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Journal: Journal of Alzheimer's disease : JAD


Amyloid-β peptide is presumably a key etiological factor involved in the pathogenesis of Alzheimer’s disease (AD), and several hypotheses exist on the possible ways Aβ contributes to the progression of the disease. There are reports on the nuclear localization of Aβ and very limited evidence on its DNA binding property. The present study provided the mechanism of Aβ enantiomers binding to DNA and showed that Aβ40L induces ψ-DNA, while Aβ40D causes only altered B-DNA. Further, we evidenced the DNA nicking property of Aβ enantiomers and endonuclease mimicking behavior. The role of Aβ in modulating DNA stability was reported by altered melting temperature and ethidium bromide binding studies. The data provides new evidence on stereospecific dependent Aβ-DNA interaction and we discuss its biological relevance to neurodegeneration. Our results imply that Aβ-DNA interaction needs to be considered a significant cause of the toxicity in the pathogenesis of AD.

Concepts: Alzheimer's disease, DNA, Critical thinking, Causality, Biology, Peptide, Ethidium bromide, Mutagen


Matrix metalloproteinases (MMPs) and their natural tissue inhibitors (TIMPs) are involved in cell signaling processes and the release of extracellular matrix (ECM) and non-ECM molecules. Nonregulated MMP activity and an imbalance between metalloproteinases and their inhibitors might contribute to various disorders, including neurodegenerative diseases such as Alzheimer’s disease (AD), which is the most common cause of dementia. There is a complex relationship between MMPs and TIMPs with AD. It has been shown that MMPs and TIMPs are localized in neuritic senile plaques and neurofibrillary tangles in the postmortem brains of patients with AD. Some MMPs have also been shown to induce tau aggregation and the formation of neurofibrillary tangles in vitro. Moreover, MMPs contribute to AD pathogenesis via the disruption of the blood-brain barrier and promotion of neurodegeneration. However, MMPs can degrade both soluble and fibrillar forms of amyloid-β (Aβ). It has also been shown that Aβ enhances the expression of MMPs in neuroglial cultures and induces the release of TIMP-1 by brain cells. Inhibition of Aβ-induced MMP activity resulted in an improvement of performance tests in mice. Moreover, simultaneous examination of MMP-9, MMP-2, and TIMP-1 in the CSF contributed to the ability to differentiate between AD and other types of dementia. Thus, the aim of this literature study was to describe the role of MMPs and TIMPs in neurodegeneration, as well as their potential usefulness as CSF or plasma biomarkers in the diagnosis of AD as well as other neurodegenerative disorders and vascular dementia.

Concepts: Alzheimer's disease, Extracellular matrix, Neurology, Neurodegeneration, Neurodegenerative disorders, Matrix metalloproteinase, Tissue inhibitor of metalloproteinases, Neurodegenerative diseases


BACKGROUND: Randomized clinical trials have evaluated the efficacy of acetylcholinesterase inhibitors (AChE-Is) and memantine across a wide range of Alzheimer’s disease (AD) severity. However, these drugs are prescribed and reimbursed according to precise upper and lower cut off scores of cognitive tests. OBJECTIVES: To verify whether the efficacy of pharmacological treatment had any dependence on the severity of dementia in AD patients. METHODS: Published English-language randomized, placebo-controlled trials evaluating the efficacy of AChE-Is or memantine at any dose, over any length of time, in patients with any severity of dementia due to AD were included. Cognitive, behavioral, and functional outcomes were extracted from each study and multiple outcomes from the same trial were pooled to obtain a unique indicator of efficacy for cognition, functional impairment, and behavioral and psychological disturbances. The existence of a relationship between size of the treatment effect and severity of dementia, measured with the Mini-Mental State Examination, was determined using parametric and non-parametric correlation analyses. RESULTS: Both AChE-Is and memantine had significant effects on cognition. Functional and psycho-behavioral outcomes were reported less frequently but also showed significant efficacy of treatment. High heterogeneity among studies was found within and between the different drugs. The efficacy of all drugs except memantine was independent from dementia severity in all domains. Memantine effect on functional impairment was better in more severe patients. CONCLUSIONS: The modest beneficial effects of anti-dementia drugs on cognition are independent from dementia severity. Memantine is more effective on functional incompetence only in severe patients.

Concepts: Alzheimer's disease, Psychology, Clinical trial, Effectiveness, Acetylcholine, Acetylcholinesterase inhibitor, Memantine, Donepezil


As the number of older adults turning to the Internet for health information increases, so does the potential for online information to have a substantial impact on the patient-physician relationship and on their health. Inaccurate information may weaken patient-physician relationships or result in increased physician visits and health-anxiety, while high quality information may allow Internet users to make better decisions about their health.

Concepts: Medicine


Alzheimer’s disease (AD) is a progressive degeneration of the brain, inducing memory decline, inability in learning, and behavioral alterations, resulting progressively in a marked deterioration of all mental activities and eventually a vegetative state. The main causative factor, however, is still unclear. The implication of amyloid-β, AβPP, tau protein, the selective loss of neurons, the alteration of the synapses, the cytoskeletal changes, and the morphological alterations of the brain capillaries contribute substantially to the pathogenetic profile of the disease, without sufficiently enlightening the initial steps of the pathological procedures. The ultrastructure of the neuronal organelles as well as histochemical studies revealed substantial alterations, primarily concerning mitochondria. In this study, the morphological and morphometric alterations of the Golgi apparatus (GA) are described in the Purkinje cells of the cerebellum in twenty AD brains, studied with electron microscopy. As it is well established, GA has a very important role to play in many procedures such as glycosylation, sulfation, and proteolysis of protein systems, which are synthesized in the endoplasmic reticulum of nerve cells and glia. GA may also play a crucial role in protein trafficking and in misfolding of protein aggregates. In addition, the hyperphosphorylation of tau protein is closely related with the pathology of GA. In AD cases, described in this study, an obvious fragmentation of the cisternae of GA was observed in the Purkinje cells of the vermis and the cerebellar hemispheres. This alteration of GA may be associated with alterations of microtubules, impaired protein trafficking, and dendritic, spinal, and synaptic pathology, since protein trafficking plays an essential role in the three dimensional organization of the dendritic arbor and in the integrity of the synaptic components.

Concepts: Neuron, Cell, Brain, Golgi apparatus, Endoplasmic reticulum, Human brain, Cerebellum, Purkinje cell


Traumatic brain injury (TBI) is thought to be a risk factor for dementia, including dementia due to Alzheimer’s disease (AD). However, the influence of TBI history on the neuropsychological course of AD is unknown and, more broadly, the effect of TBI history on age-related cognitive change is poorly understood. We examined the relationship between history of TBI with loss of consciousness (LOC) history and cognitive change in participants with normal cognition and probable AD, stratified by APOEɛ4 allele status. The sample included 706 participants (432 with normal cognition; 274 probable AD) from the National Alzheimer’s Coordinating Center (NACC) dataset that completed the Uniform Data Set evaluation between 2005 and 2014. Normal and probable AD participants with a history of TBI were matched to an equal number of demographically and clinically similar participants without a TBI history. In this dataset, TBI with LOC was defined as brain trauma with brief or extended unconsciousness. For the normal and probable AD cohorts, there was an average of 3.2±1.9 and 1.8±1.1 years of follow-up, respectively. 30.8% of the normal cohort were APOEɛ4 carriers, whereas 70.8% of probable AD participants were carriers. Mixed effects regressions showed TBI with LOC history did not affect rates of cognitive change in APOEɛ4 carriers and non-carriers. Findings from this study suggest that TBI with LOC may not alter the course of cognitive function in older adults with and without probable AD. Future studies that better characterize TBI (e.g., severity, number of TBIs, history of subconconcussive exposure) are needed to clarify the association between TBI and long-term neurocognitive outcomes.

Concepts: Psychology, Brain, Traumatic brain injury, Neurocognitive, Cognition, Dementia, Mind, Cognitive neuroscience


Chronic traumatic encephalopathy (CTE) is a tauopathy associated with prior exposure to repetitive head impacts, such as those incurred through American football and other collision sports. Diagnosis is made through neuropathological examination. Many of the clinical features of CTE are common in the general population, with and without a history of head impact exposure, making clinical diagnosis difficult. As is now common in the diagnosis of other neurodegenerative disorders, such as Alzheimer’s disease, there is a need for methods to diagnose CTE during life through objective biomarkers.

Concepts: Alzheimer's disease, Greek loanwords, Neurology, Neurodegenerative disorders, Dementia, Tau protein, Tauopathy, Proteopathy


The purpose of this study was to investigate the potential therapeutic qualities of Δ9-tetrahydrocannabinol (THC) with respect to slowing or halting the hallmark characteristics of Alzheimer’s disease. N2a-variant amyloid-β protein precursor (AβPP) cells were incubated with THC and assayed for amyloid-β (Aβ) levels at the 6-, 24-, and 48-hour time marks. THC was also tested for synergy with caffeine, in respect to the reduction of the Aβ level in N2a/AβPPswe cells. THC was also tested to determine if multiple treatments were beneficial. The MTT assay was performed to test the toxicity of THC. Thioflavin T assays and western blots were performed to test the direct anti-Aβ aggregation significance of THC. Lastly, THC was tested to determine its effects on glycogen synthase kinase-3β (GSK-3β) and related signaling pathways. From the results, we have discovered THC to be effective at lowering Aβ levels in N2a/AβPPswe cells at extremely low concentrations in a dose-dependent manner. However, no additive effect was found by combining caffeine and THC together. We did discover that THC directly interacts with Aβ peptide, thereby inhibiting aggregation. Furthermore, THC was effective at lowering both total GSK-3β levels and phosphorylated GSK-3β in a dose-dependent manner at low concentrations. At the treatment concentrations, no toxicity was observed and the CB1 receptor was not significantly upregulated. Additionally, low doses of THC can enhance mitochondria function and does not inhibit melatonin’s enhancement of mitochondria function. These sets of data strongly suggest that THC could be a potential therapeutic treatment option for Alzheimer’s disease through multiple functions and pathways.

Concepts: Alzheimer's disease, Protein, Mitochondrion, Effect, Effectiveness, Peptide, Cytotoxicity, Amyloid precursor protein


Background: The ability to predict the length of time to death and institutionalization has strong implications for Alzheimer’s disease patients and caregivers, health policy, economics, and the design of intervention studies. Objective: To develop and validate a prediction algorithm that uses data from a single visit to estimate time to important disease endpoints for individual Alzheimer’s disease patients. Method: Two separate study cohorts (Predictors 1, N = 252; Predictors 2, N = 254), all initially with mild Alzheimer’s disease, were followed for 10 years at three research centers with semiannual assessments that included cognition, functional capacity, and medical, psychiatric, and neurologic information. The prediction algorithm was based on a longitudinal Grade of Membership model developed using the complete series of semiannually-collected Predictors 1 data. The algorithm was validated on the Predictors 2 data using data only from the initial assessment to predict separate survival curves for three outcomes. Results: For each of the three outcome measures, the predicted survival curves fell well within the 95% confidence intervals of the observed survival curves. Patients were also divided into quintiles for each endpoint to assess the calibration of the algorithm for extreme patient profiles. In all cases, the actual and predicted survival curves were statistically equivalent. Predictive accuracy was maintained even when key baseline variables were excluded, demonstrating the high resilience of the algorithm to missing data. Conclusion: The new prediction algorithm accurately predicts time to death, institutionalization, and need for full-time care in individual Alzheimer’s disease patients; it can be readily adapted to predict other important disease endpoints. The algorithm will serve an unmet clinical, research, and public health need.

Concepts: Scientific method, Prediction, Futurology, Future, Prophecy, Hypothesis, Prediction interval, Divination


The study objective was to evaluate the safety and efficacy of deep brain stimulation (DBS) at the ventral capsule/ventral striatum (VC/VS) region to specifically modulate frontal lobe behavioral and cognitive networks as a novel treatment approach for Alzheimer’s disease (AD) patients. This is a non-randomized phase I prospective open label interventional trial of three subjects with matched comparison groups. AD participants given DBS for at least 18 months at the VC/VS target were compared on the Clinical Dementia Rating-Sum of Boxes (CDR-SB), our primary outcome clinical measure, to matched groups without DBS from the AD Neuroimaging Initiative (ADNI) cohort. Serial 2-Deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET) images of AD participants were also compared longitudinally over time. Three AD DBS participants were matched to subjects from the ADNI cohort. All participants tolerated DBS well without significant adverse events. All three AD DBS participants had less performance decline and two of them meaningfully less decline over time on our primary outcome measure, CDR-SB, relative to matched comparison groups from the ADNI using score trajectory slopes. Minimal changes or increased metabolism on FDG-PET were seen in frontal cortical regions after chronic DBS at the VC/VS target. The first use of DBS in AD at a frontal lobe behavior regulation target (VC/VS) was well-tolerated and revealed less performance decline in CDR-SB. Frontal network modulation to improve executive and behavioral deficits should be furthered studied in AD.

Concepts: Alzheimer's disease, Psychology, Clinical trial, Medical imaging, Positron emission tomography, Neuroimaging, Positron, Cerebral cortex