Journal of Alzheimer's Disease - Volume 44, issue 3

Authors: Perry, George

Article Type: Editorial

DOI: 10.3233/JAD-142264

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 725-725, 2015

Authors: Merril, Carl R. | Ghanbari, Hossein A.

Article Type: Editorial

DOI: 10.3233/JAD-142263

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 727-728, 2015

Authors: Khan, Tapan K. | Alkon, Daniel L.

Article Type: Review Article

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. AD biomarker technologies currently under development include in vivo brain imaging with PET and MRI …(i.e., imaging of amyloid plaques, biochemical assays 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 lumbar puncture, 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 (a few with high sensitivity and specificity) that require minimally invasive skin or blood samples. Show more

Keywords: Alzheimer's disease biomarkers, blood cell-based biomarkers, fibroblast-based biomarkers, lipidomic biomarkers, metabolic biomarkers, peripheral biomarkers, proteomic biomarkers

DOI: 10.3233/JAD-142262

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 729-744, 2015

Authors: Ingenbleek, Yves | Bernstein, Larry H.

Article Type: Review Article

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 (H2 S) impairing anti-oxidative capacities. Elderly persons constitute a vulnerable population group exposed to increasing Hcy burden and declining H2 S 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. Show more

Keywords: Alzheimer's disease, homocysteine, hydrogen sulfide, lean body mass, nutritional assessment, retinoids, transthyretin

DOI: 10.3233/JAD-141950

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 745-754, 2015

Authors: Marchant, Natalie L. | Howard, Robert J.

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, anxiety, APOE, cognitive reserve, depression, mindfulness, neuroticism, PTSD, sleep, stress

DOI: 10.3233/JAD-141515

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 755-770, 2015

Authors: Hascup, Kevin N. | Hascup, Erin R.

Article Type: Short Communication

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.

Keywords: Alzheimer's disease, biological markers, cognition, glutamic acid

DOI: 10.3233/JAD-142160

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 771-776, 2015

Authors: Okamoto, Nozomi | Morikawa, Masayuki | Tomioka, Kimiko | Yanagi, Motokazu | Amano, Nobuko | Kurumatani, Norio

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, dementia, memory, periodontal disease, prospective cohort study, tooth loss

DOI: 10.3233/JAD-141665

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 777-786, 2015

Authors: Foley, Avery M. | Ammar, Zeena M. | Lee, Robert H. | Mitchell, Cassie S.

Article Type: Research Article

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. Show more

Keywords: Amyloid-β, cognitive deficit, memory, Morris water maze, mouse model, novel object recognition, Tg2576

DOI: 10.3233/JAD-142208

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 787-795, 2015

Authors: Rangaraju, Srikant | Gearing, Marla | Jin, Lee-Way | Levey, Allan

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, Kv1.3, microglia, neuroinflammation, potassium channel

DOI: 10.3233/JAD-141704

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 797-808, 2015

Authors: Teunissen, Charlotte E. | van der Flier, Wiesje M. | Scheltens, Philip | Duits, Anneli | Wijnstok, Nienke | Nijpels, Giel | Dekker, Jacqueline M. | Blankenstein, M.A. | Heijboer, Annemieke C.

Article Type: Research Article

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 cognitive decline 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 and were not related to cognitive decline. These results suggest that peripheral leptin levels do not play a role in evolution of AD pathology. Show more

Keywords: Alzheimer's disease, atrophy, blood-based biomarker, cognition, leptin, vascular dementia

DOI: 10.3233/JAD-141503

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 809-813, 2015