significant SNP (rs11770199; p=0.0003) in single-site analysis was located on chromosome 7 in the GRB10 gene. Gene-based analyses revealed four significant associations in the WT1, ZC3H12C, DLGAP2, and GPR1 genes at p<0.05. The haplotype analysis also revealed significant associations with three genes (ZC3H12C, DLGAP2, and GPR1). These findings suggest a possible role of imprinted genes in AD pathogenesis that show specific expression in the brain.
Pages 995-1005
Jennifer K. Callaway, Nigel C. Jones, Alistair G. Royse, Colin F. Royse (Handling Associate Editor: Pravat Mandal)
Memory Impairment in Rats after Desflurane Anesthesia is Age and Dose Dependent
Abstract: Post-operative cognitive dysfunction (POCD) predominantly affects the elderly who suffer memory and concentration deficits after anesthesia and surgery. Animal studies have demonstrated anesthetic alone may contribute to POCD but results are variable and little is known about common anesthetics other than isoflurane. The present study investigated dose-dependence of desflurane anesthesia in young adult and aged rats. We hypothesize higher concentrations of desflurane will result in memory impairment in the water maze and that impairment will be worse in aged rats. Effects of anesthesia (1 or 1.5 MAC, 4 h) desflurane, or sham exposure on cognition were investigated in young adult (3 months) and aged (20-24 months) rats at 1, 4, and 12 weeks post-exposure. The Morris water maze was used to assess acquisition and retention of spatial reference memory. Latency to find the hidden platform and swimming speed were compared between treatments. Aged rats showed significant impairment in task acquisition after exposure to 1.5 MAC, but not 1.0 MAC desflurane anesthetic when tested 1 week following exposure. Latency to find the platform and distance travelled were significantly longer in aged rats given 1.5 MAC desflurane (latency: F(1,108) = 19.71, p < 0.0001; distance: F(1,108) = 5.79, p = 0.018). Deficits were not long-lasting and were no longer present at 4 or 12 weeks. In contrast, young adult rats performed equally as well as sham-exposed control rats irrespective of desflurane dose. This study showed the effects of desflurane on learning and memory in the water maze are age and dose dependent and are brief in duration.
Pages 1007-1013
Juho Tynkkynen, Tiina Laatikainen, Veikko Salomaa, Aki S. Havulinna, Stefan Blankenberg, Tanja Zeller, Jussi A. Hernesniemi
NT-proBNP and the Risk of Dementia: A Prospective Cohort Study with 14 Years of Follow-Up
Abstract: Background: Memory disorders and Alzheimer’s disease (AD) share the same risk factors with cardiovascular diseases. Objective: We tested whether elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) levels would predict any incident dementia or AD. Methods: The association between NT-proBNP and the risk of dementia was evaluated in a total of 7,158 subjects without previous memory disorders in a prospective study with a median follow-up of 13.8 years. Results: A total of 220 new dementia cases occurred, of which 149 were AD. Baseline logNT-proBNP levels were associated significantly with the risk of dementia in the entire study population (HR 1.32, 95%CI 1.17-1.56, p=0.001) per 1SD difference, adjusted for multiple cardiovascular risk factors. Integrated discrimination improvement (IDI) and continuous net-reclassification improvement (continuous NRI) were improved in the study population over 40 years of age: continuous NRI was 17.5% (95%CI 4.4-30.6%, p=0.009) and IDI was 0.005 (95%CI 0.001-0.010, p=0.021). Regarding AD, the HR for 1SD logNT-proBNP change was 1.23 (95%CI 1.01-1.49, p=0.040) in the entire study population, but no IDI or continuous NRI improvement was seen. Conclusion: NT-proBNP is also an independent risk marker for dementia, and patient discrimination regarding dementia risk could be improved by using it.
Pages 1015-1021
Diana Wucherer, Tilly Eichler, Ingo Kilimann, Johannes Hertel, Bernhard Michalowsky, Jochen René Thyrian, Stefan Teipel, Wolfgang Hoffmann
Antidementia Drug Treatment in People Screened Positive for Dementia in Primary Care
Abstract: Background: There is a lack of knowledge about antidementia drug treatment in community dwelling people with dementia in Germany. Objective: To determine the frequency of treatment with antidementia drugs in patients in primary care, and the socio-demographic and clinical variables associated with antidementia drug treatment. Methods: Present analyses are based on preliminary data from the DelpHi-trial, an ongoing GP-based, cluster-randomized, controlled intervention trial to implement and evaluate an innovative concept of collaborative dementia care management in Germany. Our sample consists of n=243 subjects who screened positive for dementia. Results: 29.6% (n=72) of participants received antidementia drugs: memantine 44.4% (n=32); donepezil 30.5% (n=22); rivastigmine 13.9% (n=10); galantamine 11.1% (n=8). A total of 46.4% (n=45) of the subgroup of participants with a formal dementia diagnosis received antidementia drug treatment. Approximately 37.5% (n=27) of our sample received treatment with antidementia drugs without having a formal diagnosis. Treatment with antidementia drugs was significantly associated with more severe cognitive impairment and having a formal dementia diagnosis. Conclusions: One in three people who screen positive for dementia in primary care receive antidementia drug treatment, indicating the frequent use of this class of drugs. For those with a formal dementia diagnosis, these drug treatment rates are more than triple, compared to those in nursing homes.
Pages 1023-1034
Jae-Won Jang, So Young Park, Young Ho Park, Min Jae Baek, Jae-Sung Lim, Young Chul Youn, SangYun Kim (Handling Associate Editor: YongSoo Shim)
A Comprehensive Visual Rating Scale of Brain Magnetic Resonance Imagine: Application in Elderly Subjects with Alzheimer’s Disease, Mild Cognitive Impairment, and Normal Cognition
Abstract: Background: Brain magnetic resonance imaging (MRI) shows cerebral structural changes. However, a unified comprehensive visual rating scale (CVRS) has seldom been studied. Thus, we combined brain atrophy and small vessel disease scales and used an MRI template as a CVRS. Objective: The aims of this study were to design a simple and reliable CVRS, validate it by investigating cerebral structural changes in clinical groups, and made comparison to the volumetric measurements. Methods: Elderly subjects (n = 260) with normal cognition (NC, n = 65), mild cognitive impairment (MCI, n = 101), or Alzheimer’s disease (AD, n = 94) were evaluated with brain MRI according to the CVRS of brain atrophy and small vessel disease. Validation of the CVRS with structural changes, neuropsychological tests, and volumetric analyses was performed. Results: The CVRS revealed a high intra-rater and inter-rater agreement and it reflected the structural changes of subjects with NC, MCI, and AD better than volumetric measures (CVRS-coronal: F = 13.5, p < 0.001; CVRS-axial: F = 19.9, p < 0.001). The area under the receiver operation curve (aROC) of the CVRS showed higher accuracy than volumetric analyses. (NC versus MCI aROC: CVRS-coronal, 0.777; CVRS-axial, 0.773; MCI versus AD aROC: CVRS-coronal, 0.680; CVRS-axial, 0.681). Conclusion: The CVRS can be used clinically to conveniently measure structural changes of brain. It reflected cerebral structural changes of clinical groups and correlated with the age better than volumetric measures.
