Dementia-related psychosis (DRP) is common among patients with Alzheimer’s disease (AD), Parkinson’s disease (PD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and vascular dementia (VaD) and is associated with poor outcomes. HARMONY (NCT03325556) was a Phase 3, placebo-controlled, randomized, relapse-prevention study evaluating the efficacy and safety of pimavanserin for treating hallucinations and delusions associated with DRP. Patients with dementia and moderate-severe psychosis received open-label (OL) pimavanserin for 12 weeks. Patients with a sustained response (≥30% reduction in Scale for the Assessment of Positive Symptoms hallucinations+delusions Total Score AND Clinical Global Impression-Improvement score of much/very much improved) at Weeks 8 and 12 were randomized 1:1 to continue pimavanserin or receive placebo for up to 26 weeks in the double-blind (DB) period. The primary endpoint was time from randomization to relapse of DRP. 392 patients enrolled. 217 (61.8%) eligible patients experienced sustained response and were randomized. OL response was similar regardless of dementia subtype (randomization rates: 59.8% AD, 71.2% PDD, 71.4% VaD, 45.5% DLB, 50.0% FTD), baseline disease characteristics, age, dementia severity, or previous drug therapy. The study stopped early for superior efficacy when a prespecified interim analysis revealed >2.8-fold reduction in risk of relapse with pimavanserin (hazard ratio: 0.353; 95% CI: 0.172, 0.727; 1-sided p=0.0023). Adverse event rates were low and balanced (OL: 36.2%; DB: 41.0% pimavanserin, 36.6% placebo). No negative trends for worsening in cognition (as assessed by the Mini-Mental State Examination) or motor function were observed. The HARMONY study demonstrated a robust decrease in hallucinations and delusions and significant maintenance of efficacy with pimavanserin treatment in DRP.

Study Sponsored By: ACADIA Pharmaceuticals Inc.

Similar patterns of parasite prevalence in animal communities may be driven by a range of different mechanisms. The influences of host heterogeneity and host–parasite interactions in host community assemblages are poorly understood. We sampled birds at 27 wetlands in South Africa to compare four hypotheses explaining how host community heterogeneity influences host specificity in avian haemosporidia communities: the host-neutral hypothesis, the super-spreader hypothesis, the host specialist hypothesis and the heterogeneity hypothesis. A total of 289 birds (29%) were infected with Plasmodium, Haemoproteus and/or Leucocytozoon lineages. Leucocytozoon was the most diverse and generalist parasite genus, and Plasmodium the most conservative. The host-neutral and host specialist hypotheses received the most support in explaining prevalence by lineage (Leucocytozoon) and genus (Plasmodium and Haemoproteus), respectively. We observed that haemosporidian prevalence was potentially amplified or reduced with variation in host and/or parasitic taxonomic levels of analysis. Our results show that Leucocytozoon host abundance and diversity was influential to parasite prevalence at varying taxonomic levels, particularly within heterogeneous host communities. Furthermore, we note that prevalent mechanisms of infection can potentially act as distinct roots for shaping communities of avian haemosporidia.

We appear to be on the brink of a new epoch of treatment for Alzheimer's disease. Compelling evidence suggests that Aβ42 secretion is the triggering event in the pathogenesis of Alzheimer's disease, and that tau aggregation may be an important secondary event linked to neurodegeneration. Prophylactic administration of anti-amyloid agents designed to prevent Aβ accumulation in persons with subclinical disease is likely to be more effective than therapeutic interventions in established Alzheimer's disease. Drug development programs in Alzheimer's disease focus primarily on agents with anti-amyloid disease-modifying properties, and many different pharmacologic approaches to reducing amyloid pathology and tauopathy are being studied. Classes of therapeutic modalities currently in advanced-stage clinical trial testing include forms of immunotherapy (active β -amyloid immunoconjugate and human intravenous immunoglobulin), a γ-secretase inhibitor, the selective Aβ42-lowering agent R-flurbiprofen, and the anti-aggregation agent tramiprosate. Non-traditional dementia therapies such as the HMG-CoA reductase inhibitors (statins), valproate, and lithium are now being assessed for clinical benefit as anti-amyloid disease-modifying treatments. Positive findings of efficacy and safety from clinical studies are necessary but not sufficient to demonstrate that a drug has disease-modifying properties. Definitive proof of disease-modification requires evidence from validated animal models of Alzheimer's disease; rigorously controlled clinical trials showing a significantly improved, stabilized, or slowed rate of decline in cognitive and global function compared to placebo; and prospectively obtained evidence from surrogate biomarkers that the treatment resulted in measurable biological changes associated with the underlying disease process.

Drs. McCaddon and Hudson provide a thorough review of the multiple ways in which vitamin B12, vitamin B6, folate, and homocysteine (Hey) are implicated in the pathogenesis of Alzheimer's disease (AD). They noted that Hey is more often elevated in AD and in mild cognitive impairment (MCI) than in cognitively healthy elderly; phosphatases needed to limit tau hyperphosphoryalation and neurofibrillary tangle formation require methylation and are dependent on folate and methylation status; cerebrospinal fluid (CSF) tau levels correlated with markers of methylation status; reduced folate and B12 levels lead to increase β-secretase and pesenilin 1 (PS1) actions leading to greater amyloid-β production in in vitro models; elevated Hey levels in rates are associated with increased PS1 activity and spatial memory deficits that are reversed following treatment with B12 and folate; raised Hey levels in vitro increase amyloid-β protein neurotoxicity; methylation impacts transmitters and transmitter function relevant to AD; in cultured neurons, Hey induces injury in DNA and stimulates cell death pathways. B12 deficiency leads to accumulation of methyl malonic acid, which inhibits mitochondrial function and may compromise energy generation and impair maintenance of synaptic plasticity. Methylation abnormalities result in excessive generation of reactive oxygen species that contribute importantly to cell injury. Biomarkers of oxidative injury, such as isoprostanes, are elevated in AD and suggest excess oxidation. Thus, there are multiple pathways through which deficient methylation may contribute to AD. In some cases, the observations are derived from models with B12 or folate deficiency and some in vitro observations have not been tested in in vivo models. There are no biomarkers specific to some of the pathways implicated and the magnitude of the impact of the deficiency or its treatment has not been established for all the relationships. Two open-label experiments in early- and late-stage AD patients have suggested benefit.

Behavioral and psychological symptoms of dementia pose significant challenges in the management of patients with Alzheimer's disease. Neuropsychiatric symptoms are associated with cognitive decline, highly impaired activities of daily living, and frontal lobe pathology. Moreover, behavioral and psychological symptoms can diminish patient quality of life, increase caregiver distress, and accelerate nursing home placement. Although these symptoms are often associated with the later stages of Alzheimer's disease, a high percentage of individuals with mild cognitive impairment or mild Alzheimer's report symptoms as well. This article provides an overview of behavioral and neuropsychiatric symptoms associated with Alzheimer's disease and discusses nonpharmacologic and pharmacologic approaches to the management of such symptoms. For patients with severe behavioral and psychological symptoms of dementia, pychotropic agents may be warranted, whereas approved therapies for Alzheimer's, including cholinesterase inhibitors and the N-methyl-D-aspartate receptor antagonist memantine, may be appropriate in less severe cases.

Involuntary emotional expression disorder (IEED), a distressing and potentially debilitating condition characterized by uncontrollable episodes of laughing and/or crying, causes extensive social and occupational dysfunction amongst patients. However, despite affecting more than one million people worldwide, IEED is often overlooked or misdiagnosed, and current treatments are compromised by uncertain efficacy. In this supplement we review the epidemiology and pathophysiology of IEED, and discuss new pharmacologic interventions which may afford opportunities for symptom control amongst IEED sufferers.

Although the uncontrollable episodes of emotion which characterize IEED were first described more than a century ago, a bewildering profusion of terminology has since confused and hampered the efforts of physicians to recognize and treat this condition. In the first article, John E. Duda, MD, examines the history of IEED in the medical literature, and evaluates the prevalence of the condition amongst patients in whom emotional or affective motor control has become dysregulated, either as a result of brain damage from neurological disease or as a result of brain injury.

Alzheimer’s disease (AD) research is progressing rapidly and on multiple fronts. Advances are being made in early diagnosis, neuroimaging, and biomarkers; optimal care uses currently available medications and strategies; and new therapies are emerging. Early diagnosis is necessary for optimal patient management. Biomarkers are critical to early diagnosis, and biomarker development is dependent on better understanding of disease pathophysiology (Slide 1). The discussions in this supplement examine how progress in AD research can be translated into clinical care.

Primary care practitioners (PCPs) provide most of the care of patients with AD, and these clinicians are optimally poised to discover new cases emerging among elderly patients. Caregivers are most likely to voice concerns about declining memory in a family member to a PCP before seeking specialty evaluation. PCPs, however, have little time to devote to complex assessments and cannot have specialty-level expertise in all disorders. PCPs must have clinical tools that assist them in rapidly identifying potential problems and triaging them for further evaluation or specialty referral.

Alzheimer's disease was first described by Alois Alzheimer in 1906, and first appeared in the medical literature in 1907. The medical community has been ruminating about Alzheimer's disease for over 100 years, and only recently have Alzheimer's disease therapies begun to emerge. However, many vital questions remain, pertinent not only to physicians but to the public at large. For example, how likely is it that a particular individual will develop Alzheimer's disease? What can one do to avoid getting Alzheimer's disease? What are the current and promising treatments for Alzheimer's disease? While there are grey areas, the Alzheimer's disease field is beginning to find solid answers to these questions. There are risk factors that individuals can control, and emerging treatments are cause for optimism.

Uncontrollable episodes of emotional expression occur in a variety of neurological conditions. This emotional disinhibition syndrome is characterized by episodes of crying or laughing that are unrelated to or out of proportion to the eliciting stimulus. This syndrome is common among patients with amyotrophic lateral sclerosis, multiple sclerosis, stroke, and traumatic brain injury and a variety of terms and definitions have been used to describe it. The confusing nomenclature has been a barrier to understanding, diagnosis, and treatment of this disorder. The authors propose a unifying term, involuntary emotional expression disorder (IEED), and provide diagnostic criteria for this disorder.

Involuntary emotional expression disorder (IEED) is a syndrome in which emotional or affective motor control becomes dysregulated as a result of brain damage from neurological disease or as a result of brain injury. A debilitating disorder with persistent symptoms, IEED has a significant impact upon the lives of patients and caregivers, but is often overlooked or misdiagnosed. IEED is a clinically well-defined disorder, and specific criteria may be used when making a diagnosis. It must be distinguished from depression or other psychological and neurological conditions. Several assessment scales have been validated for use in IEED, in order to evaluate the baseline severity and to track the course of the disorder and response to treatment.

Although treatments for Alzheimer’s disease (AD) currently focus on symptomatic therapies, we are entering into an era of disease-modifying therapies. Central to disease modification is early diagnosis; the disease should be slowed as early as possible, maximizing the preservation of cognitive integrity. Ideally, AD should be diagnosed before the onset of dementia, perhaps with the use of biomarkers.

Some therapies suggest that cholinesterase inhibitors and memantine have disease-modifying properties, though not all studies agree. Doody and colleagues have produced data suggesting that these agents may modify the course of AD, but it is not clear that they affect the underlying mechanisms that lead to cell death. Rather than being disease-modifying agents, cholinesterase inhibitors and memantine have potential as disease-course-modifying agents. Language precision will be extremely important in describing these therapies. One European consensus conference concluded that affecting disease course is not adequate for disease modification, but this has not been largely endorsed.

Symptomatic therapies are those affecting the course of the disease. Their benefits are multidimensional, improving cognition, global assessment, activities of daily living, behavior, and caregiver burden. Symptomatic therapies should defer decline. Clinical trials show that symptomatic therapies produce an initial improvement above baseline. However, some patients experience observable changes and some experience none. These therapies are believed to produce ~1 point improvement on the Mini-Mental State Examination (MMSE) average, and a decline that is otherwise parallel to a placebo group after a period of delayed progression (Slide 1).

Impairments in learning and recall have been well established in amnestic mild cognitive impairment (aMCI). However, a relative dearth of studies has examined the profiles of memory strategy use in persons with aMCI relative to those with Alzheimer's disease (AD). Participants with aMCI, nonamnestic MCI, AD, and healthy older adults were administered the California Verbal Learning Test-II (CVLT-II). Measures of semantic clustering and recall were obtained across learning and delayed recall trials. In addition, we investigated whether deficits in semantic clustering were related to progression from healthy aging to aMCI and from aMCI to AD. The aMCI group displayed similar semantic clustering performance as the AD participants, whereas the AD group showed greater impairments on recall relative to the aMCI participants. Control participants who progressed to aMCI showed reduced semantic clustering at the short delay at baseline compared to individuals who remained diagnostically stable across follow-up visits. These findings show that the ability to engage in an effective memory strategy is compromised in aMCI, before AD has developed, suggesting that disruptions in semantic networks are an early marker of the disease. (JINS, 2014, 20, 1–11)

Alzheimer's disease (AD) is an urgent public health challenge that is rapidly approaching epidemic proportions. New therapies that defer or prevent the onset, delay the decline, or improve the symptoms are urgently needed. All phase 3 drug development programs for disease-modifying agents have failed thus far. New approaches to drug development are needed. Translational neuroscience focuses on the linkages between basic neuroscience and the development of new diagnostic and therapeutic products that will improve the lives of patients or prevent the occurrence of brain disorders. Translational neuroscience includes new preclinical models that may better predict human efficacy and safety, improved clinical trial designs and outcomes that will accelerate drug development, and the use of biomarkers to more rapidly provide information regarding the effects of drugs on the underlying disease biology. Early translational research is complemented by later stage translational approaches regarding how best to use evidence to impact clinical practice and to assess the influence of new treatments on the public health. Funding of translational research is evolving with an increased emphasis on academic and NIH involvement in drug development. Translational neuroscience provides a framework for advancing development of new therapies for AD patients.

Background: The Neuropsychiatric Inventory (NPI) is widely used to assess psychopathology in dementia. The scoring involves ratings of frequency and severity, as well as the calculation of a composite score. It was suggested recently that, due to lower variance, the frequency score might be more sensitive to detect treatment-related change and to discriminate active treatment from placebo than the composite score, particularly in milder forms of the disease.

Methods: Based on data from three randomized controlled trials in patients with mild to moderate dementia, standardized changes were calculated for both frequency and composite scores for two strata of disease severity. The two strata were formed by dichotomizing the sample along the median score of the short cognitive performance test (SKT) battery.

Results: Across all studies and for both severity strata, standardized changes in frequency scores were not consistently larger than those in composite scores and both scores discriminated active treatment from placebo at similar probabilities for type-1 error.

Conclusion: Our findings do not support the notion that there is a difference between frequency score and composite score with respect to their sensitivity to treatment-related change.

The relevance of spatial variation in the environment and host communities for parasite community composition is poorly documented, creating a need for additional case studies from which general principles can be developed. Avian malaria in southern African waterfowl has not previously been studied. As a first step towards documenting and understanding its biogeography, we used PCR and molecular sequencing techniques to analyse 454 blood samples from Afrotropical ducks from 5 different locations (spread around the subregion) for avian malaria. Fifty-five blood samples were positive for one or more genera of haematozoa. The regional infection rate across all sites and sampling periods was 12·1%. Nine individuals carried dual infections containing multiple haematozoa. Fifteen different cytochrome b haplotypes among 52 positives (3 samples failed to sequence) and 61 total sequences were found. Eleven haplotypes closely matched Plasmodium, whereas 4 were more similar to Haemoproteus. Five distinct haematozoan clades were identified. Haemoproteus parasites appeared to be more host-specific than Plasmodium, which occurred at every sampling location and in every host species examined. There were no significant differences in overall parasite prevalence attributable to either site or species, although Plasmodium and Haemoproteus occurrences differed by site-species combination and the borderline significance of our test for between-site variation (P < 0·06) implied that with a larger sample size, differences in parasite prevalence among locations might be detectable.