Clinical Characterization of Veterans With Alzheimer Disease by Disease Severity in the United States.

PURPOSE: We aimed to examine the clinical characteristics of US veterans who underwent neurocognitive test score-based assessments of Alzheimer disease (AD) stage in the Veterans Affairs Healthcare System (VAHS). METHODS: Test dates for specific stages of AD were referenced as index dates to study behavioral and psychological symptoms of dementia (BPSD) and other patient characteristics related to utilization/work-up and time to death. PATIENTS: We identified veterans with AD and neurocognitive evaluations using the VAHS Electronic Health Record (EHR). RESULTS: Anxiety and sleep disorders/disturbances were the most documented BPSDs across all AD severity stages. Magnetic resonance imaging, neurology and psychiatry consultations, and neuropsychiatric evaluations were slightly higher in veterans with mild AD than in those at later stages. The overall average time to death from the first AD severity record was 5 years for mild and 4 years for moderate/severe AD. CONCLUSION: We found differences in clinical symptoms, healthcare utilization, and survival among the mild, moderate, and severe stages of AD. These differences are limited by the low documentation of BPSDs among veterans with test score-based AD stages. These data support the hypothesis that our cohorts represent coherent subgroups of patients with AD based on disease severity.

Network topology and patch connectivity affect dynamics in experimental and model metapopulations.

Biological populations are rarely isolated in space and instead interact with others via dispersal in metapopulations. Theory predicts that network connectivity patterns can have critical effects on network robustness, as certain topologies, such as scale-free networks, are more tolerant to disturbances than other patterns. However, at present, experimental evidence of how these topologies affect population dynamics in a metapopulation framework is lacking. We used experimental metapopulations of the aquatic protist Paramecium tetraurelia to determine how network topology influences occupation patterns. We created metapopulations engineered to be comparable in linkage density, but differing in their degree distribution. We compared random networks to scale-free networks by evaluating local population occupancy and abundance throughout 18-30 protist generations. In parallel, we used simulations to explore differences in patch occupation patterns among topologies. Our experimental results highlighted the importance of the balance between dispersal and extinction in the interaction with spatial network topology. Under low dispersal conditions, random metapopulations of P. tetraurelia reached higher abundance and higher occupancy (proportion of occupied patches) compared to scale-free systems in both experimental and simulated systems. Under high dispersal conditions, we did not detect differences between types of metapopulations. Increasing patch degree (i.e. number of connections per patch) reduced the probability of extinction of local populations in both types of networks. We suggest the interaction between colonization/extinction rates and network topology alters the likelihood of rescue effects which results in differential patterns of occupancy and abundance in metapopulations.

Using Video Telehealth to Deliver Patient-Centered Collaborative Care: The G-IMPACT Pilot.

Objectives: This pilot project aimed to explore a new model of healthcare delivery to older adult medically complex Veterans by combining telehealth technology with an interdisciplinary medical team operating in real time.Methods: The Geriatric-Interdisciplinary Mobile Patient Access Team (G-IMPACT) was comprised of a field team including a nurse practitioner and technology assistant who visited enrolled patients in their homes using synchronous video to link to a suite of geriatric specialists in a video-enabled room at a Veterans Affairs hospital. Clinicians interacted with patients, caregivers, and each other to develop mutually agreed upon treatment plans that were then immediately implemented in the field.Results: 11 total visits were conducted with 9 Veteran patients aged 55-91 (mean = 75.3 years). Both patients and clinicians reported a high level of satisfaction across multiple metrics, including visit quality, and positive indirect indicators of effectiveness were apparent from qualitative data.Conclusions: Nurse practitioner facilitated video visits allowed geriatric patients to meet with multiple specialists simultaneously with both high patient satisfaction and increased real-time care coordination.Clinical Implications: This project identified challenges and opportunities afforded by this type of real-time telehealth care delivery and can inform the development of future interdisciplinary mobile medical teams.

Evolution alters post-invasion temporal dynamics in experimental communities.

The causes and consequences of temporal variation in the abundance of organisms constitute central themes in ecological inquiry. Rapid evolution can occur over ecological time-scales, potentially resulting in altered temporal variation in abundance and complicating inferences about the consequences of temporal variation. We assessed whether evolution altered the temporal variability in species' abundances in simple assemblages of species. We then compared experimental results to predictions from two-species models to better understand our results in the context of competitive and predator-prey interactions. We compared founder populations and their evolved descendants in experimental communities of ciliates and rotifers. Using a series of orthogonal contrasts, we then evaluated whether: (a) evolutionary history of invaders or (b) residents, (c) co-evolution among invaders and residents, and (d) invasion itself altered temporal variability in species abundances following invasion by a novel species. Using two-species competition and predator-prey models, we also generated predictions to better understand the effects of evolution on temporal variation in the abundances of interacting species. Finally, we compared experimental and modelling results to aid in the interpretation of which interspecific interactions might be affected by ongoing evolution in our communities. In experimental populations, differing evolutionary histories resulted in significant differences among treatments in abundances and temporal variation in abundances of both resident and invading species. For the contrasts, we found evidence that evolutionary history of the invader and residents, co-evolution among invaders and residents, and invasion itself affected temporal variability in abundance, but the importance of each differed for the two communities and the species within those communities. When comparing experimental results to model predictions, the increased abundance and decreased temporal variation in one invader, Euplotes daidaleos, are potentially consistent with evolution resulting in reduced attack rates in the novel community. Evolutionary history alone can affect temporal variation in the abundances of species, generating important consequences for interspecific interactions among species and complicating inferences about the consequences of temporal variability in biological communities.

Amyloid ß synaptotoxicity is Wnt-PCP dependent and blocked by fasudil.

INTRODUCTION: Synapse loss is the structural correlate of the cognitive decline indicative of dementia. In the brains of Alzheimer's disease sufferers, amyloid ß (Aß) peptides aggregate to form senile plaques but as soluble peptides are toxic to synapses. We previously demonstrated that Aß induces Dickkopf-1 (Dkk1), which in turn activates the Wnt-planar cell polarity (Wnt-PCP) pathway to drive tau pathology and neuronal death. METHODS: We compared the effects of Aß and of Dkk1 on synapse morphology and memory impairment while inhibiting or silencing key elements of the Wnt-PCP pathway. RESULTS: We demonstrate that Aß synaptotoxicity is also Dkk1 and Wnt-PCP dependent, mediated by the arm of Wnt-PCP regulating actin cytoskeletal dynamics via Daam1, RhoA and ROCK, and can be blocked by the drug fasudil. DISCUSSION: Our data add to the importance of aberrant Wnt signaling in Alzheimer's disease neuropathology and indicate that fasudil could be repurposed as a treatment for the disease.

Pervasive interactions between foliar microbes and soil nutrients mediate leaf production and herbivore damage in a tropical forest.

Producing and retaining leaves underlie the performance and survivorship of seedlings in deeply shaded tropical forests. These habitats are characterized by conditions ideal for foliar bacteria, which can be potent plant pathogens. Leaf production, retention and susceptibility to enemies may ultimately depend upon interactions among soil nutrients and foliar microbes, yet this has never been tested. We experimentally evaluated the degree that foliar bacteria and soil resource supply mediate leaf dynamics for five common tree species (five different families) in a Panamanian forest. We reduced foliar bacteria with antibiotics for 29 months and measured leaf production, retention and damage for seedlings nested within a replicated 15-yr factorial nutrient enrichment experiment (nitrogen, N; phosphorus, P; potassium, K). Our results demonstrate that when we applied antibiotics, soil nutrients - particularly N - always regulated seedling leaf production (and to a lesser extent herbivore damage) for all five tree species. In addition, it was common for two macronutrients together to negate or completely reverse the impact of applying either one alone. Our findings of frequent plant-microbe-nutrient interactions are novel and suggest that these interactions may reinforce plant species-environment associations, thereby creating a fairly cryptic and fine-scale dimension of niche differentiation for coexisting tree species.

Foliar bacteria and soil fertility mediate seedling performance: a new and cryptic dimension of niche differentiation.

The phyllosphere (comprising the leaf surface and interior) is one of the world's largest microbial habitats and is host to an abundant and diverse array of bacteria. Nonetheless, the degree to which bacterial communities are benign, harmful, or beneficial to plants in situ is unknown. We tested the hypothesis that the net effect of reducing bacterial abundance and diversity would vary substantially among host species (from harmful to beneficial) and this would be strongly mediated by soil resource availability. To test this, we monitored tree seedling growth responses to commercial antibiotics among replicated resource supply treatments (N, P, K) in a tropical forest in Panama for 29 months. We applied either antibiotics or control water to replicated seedlings of five common tree species (Alseis blackiana, Desmopsis panamensis, Heisteria concinna, Sorocea affinis, and Tetragastris panamensis). These antibiotic treatments significantly reduced both the abundance and diversity of bacteria epiphytically as well as endophytically. Overall, the effect of antibiotics on performance was highly host specific. Applying antibiotics increased growth for three species by as much as 49% (Alseis, Heisteria, and Tetragastris), decreased growth for a fourth species by nearly 20% (Sorocea), and had no impact on a fifth species (Desmopsis). Perhaps more importantly, the degree to which foliar bacteria were harmful or not varied with soil resource supply. Specifically, applying antibiotics had no effect when potassium was added but increased growth rate by almost 40% in the absence of potassium. Alternatively, phosphorus enrichment caused the effect of bacteria to switch from being primarily beneficial to harmful or vice versa, but this depended entirely on the presence or absence of nitrogen enrichment (i.e., important and significant interactions). Our results are the first to demonstrate that the net effect of reducing the abundance and diversity of bacteria can have very strong positive and negative effects on seedling performance. Moreover, these effects were clearly mediated by soil resource availability. Though speculative, we suggest that foliar bacteria may interact with soil fertility to comprise an important, yet cryptic dimension of niche differentiation, which can have important implications for species coexistence.

Alzheimer's Disease Stage Transitions Among United States Veterans.

BACKGROUND: Alzheimer's disease (AD) and related dementias are progressive neurological disorders with stage-specific clinical features and challenges. An important knowledge gap is the "window of time" within which patients transition from mild cognitive impairment or mild AD to moderate or severe AD. Better characterization/establishment of transition times would help clinicians initiating treatments, including anti-amyloid therapy. OBJECTIVE: To describe cognitive test score-based AD stage transitions in Veterans with AD in the US Veterans Affairs Healthcare System (VAHS). METHODS: This retrospective analysis (2010-2019) identified Veterans with AD from the VAHS Electronic Health Record (EHR) notes. AD stage was based on Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), or Saint Louis University Mental Status (SLUMS) Examination scores in the EHR. RESULTS: We identified 296,519 Veterans with cognitive test-based AD staging. Over the 10-year study, the proportion of veterans with MMSE scores declined from 24.9% to 9.5% while those with SLUMS rose from 9.0% to 17.8%; and MoCA rose from 5.0% to 25.4%. The average forward transition times between each stage were approximately 2-4 years, whether assessed by MMSE, MoCA, or SLUMS. CONCLUSION: The average transition time for cognitive test-based assessments of initial cognitive decline, early-stage AD, and moderate/severe AD in the VAHS is 2-4 years. In view of the short window for introducing disease-modifying therapy and the significant benefits of early treatment of AD, our data suggest a critical need for treatment guidelines in the management of AD.

Effect of the ROCK inhibitor fasudil on the brain proteomic profile in the tau transgenic mouse model of Alzheimer's disease.

Introduction: The goal of this study is to explore the pharmacological potential of the amyloid-reducing vasodilator fasudil, a selective Ras homolog (Rho)-associated kinases (ROCK) inhibitor, in the P301S tau transgenic mouse model (Line PS19) of neurodegenerative tauopathy and Alzheimer's disease (AD). Methods: We used LC-MS/MS, ELISA and bioinformatic approaches to investigate the effect of treatment with fasudil on the brain proteomic profile in PS19 tau transgenic mice. We also explored the efficacy of fasudil in reducing tau phosphorylation, and the potential beneficial and/or toxic effects of its administration in mice. Results: Proteomic profiling of mice brains exposed to fasudil revealed the activation of the mitochondrial tricarboxylic acid (TCA) cycle and blood-brain barrier (BBB) gap junction metabolic pathways. We also observed a significant negative correlation between the brain levels of phosphorylated tau (pTau) at residue 396 and both fasudil and its metabolite hydroxyfasudil. Conclusions: Our results provide evidence on the activation of proteins and pathways related to mitochondria and BBB functions by fasudil treatment and support its further development and therapeutic potential for AD.

Prevalence of Mild Cognitive Impairment and Alzheimer's Disease Identified in Veterans in the United States.

Background: Diagnostic codes can be instrumental for case identification in Alzheimer's disease (AD) research; however, this method has known limitations and cannot distinguish between disease stages. Clinical notes may offer more detailed information including AD severity and can complement diagnostic codes for case identification. Objective: To estimate prevalence of mild cognitive impairment (MCI) and AD using diagnostics codes and clinical notes available in the electronic healthcare record (EHR). Methods: This was a retrospective study in the Veterans Affairs Healthcare System (VAHS). Health records from Veterans aged 65 years or older were reviewed during Fiscal Years (FY) 2010-2019. Overall, 274,736 and 469,569 Veterans were identified based on a rule-based algorithm as having at least one clinical note for MCI and AD, respectively; 201,211 and 149,779 Veterans had a diagnostic code for MCI and AD, respectively. During FY 2011-2018, likely MCI or AD diagnosis was defined by≥2 qualifiers (i.e., notes and/or codes)≥30 days apart. Veterans with only 1 qualifier were considered as suspected MCI/AD. Results: Over the 8-year study, 147,106 and 207,225 Veterans had likely MCI and AD, respectively. From 2011 to 2018, yearly MCI prevalence increased from 0.9% to 2.2%; yearly AD prevalence slightly decreased from 2.4% to 2.1%; mild AD changed from 22.9% to 26.8%, moderate AD changed from 26.5% to 29.1%, and severe AD changed from 24.6% to 30.7. Conclusions: The relative distribution of AD severities was stable over time. Accurate prevalence estimation is critical for healthcare resource allocation and facilitating patients receiving innovative medicines.

Clinical and Scientific Challenges to Effectiveness Studies Under Coverage with Evidence Development in Alzheimer's Disease.

The Centers for Medicare and Medicaid Services (CMS) has recently issued a national coverage determination for US Food and Drug Administration (FDA)-approved anti-amyloid monoclonal antibodies (mAbs) for the treatment of Alzheimer's disease (AD) under coverage with evidence development (CED). CED schemes are complex, costly, and challenging, and often fail to achieve intended objectives because of administrative and implementation issues. AD is a heterogeneous, progressive neurodegenerative disorder with complex care pathway that additionally presents scientific challenges related to the choice of study design and methods used in evaluating CED schemes. These challenges are herein discussed. Clinical findings from the US Veterans Affairs healthcare system help inform our discussion of specific challenges to CED-required effectiveness studies in AD.

Reduction of Phosphorylated Tau in Alzheimer's Disease Induced Pluripotent Stem Cell-Derived Neuro-Spheroids by Rho-Associated Coiled-Coil Kinase Inhibitor Fasudil.

BACKGROUND: Alzheimer's disease (AD) is the most predominant form of dementia. Rho-associated coiled coil kinase (ROCK) inhibitor, fasudil, is one of the candidate drugs against the AD progression. OBJECTIVE: We aimed to investigate possible changes of AD associated markers in three-dimensional neuro-spheroids (3D neuro-spheroids) generated from induced pluripotent stem cells derived from AD patients or healthy control subjects (HC) and to determine the impact of pharmacological intervention with the ROCK inhibitor fasudil. METHODS: We treated 3D neuro-spheroids with fasudil and tested the possible effect on AD markers by ELISA, transcriptomic and proteomic analyses. RESULTS: Transcriptomic analysis revealed a reduction in the expression of AKT serine/threonine-protein kinase 1 (AKT1) in AD neuro-spheroids, compared to HC. This decrease was reverted in the presence of fasudil. Proteomic analysis showed up- and down-regulation of proteins related to AKT pathway in fasudil-treated neuro-spheroids. We found an evident increase of phosphorylated tau at four different residues (pTau181, 202, 231, and 396) in AD compared to HC-derived neuro-spheroids. This was accompanied by a decrease of secreted clusterin (clu) and an increase of intracellular clu levels in AD patient-derived neuro-spheroids. Increases of phosphorylated tau in AD patient-derived neuro-spheroids were suppressed in the presence of fasudil. CONCLUSIONS: Fasudil modulates clu protein levels and enhances AKT1 that results in the suppression of AD associated tau phosphorylation.

Rule-Based Identification of Individuals with Mild Cognitive Impairment or Alzheimer's Disease Using Clinical Notes from the United States Veterans Affairs Healthcare System.

BACKGROUND: Early identification of individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD) is a clinical and research imperative. Use of diagnostic codes for MCI and AD identification has limitations. We used clinical notes to supplement diagnostic codes in the Veterans Affairs Healthcare System (VAHS) electronic health records (EHR) to identify and establish cohorts of Veterans recorded with MCI or AD. METHODS: Targeted keyword searches for MCI ("Mild cognitive impairment;" "MCI") and AD ("Alz*") were used to extract clinical notes from the VAHS EHR from fiscal year (FY) 2010 through FY 2019. Iterative steps of inclusion and exclusion were applied until searches achieved a positive predictive value ≥ 80%. MCI and AD cohorts were identified via clinical notes and/or diagnostic codes (i.e., including Veterans recorded by "Notes Only," "Notes + Code," or "Codes Only"). RESULTS: A total of 2,134,661 clinical notes from 339,007 Veterans met the iterative search criteria for MCI due to any cause and 4,231,933 notes from 572,063 Veterans met the iterative search criteria for AD. Over the 10-year study period, the number of clinical notes recording AD was generally stable, whereas the number for MCI more than doubled. More Veterans were identified for the MCI or AD cohorts via clinical notes than by diagnostic codes, particularly in the AD cohort. Among Veterans identified by having "Notes + Code" for MCI, the number first recorded by a code was lower than the number first recorded by a note until FY 2015 and then gradually became comparable after FY 2015. Among Veterans identified by having "Notes + Code" for AD, the number first recorded by a note was more than double the number first recorded by a code AD in each of the FYs. CONCLUSIONS: Clinical note-based identification captured more Veterans recorded with MCI and AD than diagnostic code-based identification.

Historical contingency and the role of post-invasion evolution in alternative community states.

Historical contingency has long figured prominently in the conceptual frameworks of evolutionary biology and community ecology. Evolutionary biologists typically consider the effects of chance mutation and historical contingency in driving divergence and convergence of traits in populations, whereas ecologists instead are often interested in the role of historical contingency in community assembly and succession. Although genetic differences among individuals in populations can influence community interactions, variability among populations of the same species has received relatively little attention for its potential role in community assembly and succession. We used a community-level study of experimental evolution in two compositionally different assemblages of protists and rotifers to explore whether initial differences in species abundances among communities attributed to differences in evolutionary history, persisted as species that continued to evolve over time. In each assemblage, we observed significant convergence between two invaded treatments initially differing in evolutionary history over an observation period equal to ~40-80 generations for most species. Nonetheless, community structure failed to converge completely across all invaded treatments within an assemblage to a single structure. This suggests that whereas the species in the assemblage represent a common selective regime, differences in populations reflecting their evolutionary history can produce long-lasting transient alternative community states. In one assemblage, we also observed increasing within-treatment variability among replicate communities over time, suggesting that ecological drift may be another factor contributing to community change. Although subtle, these transient alternative states, in which communities differed in the abundance of interacting species, could nonetheless have important functional consequences, suggesting that the role of evolution in driving these states deserves greater attention.

Clinical Staging of Alzheimer's Disease: Concordance of Subjective and Objective Assessments in the Veteran's Affairs Healthcare System.

INTRODUCTION: Uncertainty surrounding the accurate assessment of the early-stage Alzheimer's disease (AD) may cause delayed care and inappropriate patient access to new AD therapies. METHODS: To analyze clinical assessments of patients with AD in the Veteran's Affairs (VA) Healthcare System and evaluate concordance between subjective and objective assessments, we processed clinical notes extracted by text integration utilities between April 1, 2008 and October 14, 2021. Veterans who had mild, moderate, or severe AD with clinical notes documenting both clinician's judgement of AD severity and objective test scores from the Mini-Mental State Examination or the Montreal Cognitive Assessment were included. Using clinician-defined severity cohorts, we determined concordance between the clinician's (subjective) assessments and the test-derived (objective) assessments of AD severity. Concordance was assessed over time and by selected symptoms and comorbidities, as well as healthcare system factors. RESULTS: A total of 8888 notes were initially extracted; the final analysis sample included 7514 notes corresponding to 4469 unique patients (mean [standard deviation] age of 78 [9] years; 96.5% male; 77.8% White). Subjective and objective assessments were concordant in approximately half (53%) of overall notes. In the mild Alzheimer's cohort, patients were assessed to have more severe disease by objective test scores in 40% of notes. Concordance varied about 21-73%, 47-58%, and 40-64% across symptoms/comorbidities, clinician types, and Veteran's Integrated Service Networks, respectively. The proportion of concordant notes was higher in visits to dementia (61%) instead of non-dementia clinics (53%). CONCLUSIONS: We found higher concordance between clinician's assessment and test-based assessment of Alzheimer's disease severity in dementia specialty clinics. Discordance is especially high for the subjectively assessed mild AD cohort where objective assessments showed a higher severity level in 40% of notes. These data indicate a critical need for improved understanding of clinical assessments and decision-making to identify appropriate patients for anti-amyloid therapy.

Retromer disruption promotes amyloidogenic APP processing.

Retromer deficiency has been implicated in sporadic AD and animals deficient in retromer components exhibit pronounced neurodegeneration. Because retromer performs retrograde transport from the endosome to the Golgi apparatus and neuronal Aß is found in late endosomal compartments, we speculated that retromer malfunction might enhance amyloidogenic APP processing by promoting interactions between APP and secretase enzymes in late endosomes. We have evaluated changes in amyloid precursor protein (APP) processing and trafficking as a result of disrupted retromer activity by knockdown of Vps35, a vacuolar sorting protein that is an essential component of the retromer complex. Knocking down retromer activity produced no change in the quantity or cellular distribution of total cellular APP and had no affect on internalization of cell-surface APP. Retromer deficiency did, however, increase the ratio of secreted Aß42:Aß40 in HEK-293 cells over-expressing APP695, due primarily to a decrease in Aß40 secretion. Recent studies suggest that the retromer-trafficked protein, Wntless, is secreted at the synapse in exosome vesicles and that these same vesicles contain Aß. We therefore hypothesized that retromer deficiency may be associated with altered exosomal secretion of APP and/or secretase fragments. Holo-APP, Presenilin and APP C-terminal fragments were detected in exosomal vesicles secreted from HEK-293 cells. Levels of total APP C-terminal fragments were significantly increased in exosomes secreted by retromer deficient cells. These data suggest that reduced retromer activity can mimic the effects of familial AD Presenilin mutations on APP processing and promote export of amyloidogenic APP derivatives.

Suppression of Nrdp1 toxicity by Parkin in Drosophila models.

Nrdp1 is a RING finger ubiquitin E3 ligase that interacts with Parkin, and promotes the degradation of Parkin, a causative protein for early onset Autosomal Recessive Juvenile Parkinsonism (AR-JP). To investigate if Nrdp1 plays a role in the pathogenesis of Parkinson's disease, we generated transgenic Drosophila that expressed Drosophila Nrdp1 (dNrdp1) and dNrdp1(D56V), an aspartic acid to valine mutant at residue 56 that disrupts its ring finger domain, resulting in impaired capacity to degrade its substrate ErbB3. Our data show that a pan-neuronal expression of transgenic dNrdp1 but not dNrdp1(D56V) mutant leads to the loss of dopaminergic neurons in brains, resulting in reduction of dopamine production. These flies also manifested decreased flight ability. Co-expression of human Parkin (hParkin) provides protection against toxicity induced by over-expression of dNrdp1, reversing the effects of dNrdp1 on death of dopaminergic neurons, reduction of dopamine production, and decreased flight ability. Taken together, we conclude that Nrdp1 plays a role in neurodegeneration and could be potentially targeted as a therapeutic strategy for Parkinson's disease.

Productivity-biodiversity relationships depend on the history of community assembly.

Identification of the causes of productivity-species diversity relationships remains a central topic of ecological research. Different relations have been attributed to the influence of disturbance, consumers, niche specialization and spatial scale. One unexplored cause is the history of community assembly, the partly stochastic sequential arrival of species from a regional pool of potential community members. The sequence of species arrival can greatly affect community structure. If assembly sequence interacts with productivity to influence diversity, different sequences can contribute to variation in productivity-diversity relationships. Here we report a test of this hypothesis by assembling aquatic microbial communities at five productivity levels using four assembly sequences. About 30 generations after assembly, productivity-diversity relationships took various forms, including a positive, a hump-shaped, a U-shaped and a non-significant pattern, depending on assembly sequence. This variation resulted from idiosyncratic joint effects of assembly sequence, productivity and species identity on species abundances. We suggest that the history of community assembly should be added to the growing list of factors that influence productivity-biodiversity patterns.

Microbial biogeography: putting microorganisms on the map.

We review the biogeography of microorganisms in light of the biogeography of macroorganisms. A large body of research supports the idea that free-living microbial taxa exhibit biogeographic patterns. Current evidence confirms that, as proposed by the Baas-Becking hypothesis, 'the environment selects' and is, in part, responsible for spatial variation in microbial diversity. However, recent studies also dispute the idea that 'everything is everywhere'. We also consider how the processes that generate and maintain biogeographic patterns in macroorganisms could operate in the microbial world.

A role for APP in Wnt signalling links synapse loss with ß-amyloid production.

In Alzheimer's disease (AD), the canonical Wnt inhibitor Dickkopf-1 (Dkk1) is induced by ß-amyloid (Aß) and shifts the balance from canonical towards non-canonical Wnt signalling. Canonical (Wnt-ß-catenin) signalling promotes synapse stability, while non-canonical (Wnt-PCP) signalling favours synapse retraction; thus Aß-driven synapse loss is mediated by Dkk1. Here we show that the Amyloid Precursor Protein (APP) co-activates both arms of Wnt signalling through physical interactions with Wnt co-receptors LRP6 and Vangl2, to bi-directionally modulate synapse stability. Furthermore, activation of non-canonical Wnt signalling enhances Aß production, while activation of canonical signalling suppresses Aß production. Together, these findings identify a pathogenic-positive feedback loop in which Aß induces Dkk1 expression, thereby activating non-canonical Wnt signalling to promote synapse loss and drive further Aß production. The Swedish familial AD variant of APP (APPSwe) more readily co-activates non-canonical, at the expense of canonical Wnt activity, indicating that its pathogenicity likely involves direct effects on synapses, in addition to increased Aß production. Finally, we report that pharmacological inhibition of the Aß-Dkk1-Aß positive feedback loop with the drug fasudil can restore the balance between Wnt pathways, prevent dendritic spine withdrawal in vitro, and reduce Aß load in vivo in mice with advanced amyloid pathology. These results clarify a relationship between Aß accumulation and synapse loss and provide direction for the development of potential disease-modifying treatments.