Obesity differentially effects the somatosensory cortex and striatum of TgF344-AD rats.

Lifestyle choices leading to obesity, hypertension and diabetes in mid-life contribute directly to the risk of late-life Alzheimer's disease (AD). However, in late-life or in late-stage AD conditions, obesity reduces the risk of AD and disease progression. To examine the mechanisms underlying this paradox, TgF344-AD rats were fed a varied high-carbohydrate, high-fat (HCHF) diet to induce obesity from nine months of age representing early stages of AD to twelve months of age in which rats exhibit the full spectrum of AD symptomology. We hypothesized regions primarily composed of gray matter, such as the somatosensory cortex (SSC), would be differentially affected compared to regions primarily composed of white matter, such as the striatum. We found increased myelin and oligodendrocytes in the somatosensory cortex of rats fed the HCHF diet with an absence of neuronal loss. We observed decreased inflammation in the somatosensory cortex despite increased AD pathology. Compared to the somatosensory cortex, the striatum had fewer changes. Overall, our results suggest that the interaction between diet and AD progression affects myelination in a brain region specific manner such that regions with a lower density of white matter are preferentially affected. Our results offer a possible mechanistic explanation for the obesity paradox.

Obesity differentially effects the somatosensory cortex and striatum of TgF344-AD rats.

Lifestyle choices leading to obesity, hypertension and diabetes in mid-life contribute directly to the risk of late-life Alzheimer's disease (AD). However, in late-life or in late-stage AD conditions, obesity reduces the risk of AD and disease progression. To examine the mechanisms underlying this paradox, TgF344-AD rats were fed a varied high-carbohydrate, high-fat (HCHF) diet to induce obesity from nine months of age representing early stages of AD to twelve months of age in which rats exhibit the full spectrum of AD symptomology. We hypothesized regions primarily composed of gray matter, such as the somatosensory cortex (SSC), would be differentially affected compared to regions primarily composed of white matter, such as the striatum. We found increased myelin and oligodendrocytes in the somatosensory cortex of rats fed the HCHF diet with an absence of neuronal loss. We observed decreased inflammation in the somatosensory cortex despite increased AD pathology. Compared to the somatosensory cortex, the striatum had fewer changes. Overall, our results suggest that the interaction between diet and AD progression affects myelination in a brain region specific manner such that regions with a lower density of white matter are preferentially effected. Our results offer a possible mechanistic explanation for the obesity paradox.

Obesity Facilitates Sex-Specific Improvement In Cognition And Neuronal Function In A Rat Model Of Alzheimer's Disease.

Obesity reduces or increases the risk of developing Alzheimer's disease (AD) depending on whether it is assessed in mid-life or late-life. There is currently no consensus on the relationship between obesity and AD or the mechanism or their interaction. Here, we aim to differentiate the cause-and-effect relationship between obesity and AD in a controlled rat model of AD. We induced obesity in 9-month-old TgF344-AD rats, that is pathology-load wise similar to early symptomatic phase of human AD. To more accurately model human obesity, we fed both TgF344-AD and non-transgenic littermates a varied high-carbohydrate-high-fat diet consisting of human food for 3 months. Obesity increased overall glucose metabolism and slowed cognitive decline in TgF344-AD rats, specifically executive function, without affecting non-transgenic rats. Pathological analyses of prefrontal cortex and hippocampus showed that obesity in TgF344-AD rats produced varied effects, with increased density of myelin and oligodendrocytes, lowered density and activation of microglia that we propose contributes to the cognitive improvement. However, obesity also decreased neuronal density, and promoted deposition of amyloid-beta plaques and tau inclusions. After 6 months on the high-carbohydrate-high-fat diet, detrimental effects on density of neurons, amyloid-beta plaques, and tau inclusions persisted while the beneficial effects on myelin, microglia, and cognitive functions remained albeit with a lower effect size. By examining the effect of sex, we found that both beneficial and detrimental effects of obesity were stronger in female TgF344-AD rats indicating that obesity during early symptomatic phase of AD is protective in females.

Compromised Cortical-Hippocampal Network Function From Transient Hypertension: Linking Mid-Life Hypertension to Late Life Dementia Risk.

Mid-life hypertension is a major risk factor for developing dementia later in life. While anti-hypertensive drugs restore normotension, dementia risk remains above baseline suggesting that brain damage sustained during transient hypertension is irreversible. The current study characterized a rat model of transient hypertension with an extended period of normotensive recovery: F344 rats were treated with L-NG-Nitroarginine methyl ester (L-NAME) for 1 month to induce hypertension then allowed up to 4 months of recovery. With respect to cognitive deficits, comparison between 1 month and 4 months of recovery identified initial deficits in spatial memory that resolved by 4 months post-hypertension; contrastingly, loss of cognitive flexibility did not. The specific cells and brain regions underlying these cognitive deficits were investigated. Irreversible structural damage to the brain was observed in both the prefrontal cortex and the hippocampus, with decreased blood vessel density, myelin and neuronal loss. We then measured theta-gamma phase amplitude coupling as a readout for network function, a potential link between the observed cognitive and pathological deficits. Four months after hypertension, we detected decreased theta-gamma phase amplitude coupling within each brain region and a concurrent increase in baseline connectivity between the two regions reflecting an attempt to maintain function that may account for the improvement in spatial memory. Our results demonstrate that connectivity between prefrontal cortex and hippocampus is a vulnerable network affected by transient hypertension which is not rescued over time; thus demonstrating for the first time a mechanistic link between the long-term effects of transient hypertension and dementia risk.

Parvalbumin neuroplasticity compensates for somatostatin impairment, maintaining cognitive function in Alzheimer's disease.

BACKGROUND: Patient-to-patient variability in the degree to which ß-amyloid, tau and neurodegeneration impact cognitive decline in Alzheimer's disease (AD) complicates disease modeling and treatment. However, the underlying mechanisms leading to cognitive resilience are not resolved. We hypothesize that the variability in cognitive function and loss relates to neuronal resilience of the hippocampal GABAergic network. METHODS: We compared TgF344-AD and non-transgenic littermate rats at 9, 12, and 15 months of age. Neurons, ß-amyloid plaques and tau inclusions were quantified in hippocampus and entorhinal cortex. Somatostatin (SST) and parvalbumin (PVB) interneurons were traced to examine hippocampal neuroplasticity and cognition was tested in the Barnes maze. RESULTS: The 9-month-old TgF344-AD rats exhibited loss of neurons in the entorhinal cortex and hippocampus. Hippocampal neuronal compensation was observed in 12-month TgF344-AD rats, with upregulation of GABAergic interneuronal marker. By 15 months, the TgF344-AD rats had robust loss of excitatory and inhibitory neurons. ß-Amyloid and tau pathology accumulated continuously across age. SST interneurons exhibited tau inclusions and atrophy from 9 months, whereas PVB interneurons were resilient until 15 months. The hippocampal PVB circuit underwent neuroplastic reorganization with increased dendritic length and complexity in 9- and 12-month-old TgF344-AD rats, before atrophy at 15 months. Strikingly, 12-month-old TgF344-AD rats were resilient in executive function and cognitive flexibility. Cognitive resilience in TgF344-AD rats occurred as maintenance of function between 9 and 12 months of age despite progressive spatial memory deficits, and was sustained by PVB neuroplasticity. CONCLUSIONS: Our results demonstrate the inherent neuronal processes leading to cognitive maintenance, and describe a novel finding of endogenous cognitive resilience in an AD model.

Cerebrovascular damage after midlife transient hypertension in non-transgenic and Alzheimer's disease rats.

Hypertension, including transient events, is a major risk factor for developing late-onset dementia and Alzheimer's disease (AD). Anti-hypertensive drugs facilitate restoration of normotension without amelioration of increased dementia risk suggesting that transient hypertensive insults cause irreversible damage. This study characterized the contribution of transient hypertension to sustained brain damage as a function of normal aging and AD. To model transient hypertension, we treated F344TgAD and non-transgenic littermate rats with L-NG-Nitroarginine methyl ester (L-NAME) for one month, ceased treatment and allowed for a month of normotensive recovery. We then examined the changes in the structure and function of the cerebrovasculature, integrity of white matter, and progression of AD pathology. As independent factors, both transient hypertension and AD compromised structural and functional integrity across the vascular bed, while combined effects of hypertension and AD yielded the largest deficits. Combined effects of transient hypertension and AD genotype resulted in loss of cortical myelin particularly in the cingulate cortex which is crucial for cognitive function. Increased cerebral amyloid angiopathy, a prominent pathology of AD, was detected after transient hypertension as were up- and down-regulation of proteins associated with cerebrovascular remodeling - osteopontin, ROCK1 and ROCK2, in F344TgAD rats even 30 days after restoration of normotension. In conclusion, transient hypertension caused permanent cerebrovasculature and brain parenchymal damage in both normal aging and AD. Our results corroborate human studies that have found close correlation between transient hypertension in midlife and white matter lesions later in life outlining vascular pathologies as pathological links to increased risk of dementia.

A comparison between the effectiveness of a gamified approach with the conventional approach in point-of-care ultrasonographic training.

BACKGROUND: Although gamification increases user engagement, its effectiveness in point-of-care ultrasonographic training has yet to be fully established. This study was conducted with the primary outcome of evaluating its effectiveness in point-of-care ultrasonographic training as compared to conventional approach. METHODS: Participants consisting of junior doctors were randomized into either the (1) gamified or the (2) conventional educational approach for ultrasonographic training. RESULTS: A total of 31 junior doctors participated in this study (16 participants in gamified arm, 15 in the conventional arm after one participant from the conventional arm dropped out due to work commitment). Two-way mixed ANOVA test showed that there was no statistically significant interaction between the types of educational approach and time of testing (pre-test, post-test, 2 months post-training) for both theoretical knowledge score and practical skills score, with F(2, 58) = 39.6, p < 0.001, partial η2 = 0.4 and F(2, 58) = 3.06, p = 0.06, partial η2 = 0.095, respectively. For theoretical knowledge score, pairwise comparisons showed that the mean 2 months post-training scores (20.28 +/- 0.70, 95% CI 18.87-21.69) and mean post-test scores (20.27 +/- 0.65, 95% CI 18.94-21.60) were better than the pre-test scores (12.99 +/- 0.50, 95% CI 11.97-14.00) with p-values < 0.001 for both comparisons respectively. Similarly, for practical skill score, pairwise comparisons showed that the mean 2 months post-training scores (20.28 +/- 0.70, 95% CI 18.87-21.69) and mean post-test scores (20.27 +/- 0.65, 95% CI 18.94-21.60) were also better than the pre-test scores (12.99 +/- 0.50, 95% CI 11.97-14.00) with p-values < 0.001 for both comparisons respectively. Participants in the gamification arm generally perceived the various game elements and game mechanics as useful in contributing and motivating them to learn ultrasonography. CONCLUSIONS: Gamification approach could be an effective alternative to conventional approach in point-of-care ultrasonographic training.

Combinatorial Treatment Using Umbilical Cord Perivascular Cells and Aß Clearance Rescues Vascular Function Following Transient Hypertension in a Rat Model of Alzheimer Disease.

Transient hypertension is a risk factor for Alzheimer disease (AD), but the effects of this interaction on brain vasculature are understudied. Addressing vascular pathology is a promising avenue to potentiate the efficacy of treatments for AD. We used arterial spin labeling magnetic resonance imaging to longitudinally assess brain vascular function and immunohistopathology to examine cerebrovascular remodeling and amyloid load. Hypertension was induced for 1 month by administration of l-NG-nitroarginine-methyl-ester in TgF344-AD rats at the prodromal stage. Following hypertension, nontransgenic rats showed transient cerebrovascular changes, whereas TgF344-AD animals exhibited sustained alterations in cerebrovascular function. Human umbilical cord perivascular cells in combination with scyllo-inositol, an inhibitor of Aß oligomerization, resulted in normalization of hippocampal vascular function and remodeling, in contrast to either treatment alone. Prodromal stage hypertension exacerbates latter AD pathology, and the combination of human umbilical cord perivascular cells with amyloid clearance promotes cerebrovascular functional recovery.

Imaging the Effects of ß-Hydroxybutyrate on Peri-Infarct Neurovascular Function and Metabolism.

Background and Purpose- Recent evidence suggests great potential of metabolically targeted interventions for treating neurological disorders. We investigated the use of the endogenous ketone body ß-hydroxybutyrate (BHB) as an alternate metabolic substrate for the brain in the acute phase of ischemia because postischemic hyperglycemia and brain glucose metabolism elevation compromise functional recovery. Methods- We delivered BHB (or vehicle) 1 hour after ischemic insult induced by cortical microinjection of endothelin-1 in sensorimotor cortex of rats. Two days after ischemic insult, the rats underwent multimodal characterization of the BHB effects. We examined glucose uptake on 2-Deoxy-d-glucose chemical exchange saturation transfer magnetic resonance imaging, cerebral hemodynamics on continuous arterial spin labeling magnetic resonance imaging, resting-state field potentials by intracerebral multielectrode arrays, Neurological Deficit Score, reactive oxygen species production, and astrogliosis and neuronal death. Results- When compared with vehicle-administered animals, BHB-treated cohort showed decreased peri-infarct neuronal glucose uptake which was associated with reduced oxidative stress, diminished astrogliosis and neuronal death. Functional examination revealed ameliorated neuronal functioning, normalized perilesional resting perfusion, and ameliorated cerebrovascular reactivity to hypercapnia, suggesting improved functioning. Cellular and functional recovery of the neurogliovascular unit in the BHB-treated animals was associated with improved performance on the withdrawal test. Conclusions- We characterize the effects of the ketone body BHB administration at cellular and system levels after focal cortical stroke. The results demonstrate that BHB curbs the peri-infarct glucose-metabolism driven production of reactive oxygen species and astrogliosis, culminating in improved neurogliovascular and functional recovery.

Early-stage attenuation of phase-amplitude coupling in the hippocampus and medial prefrontal cortex in a transgenic rat model of Alzheimer's disease.

Alzheimer's disease (AD) is pathologically characterized by amyloid-ß peptide (Aß) accumulation, neurofibrillary tangle formation, and neurodegeneration. Preclinical studies on neuronal impairments associated with progressive amyloidosis have demonstrated some Aß-dependent neuronal dysfunction including modulation of gamma-aminobutyric acid-ergic signaling. The present work focuses on the early stage of disease progression and uses TgF344-AD rats that recapitulate a broad repertoire of AD-like pathologies to investigate the neuronal network functioning using simultaneous intracranial recordings from the hippocampus (HPC) and the medial prefrontal cortex (mPFC), followed by pathological analyses of gamma-aminobutyric acid (GABAA ) receptor subunits α1, α5, and δ, and glutamic acid decarboxylases (GAD65 and GAD67). Concomitant to amyloid deposition and tau hyperphosphorylation, low-gamma band power was strongly attenuated in the HPC and mPFC of TgF344-AD rats in comparison to those in non-transgenic littermates. In addition, the phase-amplitude coupling of the neuronal networks in both areas was impaired, evidenced by decreased modulation of theta band phase on gamma band amplitude in TgF344-AD animals. Finally, the gamma coherence between HPC and mPFC was attenuated as well. These results demonstrate significant neuronal network dysfunction at an early stage of AD-like pathology. This network dysfunction precedes the onset of cognitive deficits and is likely driven by Aß and tau pathologies. This article is part of the Special Issue "Vascular Dementia".

Rho-associated protein kinases as therapeutic targets for both vascular and parenchymal pathologies in Alzheimer's disease.

The causes of late-onset Alzheimer's disease are unclear and likely multifactorial. Rho-associated protein kinases (ROCKs) are ubiquitously expressed signaling messengers that mediate a wide array of cellular processes. Interestingly, they play an important role in several vascular and brain pathologies implicated in Alzheimer's etiology, including hypertension, hypercholesterolemia, blood-brain barrier disruption, oxidative stress, deposition of vascular and parenchymal amyloid-beta peptides, tau hyperphosphorylation, and cognitive decline. The current review summarizes the functions of ROCKs with respect to the various risk factors and pathologies on both sides of the blood-brain barrier and present support for targeting ROCK signaling as a multifactorial and multi-effect approach for the prevention and amelioration of late-onset Alzheimer's disease. This article is part of the Special Issue "Vascular Dementia".

Early neurovascular dysfunction in a transgenic rat model of Alzheimer's disease.

Alzheimer's disease (AD), pathologically characterized by amyloid-ß peptide (Aß) accumulation, neurofibrillary tangle formation, and neurodegeneration, is thought to involve early-onset neurovascular abnormalities. Hitherto studies on AD-associated neurovascular injury have used animal models that exhibit only a subset of AD-like pathologies and demonstrated some Aß-dependent vascular dysfunction and destabilization of neuronal network. The present work focuses on the early stage of disease progression and uses TgF344-AD rats that recapitulate a broader repertoire of AD-like pathologies to investigate the cerebrovascular and neuronal network functioning using in situ two-photon fluorescence microscopy and laminar array recordings of local field potentials, followed by pathological analyses of vascular wall morphology, tau hyperphosphorylation, and amyloid plaques. Concomitant to widespread amyloid deposition and tau hyperphosphorylation, cerebrovascular reactivity was strongly attenuated in cortical penetrating arterioles and venules of TgF344-AD rats in comparison to those in non-transgenic littermates. Blood flow elevation to hypercapnia was abolished in TgF344-AD rats. Concomitantly, the phase-amplitude coupling of the neuronal network was impaired, evidenced by decreased modulation of theta band phase on gamma band amplitude. These results demonstrate significant neurovascular network dysfunction at an early stage of AD-like pathology. Our study identifies early markers of pathology progression and call for development of combinatorial treatment plans.

Can Team Triage Improve Patient Flow in the Emergency Department? A Systematic Review and Meta-Analysis.

This systematic review was performed as a feasibility study for revamping the triage service of an emergency department (ED) in a district hospital. In view of the overcrowding problem that plagues EDs worldwide, we reviewed evidence from randomized controlled trials (RCTs) to determine whether ED team triage improves patient flow in comparison with single-nurse triage. We measured improvement in patient flow in terms of the reduction in length of stay (LOS) or wait time (WT) for all ED patients. Adopting the Cochrane methodology, we searched and evaluated data sources for RCTs comparing patients assessed by an ED triage team, with patients receiving single-nurse triage at the same site. The data extracted were independently reviewed by 2 authors for inclusion and quality assessment. As for risk of bias across studies, there was an overall assessment of every outcome across the included studies according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria for RCTs. In total, 2,164 studies were identified and 2,106 were excluded on the basis of title/abstract, leaving 58 articles for full assessment. Four trials (all cluster RCTs) involving 14,772 patients (165 clusters) met the inclusion criteria. On the basis of our analysis, there was no statistically significant or clinically relevant reduction of LOS and WT for all patients in these studies. One study reported death as an outcome: Relative risk was 0.34 (95% CI [0.01, 8.24]), which suggested that team triage might reduce mortality. Overall, although we have found no conclusive evidence from RCTs to support the use of team triage for improving patient flow in the ED, the results need not deter nursing managers intending to introduce team triage for improving the morale of the triage nurse. However, they may need to consider economic and organizational factors, such as resource reallocation and staff receptiveness, in implementing the new practice.

Finding Text-Supported Gene-to-Disease Co-appearances with MOPED-Digger.

Gene/disease associations are a critical part of exploring disease causes and ultimately cures, yet the publications that might provide such information are too numerous to be manually reviewed. We present a software utility, MOPED-Digger, that enables focused human assessment of literature by applying natural language processing (NLP) to search for customized lists of genes and diseases in titles and abstracts from biomedical publications. The results are ranked lists of gene/disease co-appearances and the publications that support them. Analysis of 18,159,237 PubMed title/abstracts yielded 1,796,799 gene/disease co-appearances that can be used to focus attention on the most promising publications for a possible gene/disease association. An integrated score is provided to enable assessment of broadly presented published evidence to capture more tenuous connections. MOPED-Digger is written in Java and uses Apache Lucene 5.0 library. The utility runs as a command-line program with a variety of user-options and is freely available for download from the MOPED 3.0 website (moped.proteinspire.org).

Venular degeneration leads to vascular dysfunction in a transgenic model of Alzheimer's disease.

Most patients with Alzheimer's disease exhibit accumulation of amyloid-ß peptide on leptomeningeal and cortical arterioles, or cerebral amyloid angiopathy, which is associated with impaired vascular reactivity and accelerated cognitive decline. Despite widespread recognition of the significance of vascular dysfunction in Alzheimer's disease aetiology and progression, much uncertainty still surrounds the mechanism underlying Alzheimer's disease vascular injury. Studies to date have focused on amyloid-ß-induced damage to capillaries and plaque-associated arterioles, without examining effects across the entire vascular bed. In the present study, we investigated the structural and functional impairment of the feeding arteriolar versus draining venular vessels in a transgenic murine Alzheimer's disease model, with a particular focus on the mural cell populations that dictate these vessels' contractility. Although amyloid-ß deposition was restricted to arterioles, we found that vascular impairment extended to the venules, which showed significant depletion of their mural cell coverage by the mid-stage of Alzheimer's disease pathophysiology. These structural abnormalities were accompanied by an abolishment of the normal vascular network flow response to hypercapnia: this functional impairment was so severe as to result in hypercapnia-induced flow decreases in the arterioles. Further pharmacological depletion of mural cells using SU6668, a platelet-derived growth factor receptor-ß antagonist, resulted in profound structural abnormalities of the cortical microvasculature, including vessel coiling and short-range looping, increased tortuosity of the venules but not of the arterioles, increased amyloid-ß deposition on the arterioles, and further alterations of the microvascular network cerebral blood flow response to hypercapnia. Together, this work shows hitherto unrecognized structural alterations in penetrating venules, demonstrates their functional significance and sheds light on the complexity of the relationship between vascular network structure and function in Alzheimer's disease.

scyllo-Inositol promotes robust mutant Huntingtin protein degradation.

Huntington disease is characterized by neuronal aggregates and inclusions containing polyglutamine-expanded huntingtin protein and peptide fragments (polyQ-Htt). We have used an established cell-based assay employing a PC12 cell line overexpressing truncated exon 1 of Htt with a 103-residue polyQ expansion that yields polyQ-Htt aggregates to investigate the fate of polyQ-Htt-drug complexes. scyllo-Inositol is an endogenous inositol stereoisomer known to inhibit accumulation and toxicity of the amyloid-ß peptide and α-synuclein. In light of these properties, we investigated the effect of scyllo-inositol on polyQ-Htt accumulation. We show that scyllo-inositol lowered the number of visible polyQ-Htt aggregates and robustly decreased polyQ-Htt protein abundance without concomitant cellular toxicity. We found that scyllo-inositol-induced polyQ-Htt reduction was by rescue of degradation pathways mediated by the lysosome and by the proteasome but not autophagosomes. The rescue of degradation pathways was not a direct result of scyllo-inositol on the lysosome or proteasome but due to scyllo-inositol-induced reduction in mutant polyQ-Htt protein levels.

Amyloid-ß-dependent compromise of microvascular structure and function in a model of Alzheimer's disease.

The majority of patients with Alzheimer's disease have cerebral amyloid angiopathy, thus showing deposition of amyloid-ß peptides in the walls of leptomeningeal and cortical arterioles. These deposits are believed to result from impaired clearance of parenchymal amyloid-ß peptides. In the current work, we examined the changes in cortical microvascular structure and function in situ in TgCRND8, a transgenic mouse model of Alzheimer's disease. In contrast to venules, cortical arterioles were shown to increase in tortuosity and decrease in calibre with amyloid-ß peptide accumulation. These structural changes were accompanied by progressive functional compromise, reflected in higher dispersion of microvascular network transit times, elongation of the transit times, and impaired microvascular reactivity to hypercapnia in the transgenic mice. Moreover, inhibition of amyloid-ß peptide oligomerization and fibrillization via post-weaning administration of scyllo-inositol, a naturally occurring stereoisomer of myo-inositol, rescued both structural and functional impairment of the cortical microvasculature in this Alzheimer's disease model. These results demonstrate that microvascular impairment is directly correlated with amyloid-ß accumulation and highlight the importance of targeting cerebrovascular amyloid angiopathy clearance for effective diagnosis, monitoring of disease progression and treatment of Alzheimer's disease.

Inhibition of amyloid-beta peptide aggregation rescues the autophagic deficits in the TgCRND8 mouse model of Alzheimer disease.

scyllo-Inositol (SI) is an endogenous inositol stereoisomer known to inhibit aggregation and fibril formation of the amyloid-beta peptide (Aß). Human clinical trials using SI to treat Alzheimer disease (AD) patients have shown potential benefits. In light of the growing therapeutic potential of SI, the objective of our study was to gain a more thorough understanding of the mechanism of action. In addition to Aß plaques, a prominent pathological feature of AD is the extensive accumulation of autophagic vacuoles (AVs) suggesting dysfunction in this degradation pathway. Using the TgCRND8 mouse model for AD, we examined SI treatment effects on various components of the autophagic pathway. Autophagy impairment in TgCRND8 mice occurs in the latter stages of the pathway where AV-lysosome fusion and lysosomal degradation take place. SI treatment attenuated this impairment with a decrease in the size and the number of accumulated AVs. We propose that the beneficial effects of SI-Aß interactions may resolve autophagic deficiencies in the AD brains.

Clearance of amyloid-ß peptides by microglia and macrophages: the issue of what, when and where.

Accumulation of senile plaques consisting of amyloid-ß peptide (Aß) aggregates is a prominent pathological feature in Alzheimer's disease. Effective clearance of Aß from the brain parenchyma is thought to regulate the development and progression of the disease. Macrophages in the brain play an important role in Aß clearance by a variety of phagocytic and digestive mechanisms. Subpopulations of macrophages are heterogeneous such that resident microglia in the parenchyma, blood macrophages infiltrating from the periphery, and perivascular macrophages residing along cerebral vessels make functionally distinct contributions to Aß clearance. Despite phenotypic similarities between the different macrophage subsets, a series of in vivo models have been derived to differentiate their relative impacts on Aß dynamics as well as the molecular mechanisms underlying their activities. This review discusses the key findings from these models and recent research efforts to selectively enhance macrophage clearance of Aß.

Can familism be justified?

This paper argues against the continued practice of Confucian familism, even in its moderate form, in East Asian hospitals. According to moderate familism, a physician acting in concert with the patient's family may withhold diagnostic information from the patient, and may give it to the patient's family members without her prior approval. There are two main approaches to defend moderate familism: one argues that it can uphold patient's autonomy and protect her best interests; the other appeals to cultural relativism by construing the principle of 'family autonomy' to be incommensurable with that of individual autonomy. We respond to the first approach by explaining how the familist arguments either depend on some unreasonable assumptions or simply fail to articulate. The critique of the second approach is based on our recent survey showing that there is no dichotomy of relevant values between the East and the West: we believe that the result can effectively block the familist's reliance on certain traditional or cultural values to explain their resistance to the incorporation of pluralist values. Despite our disagreement with familism, we consider the Eastern emphasis on the family to be conducive to the communication between patient, family members and medical personnel, which is indispensible to the patient's well being and autonomy. We conclude that respect for patient autonomy is perfectly consistent with the involvement of the family in making medical decision as long as the family plays a merely consultant role.