Alzheimer Disease: California

McConnell LM, Koenig BA, Greely HT, Raffin TA. · Stanford Program in Genomics, Ethics, and Society, Stanford University Medical Center, Palo Alto, CA 94304, USA. · Genet Test. · Pubmed #10464572 No free full text.

Abstract: Several genes associated with Alzheimer disease (AD) have been localized and cloned; two genetic tests are already commercially available, and new tests are being developed. Genetic testing for AD--either for disease prediction or for diagnosis--raises critical ethical concerns. The multidisciplinary Alzheimer Disease Working Group of the Stanford Program in Genomics, Ethics, and Society (PGES) presents comprehensive recommendations on genetic testing for AD. The Group concludes that under current conditions, genetic testing for AD prediction or diagnosis is only rarely appropriate. Criteria for judging the readiness of a test for introduction into routine clinical practice typically rely heavily on evaluation of technical efficacy. PGES recommends a broader and more comprehensive approach, considering: 1) the unique social and historical meanings of AD; 2) the availability of procedures to promote good surrogate decision making for incompetent patients and to safeguard confidentiality; 3) access to sophisticated genetic counselors able to communicate complex risk information and effectively convey the social costs and psychological burdens of testing, such as unintentional disclosure of predictive genetic information to family members; 4) protection from inappropriate advertising and marketing of genetic tests; and 5) recognition of the need for public education about the meaning and usefulness of predictive and diagnostic tests for AD. In this special issue of Genetic Testing, the PGES recommendations are published along with comprehensive background papers authored by Working Group members.

Aisen PS. · Department of Neurosciences, University of California at San Diego, La Jolla, CA, USA. · Alzheimers Dement. · Pubmed #19328440 No free full text.

This publication has no abstract.

Cummings JL. · Mary S. Easton Center for Alzheimer's Disease Research at UCLA, Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. · Alzheimers Dement. · Pubmed #19328437 No free full text.

This publication has no abstract.

Schneider LS, Lahiri DK. · Departments of Psychiatry, Neurology, and Gerontology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA. · Curr Alzheimer Res. · Pubmed #19199878 No free full text.

This publication has no abstract.

Schenk D. · Chief Scientific Officer, Elan Corporation, 800 Gateway Blvd., South San Francisco, CA 9480, USA. · Curr Alzheimer Res. · Pubmed #16842091 No free full text.

This publication has no abstract.

Barceloux DG. · Emergency Department, Pomona Valley Hospital Medical Center, Pomona, California, USA. · Dis Mon. · Pubmed #19446678 No free full text.

This publication has no abstract.

Henderson VW. · Departments of Health Research & Policy (Epidemiology) and of Neurology & Neurological Sciences, Stanford University, Stanford, California 94305-5405, USA. · Semin Reprod Med. · Pubmed #19401959 No free full text.

Abstract: Estrogen-containing hormone therapy initiated during late postmenopause does not improve episodic memory (an important early symptom of Alzheimer's disease), and it increases dementia risk. Cognitive consequences of exogenous estrogen exposures during midlife are less certain. Observational evidence implies that use of hormone therapy at a younger age close to the time of menopause may reduce risk of Alzheimer's disease later in life. However, there are concerns that observational findings may be systematically biased. Partial insight on this critical issue may be gleaned from results of ongoing clinical trials involving midlife postmenopausal women (Early versus Late Intervention Trial with Estrogen; Kronos Early Estrogen Prevention Study). The effects of exogenous midlife estrogen exposures and Alzheimer risk can also be approached through better animal models, through carefully designed cohort studies, and through use of surrogate outcomes in randomized controlled trials in midlife women. Selective estrogen receptor modulators have the potential to affect cognitive outcomes and also merit additional study.

Ghochikyan A. · The Institute for Molecular Medicine, Department of Immunology, Huntington Beach, CA 92647, USA. · CNS Neurol Disord Drug Targets. · Pubmed #19355933 No free full text.

Abstract: Amyloid-beta (Abeta) immunotherapy has received considerable attention as a promising approach for reducing the level of Abeta in the CNS of Alzheimer's disease patients. However, the first Phase II clinical trial, for the immune therapy AN1792, was halted when a subset of those immunized with Abeta(42) developed adverse events in the central nervous system. In addition, data from the trial indicated that there was a low percentage of responders and generally low to moderate titers in the patients that received the vaccine. Generated antibodies reduced beta-amyloid deposits in the parenchyma of patients' brains, but no reduction in soluble Abeta or significant improvements in cognitive function of patients were observed. These data and data from pre-clinical studies suggest that reduction in the most toxic oligomeric forms of Abeta is important for prevention or slowing down of the progression of cognitive decline, and that vaccination should be started prior to irreversible accumulation of the oligomeric Abeta, at the early stages of AD. Protective immunotherapy requires a development of safe and effective strategy for Abeta immunotherapy. In this review, the rationale for developing epitope vaccines for the treatment of AD will be discussed. We believe that an epitope vaccine will induce an adequate anti-Abeta antibody response in the absence of potentially adverse self T cell-mediated events, making it possible to start immunization at the early stages of AD.

Town T. · Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. · CNS Neurol Disord Drug Targets. · Pubmed #19355932 links to  free full text

Abstract: In a seminal report in 1999, Schenk and colleagues demonstrated that vaccination of a mouse model of Alzheimer's disease (AD) with amyloid-beta(1-42) peptide (Abeta(1-42)) and adjuvant resulted in striking mitigation of AD-like pathology - giving rise to the field of AD immunotherapy. Later studies confirmed this result in other mouse models of AD and additionally showed cognitive improvement after Abeta vaccination. Based on these results, early developmental clinical trials ensued to immunize AD patients with Abeta(1-42) plus adjuvant (so-called "active" Abeta immunotherapy; trade name AN-1792; Elan Pharmaceuticals, Dublin, Ireland). However, the phase IIa trial was halted after 6 % of patients developed aseptic meningoencephalitis. Despite occurrence of this adverse event, many individuals demonstrated high serum antibody titres to Abeta and histological evidence of clearance of the hallmark AD pathology, beta-amyloid plaques. While raising justifiable safety concerns, these important results nonetheless demonstrated the feasibility of the active Abeta immunotherapy approach. This review focuses on alternative approaches to active Abeta vaccination that are currently in various stages of development - from pre-clinical studies in animal models to current clinical trials. Specifically, the focus is on those strategies that target inflammatory and immune aspects of AD, and can therefore be classified as immunotherapeutic in a broad sense.

Vasilevko V, Head E. · Institute for Brain Aging & Dementia, University of California, Irvine, CA 92697-4540, USA. · CNS Neurol Disord Drug Targets. · Pubmed #19355931 No free full text.

Abstract: Alzheimer disease (AD) is the most common form of dementia in the elderly and the number of individuals developing the disease is rapidly rising. Interventions focused on reducing beta-amyloid (Abeta), a component of senile plaques within the AD brain offer a promising approach to prevent or slow disease progression. In this review, we describe the immune system and cognitive and neurobiological features of a natural model of human brain aging, the beagle. The immune system of dogs shares many features of the human immune system, including developmental and aging characteristics. Further, dogs naturally accumulate human sequence Abeta as they age, which coincides with declines in learning and memory. A longitudinal study (approximately 2 years) of the response of aged beagles to vaccination with fibrillar Abeta1-42 indicated that despite significant clearance of Abeta, there were limited benefits in cognitive function. However, there was evidence for maintenance of executive function over time. These results are strikingly similar to reports of human clinical immunotherapy trials. We propose that the canine model complements existing animal models and will be helpful in developing new vaccine approaches to slowing or preventing Abeta pathology that can be translated to human clinical trials.

Caccamo A, Fisher A, LaFerla FM. · Department of Neurobiology, University of California, Irvine, Irvine, CA 92697, USA. · Curr Alzheimer Res. · Pubmed #19355845 No free full text.

Abstract: Cholinergic deficit is a cardinal feature of Alzheimer's disease, and cholinesterase inhibitors represent one of the most prominent means of mitigating this dysfunction. Cholinesterase inhibitors provide mild symptomatic relief, although they lose their efficacy over time most likely because they are not disease-modifying agents. An alternative strategy for restoring cholinergic function and attenuating the cognitive decline involves acting on the receptors on which acetylcholine acts. Stimulation of muscarinic acetylcholine receptors and in particular the M1 subtype has been shown to have a beneficial effect in restoring cognition in patients with Alzheimer's disease and in attenuating Abeta and tau pathology in different animal models. In this review, we discuss the role of M1 agonists as a potential disease-modifying therapy for Alzheimer's disease.

Schneider LS. · Department of Psychiatry and Behavioral Sciences and Department of Neurology, Keck School of Medicine, and Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA. · Alzheimers Dement. · Pubmed #19328454 No free full text.

This publication has no abstract.

Ringman JM, Grill J, Rodriguez-Agudelo Y, Chavez M, Xiong C. · Mary S. Easton Center for Alzheimer's Disease Research, UCLA Department of Neurology, Los Angeles, CA, USA. · Alzheimers Dement. · Pubmed #19328453 No free full text.

This publication has no abstract.

Bookheimer S, Burggren A. · Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California-Los Angeles, CA 90095, USA. · Annu Rev Clin Psychol. · Pubmed #19327032 No free full text.

Abstract: Many years before receiving a clinical diagnosis of Alzheimer's disease (AD), patients experience evidence of cognitive decline. Recent studies using a variety of brain imaging technologies have detected subtle changes in brain structure and function in normal adults with a genetic risk for AD; these brain changes have similar pathological features as AD, and some appear to be predictive of future cognitive decline. This review examines the most recent data on brain changes in genetic risk for AD and discusses the benefits and potential risks of detecting individuals at risk.

Rafii MS, Aisen PS. · Department of Neurosciences, University of California-San Diego, Gilman Drive M/C 0949, La Jolla, CA 92093, USA. · BMC Med. · Pubmed #19228370 links to  free full text

Abstract: Alzheimer's disease is a devastating neurological disorder that affects more than 37 million people worldwide. The economic burden of Alzheimer's disease is massive; in the United States alone, the estimated direct and indirect annual cost of patient care is at least $100 billion. Current FDA-approved drugs for Alzheimer's disease do not prevent or reverse the disease, and provide only modest symptomatic benefits. Driven by the clear unmet medical need and a growing understanding of the molecular pathophysiology of Alzheimer's disease, the number of agents in development has increased dramatically in recent years. Truly *'disease-modifying' therapies that target the underlying mechanisms of Alzheimer's disease have now reached late stages of human clinical trials. Primary targets include beta-amyloid, whose presence and accumulation in the brain is thought to contribute to the development of Alzheimer's disease, and tau protein which, when hyperphosphorylated, results in the self-assembly of tangles of paired helical filaments also believed to be involved in the pathogenesis of Alzheimer's disease. In this review, we briefly discuss the current status of Alzheimer's disease therapies under study, as well the scientific context in which they have been developed.

Palop JJ, Mucke L. · Gladstone Institute of Neurological Disease and Department of Neurology, University of California, San Francisco, CA 94158, USA. · Arch Neurol. · Pubmed #19204149 No free full text.

Abstract: Alzheimer disease (AD) is associated with cognitive decline and increased incidence of seizures. Seizure activity in AD has been widely interpreted as a secondary process resulting from advanced stages of neurodegeneration, perhaps in combination with other age-related factors. However, recent findings in animal models of AD have challenged this notion, raising the possibility that aberrant excitatory neuronal activity represents a primary upstream mechanism that may contribute to cognitive deficits in these models. The following observations suggest that such activity may play a similar role in humans with AD: (1) patients with sporadic AD have an increased incidence of seizures that appears to be independent of disease stage and highest in cases with early onset; (2) seizures are part of the natural history of many pedigrees with autosomal dominant early-onset AD, including those with mutations in presenilin-1, presenilin-2, or the amyloid precursor protein, or with duplications of wild-type amyloid precursor protein; (3) inheritance of the major known genetic risk factor for AD, apolipoprotein E4, is associated with subclinical epileptiform activity in carriers without dementia; and (4) some cases of episodic amnestic wandering and disorientation in AD are associated with epileptiform activity and can be prevented with antiepileptic drugs. Here we review recent experimental data demonstrating that high levels of beta-amyloid in the brain can cause epileptiform activity and cognitive deficits in transgenic mouse models of AD. We conclude that beta-amyloid peptides may contribute to cognitive decline in AD by eliciting similar aberrant neuronal activity in humans and discuss potential clinical and therapeutic implications of this hypothesis.

Seeley WW. · Department of Neurology, University of California, San Francisco, and UCSF Memory and Aging Center, San Francisco, CA 94143-1207, USA. · Front Neurol Neurosci. · Pubmed #19182474 No free full text.

Abstract: Frontotemporal dementia represents an important cause of dementia that requires differentiation from Alzheimer's disease. As molecular therapies for both diseases begin to emerge, neuroimaging biomarkers will be needed that can improve diagnostic accuracy and enable treatment monitoring.At present, structural magnetic resonance imaging provides a useful adjunct to clinical assessment,helping to distinguish frontotemporal dementia from Alzheimer's disease and from nonneurodegenerative disease. Future imaging research will seek to more directly assay disease by assessing network level pathophysiology and accumulation of misfolded proteins in cerebral tissues.

Zhongling Feng, Gang Zhao, Lei Yu. · Bio Group, Nitto Denko Technical Corporation, Oceanside, California 92058, USA. · Am J Alzheimers Dis Other Demen. · Pubmed #19116300 No free full text.

Abstract: Alzheimer's disease is characterized by degeneration and dysfunction of synapses and neurons in brain regions critical for learning and memory functions. The endogenous generation of new neurons in certain regions of the mature brain, derived from primitive cells termed neural stem cells, has raised hope that neural stem cells may be recruited for structural brain repair. Stem cell therapy has been suggested as a possible strategy for replacing damaged circuitry and restoring learning and memory abilities in patients with Alzheimer's disease. In this review, we outline the promising investigations that are raising hope, and understanding the challenges behind translating underlying stem cell biology into novel clinical therapeutic potential in Alzheimer's disease.

Cotman CW, Head E. · Institute for Brain Aging & Dementia, Department of Neurology, University of California, Irvine, CA 92697-4540, USA. · J Alzheimers Dis. · Pubmed #19096165 No free full text.

Abstract: Aged dogs (beagles) develop losses in executive function, learning and memory. The severity of decline in these cognitive domains represents a spectrum that captures normal aging, mild cognitive impairment and early/mild Alzheimer's disease (AD) in humans. In parallel, dogs naturally accumulate several types of neuropathology (although not all) consistent with human brain aging and AD including cortical atrophy, neuron loss, loss of neurogenesis, amyloid-beta (Abeta) plaques, cerebral amyloid angiopathy and oxidative damage. Many of these neuropathological features correlate with the extent of cognitive decline in a brain region-dependent manner. Dogs are ideally suited for longitudinal studies, and we provide a summary of the beneficial effects of an antioxidant diet, behavioral enrichment, and Abeta immunotherapy. In addition, combinatorial treatment approaches can be a powerful strategy for improving brain function through enhancement of multiple molecular pathways.

Cashman JR, Ghirmai S, Abel KJ, Fiala M. · Human BioMolecular Research Institute, San Diego, CA 92121, USA. · BMC Neurosci. · Pubmed #19090986 links to  free full text

Abstract: Alzheimer's disease (AD) is a neurodegenerative disease characterized by the accumulation of intracellular and extracellular aggregates. According to the amyloid beta (Abeta) hypothesis, amyloidosis occurring in the brain is a leading cause of neurodegeneration in AD. Defects in the innate immune system may decrease the clearance of Abeta in the brain. Macrophages of most AD patients do not transport Abeta into endosomes and lysosomes, and monocytes from AD patients do not efficiently clear Abeta from AD brain. After stimulation with Abeta, mononuclear cells of normal subjects display up-regulated transcription of MGAT3, which encodes beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase, and Toll-like receptor (TLR) genes. Monocytes of AD patients generally down-regulate these genes. A commonly used, naturally occurring material from a spice that enhances certain key functions defective in cells of innate immunity of many AD patients has shown epidemiologic rationale for use in AD treatment. Bisdemethoxycurcumin, a natural curcumin, is a minor constituent of turmeric (curry), and it enhances phagocytosis and clearance of Abeta in cells from most AD patients. We confirmed the effectiveness of a synthetic version of the same compound. In mononuclear cells of most AD patients, bisdemethoxycurcumin enhanced defective phagocytosis of Abeta and increased the transcription of MGAT3 and TLR genes. The potency of bisdemethoxycurcumin as a highly purified compound in facilitating the clearance of Abeta in mononuclear cells suggests the promise of enhanced effectiveness compared to curcuminoid mixtures. Bisdemethoxycurcumin appears to enhance immune function in mononuclear cells of AD patients and may provide a novel approach to AD immunotherapy.

Webster NJ, Pirrung MC. · Veterans Medical Research Foundation and VA San Diego Healthcare System, San Diego, CA 92161, USA. · BMC Neurosci. · Pubmed #19090982 links to  free full text

Abstract: The neurotrophin signaling network is critical to the development and survival of many neuronal populations. Especially sensitive to imbalances in the neurotrophin system, cholinergic neurons in the basal forebrain are progressively lost in Alzheimer's disease. Therapeutic use of neurotrophins to prevent this loss is hampered, however, by a number of pharmacological challenges. These include a lack of transport across the blood-brain barrier, rapid degradation in the circulation, and difficulty in production. In this review we discuss the evidence supporting the neurotrophin system's role in preventing neurodegeneration and survey some of the pharmacological strategies being pursued to develop effective therapeutics targeting neurotrophin function.

Yamin G, Ono K, Inayathullah M, Teplow DB. · Department of Neurology, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South (Room 445), Los Angeles, California 90095, USA. · Curr Pharm Des. · Pubmed #19075703 No free full text.

Abstract: Alzheimer's disease (AD), the most common neurodegenerative disorder in the aged, is characterized by the cerebral deposition of fibrils formed by the amyloid beta-protein (Abeta), a 40-42 amino acid peptide. The folding of Abeta into neurotoxic oligomeric, protofibrillar, and fibrillar assemblies is hypothesized to be the key pathologic event in AD. Abeta is formed through cleavage of the Abeta precursor protein by two endoproteinases, beta-secretase and gamma-secretase, that cleave the Abeta N-terminus and C-terminus, respectively. These facts support the relevance of therapeutic strategies targeting Abeta production, assembly, clearance, and neurotoxicity. Currently, no disease-modifying therapeutic agents are available for AD patients. Instead, existing therapeutics provide only modest symptomatic benefits for a limited time. We summarize here recent efforts to produce therapeutic drugs targeting Abeta assembly. A number of approaches are being used in these efforts, including immunological, nutraceutical, and more classical medicinal chemical (peptidic inhibitors, carbohydrate-containing compounds, polyamines, "drug-like" compounds, chaperones, metal chelators, and osmolytes), and many of these have progressed to phase III clinical trails. We also discuss briefly a number of less mature, but intriguing, strategies that have therapeutic potential. Although initial trials of some disease-modifying agents have failed, we argue that substantial cause for optimism exists.

Britschgi M, Wyss-Coray T. · Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305-5235, USA. · Arch Neurol. · Pubmed #19064741 No free full text.

Abstract: Alzheimer disease (AD) has become one of the main health concerns for the elderly population in the United States. Current treatments target symptoms only, but several advanced clinical trials are testing new drugs that are potentially disease modifying. Because AD is still difficult to diagnose in its earliest stages and the disease process is estimated to start many years before current clinical diagnosis is made, accurate and simple diagnostic tools are urgently needed. We recently described a blood-based panel of secreted signaling proteins that distinguishes between blinded samples from patients with AD and control subjects with high accuracy. The same proteins also predicted progression to AD in preclinical patients with mild cognitive impairment several years before clinical diagnosis for AD was made. Herein, we describe these findings and discuss the potential for a more general application of our proteomic approach in understanding and diagnosing disease.

Murphy C. · Department of Psychology, San Diego State University, 6363 Alvarado Court, San Diego, CA 92120, USA. · J Nutr Elder. · Pubmed #19042574 No free full text.

Abstract: Taste and smell are critical to dietary selection, especially for older adults, whose appetite is reduced. Neuroimaging studies can elucidate the process that causes the decrease of chemosensory functions with aging. The profound lost of olfactory functions in persons with Alzheimer disease accentuate the problem of inadequate food intake and disease progression.

Tobinick E. · Institute for Neurological Research, a private medical group, inc. 100 UCLA Medical Plaza, Suites 205-210, Los Angeles, CA 90095, United States. · Drug Discov Today. · Pubmed #19027875 No free full text.

Abstract: Excess TNF is centrally involved in the pathogenesis of a variety of neuroinflammatory disorders, including Alzheimer's disease, other forms of dementia, intervertebral disc-related pain, and related disorders. TNF causes neuronal dysfunction, regulates synaptic mechanisms, and mediates amyloid-induced disruption of molecular mechanisms involved in memory. Perispinal administration of etanercept, a potent anti-TNF fusion protein, is a treatment modality whose rapid clinical effects may be related to modulation of these TNF-related mechanisms, particularly the role of TNF as a gliotransmitter capable of regulating synaptic transmission. This approach utilizes therapeutic delivery of etanercept across the dura via the cerebrospinal venous system, a confluence of the venous plexuses of the spine and the brain, in which flow is bi-directional owing to the absence of venous valves.