Immunotherapy for Alzheimer's disease and other dementias

PURPOSE OF REVIEW: The aim of this article is to review the role of immunotherapy in the removal of proteins which accumulate abnormally in neurodegenerative disorders associated with dementia, in particular amyloid-beta accumulation in Alzheimer's disease. RECENT FINDINGS: In both transgenic mouse models and in two trials of amyloid-beta immunotherapy for human Alzheimer's disease, active immunization with amyloid-beta 1-42 results in the removal of amyloid-beta plaques from the cerebral cortex associated with, in the mouse models, improvement in cognitive function. Cerebral amyloid angiopathy and neurofibrillary tangles persist, however, and there is also concern about T lymphocyte immune reactions in the meninges in the human cases. Active immunization schedules are being developed to minimize T lymphocyte reactions and to maximize antibody production and passive immunization protocols are being devised. Immunotherapy for removal of the proteins which accumulate in other neurodegenerative disorders associated with dementia such as prion proteins and alpha-synuclein are in the early stages of development. SUMMARY: Dementias in the elderly are an increasing medical, social and economic problem and current treatments are only effective. In the majority of dementias, proteins accumulate within cells and in the extracellular compartments of the brain. In the most common dementia, Alzheimer's disease, amyloid-beta accumulates as plaques in the extracellular space of the grey matter and in artery walls as cerebral amyloid angiopathy and tau protein accumulates as neurofibrillary tangles within neurons.     

Immunotherapy for Alzheimer's disease and other dementias

OBJECTIVE: The aim of this article is to review the role of immunotherapy in the removal of proteins which accumulate abnormally in neurodegenerative disorders associated with dementia, in particular amyloid-beta accumulation in Alzheimer's disease. RESULTS: In both transgenic mouse models and in two trials of amyloid-beta immunotherapy for human Alzheimer's disease, active immunization with amyloid-beta 1-42 results in the removal of amyloid-beta plaques from the cerebral cortex associated with, in the mouse models, improvement in cognitive function. Cerebral amyloid angiopathy and neurofibrillary tangles persist, however, and there is also concern about T lymphocyte immune reactions in the meninges in the human cases. Active immunization schedules are being developed to minimize T lymphocyte reactions and to maximize antibody production and passive immunization protocols are being devised. Immunotherapy for removal of the proteins which accumulate in other neurodegenerative disorders associated with dementia such as prion proteins and alpha-synuclein are in the early stages of development. CONCLUSION: Dementias in the elderly are an increasing medical, social and economic problem and current treatments are only effective. In the majority of dementias, proteins accumulate within cells and in the extracellular compartments of the brain. In the most common dementia, Alzheimer's disease, amyloid-beta accumulates as plaques in the extracellular space of the grey matter and in artery walls as cerebral amyloid angiopathy and tau protein accumulates as neurofibrillary tangles within neurons.     

Synaptic loss in Alzheimer's disease and other dementias

The extent and location of neuronal losses necessary or sufficient to produce dementia in patients with Alzheimer's Disease (AD) is unknown. To approach this question, we studied synaptic terminals in postmortem brain tissue utilizing immunohistochemical techniques. We used antibodies against two proteins found in synaptic terminals--synapsin I and synaptophysin--as synaptic markers in the hippocampal complexes of eight patients with autopsy-proven AD and eight nondemented control subjects. Quantitative microscopy measured the regional density of synaptic staining. All AD patients showed a striking decrease in synaptic staining in the outer half of the molecular layer of the dentate gyrus compared with control brains, where the density of synaptic terminals was uniform throughout. In an additional patient with progressive degenerative dementia but without plaques or tangles on neuropathologic examination, similar depletion of synaptic staining was seen in the dentate gyrus. Quantitative densitometric analyses confirmed the focal decrease in synaptic staining in the outer half of the molecular layer in demented patients. We also found a slight increase in synaptic staining in the inner half of this layer.     

Alzheimer's disease and other dementias: a review

Dementia and its associated diseases are important causes of disability and morbidity in developed countries, especially in the aged population. As the babyboomers arrive at retirement and individuals over 100 are one of the fastest growing segments of our nation's population, we may realize the substantial cost these diseases bring to society. Dementia is characterized by a significant loss of cognitive function and should be clinically distinguished from an acute delirium or decreased arousal. Its manifestations cause anguish to millions of caregivers and family members, who are pressed to cope with their loved one's unfortunate decline in multiple cognitive domains, functioning, and behavior. Early detection and management may prevent overuse of costly medical resources and allow patients and family members time to prepare for future medical, financial, and emotional challenges. Diagnostic clues to the etiology of the patient's dementia can be found in a medical workup in which the neurologic history and examination (including mental status examination) are essential and neuroimaging is indicated. Herein, the concept of central nervous system (CNS) degenerative diseases as disorders of specific proteins is introduced. This review is intended to summarize clinical, biological, and genetic features of the common subtypes of dementia, and bring light to potential benefits of early and accurate diagnoses to optimize treatment. Details of the various diseases remain only partially uncovered, raising extensive prospects for future research and therapy for patients with dementia.     

Cognitive pharmacotherapy of Alzheimer's disease and other dementias.

OBJECTIVE: The objective of this paper is to review the randomized controlled trials (RCTs) on the pharmacotherapy of Alzheimer's disease and other dementias and to provide evidence-based recommendations for treatment of the cognitive impairment associated with these disorders. METHOD: A Medline search was conducted for RCTs, using the following key words: Alzheimer's disease, dementia, therapy, cholinesterase inhibitor, donepezil, rivastigmine, and galantamine. Studies were critically appraised, followed by a review of published major clinical practice guidelines. Recommendations for treatment were made based on best available evidence. RESULTS: The pharmacotherapy of Alzheimer's disease should include the meticulous management of vascular risk factors (for example, hypertension, diabetes, cholesterol, and stroke prophylaxis) and consideration for supplementation with folate, vitamin B complex, and vitamin E. Patients should be offered at least 1 trial of a cholinesterase inhibitor, with the possibility of another trial if the first is poorly tolerated or ineffective. Patients with vascular dementia and dementia with Lewy bodies should also be offered treatment with cholinesterase inhibitors. At this time, we lack sufficient data to recommend the use of hormone replacement or antiinflammatory therapy for treatment of dementia as the primary indication. CONCLUSION: Reasonable evidence exists to provide recommendations for the pharmacotherapy of dementia. Treatment will likely result in modest but important benefits to patients, caregivers, and society.     

Nitric oxide pathways in Alzheimer's disease and other neurodegenerative dementias

Nitric oxide (NO) is an enzymatic product of nitric oxide synthase (NOS). NO has significant physiological functions and an increasing body of evidence suggests that NO pathways are implicated in a number of neurological disorders, including Alzheimer's disease (AD) and other neurodegenerative dementias. NO is continuously released by endothelial cells in the vascular system, whereas advanced age in the presence of vascular risk factor causes a decrease in cerebral blood flow, involving microvasculopathy with impaired NO release, which in turn results in regional metabolic dysfunction. This finding suggests that vascular pathology plays a crucial role in the pathogenesis of so-called neurodegenerative dementias. Inflammatory responses are commonly found in the brain under a variety of neurodegenerative dementias, including AD and dementia with Lewy bodies, in which up-regulation of NOS expression, suggesting overproduction of NO, is found in neurons and glia. NO is thought to be involved in such neuroinflammation due to its free radical properties, which compromise cellular integrity and viability via mitochondrial damage. Further studies to elucidate NO pathways in neurodegenerative dementias could lead to a better understanding of their pathogenesis and improved therapeutic strategies, and therefore are certainly warranted.     

Genetic aspects of Alzheimer's disease, Pick's disease, and other dementias

Although genetic testing is available for some degenerative diseases, in most types of dementia, both genetic and environmental factors are involved. Overall, dementing diseases can be either sporadic or inherited, and in general, the earlier the onset, the more likely a disease is to be inherited. Before genetic testing is performed, the ethical issues, such as the effect the tests might have on asymptomatic children, should be considered. The ethical use of DNA samples in research is another genetic testing issue to be considered.     

Memantine: targeting glutamate excitotoxicity in Alzheimer's disease and other dementias

The management of dementia has changed since the development of new antidementia drugs. The benefits observed in Alzheimer's disease (AD) with selective cholinergic transmission treatments are mainly symptomatic, without clear evidence of neuroprotection. The hypothesis that glutamate-mediated neurotoxicity is involved in the pathogenesis of AD is finding increasingly more acceptance in the scientific community. Glutamate receptors are overactive, and N-methyl-D-aspartate (NMDA) receptor antagonists have therapeutic potential for the treatment of AD and other neurological disorders. Memantine is a noncompetitive NMDA antagonist that is considered a neuroprotective drug. Memantine's capacity has been demonstrated in preclinical studies, and it is considered a useful symptomatic treatment for AD. Memantine has been shown to benefit cognition, function, and global outcome in patients with moderate to severe AD, and it is currently approved by the US Food and Drug Administration (FDA) for the treatment of moderate to severe AD. Recently, memantine has also demonstrated efficacy in the initial stages of AD, although FDA authorization is pending. This review highlights the important pharmacological and clinical aspects of memantine, as well as some basic mechanisms mediating glutamatergic neurodegeneration.     

Contribution of neuroimaging in the diagnosis of Alzheimer's disease and other dementias

This paper reviews the use of neuroimaging in the diagnosis of dementia, especially Alzheimer's disease. Computed tomography is still used to determine reversible causes of dementia; however, without clinical symptoms these causes are hard to find and computed tomography scanning is only cost-effective in a defined group of patients. Using magnetic resonance imaging, atrophy of the medial temporal lobe can be assessed volumetrically and visually, with a high correlation between the two methods. Medial temporal lobe atrophy is highly predictive of Alzheimer's disease, and correlates with neuropsychological performance and postmortem histologically measured volume. Cerebral volume changes over time seem to differentiate Alzheimer's disease and mild cognitive impairment progressing to Alzheimer's disease from controls with high accuracy. Studies of the corpus callosum in dementia indicate a cortico-cortical disconnection caused by atrophy. Of the new techniques, functional magnetic resonance imaging seems the most promising. This technique can possibly play a role in predicting Alzheimer's disease in patients with mild cognitive impairment. The use of single-photon emission computed tomography and positron emission tomography in (early) differential diagnoses seems limited. Lower regional cerebral blood flow is related to the severity of dementia and survival. Iodine-123 iodobenzamide single-photon emission computed tomography in dementia with Lewy bodies seems promising. Current and future positron emission tomography studies concentrate on memory function and receptor imaging. The focus in neuroimaging, especially magnetic resonance imaging, has shifted to early diagnosis and monitoring of the disease course, with a special interest in predicting dementia in patients with mild cognitive impairment.     

Subtypes of depression among patients with Alzheimer's disease and other dementias

ObjectivesWe compared the prevalence of subtypes of depression in patients with Alzheimer's disease (AD), vascular dementia (VaD), and unspecified dementia (UD).MethodsUsing the Integrated Healthcare Information Services database, we conducted an analysis of subtypes of depression (major depressive disorder, depressive disorder not otherwise specified, dysthymic disorder; depressive psychosis, and adjustment disorder depressive) among patients with AD, VaD, and UD. Six thousand four hundred and forty patients aged 60 years or older with dementia (2947 with AD, 725 with VaD, and 2768 with UD) were identified from January 1 to December 31, 2001. Both subtypes of depression and dementia subgroups were diagnosed using criteria from the International Classification of Diseases, 9th version.ResultsThe overall prevalence of depressive disorders was 27.41%. The prevalence of depressive disorders was significantly higher in VaD (44.14%) and UD (32.48%) patients compared with AD (18.53%, P < .0001) patients. The AD patients had the lowest prevalence of all subtypes of depression. The VaD patients, compared with both AD and UD (P < .005), had a significantly higher prevalence of: 1) depressive disorder not otherwise specified, 2) major depressive disorder, and 3) dysthymic disorder. Adjustment disorder with depressive symptoms was more common in the UD subgroup, whereas the rate of depressive psychosis was similar in all dementia subgroupsConclusionsThis study supports the view that depressive disorders are more prevalent in VaD compared with UD and AD, and provides indicators to the clinician for further evaluation of depression in dementia subgroups     

Genetic counselling and genetic screening for Alzheimer's disease and other dementias

Genetic and nongenetic factors have been identified to have roles in the etiology of dementia. Etiologic heterogeneity and genetic heterogeneity are recognized, especially for Alzheimer's disease which is the most common form of dementia. Asymptomatic individuals are increasingly requesting genetic services such as genetic counselling, predictive testing and screening for genetic risk factors. This paper provides an overview of the current knowledge about genetic counselling and genetic screening for dementia as well as guidelines for the physician.     

Emotional reactions to predictive testing in Alzheimer's disease and other inherited dementias

This work describes the reasons and emotional responses of healthy descendants after counseling for presenilin mutations in early-onset familial Alzheimer's disease (EOFAD), tau mutations in familial frontotemporal dementia (FTD), and prion mutations in fatal familial insomnia (FFI). A multidisciplinary protocol following Huntington's disease counseling guidelines and a post-test follow-up program were developed to counsel healthy descendants of affected families. The psychological consequences, anxiety levels, and depression status were assessed through validated scales before and after disclosing the information. Nine people from three different families, one with EOFAD, another with FTD, and the other with FFI came for counseling. Their main reason for testing was to initiate early treatment in the future. Disclosing the information decreased anxiety in two carriers, increased it temporarily in one, and had no effect in another. All noncarriers felt relieved. Overall, after a mean of 30 months of follow-up, no negative psychological reactions were observed. All participants positively valued the program. Although preliminary, our observations suggest that predictive testing in EOFAD, FTD, and FFI is safe and may be of benefit when performed with a delicate approach under strict pretest counseling protocols and post-test follow-up programs. The emotional reactions were similar, although the diseases, their phenotype, and mutation characteristics were different.     

Survival in Alzheimer's disease and vascular dementias

Over 5 years, we followed 199 patients with dementia of the Alzheimer type (DAT), 69 with multi-infarct dementia (MID), and 43 with mixed dementia (MIX). All three diagnostic categories had comparable progression of behavioral and cognitive impairment and need for home care or institutionalization at follow-up. However, 50% survival from diagnosis was 2.6 years for MID and 2.5 years for MIX, compared with 3.4 years for DAT. The 50% survivals from onset were longer than previous reports would suggest (8.1 years for DAT, 6.7 for MID, and 6.2 for MIX). Vascular dementias have higher mortality than DAT, even when associated with comparable cognitive and behavioral impairment.     

Measurement of thirteen biological markers in CSF of patients with Alzheimer's disease and other dementias

Cerebrospinal fluid (CSF) biological markers may be of valuable help in the diagnosis of dementia. The aim of the present study was to evaluate CSF levels of 13 potential biomarkers in patients with Alzheimer's disease (AD), frontotemporal lobe dementia, alcohol dementia, major depression and control patients without any neuropsychiatric disease. The study was performed using beta-amyloid 1-42 (Abeta42), total tau and phosphorylated tau-181 (P-tau181) as core markers. The ratio P-tau181/Abeta42 could significantly distinguish AD patients from all other diagnostic subgroups. CSF levels of 5 growth factors (HGF, GDNF, VEGF, BDNF, FGF-2) and 3 cytokines/chemokines (TNF-alpha, TGF-beta1, MIP-1alpha) did not significantly differentiate between the studied groups. However, depending on the degree of neurodegeneration (as expressed by the ratio P-tau181/Abeta42), patients with AD displayed significantly increased CSF levels of nerve growth factor (NGF) as compared to healthy controls. CSF levels of monocyte chemoattractant protein 1 (MCP-1) were found to be significantly increased with age in all groups but did not distinguish AD patients from healthy controls. The results confirmed the suitability of the ratio P-tau181/Abeta42 for the diagnosis of AD, while CSF levels of NGF and MCP-1 are less specific and reliable for AD. It is suggested that the increase in NGF depends on the extent of neurodegeneration of the AD type and the increase in MCP-1 on age.     

Tau and apo E in CSF: potential aid for discriminating Alzheimer's disease from other dementias

To evaluate the usefulness of tau proteins as biological markers in the diagnosis of dementia of the Alzheimer type (DAT), we analyzed the concentration of tau proteins in 253 cerebrospinal fluid (CSF) samples from patients with or without neurological disorders. Our study showed a significant increase of the mean CSF tau concentration in DAT patients compared with that from non-DAT patients. Interestingly, a significative decrease of CSF tau in patients with frontotemporal dementia was found. We also observed a positive correlation between the CSF-tau concentration and the number of apoepsilon4 alleles. The CSF apolipoprotein E concentration was evaluated and revealed no variation between the groups, although we observed a significant correlation between CSF tau and apolipoprotein E in DAT patients.