Treatment Of Alzheimer's Disease Patients Research Articles

Reduced anxiety in the mice expressing mutant (N141I) presenilin 2

Alzheimer's disease (AD) is characterized by progressive cognitive impairment. The effect of presenilin 1 (PS1) and PS2 mutation on cognition has been well characterized in a variety of transgenic mice. However, noncognitive behaviors have not been considered in these mice. In the present study, we found that transgenic mice expressing mutant PS2 (N141I) displayed decreased anxiety behavior determined by the elevated plus maze test and the light dark box test. However, these mice showed biphasic ambulatory activity (hyperactivity followed by hypoactivity) in an open field test. Correlated well with the reduced anxiety, expression of GABA(A)alpha(1) receptor was higher whereas c-Fos was lower in the cortex, hippocampus, and amygdala of the mice expressing PS2 mutation than those of the wild-type PS2 or nontransgenic control mice. These data indicate that PS2 mutation causes reduction of anxiety, and this effect may be related to the change of the expression of GABA(A)alpha(1) receptor and c-Fos. These findings could be useful in the understanding and the treatment of AD patients.

The neuroprotective role of melatonin against amyloid β peptide injected mice

Widespread cerebral deposition of a 40–42 amino acid peptide called amyloid β peptide (Aβ) in the form of amyloid fibrils is one of the most prominent neuropathologic features of Alzheimer's disease (AD). The clinical study provides evidence that accumulation of protofibrils due to the Arctic mutation (E22G) causes early AD onset. Melatonin showed beneficial effects in an AD mouse model. Mice were divided into four different groups (n=8 per group): (i) control group, (ii) scrambled Aβ-injected group, (iii) Aβ protofibril-injected group and (iv) melatonin-treated group. A single dose of (5 µg) Aβ protofibril was administered to the Aβ protofibril-injected and melatonin-treated groups via intracerebroventricular injections. The results demonstrate that melatonin treatment significantly reduces Aβ protofibril-induced reactive oxygen species (ROS) production, intracellular calcium levels and acetylcholinesterase activity in the neocortex and hippocampus regions. Based on these findings it is suggested that melatonin therapy might be a useful treatment for AD patients.

Change in circulating C-reactive protein is not associated with atorvastatin treatment in Alzheimer's disease

Amyloid containing senile plaques (SP) and neurofibrillary tangles (NFT) are histologic hallmarks of Alzheimer's disease (AD). Interestingly the SP and NFT found in non-demented, age-matched individuals with ischemic heart disease and/or hypertension are morphologically and topographically identical to those in AD. Cholesterol plays a significant role in production and accumulation of amyloid beta (Aβ) and progression of AD. Cholesterol is also a major contributor in atherosclerotic changes and cardiovascular disease. Numerous studies acknowledged benefits of cholesterol-lowering statins in slowing down the progression of AD, improving cognitive status and significantly reducing risk of cardiovascular events. Accumulating evidence suggests that there is a chronic inflammatory reaction in the areas of the brain affected by AD and C-reactive protein (CRP) is identified as a key molecule of acute phase of inflammation. CRP is also a very sensitive marker for cardiovascular events and excellent prognostic tool in post-heart attack and post-coronary artery bypass surgery recovery. Here we report that cholesterol lowering with atorvastatin produces no significant change in CRP levels in treating AD patients who participated in ADCLT (AD cholesterol lowering trial).

Amelioration of amyloid load by anti-Aβ single-chain antibody in Alzheimer mouse model

Parenteral immunization of transgenic mouse models of Alzheimer disease (AD) with synthetic amyloid β-peptide (Aβ) prevented or reduced Aβ deposits and attenuated their memory and learning deficits. A clinical trial of immunization with synthetic Aβ, however, was halted due to brain inflammation, presumably induced by a toxic Aβ, T-cell- and/or Fc-mediated immune response. Another issue relating to such immunizations is that some AD patients may not be able to raise an adequate immune response to Aβ vaccination due to immunological tolerance or age-associated decline. Because peripheral administration of antibodies against Aβ also induced clearance of amyloid plaques in the model mice, injection of humanized Aβ antibodies has been proposed as a possible therapy for AD. By screening a human single-chain antibody (scFv) library for Aβ immunoreactivity, we have isolated a scFv that specifically reacts with oligomeric Aβ as well as amyloid plaques in the brain. The scFv inhibited Aβ amyloid fibril formation and Aβ-mediated cytotoxicity in vitro. We have tested the efficacy of the human scFv in a mouse model of AD (Tg2576 mice). Relative to control mice, injections of the scFv into the brain of Tg2576 mice reduced Aβ deposits. Because scFvs lack the Fc portion of the immunoglobulin molecule, human scFvs against Aβ may be useful to treat AD patients without eliciting brain inflammation.

Mitochondria are a direct site of Aβ accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression

Alzheimer's disease (AD) is a complex, neurodegenerative disease characterized by the impairment of cognitive function in elderly individuals. In a recent global gene expression study of APP transgenic mice, we found elevated expression of mitochondrial genes, which we hypothesize represents a compensatory response because of mitochondrial oxidative damage caused by the over-expression of mutant APP and/or amyloid beta (Abeta). We investigated this hypothesis in a series of experiments examining what forms of APP and Abeta localize to the mitochondria, and whether the presence of these species is associated with mitochondrial dysfunction and oxidative damage. Using immunoblotting, digitonin fractionation, immunofluorescence, and electron microscopy techniques, we found a relationship between mutant APP derivatives and mitochondria in brain slices from Tg2576 mice and in mouse neuroblastoma cells expressing mutant human APP. Further, to determine the functional relationship between mutant APP/Abeta and oxidative damage, we quantified Abeta levels, hydrogen peroxide production, cytochrome oxidase activity and carbonyl proteins in Tg2576 mice and age-matched wild-type (WT) littermates. Hydrogen peroxide levels were found to be significantly increased in Tg2576 mice when compared with age-matched WT littermates and directly correlated with levels of soluble Abeta in Tg2576 mice, suggesting that soluble Abeta may be responsible for the production of hydrogen peroxide in AD progression in Tg2576 mice. Cytochrome c oxidase activity was found to be decreased in Tg2576 mice when compared with age-matched WT littermates, suggesting that mutant APP and soluble Abeta impair mitochondrial metabolism in AD development and progression. An increase in hydrogen peroxide and a decrease in cytochrome oxidase activity were found in young Tg2576 mice, prior to the appearance of Abeta plaques. These findings suggest that early mitochondrially targeted therapeutic interventions may be effective in delaying AD progression in elderly individuals and in treating AD patients.

Investigations with cultured human microglia on pathogenic mechanisms of Alzheimer's disease and other neurodegenerative diseases

Inflammation-mediated mechanisms for human neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) have evolved from being on the fringe of medical hypotheses to mainstream thinking. Pioneering immunopathology studies with human brain tissues identified microglia associated with neuropathologic hallmarks of these diseases. As activated macrophages were known to produce many potential toxic products, this gave rise to the hypothesis that activated microglia (brain resident macrophages) could be contributing to the degeneration of key target neurons in these diseases, as well as potential vascular dysfunction. Studies with microglia derived from different sources, including human brains, have confirmed that activated microglia can mediate neuronal cell death. Based on these theories, a number of human clinical trials with antiinflammatory agents have been carried out on AD patients. Results to date have indicated a lack of effectiveness at slowing disease progression and have begun to cast doubt on the significance of inflammation in AD. It has been shown recently that activating microglia through immunization of amyloid plaque-developing mice with amyloid beta peptide (Abeta) has promise as a therapeutic strategy and despite some setbacks, has potential as a treatment for AD patients. This article will consider experimental data with microglia to determine whether the additional targets need to be investigated. The use of human microglia cultures, in particular those derived from elderly diseased human brains, offers an experimental system that can closely model the cell type activated in human neurodegenerative diseases. Experimental data produced by our laboratory and others is reviewed to determine the contribution of this unique experimental model to understanding disease mechanisms and possibly discovering new therapeutic targets.

Analysis of Genetic Polymorphisms in Acetylcholinesterase as Reflected in Different Populations

Acetylcholinesterase (AChE) plays a crucial physiological role in termination of impulse transmission at cholinergic synapses through rapid hydrolysis of acetylcholine. In addition, it was implicated in amyloid plaque formation, a hallmark of Alzheimer's disease (AD), and most of the drugs used in AD treatment are AChE inhibitors. Thus ACHE is an obvious candidate gene for pharmacogenetic study of AD treatment. However, AChE is a highly conserved molecule, and only a few naturally occurring genetic polymorphisms have been reported in the human gene. The goals of this study were to make a systematic effort to identify natural single nucleotide polymorphisms (SNPs) in the human ACHE gene, and to reveal their population specific architecture. To this end, the genomic coding sequences for AChE of 96 unrelated control individuals from three distinct ethnic groups, African Americans, Ashkenazi Jews and Israeli Arabs, were analyzed. Thirteen ACHE SNPs were identified, ten of which are newly described, and five of which should produce amino-acid substitutions (Arg34Gln, Gly57Arg, Glu344Gly, His353Asn and Pro592Arg). Population frequencies of 11 of the 13 SNPs were established in four different populations, African Americans, Ashkenazi Jews, Sephardic Jews and Israeli Arabs; 17 haplotypes and 5 ethno-specific alleles were identified, and a cladogram of ACHE haplotypes was constructed. Among the SNPs resulting in an amino-acid substitution, three are within the mature protein, mapping on its external surface; they are thus unlikely to affect its catalytic properties, yet could have antigenic consequences or affect putative protein-protein interactions. Furthermore, the newly identified SNPs open the door to a study of the possible association of AChE with deleterious phenotypes - such as adverse drug responses to AChE inhibitors employed in treatment of AD patients and hypersensitivity to pesticides.

Autoantibodies to Redox-modified Oligomeric Aβ Are Attenuated in the Plasma of Alzheimer's Disease Patients

Accumulation of Abeta protein in beta-amyloid deposits is a hallmark event in Alzheimer's disease (AD). Recent findings suggest anti-Abeta autoantibodies may have a role in AD pathology. However, a consensus has yet to emerge as to whether endogenous anti-Abeta autoantibodies are elevated, depressed, or unchanged in AD patients. Whereas experiments to date have used synthetic unmodified monomeric Abeta (Abetamon) to test autoimmunity, up to 40% of the Abeta pool inB AD brain consists of low molecular weight oligomeric cross-linked beta-amyloid protein species (CAPS). Recent studies also suggest that CAPS may be the primary neurotoxic agent in AD. In the present study, AD and nondemented control plasma were analyzed for immunoreactivity to CAPS and Abetamon. Plasma of both nondemented and AD patients were found to contain autoantibodies specific for soluble CAPS. Nondemented control and AD plasmas demonstrated similar immunoreactivity to Abetamon. In contrast, anti-CAPS antibodies in AD plasma were found to be significantly reduced compared with nondemented controls (p=0.018). Furthermore, age at onset for AD correlated significantly (p=0.041) with plasma immunoreactivity to CAPS. These data suggest that autoantibodies to CAPS are depleted in AD patients and raise the prospect that immunization with anti-CAPS antibodies might provide therapeutic benefit for AD.

Non-steroidal anti-inflammatory drugs and cyclooxygenase in Alzheimer's disease.

Epidemiological studies indicate that anti-inflammatory drugs, especially the non-steroidal anti-inflammatory drugs (NSAIDs), decrease the risk of developing Alzheimer's disease (AD). Their beneficial effects may be due to interference in the chronic inflammatory reaction, that takes place in AD. The best-characterized action of NSAIDs is the inhibition of cyclooxygenase (COX). There is special interest for anti-inflammatory treatment of AD using selective COX-2 inhibitors. These inhibitors reduce the inflammatory reaction but lack the side effects observed with non-selective NSAIDs. So far, clinical trials designed to inhibit inflammation or COX-2 activity have failed in the treatment of AD patients. Several lines of evidence can explain the failures of the anti-inflammatory and anti-COX-2 trials on AD patients. In this review we will focus on the role, expression and regulation of COX-1 and COX-2 in AD brain. Understanding the role of COX in AD pathogenesis could contribute to the development of an anti-inflammatory therapy for the treatment or prevention of AD.

Long-term cholinesterase inhibitor therapy for Alzheimer's disease: implications for long-term care.

As the population ages and Alzheimer's disease (AD) becomes more prevalent, nursing facilities will be faced with managing more AD patients than in previous decades. Managing this population will pose a significant challenge for the resources of long-term care facilities. In short- and long-term studies, cholinesterase (ChE) inhibitor treatment has been shown to benefit the symptoms of mild to moderate AD. Donepezil trials have extended this finding to patients with moderate to severe AD as well as the more severe symptoms of AD patients residing in nursing home settings. Results from long-term ChE inhibitor trials and the benefits that may be gained by treating AD patients residing in nursing facilities are presented.

Induction of NGF synthesis in astrocytes by onjisaponins of Polygala tenuifolia, constituents of Kampo (Japanese herbal) medicine, Ninjin-Yoei-To

The effect of a kampo medicine, Ninjin-yoei-to (NYT; Ren-shen-yang-rong-tang in Chinese) on nerve growth factor (NGF) secretion from the cultured rat astrocytes was examined in vitro. When rat embryo astrocytes were cultured in the presence of NYT for 24 h, the amount of NGF in the medium was significantly increased in a dose dependent manner. Among 14 kinds of component herbs in NYT, the roots of Polygala tenuifolia and roots of Panax ginseng extracts increased NGF levels from the astrocytes. Saponin fraction from the roots of P. tenuifolia enhanced the production of NGF, however phenolic glycoside fraction showed no effect. Onjisaponins A, B, E, F and G as major saponins of the root of P. tenuifolia strongly increased the NGF level, whereas ginsenosides Rb1 and Rg1 did not affect the NGF level. Onjisaponin F also induced ChAT mRNA level in rat basal forebrain cells. These results indicate the possibility that NYT and/or onjisaponins in P. tenuifolia may have potential therapeutic effects for the treatment of Alzheimer disease patients.

Donepezil for the treatment of behavioral disturbances in Alzheimer's disease: a 6-month open trial

Behavioral and psychological signs of dementia (BPSD) are common clinical characteristics of Alzheimer's disease (AD). They result in patient and caregivers distress, decreased quality of life and placement in nursing homes. Treatment of BPSD with antidepressant and antipsychotic medications is not without complications and serious adverse effects. The acetylcholinesterase inhibitors (AChEI) show preliminary promise as psychotropic agents possibly able to improve BPSD in AD patients. The present study aimed to evaluate the effect of donepezil (an AChEI) as an only treatment for AD patients with BPSD. Ten consecutive AD patients hospitalized at a psychogeriatric ward due to BPSD were treated with donepezil for 24 weeks. Effect was measured using the NeuroPsychiatric Inventory (NPI). Significant reduction in the presence of delusions, irritability/lability and disinhibition were achieved after 24 weeks of donepezil treatment. This was accompanied by reduction in caregivers distress. The drug was well tolerated and all patients completed the study. Our findings complement the preliminary data that donepezil as well as other AChEIs are promising candidates for further study as psychotropic agents positively affecting BPSD in AD patients.

Modulation of nicotinic receptor activity in the central nervous system: a novel approach to the treatment of Alzheimer disease.

Impaired cholinergic function in the central nervous system is an early feature of Alzheimer disease (AD). Currently, cholinergic deficit is usually corrected by increasing the amount of acetylcholine in the synapse by inhibiting acetylcholinesterase (AChE). One of the most consistent cholinergic deficits in AD is the reduced expression of nicotinic acetylcholine receptors (nAChR) in the brain. Since these receptors are essential for learning and memory, restoring nicotinic cholinergic function is a promising approach to treating AD. Allosteric modulation of nAChR is a novel approach, which circumvents development of tolerance through long-term use of conventional nicotinic agonists. Allosteric modulators interact with receptor-binding sites distinct from those capable of recognizing the natural agonist. Positive allosteric modulation of nAChR activity has no effect on conductance of single channels; instead, by facilitating channel opening, it potentiates responses evoked by the interaction of the natural agonist with presynaptic and postsynaptic nAChR. Allosteric modulation of nAChR activity could therefore potentially produce a significant benefit in AD. One such allosteric modulator is galantamine. In addition to increasing nAChR activity, galantamine also inhibits AChE. This novel, dual mechanism of action distinguishes galantamine from many other AChE inhibitors. Galantamine has been shown to improve cognitive and daily function for at least 6 months in placebo-controlled trials, and to maintain these functions at baseline levels for at least 12 months in a 6-month open-label extension study. Galantamine has positive effects on nAChR expression, which are likely to contribute to its sustained efficacy in the treatment of AD patients.

Differential increase in cerebrospinal fluid-acetylcholinesterase after treatment with acetylcholinesterase inhibitors in patients with Alzheimer's disease

The clinical significance and the effects of pharmacological treatment of patients with Alzheimer's disease (AD) were evaluated by measurement of acetylcholinesterase (AChE) in the cerebrospinal fluid (CSF). CSF–AChE of AD patients was lower, not significantly, compared with controls. However, CSF–AChE was significantly increased after treatment of AD patients with AChE inhibitors (donepezil and galantamine). The increase was higher in patients treated with donezepil than in those treated with galantamine, which might be related to different mechanisms for the substances. The increase was also dose-dependent, and was especially marked in patients showing a clinical response. These data suggest that CSF biomarkers are capable not only of identifying a biochemical effect of drugs, but also of differentiating between different compounds in a dose-dependent manner.

Regulation of gene expression by muscarinic acetylcholine receptors

In the brain, muscarinic acetylcholine receptors (mAChRs) are involved in higher cognitive functions including synaptic plasticity and memory. In Alzheimer's disease (AD) patients the cholinergic nervous system is severely damaged. In order to reinforce the cholinergic system, clinical tests were started to use cholinomimetic drugs to treat AD patients. To identify the genes involved in mAChR signalling, we used a differential display approach and found 11 genes that were readily activated by mAChR with 1 hour of activation. These included the transcription factors Egr-1, Egr-2, Egr-3, c-Jun, Jun-D and Gos-3; the growth regulator hCyr61; the signalling factors NGFi-B (nerve growth factor induced gene-B) and Etr101; the unknown gene Gig-2 (for G-protein-coupled receptor induced gene 2); and the acetylcholinesterase gene (ACHE). Our data show that multiple immediate-early genes are under the control of mAChRs, and they suggest that these genes play important roles in coupling receptor stimulation to long-term neuronal responses. The results also suggest a feedback mechanism where up-regulated ACHE expression and accelerated breakdown of acetylcholine (ACh) at the cholinergic synapses limits increases in cholinergic transmission. Three hours after m1 mAChR activation a different pattern of gene expression was demonstrated. It included the novel genes Gig-3 and Gig-4, as well as the LIM-only protein LM04. Like ACHE, these genes are target genes which may be under the control of the above immediate-early genes. Together, our data show that muscarinic receptors induce a complex and sustained pattern of gene expression that may be involved in the regulation of cholinergic transmission as well as the control of cellular functions in post-synaptic cholinergic target cells. These results may contribute to a better understanding of the effects and side effects of cholinomimetic treatment in AD patients.

Diagnosis and management of Alzheimer disease.

Alzheimer disease afflicts millions of older Americans, with an estimated cost to society approaching $100 million annually. Family physicians will care for an increasing number of patients with Alzheimer disease as well as their caregivers and families. A comprehensive and systematic review of the literature published between 1985 and 1998 about diagnosing and treating Alzheimer disease was conducted, using "dementia," "Alzheimer's disease," and "treatment" as search strategy key words. Data and information that reported significant conclusions were critically reviewed. Potentially important new data about new agents that might be of benefit when caring for patients with Alzheimer disease are discussed. The primary goals when treating Alzheimer disease patients are enhancing autonomy and functional abilities and maintaining quality of life for patients and caregivers. In addition to diagnostic and pharmacologic treatment, primary care physicians will be called upon to provide nonpharmacologic support to assist with behavioral, social, and living environment problems faced by these patients and their families. The most common pharmacologic treatment is cholinesterase inhibition. Two cholinesterase inhibitors, tacrine and donepezil, are effective in treating cognitive and global function. Newer cholinesterase inhibitors should soon be available that might offer safety advantages as well as efficacy in treating behavioral and psychiatric symptoms related to Alzheimer disease. Other agents, including vitamin E, nonsteroidal anti-inflammatory drugs, estrogen, and Ginkgo biloba, are under investigation. Nonpharmacologic measures are important components in the management of Alzheimer disease. Support groups can help to diminish behavioral problems, maintain the patient's independence, and provide relief for caregivers and families.

Behavior therapy competence training--a specific intervention with beginning Alzheimer dementia

At the Psychiatric Department, Ludwig-Maximilians-Universität, Munich, a behavioral competency training (Verhaltenstherapeutisches Kompetenztraining) VKT is offered to patients with early stages of Alzheimer's disease (AD). The primary objects of VKT are, (a) patient support in coping with the diagnosis of AD, (b) mobilization of the present personal activity resources, and (c) minimization of depressive symptoms. The VKT consists of six therapy-modules: 1. behavior analysis, 2. psychoeducation, 3. stress management, 4. increase of pleasant activities, 5. enhancement of social competency, and 6. modification of depressive cognitive patterns. The VKT is derived from scientific findings that show the involvement of psycho-social factors in the genesis of AD. Inadequate coping-behavior, unescapable stress and resulting neurodegenerative effects, a low premorbid niveau of activity and the presence of premorbid depressive symptoms outline the necessity of psychotherapeutic treatment in AD patients.

Importance of Immunological and Inflammatory Processes in the Pathogenesis and THERAPY of Alzheimer's Disease

The contribution of autoimmune processes or inflammatory components in the etiology and pathogenesis of Alzheimer's disease (AD) has been suspected for many years. The presence of antigen-presenting, HLA-DR-positive and other immunoregulatory cells, components of complement, inflammatory cytokines and acute phase reactants have been established in tissue of AD neuropathology. Although these data do not confirm the immune response as a primary cause of AD, they indicate involvement of immune processes at least as a secondary or tertiary reaction to the preexisting pathogen and point out its driving-force role in AD pathogenesis.These processes may contribute to systemic immune response. Thus, experimental and clinical studies indicate impairments in both humoral and cellular immunity in an animal model of AD as well as in AD patients.On the other hand, anti-inflammatory drugs applied for the treatment of some chronic inflammatory diseases have been shown to reduce risk of AD in these patients. Therefore, it seems that anti-inflammatory drugs and other substances which can control the activity of immunocompetent cells and the level of endogenous immune response can be valuable in the treatment of AD patients.

A comprehensive study of the spatiotemporal pattern of beta-amyloid precursor protein mRNA and protein in the rat brain: lack of modulation by exogenously applied nerve growth factor.

Nerve growth factor (NGF) is a neurotrophic factor for basal forebrain cholinergic neurons, a population that degenerates and dies in Alzheimer's disease (AD). It has been suggested that NGF be used to treat AD patients. However, in vivo administration of NGF to the developing hamster brain was shown to induce the expression of the beta-amyloid precursor protein (beta APP) gene. The association of alterations in beta APP gene expression with AD-like neuropathological changes and cognitive impairment in animals, and with AD-like neurodegeneration in Down syndrome patients suggests that NGF-mediated increases in beta APP expression could negate or attenuate NGF's neurotrophic activity in AD treatment trials. The present study was undertaken to explore further the influence of NGF on beta APP expression, and to determine which, if any, of the beta APP mRNAs is altered in response to NGF treatment. We first examined the spatiotemporal pattern of beta APP-695 and Kunitz protease inhibitor (KPI)-containing beta APP mRNA expression in the rat brain. Specific oligonucleotide probes were used to show that these mRNAs are present during embryonic development. In addition, we evaluated postnatal expression in nine brain regions and showed that beta APP mRNAs were readily detected in all regions at postnatal day 2. In human brain, the relative levels of beta APP-695 and beta APP-KPI mRNA and their protein are discordant, in that the level of beta APP-695 mRNA is slightly higher than that of beta APP-KPI, but beta APP-KPI protein predominates. In contrast, the several-fold excess of beta APP-695 mRNA relative to beta APP-KPI mRNA in the rat brain was also reflected at the protein level. Surprisingly, administration of exogenous NGF failed to affect rat beta APP mRNA levels either in vitro or during postnatal development in vivo.

Clinical studies in Alzheimer patients with positron emission tomography

Brain imaging techniques will in the future play an important role in the assessment of patients with neurogenerative disorders such as Alzheimer's disease (AD). An early diagnosis of AD is today hampered by lack of reliable diagnostic markers. Positron emission tomography (PET) permits the quantification and three-dimensional imaging of physiological variables. This provides the clinician with a non-invasive imaging technique which allows in vivo quantification of physiological processes in AD underlying dysfunction of cognition. PET studies regarding changes in cerebral blood flow and metabolism are rather consistent at least in moderate/advanced cases of AD. How early in the progress of the disease deficits in these parameters can be observed is still an open question. Longitudinal studies will here be important and especially in individuals with a family history of AD. Since deficits in cholinergic neurotransmission have been measured in autopsy AD brains attempts have also been made to visualize cholinergic activity in vivo. Nicotinic and muscarinic receptors have been visualized in normal and AD brains. A reduced uptake and binding of [ 11C]nicotine in the temporal and frontal cortices have been measured in AD patients by PET. Few treatment studies in AD have been evaluated by PET. Long-term treatment with the cholinesterase inhibitor tacrine increase the uptake of [ 11C]nicotine. Significant reduction in uptake between the two enantiomers (S)(−) and ( R)(+)-[ 11 C] nicotine has been observed compatible with a restoration of nicotinic receptors. Tacrine also significantly increased the glucose metabolism. PET studies indicate that long-term tacrine treatment in AD patients with mild dementia improves functional activities in brain. When an AD patient with moderate dementia was treated with nerve growth factor (NGF) PET studies revealed increase in cortical blood flow and nicotinic receptors. PET studies will in the future play an important role in the evaluation of new therapeutic drug strategies in AD.