5 Steps to Reverse Dementia

All About Alzheimers

All About Alzheimers

The comprehensive new ebook All About Alzheimers puts everything into perspective. Youll gain insight and awareness into the disease. Learn how to maintain the patients emotional health. Discover tactics you can use to deal with constant life changes. Find out how counselors can help, and when they should intervene. Learn safety precautions that can protect you, your family and your loved one. All About Alzheimers will truly empower you.

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Biomarkers for Early Diagnosis of Alzheimers Disease

Biomarkers for Early Diagnosis of Alzheimer's Disease Biomarkers for early diagnosis of Alzheimer's disease Daniela Galimberti and Elio Scarpani, editors. p. cm. 1. Alzheimer's disease-Diagnosis. 2. Biochemical markers. I. Galimberti, Daniela. II. Scarpani, Elio. DNLM 1. Alzheimer Disease diagnosis. 2. Alzheimer Disease metabolism. 3. Biological Markers-metabolism. 4. Early Diagnosis. WT 155 B6155 2008 RC523.B58 2008 616.8'31075--dc22

Acquired immune deficiency syndrome dementia

Dementia in AIDS is an exclusionary diagnosis characterized by cognitive and motor disturbances and behavioral changes including impaired short- and long-term memory, decreased concentration, and slowed thought processing. The pathophysiology involves neurovirulent strains of HIV, excitotoxicity, and inflammation. AIDS dementia is treated with the antiviral zidovidine, together with drugs for the treatment of the associated psychosis and depression. Parkinson's disease16 afflicts 1.5 million Americans with an additional 60 000 cases diagnosed each year (see 6.08 Neurodegeneration). The cardinal symptoms of Parkinson's desease include tremor, bradykinesia, rigidity, and postural instability, the result of the loss of DA-containing cells in the substania nigra. Parkinson's disease patients also suffer from a variety of nonmotor symptoms including sleep disturbance, depression, and dementia. As with AD, Parkinson's disease is a disease that predominately affects those over the age of 65...

HIVAssociated Dementia

It is worth noting that the classification of these neuropsychiatric manifestations of HIV infection is undergoing revision after a joint conference of the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke on June 13, 2005, identified and defined criteria for three levels of HIV-associated neurocognitive disorders or conditions asymptomatic neurocognitive impairment, mild neurocognitive disorder (previously MCMD), and HIV-associated dementia. Clinicians should update themselves regularly by accessing Web sites such as that of the American Psychiatric Association's Office of HIV Psychiatry (www.psych.org hiv), which has downloadable curricula on the complete array of HIV-related neuropsychiatric conditions.

Alzheimers Disease and Vascular Dementia

Although depressive symptoms are commonly seen in patients at various stages of Alzheimer's disease, major depression per se is relatively uncommon. Ballard et al. (2000) found a 1-month prevalence of 8 (on the basis of DSM-III-R criteria), compared with 19 in patients with vascular dementia. In the Alzheimer's disease group, depression was equally common at all severities, whereas in vascular dementia, depression was more frequent in patients with Mini-Mental State Examination (MMSE) scores lower than 20. Vascular dementia patients with major depression in the month prior to assessment were significantly older, more likely to have a history of depression, and less likely to have experienced a major stroke event than were those without major depression. Lyketsos and colleagues (2000) reported a similar prevalence when the Neuropsychiatric Inventory was used. They found depression in 20 of the subjects with a diagnosis of Alzheimer's disease, compared with 32 of the participants with...

Diffuse Cortical Dementias Alzheimers Disease

Alzheimer's disease (AD), the most common cause of organic dementias, affects an estimated 4 million individuals in the United States, where it is the fourth major cause of death. Primarily a disease of the elderly, it affects more women than men. The onset is usually after the age of 50 to 55 years, and the incidence increases steadily with advancing age. It affects 10 of the population over age 65 years and 40 over 85 years. The disease has a worldwide distribution. It occurs sporadically or is inherited in an autosomal dominant pattern. About half of early-onset AD cases are familial. The diagnostic evaluation of patients with suspected AD requires a multidisciplinary approach and close monitoring of the progression of cognitive decline. Structural imaging using computed tomography (CT) scan and magnetic resonance imaging (MRI) is standard procedure. These imaging procedures are important in eliminating diseases that are not degenerative. Their usefulness in the decisive diagnosis...

Alzheimers Disease Biomarkers From Concept to Clinical Utility

Innogenetics NV, Gent, Belgium 2Memory Clinic and Department of Neurology, Middelheim General Hospital (ZNA) and Laboratory of Neurochemistry and Behavior, Institute Born-Bunge University of Antwerp, Antwerp, Belgium 3Department of Pathology and Laboratory Medicine, Institute on Aging Alzheimer's Disease Center, Center for Neurodegenerative Disease Research University of Pennsylvania School of Medicine, Philadelphia, PA, USA.

Dementia with Lewy Bodies

Dementia with Lewy bodies (DLB), also called diffuse Lewy body dementia (DLBD), is the second most common degenerative dementia in the elderly, after AD. It is somewhat more common in men. It may coexist with AD and Parkinson's disease. Cognitive decline, visual hallucinations, parkinsonian features, syncope, sensitivity to neuroleptics, sleep abnormalities, and a slowly progressive and fluctuating course are characteristic. Diffuse Lewy body dementia. A man diagnosed with dementia and Parkinson's disease at age 55 years steadily deteriorated, at times reporting visual and auditory hallucinations. After an approximate 11-year clinical course, he died at age 66. A. Atrophy of the frontal lobes. B. Lewy body in a cortical neuron (HE). C. Immunoreactivity of cortical Lewy bodies for a-synuclein (immunostain). Diffuse Lewy body dementia. A man diagnosed with dementia and Parkinson's disease at age 55 years steadily deteriorated, at times reporting visual and auditory hallucinations. After...

Rare Pathologic Forms of Dementias

Tangle-only and neuritic plaque-only dementias are variants of AD. The former is characterized by neurofi-brillary tangles and an almost total absence of neuritic plaques, whereas the latter is the opposite neuritic plaques are present and tangles absent. Argyrophilic grain dementia is characterized by the presence of argyrophilic and tau- positive, small, spindle-shaped grains in the hippocampus, amygdala, and temporoinsular and orbitofrontal regions. The clinical presentation is similar to that of AD.

Frontotemporal Lobar Dementias

A selective degeneration of the frontal and temporal lobes is the distinctive feature of a group of dementias estimated to comprise 15 to 20 of all dementia cases. Frontotemporal lobar dementias (FTLD) are not common, but their incidence is increasing as more cases are recognized. Individuals from early to late midlife are affected, and the clinical course averages from 5 to 15 years. Most diseases are sporadic, but familial examples with autosomal dominant inheritance also have been identified. The clinical presentation varies greatly among the diseases but all share neuropsychiatric symptoms, cognitive decline, and neurologic disorders. Neuropsy-chiatric symptoms in various combinations are usually in the foreground of the clinical picture, including behavioral and personality changes, emotional lability, depression, anxiety, restlessness, agitation, social disinhibition, and lack of initiative, planning, organizing (executive functions), insight, and judgment. Adding to the...

Tau Protein And Alzheimers Disease

The principle component of the PHFs, which make up NFTs, neuropil threads, and senile plaque neurites, is an abnormally hyperphosphorylated form of the microtubule-associated protein tau. Human brain tau occurs as six different isoforms that are normally located in the axons, where they bind to tubulin, thereby promoting microtubule assembly and stability. The microtubule stabilizing function of tau is greatly diminished by its hyper-phosphorylation to PHF-tau, which binds poorly to tubulin. The concentration of PHF-tau has been shown to be increased in Alzheimer's disease cerebral cortex, whereas the concentration of normal tau is reduced, suggesting that the hyperphosphorylation of normal tau rather than an increased synthesis of tau protein is important in Alzheimer's disease (12). Both proline-directed and non-proline-dependent protein kinases are likely to be important for PHF-tau hyperphosphorylation (10,13). The pro-line-directed protein kinases that have been studied with...

Contributor To Alzheimers Disease Pathology

As mentioned previously, disease-causing mutations in the APP and PS genes account for only a small minority of all Alzheimer's disease cases. In the vast majority of sporadic cases, it remains unclear as to the mechanisms that cause the presumed APP mismetabolism leading to senile plaque formation, as well as tau protein hyperphosphorylation to produce PHFs and NFTs. One factor that may underly the hallmark pathologies of sporadic Alzheimer's disease is that of altered signal transduction via the neurotransmitter receptor-G-protein-mediated PLC PKC and AC PKA pathways. The following section provides a brief overview of the experimental evidence showing how these signaling pathways contribute to APP metabolism and tau protein phosphorylation. A scheme of these pathways, adapted from a recent review by Lovestone and Reynolds (10), is given in Fig. 1. Having provided a theoretical basis by which altered neurotransmitter receptor-G-protein-mediated PLC PKC and AC PKA signal transduction...

Alzheimers Disease The Search for Validated Biomarkers

However, when it comes to the dementing diseases, this dynamic scenario does not fully apply. Even some one hundred years after the discovery of Alzheimer's disease (AD), the principal form of dementia, there are still no universally validated tests for early and accurate diagnosis of the disease or its progression, and there is no consensus on biomarkers that can objectively measure the effects of potential disease-modifying therapies. The development of such biomarkers has become a public health priority in those many parts of the world affected by the age-related surge in the number of people with dementia. Section 3 of this chapter then summarizes the product qualification of this assay, including selection of raw materials, and the steps needed to ensure their quality control. Following this, Section 4 describes the analytical qualification of the multiplex test in detail. Section 5 examines the clinical qualification of the test using autopsy-confirmed samples from demented...

Pathway In Alzheimers Disease

The phosphoinositide hydrolysis pathway (as shown in its simplest form in Fig. 2) has been shown to be disrupted at a number of levels in Alzheimer's disease brain. The first evidence suggesting that this pathway was impaired in Alzheimer's disease was provided by Stokes and Hawthorne, who reported large (30-50 ) decreases in the levels of phosphatidylinositol, phosphati-dylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate in Alzheimer's disease anterior temporal cortex (46). Subsequently, others reported that coupling of acetylcholine muscarinic Ml receptors, presumably to the Gq-protein that modulates PLC, was disrupted in Alzheimer's disease parietal (47) and frontal (48) cortices and thalamus (49). More recently, Ladner and colleagues showed that acetylcholine muscarinic Ml receptor-G-pro-tein coupling was disrupted in Alzheimer's disease superior frontal and pri- mary visual cortices, but not in dorsal striatum. Based on the differential pathology seen in these...

Role in Disease Pathogenesis A Alzheimers

Patients with Alzheimer's Disease have extensive neurofibrillary tangles, senile plaques, and vascular amyloid angiopathy in their brain tissue (134). The Heparan sulfate proteoglycans identified in Alzheimer's patients include perlecan, agrin, syndecan-1 through -3, and glypican-1. Perlecan expression is limited to senile plaques in the cortex but not cerebellum. The cortex is not the usual site for senile plaque formation (140). Based on the binding of perlecan to amyloid (3 protein and the amyloid precursor protein, it is possible that perlecan may play a role in amyloid fibril formation (141). Verbeek et al. (142) through immunohistochemical analysis showed that agrin is localized in senile plaques, neurofibrillary tangles, and cerebral blood vessels. Syndecan-1 through -3 and glypican-1 were also identified in the senile plaques and neurofibrillary tangles at a lower frequency than agrin. These results suggest that agrin, syndecans-1 through -3, and glypican-1 may play a role in...

Parkinsonism Dementia Complex of Guam

This disease occurs among the Chamorro tribe of Guam. It presents with parkinsonian features and progressive dementia, and it may be associated with ALS (see the section, Motor Neuron Diseases). Grossly, the brain is atrophic, and the substantia nigra and locus ceruleus are discolored. The histology is characterized by neuronal losses that are particularly severe in the hippocampus,

Alcohol Induced Persisting Dementia

This disorder develops in approximately 9 of alcoholics (Evert & Oscar-Berman, 1995) and consists of memory impairment combined with aphasia, apraxia, agnosia, and impairment in executive functions, such as planning, organizing, sequencing, and abstracting. These deficits are not part of a delirium and persist beyond intoxication and withdrawal. The dementia is caused by the direct effects of alcohol, as well as by vitamin deficiencies. individual with a history of alcoholism are early clues suggestive of alcohol-induced persisting dementia.

Inflammation In Alzheimer Dementia

There is now substantial epidemiological evidence of the involvement of inflammation in Alzheimer's dementia. There are now about 20 reports on the incidence of Alzheimer's dementia in populations with a long antiinflammatory drug consumption history. Nearly all of these studies showed a lower AD incidence with a decrease of 50 or a delay in onset of 5-7 yr, and, in one prospective study, the relative risk fell with increasing duration of drug use (16). Clinical trials with indomethacin or propentofylline, another agent with antiinflammatory properties, showed both a significant cognitive improvement (17,18), whereas one study on diclofenac and one recent study on hydroxychloroquine did not demonstrate a positive effect on the progression of the disorder (19,20). Alzheimer's dementia shows an apolipoprotein E (ApoE) genotype susceptibility with ApoE4 as a risk factor. Interestingly, ApoE4 seems essential Ap protein precipitation and the ensuing neurodegeneration are the most likely...

Relationship to Alzheimers Disease

Alzheimer's disease is neuropathologically defined by the presence in the brain of two features, amyloid deposits of the Ap peptide and neurofibrillary tangles (NFT) of the tau protein. The risk of AD is increased by inheritance of the e4 allele of apoE, and decreased by inheritance of the e2 allele of apoE.1 Apolipoprotein E e4 is associated with increased amy-loid,23,77,78 but not increased NFTs.78 Thus, it has been postulated that apoE4 is involved either in increased deposition of Ap, or decreased clearance of Ap. In summary, recent investigations have revealed a complex family of exchangeable apolipoproteins which can be synthesized by resident CNS cells and contribute to the classes of lipoproteins found in the brain. These lipoproteins form a unique class of particles, distinct from that seen in the periphery, which appears to be capable of mediating both lipid removal and delivery. The CNS lipoproteins have available a wide array of at least five potential receptors, each with...

Identifying the Dementia Syndrome History

An accurate history of the current illness is particularly important in the diagnostic evaluation of dementia, in order to 1) establish the temporal relationship between possible etiological factors and the onset of cognitive decline, which can help to identify the underlying pathophysiological process causing dementia and 2) permit the potentially important distinction between early- and late-onset Alzheimer's disease. Accordingly, multiple sources of information, including the patient's medical records, should be used to supplement information provided by the patient and the patient's primary caregiver, and an attempt should be made to establish detailed timelines. It is particularly important to focus on trauma signs or symptoms of neurological or psychiatric illness substance use, including alcohol and medications past and present exposure to potential toxins past surgeries and past and present psychosocial stressors. The family history should include inquiry about Down syndrome,...

Vaccine for Alzheimers

Alzheimer's disease is a condition where the nerve cells of the brains of elderly people slowly stop working, leading to memory loss, madness, and death. Some scientists think that Alzheimer's is caused by the buildup in the brain of chemicals called amyloid-beta peptides. They are trying to make a vaccine using a kind of vaccine called a DNA vaccine. In this kind of vaccination, DNA is put into body cells. This DNA acts like a recipe for an antibody, which is a substance that helps the body's immune system recognize germs. The antibody made by cells that have received the DNA vaccine are for amyloid-beta peptides. That is, these antibodies cause the body's lymphocytes to attack amyloid-beta peptides and destroy them. Researchers have had good success in mice with DNA vaccine, but are quick to point out that human beings are not simply large mice. What works in mice often does not work in people. It will be years before we can know whether an Alzheimer's vaccine for humans is...

Common Etiologies of Dementia

Dementia may result from a diverse set of disorders and conditions some disorders invariably produce a dementia (e.g., Alzheimer's disease), whereas others result in dementia only in some cases. For some etiologies, dementia is chronic, progressive, and irreversible by currently available approaches, whereas for other causes of dementia, symptoms may be arrested or reversed to varying degrees with specific treatments. Table 5-6 lists general medical conditions and medications that can produce symptoms of dementia. In general, the list of factors capable of causing dementia increases with the age of the patient, as declining functional brain reserve reduces the individual's ability to tolerate physiological derangement. The remainder of this chapter and the next chapter are devoted to the differential diagnosis of dementia, beginning with the most common cause of dementia Alzheimer's disease. Sensitive to mild amnesia, dementia Sensitive to mild cortical and subcortical dementia...

Differential Diagnosis of Alzheimers Disease

Certain functional conditions can mimic Alzheimer's disease. They include depressive pseudodementia (see Chapter 3, Mood Disorders Diagnosis), mania, hypomania, personality disorder, Ganser syndrome, hysteria, and malingering. In most patients, the signs and symptoms of functional illness are clear, cognitive impairment is readily identified as secondary, and diagnostic error is easily avoided. Nevertheless, some cases of depression can be particularly misleading, and several authorities have recommended antidepressant treatment trials in selected patients (see related discussion in Chapter 4, Mood Disorders Treatment). Other Dementias Alzheimer's disease must be distinguished from the other degenerative dementias such as frontotemporal dementia and dementia with Lewy bodies, vascular dementia, and the dementias due to general medical conditions and substances. These are all discussed in detail in Chapter 6 (Other Dementias and Delirium). Amnestic disorders can be misdiagnosed as...

Neuropathology of Alzheimers Disease

The gross neuropathology of Alzheimer's disease consists of cortical atrophy, particularly involving anterior frontal and temporoparietal areas. Microscopic findings include NFTs, senile plaques, and granulovacuolar degeneration. Senile plaques are extracellular deposits of the 42 amino acid amyloid P-peptide that is derived from the amyloid precursor protein (APP). They are 5 150 m in diameter and appear in three major forms 1) diffuse plaques, which consist of formed filamentous and nonstructured amyloid P-peptide without attached abnormal neurites 2) neuritic plaques, which are composed of dense bundles of amyloid fibrils and dystrophic neurites (usually containing paired helical filaments) and 3) burned out plaques, in which a dense amyloid core is surrounded by reactive astrocytes but no abnormal neurites. A primitive form of neuritic plaque lacking the amyloid component of the core also has been described (Terry et al. 1994). APP is a transmembrane protein that is present in...

Neurobiochemistry of Alzheimers Disease

The first and most thoroughly confirmed neurobiochemical abnormality found in brain tissue affected by Alzheimer's disease neuropathology was reduced temporoparietal and hippocampal cortical activity of choline acetyl-transferase, an enzyme found only in cholinergic cells, which catalyzes the synthesis of acetylcholine. Biopsy studies have detected significant losses of this enzyme as early as the first symptomatic year, and autopsy studies have reported a strong correlation (r 0.8) between the degree of choline acetyl-transferase loss and premortem measurements of cognitive and functional decline. Concentrations of acetylcholinesterase and acetylcholine, both of which are less specific indicators of cholinergic cell activity than is choline acetyltransferase, also have been found to be reduced in affected brain tissue. Altogether, these findings support a working analogy between Alzheimer's disease and Parkinson's disease, in which a single neurotransmitter (dopa-mine) is also...

Genetics of Alzheimers Disease

Alzheimer's disease is transmitted as an autosomal dominant trait in about 2 of all cases. In these familial cases, which typically have early onset, several genes are responsible one (presenilin 1), found in about half of Alzheimer's disease families, is on chromosome 14 two others presenilin 2, on chromosome 1, and the gene that encodes for APP, on chromosome 21 are present in far fewer Alzheimer's disease families. Each of these genes in its pathological variant results in abnormal P-APP processing with resultant overproduction of the amyloid P-peptide 42 (St George-Hyslop 2000). The other 98 of individuals with Alzheimer's disease have sporadic disease, which appears to result from an interaction between a genetic vulnerability and environmental factors. Gatz et al. (1997) found a concordance rate for prevalence of Alzheimer's disease among monozygotic twin pairs of 67 , whereas the corresponding figure for dizygotic pairs was 22 . Pedersen et al. (2004) examined incident...

Psychosocial Therapy for Persons With Alzheimers Disease

Psychosocial therapies developed for persons with Alzheimer's disease and other dementias have attempted to minimize disruptive behaviors or increase positive behaviors, support mood and a sense of well-being, or improve or support memory. In early studies with a single dementia patient or a small number of patients, behavior modification approaches using techniques such as time-outs, activity diversion, and selective reinforcement were shown to be effective in reducing urinary incontinence or reinstating important self-care Reminiscence therapy, which involves the discussion of past activities, events, and experiences, usually with the aid of tangible prompts such as photographs or music, has become an increasingly popular intervention. It can be used by staff at activity centers and long-term-care facilities and lends itself to involvement of family members. A recent review of the literature on reminiscence therapy in dementia found four controlled trials, all of which reported...

Psychosocial Therapy for Dementia Caregivers

Caring for a family member with Alzheimer's disease or other dementia is challenging at best and overwhelmingly stressful at worst. Increased levels of depression and anxiety, higher use of psychotropic medications, poorer physical health, and increased mortality have all been documented for family caregivers. Recognition of caregiver burden has led to numerous psychosocial interventions aimed at alleviating stress and adverse health consequences. Early forms of interventions such as peer support groups and education were found to have only very small benefits when subjected to careful study. A second generation of caregiver interventions has included individual and family counseling, case management, skills training, and combinations of these approaches. In general, multicomponent approaches that offer options to fit individual caregivers' needs and relatively intensive as opposed to brief interventions have been found to be most beneficial (Schulz et al. 2002). In the most ambitious...

Psychopharmacotherapy for Cognitive Decline in Alzheimers Disease

Several cholinesterase inhibitors (tacrine, donepezil, rivastigmine, and galan-tamine) are available for treatment of the cognitive deficits of mild to moderate Alzheimer's disease. All of these agents increase central cholinergic neurotransmission by inhibiting breakdown of acetylcholine by acetylcho-linesterase. Of these, tacrine is not recommended because of its hepatotoxic-ity, and the other three are about equally effective and equally tolerable 10 mg day of donepezil, 6 12 mg day of rivastigmine, and 16 18 mg day of galantamine can be expected to produce, on average, about a three-point improvement on the cognitive subscale of the Alzheimer's Disease Assessment Scale (Ritchie et al. 2004). Continuation treatment with cholinesterase inhibitors slows the progression of Alzheimer's disease and reduces the likelihood of nursing home placement. One 36-month follow-up study found that almost 80 fewer cholinesterase inhibitor treated subjects were admitted to nursing homes compared...

Psychopharmacotherapy for Noncognitive Symptoms of Alzheimers Disease

Perhaps the most common and most debilitating symptom complex seen in patients with Alzheimer's disease is agitation, a syndrome that occurs in almost all patients with Alzheimer's disease as they progress into the middle and late stages of illness. Agitation typically presents as restlessness, pacing, irritability, anger, anxiety and fearfulness, and refusal to accept care, often accompanied by persecutory beliefs that may reach delusional severity and verbal or physical aggressiveness. Agitation is often accompanied by impaired attention and concentration, elevated heart rate and blood pressure, and tachypnea. acology of agents useful for reducing the signs of dementia aRivastigmine is a pseudoirreversible acetylcholinesterase inhibitor that has an 8-hour half-life for the inhibition of acetylcholinesterase in the brain. Source. Adapted from Cummings JL Alzheimer's Disease. New England Journal of Medicine 351 56 67, 2004. Copyright 2004 Massachusetts Medical Society. All rights...

Treatment of Cognitive Impairment in Vascular Dementia

Three studies have reported the efficacy of cholinesterase inhibitors in vascular dementia two studies with donepezil (Black et al. 2003 Wilkinson et al. 2003) and one study with galantamine (Erkinjuntti et al. 2002 in this study, only subjects with mixed Alzheimer's disease and vascular dementia benefited from active treatment), and it is likely that rivastigmine and yet-to-be-developed cholinesterase inhibitors are equally effective. These results are presumably based on the cholinergic deficit that has been identified in vascular dementia, even though such a deficit is not required for cholinesterase inhibitors to be effective (Yesavage et al. 2002). Dosage and treatment outcomes in vascular dementia are comparable in magnitude to those seen in Alzheimer's disease but appear to be a result of improvement in cognitive function compared with placebo-treated subjects rather than a reduced rate of cognitive decline, which is the typical pattern seen with cholinesterase inhibitors in...

Treatment of Behavioral Complications Mood Disorder and Psychosis in Vascular Dementia

Psychosocial and psychopharmacological therapy for behavioral complications of vascular dementia follow the general principles outlined in Chapter 5 (Dementia and Alzheimer's Disease) for Alzheimer's disease, with the following caveat. In 2004, the U.S. Food and Drug Administration (FDA) concluded on the basis of its review of four randomized trials of risperidone in almost 1,800 elderly patients with dementia that risperidone was associated with an increased risk of ischemic stroke a subsequent analysis of a comparably large data set led to the same conclusion about olanzapine. These findings led the FDA to issue advisories to physicians and led several investigators to conduct confirmatory studies. Moretti et al. (2005) studied 346 subjects with vascular dementia and behavioral problems who were randomly assigned to 12 months of treatment with conventional neuroleptics (about half received haloperidol, and half received promazine) or olanzapine. They found that olanzapine was equal...

Dementia Due to General Medical Conditions

Although many other conditions can cause impairment in cognition severe enough to meet criteria for dementia (see Chapter 5, Dementia and Alzheimer's Disease, Table 5-6), DSM-IV-TR specifically recognizes HIV disease, head trauma, Parkinson's disease, Huntington's disease, Creutzfeldt-Jakob disease, and Pick's disease (a form of frontotemporal dementia, described earlier in the Pathology subsection of Frontotemporal Dementia) as capable of causing dementia via direct damage to brain structures (by infection, trauma, or degeneration). Differentiation of each of these conditions from Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, vascular dementia, and other dementing conditions depends on identification of the characteristic physical and laboratory abnormalities associated with each disease entity, supported by appropriate historical information. These characteristics are summarized in Table 6-5. Patients with the cognitive impairment associated with acquired...

Dementia Due to Other General Medical Conditions

Dementia also may be caused by other diseases with primarily central nervous system pathology, such as multiple sclerosis, amyotrophic lateral sclerosis, and various conditions (e.g., progressive subcortical gliosis, focal lobar atrophy) with mainly frontal lobe-type behavioral manifestations. Extracerebral pathology, both intracranial (brain tumor, subdural hematoma, hydrocephalus) and extracranial (hypothyroidism, hypercalcemia, hypoglycemia) processes, also can cause dementia via mechanical and biochemical effects on brain function. Accurate diagnosis usually depends on recognition of the characteristic clinical and laboratory features of the underlying illness. The battery suggested in Table 5-4 in Chapter 5 (Dementia and Alzheimer's Disease) is designed to have relatively high sensitivity for this purpose.

Substance Induced Persisting Dementia

Certain substances with central nervous system activity can produce both intoxication, during which cognitive impairment severe enough to otherwise qualify as dementia may be present, and dementia per se, which persists for months or years after the substance use is terminated (see Table 5-6). Alcohol is perhaps the classic example of such a substance. Some patients with a diagnosis of alcoholic dementia have Korsakoff's syndrome, which is a pure amnesia due to damage to the mammillary bodies, dorsomedial nucleus of the thalamus, and periaqueductal gray matter, with varying amounts of cortical atrophy and ventricular enlargement. The syndrome is caused by thiamine deficiency, usually in the context of severe and prolonged alcohol intake, and has been reported to be responsive to cholinesterase inhibitors (Cochrane et al. 2005) in case reports but not in a placebo-controlled, single-blind study of malnutrition-related disease (Sahin et al. 2002). Other cases of alcoholic dementia are...

Specificity to Alzheimers Disease

Upregulation of clusterin and abnormal staining of lesions for apoE is not limited to AD. Brain levels of clusterin seem to be elevated in many conditions involving injury or chronic inflammation of the brain. Elevated levels of the mRNA for clusterin are seen in the hippocampus in Pick's disease as well as in AD.4 Abnormal staining for clusterin has been seen in dystrophic neurites and some NFTs in the Parkinson's dementia complex of Guam (Fig. 7.1). It has also been seen in humans in ischemic Purkinje cells which showed the shrunken and pyknotic appearance characteristic of irreversible damage.45 Intense staining for clusterin has been seen in hypertrophic astrocytes in cases of multiple sclerosis, stroke and AIDS encephalitis. In these cases, however, the distribution of clusterin did not appear to correlate with that of the MAC,46 a correlation which does appear to occur in AD.9 Apolpoprotein E staining has been found associated with the amyloid in various types of human cerebral...

Dementia and Alzheimers Disease

Dementia is a disorder in which loss of brain cells severely impairs mentation and produces slowness of thought, memory loss, confusion, and disorientation. Advanced dementia can also cause personality changes. Dementia is common among older people -10 of people over the age of 65 have dementia and over 30 of those over 85 are affected. Alzheimer's disease is the most common cause of dementia. It is marked by loss of brain cells that produce acetylcholine, an important neurotransmitter. Another common cause of dementia is decreased blood supply to the brain, termed multi-infarct dementia. This type of dementia is the result of multiple, small strokes, each one damaging a small section of the brain. The strokes occur in an unpredictable, random pattern over months or years and, as more and more brain cells are damaged and lost, dementia develops.

Micronutrients Dementia

Deficiency in the brain may produce dementia despite normal blood levels.11 Absorption of dietary vitamin B12 is poor in many older people and in younger people with digestive disorders Vitamin B deficiencies can produce dementia, particularly in older people, those with chronic illnesses, and heavy consumers of alcohol9 Fig. 5.27 Supplemental vitamin E and Alzheimer's disease. 341 subjects with Alzheimer's disease of moderate severity were given either 2000 mg day vitamin E or placebo for 2 years. In the treated group there were significant delays in time to death, institutionalization, loss of ability to perform daily functions, or severe dementia a median of 670 days for the vitamin E group, compared with 440 days for the placebo group. Treatment with vitamin E slows progression of moderate-severity Alzheimer's disease. (Adapted from Sano M, et al. N Engl J Med. 1997 336 1216)

Dementia of the Alzheimer Type Diagnosis

The course and clinical features of Dementia of the Alzheimer Type (DAT) (see diagnostic criteria for Dementia of Alzheimer Type, page 98) parallel those discussed for dementia in general. Typically, the early course of DAT is difficult to ascertain because the individual is usually an unreliable informant, and the early signs may be so subtle as to go unnoticed even by the individual's closest associates. These early features include impaired memory, difficulty with problem solving, preoccupation with long past events, decreased spontaneity, and an inability to respond to the environment with the individual's usual speed and accuracy. Individuals with DAT may forget names, misplace household items, or forget what they were about to do. Often the individuals have insight into these memory deficits and occasionally convey their concerns to family members. Such responses as You're just getting older, and I do that sometimes myself are common from these family members and as a result the...

Vascular Dementia Diagnosis

Vascular dementia usually results from multiple CVAs or one significant CVA. It is generally considered the second most common cause of dementia after Alzheimer's disease, accounting for about 10 of all cases. Men are twice as likely as women to be diagnosed with this condition. Vascular dementia is characterized by a stepwise progression of cognitive deterioration with accompanying lateralizing signs. (See DSM-IV-TR diagnostic criteria, page 100) It is always associated with evidence of systemic hypertension and usually involves renal and cardiac abnormalities. Risk factors for the development of a vascular dementia include those generally associated with obstructive coronary artery disease, including obesity, hypercholesterolemia, smoking, hypertension, stress, and lack of exercise. The actual incidence of vascular dementia has decreased somewhat with better standards of care, improved diagnostic techniques, and lifestyle changes. Vascular dementia is characterized by the early...

Dementia Due to HIV Disease Diagnosis

Acquired Immunodeficiency Syndrome (AIDS) was first described in the United States in 1979. In the developed countries, the death rate from AIDS has been on the decline since the advent of new medication regimens utilizing traditional antiretrovirals and the newer protease inhibitors. These medication cocktails have also decreased the incidence of AIDS-dementia complex, so that physicians are now more likely to see AIDS-related delirium secondary to infection, metabolic disarray, and medication rather than traditional AIDS dementia. In the truest sense, AIDS is not a disease but an increased susceptibility to a variety of diseases caused by loss of immunocompetence due to HIV infection. - Neurological diseases (AIDS dementia complex). Individuals with AIDS dementia present with impairments of cognitive, behavioral, and motor systems. The cognitive symptoms include memory impairment, confusion, and poor concentration. Behavioral features include apathy, reclusivity, anhedo-nia,...

Dementia Due to Picks Disease

Pick's disease is a rare form of progressive dementia clinically indistinguishable from Alzheimer's disease. It is about one-fifth as common as AD. Pick's disease occurs in the sixth and seventh decades of life and has a duration that varies from 2 to 15 years. ACh levels are reduced. The pathology of Pick's disease involves prominent changes (e.g., sclerosis, atrophy) in the frontal and temporal lobes with sparing of the parietal and occipital lobes. The clinical features of Pick's disease are quite similar to those of Alzheimer's disease, and since neither condition is curable, an elaborate differential diagnosis is unnecessary. Because of parietal sparing, features such as apraxia and agnosia are less common in Pick's disease, and visual-spatial ability, often impaired in Alzheimer's disease, is preserved. Given the prominent changes in the frontal lobe, disinhibited behavior, loss of social constraints, and lack of concern about appearance and matters of personal hygiene occur...

Dementia Due to Parkinsons Disease

Although dementia rarely occurs as an initial symptom of Parkinson's disease, it is found in nearly 40 of such individuals older than 70 years of age. The prevalence in persons over 60 is 1 . The disease results from loss of dopamine production in the basal ganglia, and can be idiopathic or postencephalitic. Usually, the individual is 50 years of age or older, and unlike Alzheimer's and Pick's dementias, this disease occurs slightly more often in men. Dementia most commonly occurs in cases of Parkinson's disease in which the decline has been rapid and response to anticholinergics has been poor.

Dementia Due to Huntingtons Disease

Dementia is also a characteristic of Huntington's disease, an autosomal, dominant, inheritable condition localized to chromosome 4. Unfortunately, this condition does not become apparent until age 35 to 45 years, usually after childbearing has occurred. Fifty percent of offspring are affected. There is also a juvenile form of the disease. Huntington's disease affects about 4 in 100,000 people, making it a significant cause of dementia in middle-aged adults. The dementia typically begins 1 year before or 1 year after the chorea and, unlike individuals with other dementias, individuals with Huntington's disease are often well aware of their deteriorating mentation. This may be a factor in the high rates of suicide and alcoholism associated with this condition. Although attempts have been made to increase ACh and GABA concentrations in these individuals, such pharmacological interventions have been unsuccessful, and the dementia is untreatable. Genetic counseling is indicated.

Substance Induced Persisting Dementia Diagnosis

In instances in which the features of dementia result from central nervous system effects of a medication, toxin, or drug of abuse (including alcohol), the diagnosis of dementia due to the persisting effects of a substance should be made. The most common dementias in this category are those associated with alcohol abuse, accounting for about 10 of all dementias. The diagnosis of alcohol persisting dementia requires that the cognitive changes persist after the cessation of alcohol use and are not the result of changes in mentation associated amnestic episodes (blackouts), or Wernicke-Korsakoff syndrome. In addition to various nutritional deficiencies and the toxic effects of alcohol itself, alcohol abusers are more prone to develop dementia as a result of head trauma and chronic hepatic encephalopathy. Severe alcohol dependence is the third leading cause of dementia. Alcohol-induced dementia is a relatively late occurrence, generally following 15 to 20 years of heavy drinking. Dementia...

Dementia Due to Multiple Etiologies

Dementia may have more than one cause in a particular individual. Certain types of dementia tend to occur together, including alcohol persisting dementia and dementia caused by head trauma, vascular dementia and dementia of the Alzheimer type, and alcohol persisting dementia and a nutritional dementia. For the purpose of DSM-IV-TR diagnosis, all conditions contributing to the dementia should be diagnosed by coding the various types of dementia on Axis I, for example alcohol persisting dementia and dementia due to head trauma.

Adenylyl Cyclase In Alzheimers Disease

In contrast to the multiple deficits seen in the phosphoinositide hydrolysis pathway, it appears that disrupted AC signaling (see Fig. 2 for the scheme) in Alzheimer's disease brain is more circumscribed in that it occurs primarily at the level of neurotransmitter receptor-Gs-protein-enzyme coupling. Somewhat analogous to the deficit in acetylcholine muscarinic Ml receptor-Gq-protein coupling described earlier, it has been shown using radioligand binding techniques that P adrenoceptor coupling to presumed Gs-protein a-subunits is impaired in Alzheimer's disease temporal cortex (74). Similarly, Wang and Friedman have reported a reduced ability of the P-adreno-ceptor agonist isoprenaline to increase 35S GTPyS binding to Gsa-subunits immunoprecipitated from Alzheimer's disease frontal cortex (63). More concrete evidence for an impaired Gs-protein function in Alzheimer's disease has come from studies that have assayed AC enzyme activities in the disorder. Using assay conditions favoring...

Resources for Dementia Caregivers

Alzheimer's Association (800) 272-3900, http www.alz.org about the Family and Medical Leave Act) Kaplan M, Hoffman S (eds) Behaviors in Dementia Best Practices for Successful that are recruiting patients with Alzheimer's disease) U.S. Department of Health and Human Services, Administration on Aging (800) 677-1116, http www.aoa.gov (click on Elders and Families for help with locating services and resources for older adults)

Delirium Dementia Amnestic Disorder And Other Cognitive Disorders

In DSM-III-R, delirium, dementia, amnestic disorder, and other cognitive disorders were included in a section called organic mental disorders, which contained disorders that were due to either a general medical condition or substance use. In DSM-IV, the term organic was eliminated because of the implication that disorders not included in that section (e.g., schizophrenia, bipolar disorder) did not have an organic component. In fact, virtually all mental disorders have both psychological and biological components, and to designate some disorders as organic and the remaining disorders as nonorganic reflected a reductionistic mind-body dualism that is at odds with our understanding of the multifactorial nature of the etiological underpinnings of disorders. DSM-IV replaced each unitary organic mental disorder (e.g., organic mood disorder) with its two component parts mood disorder due to a general medical condition and substance-induced mood disorder. Because of their central roles in the...

Vascular dementia

Vascular dementia (VD) represents a heterogeneous group of disorders, approximately eight in number, the common feature being a dementia associated with a disturbance in blood supply to the brain. Diagnostic criteria for VD are not considered robust but the National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherch et l' Enseignement en Neurosciences (NINDS-AIREN) criteria15 describe VD in terms of an abrupt deterioration in cognitive function, gait disturbance or frequent falls, urinary frequency, focal neurological findings including sensory loss, lower facial weakness, depression, mood lability, and psychiatric symptoms. Treatment of VD is primary prevention with education regarding risk factors that include many of the same factors for stroke, e.g., smoking, coronary artery disease, alcohol abuse, age, etc.

Dementia

294.xx Dementia of the Alzheimer's Type, With Early Onset (also code 331.0 Alzheimer's disease on Axis III) .10 Without Behavioral Disturbance .11 With Behavioral Disturbance 294.xx Dementia of the Alzheimer's Type, With Late Onset (also code 331.0 Alzheimer's disease on Axis III) .10 Without Behavioral Disturbance .11 With Behavioral Disturbance 290.xx Vascular Dementia .40 Uncomplicated .41 With Delirium .42 With Delusions .43 With Depressed Mood Code presence or absence of a behavioral disturbance in the fifth digit for Dementia Due to a General Medical Condition 294.1x Dementia Due to HIV Disease (also code 042 HIV on Axis III) 294.1x Dementia Due to Head Trauma (also code 854.00 head injury on Axis III) 294.1x Dementia Due to Parkinson's Disease (also code 331.82 Dementia with Lewy Bodies on Axis III) 294.1x Dementia Due to Huntington's Disease (also code 333.4 Huntington's disease on Axis III) 294.1x Dementia Due to Pick's Disease (also code 331.11 Pick's disease on Axis III)...

Dementias

Dementia is defined as impairment in short- and long-term memory, associated with impairment in abstract thinking and judgment, other disturbances of higher cortical function, and personality changes. The disturbance is severe enough to interfere significantly with work or usual social activities or relationships with others. The diagnosis of dementia is not made if these symptoms occur in patients with altered levels of consciousness (Diagnostic and Statistical Manual of Mental Disorders, 4th edition, DSM-IV). Dementia is a prominent feature of a number of neurologic, general medical, and psychiatric diseases. It is imperative to identify the treatable and reversible etiologies of dementia before considering a primary neurodegenerative process as the underlying cause (Table 5.1). Degenerative dementias are a heterogeneous group. Two major forms are dementias caused by diffuse cortical degeneration and dementias caused by lobar (circumscribed) cortical degeneration. The former form...

Alzheimers Disease

Alzheimer's disease, including both early-onset (age 65 or younger, accounting for about 1 of all Alzheimer's disease cases) and late-onset (older than 65) subtypes, accounts for about 50 of all cases of primary dementia and may combine with other conditions, primarily vascular dementia, in another 10 -20 (Langa et al. 2004). Because the definitive diagnosis of Alzheimer's disease requires direct visualization of characteristic neuropathology (i.e., amyloid P-peptide containing senile plaques, neurofibrillary tangles NFTs consisting of hyperphosphorylated tau protein, neuritic degeneration and loss) in brain tissue of affected patients and brain biopsy is prohibitively risky, Alzheimer's disease is at best a probable diagnosis in the living patient.

Mixed Dementia

In a review, Langa et al. (2004) defined mixed dementia as cognitive decline sufficient to impair independent functioning in daily life resulting from the coexistence of AD Alzheimer's disease and cerebrovascular pathology, documented either by clinical criteria or by neuroimaging findings (p. 2902). As discussed earlier, the amyloid plaques and neurofibrillary tangles of Alzheimer's disease and the large infarctions, multiple lacunar infarctions, and is- chemic periventricular leukoencephalopathy of vascular dementia are often found together in the brains of individuals with dementia. Depending on the source of pathological material, from 25 to 45 of Alzheimer's disease brains have significant vascular pathology (Langa et al. 2004), and plaques and tangles are nearly always present in the brains of individuals with vascular dementia, all of which leads to the conclusion that vascular dementia is actually mixed dementia in a large percentage of cases. Treatment follows guidelines for...

Reversible Dementia

Some dementias (mainly those due to a general medical condition), at least in principle, can be arrested or reversed if the underlying condition is successfully treated before significant brain damage occurs. Clarfield (1988) re viewed several studies and found that 13 of dementias were potentially reversible, but only 11 partially and 3 fully reversed. With more conservative criteria (excluding the dementia syndrome of depression), only 8 reversed at all. Clarfield found that other than the dementia syndrome of depression, substance-induced persisting dementia metabolic dementia (including thyroid and vitamin B cobalamin deficiency) and dementia secondary to normal-pressure hydrocephalus, subdural hematoma, or brain tumor were reversible. Osimani and colleagues (2005) confirmed the reversibility of the dementia due to vitamin B deficiency and suggested that neu-ropsychological evaluation could distinguish this syndrome from Alzheimer's disease. They found more frequent psychosis,...

Diet Dementia

It is estimated that about one-quarter of all dementias are caused by nutritional factors that are, at least partially, reversible.9 Deficiencies of severalB vitamins - niacin, vitamin B12, thiamin, and folate - can cause dementia.9,14,15 Chronic heavy alcohol consumption can also produce dementia - large amounts of alcohol have a direct toxic effect on brain cells. Because multi-infarct dementia is caused by small strokes, the same dietary changes that were recommended for prevention of high blood pressure and stroke (see pp. 180) can decrease risk of this disorder and also slow down progression of the disease in affected individuals by preventing more strokes.16,17 Often, because of their disability and poor dietary habits, demented patients develop nutritional deficiencies that can sharply accelerate their disease.9

History of mci Concept

In 1907 Alois Alzheimer's reported a case of a syndrome consisting of cognitive deterioration and behavioral disturbances in a middle-aged woman with an unusual neuropathologic picture 1 , beginning the long road toward the understanding of Alzheimer's disease (AD). Since AD was first described, it become clear that symptoms develop gradually over many years. A second landmark was Katzman's notion of brain reserve, proposed in 1988. This concept was based on the apparent capacity of brain to protect itself against dementia despite the presence of neurodegeneration 2 , providing a potential explanation for the delay in clinical onset of dementia associated with many putative protective factors. It was supported by several subsequent studies ranging from brain volume size 3 to neuropathologic studies 4 . These studies, demonstrating that substantial AD pathology may exist without producing clinical symptoms, led to important considerations regarding AD and other dementia preclinical...

Clinical Definition Overlap between Normal Aging and Cognitive Impairment

The real and still ongoing challenge is the clinical definition of these conditions of slight cognitive deficit, and their distinction from normal aging this is partially due to the fact that a change in cognitive performance is commonly an expected consequence of normal aging. The ability to identify the subgroup of elderly people who will develop dementia has therefore very important practical importance in the short term the identification of these individuals would provide reliable prognostic information to patients and their families, in the long term it is the first step toward effective prophylactic and social medical intervention. 6 , but longitudinal follow-up shows this group to be heterogeneous, consisting of both individuals preserving their cognitive functions and subjects deteriorating towards dementia In 2000, the Canadian Study of Health and Aging (CSHA) defined the concept of cognitive impairment no dementia (CIND) on the basis of a consensus conference of physicians,...

Clinical Concept Heterogeneity of Mild Cognitive Impairment

MCI was proposed as a nosological entity referring to elderly people with mild cognitive deficit but no dementia. In the first criteria for MCI, which were proposed by Petersen et al in 1997 20 and 1999 14 , the emphasis was on the compulsory presence of memory problems and memory disorders, implying that cases of MCI represented a fairly uniform group of subjects. The criteria for MCI included as follows memory complaints of the subject (corroborated by an informant), objective memory disorders considering age, absence of other cognitive disorders, intact basic activities of daily living, and absence of dementia. This concept of MCI made it possible to define a group of patients at high risk of developing dementia, particularly Alzheimer-type dementia. This definition of MCI, however, has been The different clinical presentations of patients commonly observed in clinical contexts led Petersen et al to propose an extension of the concept in 2001 21 , and in 2004 22 , considering a...

Treatment Approaches for mci

Patients receiving a diagnosis of MCI fall in two groups those who will develop sign and symptoms of dementia and those who will remain stable over time or even improve. It seems obvious that patients who are in the early stages of dementia will benefit from therapies that slow the progression of the disease or enhance residual cognitive functions. This assumption is the base of several clinical trials that in the last years investigated the potential role in MCI patients of the same treatment strategies already used or under investigation for the treatment of AD. At present, no pharmacological treatment has been proven to be effective in MCI subjects. Most of the clinical trials in MCI followed individuals for several years (e.g three) and used a change in the rate of conversion from MCI to AD as the primary outcome measure. The biggest problem experienced in MCI trials was the great variability in this rate of conversion in different studies. Another significant problem was the...

Markers of early Diagnosis of ad

Gold standards, reach a diagnostic accuracy ranging from 65-96 , and a specificity against other dementias of only 23-88 (Dubois et al., 2007). This low specificity likely reflects the fact that AD shares many clinical features with other forms of dementia, and must be addressed through both revised AD and accurate non-AD dementia diagnostic criteria. During this stage, an effective treatment of AD would have the greatest impact because the cognitive function could be preserved at the highest level possible. Consequently, there has been considerable interest in recent years to characterize the earliest clinical signs of the degenerative process that is likely to evolve to AD. This effort led to the development of the concept of Mild Cognitive Impairment (MCI), which represents the transitional zone between normal aging and AD. Subjects with MCI are not demented but have significant but very mild deficits in one or more cognitive domains and have an increased risk of dementia (Petersen...

Neuroimaging as Biomarker in ad

Functional neuroimaging studies, in particular, are playing a growingly important role in neuropathological and neuropsychological research of dementia, including innovative aspects, such as cognitive activation and in vivo studies of neurotransmitter function. Figure 1. Results of a voxel based morphometry analysis of grey matter atrophy in patients with Frontotemporal Dementia (FTD), showing a different pattern of atrophy in the two major clinical variants of FTD frontal variant (upper panel) and temporal variant (lower panel). See text for details. Figure 1. Results of a voxel based morphometry analysis of grey matter atrophy in patients with Frontotemporal Dementia (FTD), showing a different pattern of atrophy in the two major clinical variants of FTD frontal variant (upper panel) and temporal variant (lower panel). See text for details. Although there is some overlap between the brain regions with the most pronounced atrophy in AD and atrophied brain in other types of dementia,...

Ttau and ap combination

The combined evaluation of T-tau and Ap levels satisfy the criteria for reliable biomarkers described above (The Ronald and Nancy Regan Research Institute of the Alzheimer's Association, 1998). Discrimination of AD from other disorders not associated with pathologic conditions of the brain (CON), other neurologic disorders (ND) and non-AD types of dementia (NAD) was significantly improved by the combined assessment of Ap42 and tau (Hulstaert et al., 1999). At 85 sensitivity, specificity of the combined test was 86 (95 CI 81 to 91 ) to discriminate between presence or absence of dementia compared with 55 (95 CI 47 to 62 ) for Ap42 alone and 65 (95 CI 58 to 72 ) for tau alone. The combined test at 85 sensitivity was 58 (95 CI 47 to 69 ) specific for NAD. Lastly, the combined measure of CSF Ap42 and tau meets the requirement for clinical use in discriminating AD from normal aging and other neurological disorders (Hulstaert et al., 1999).

Csf Biomarkers in mild Cognitive Impairment

So far, there is no established method to predict progression to Alzheimer's disease in individuals with MCI. Early studies indicated that CSF biomarkers could be useful for defining a subgroup of patients with MCI at especially high risk of developing AD (Blennow, Hampel, 2003 Hampel et al., 2004 Maruyama et al., 2004).

As A Consequence Of The Disease Process

From the above discussion, it is clear that both the receptor-G-protein, mediated PLC PKC and AC PKA pathways are severely disrupted in Alzheimer's disease brain. So far, disruptions to these pathways have been presented from the point of view of contributing to Alzheimer's disease senile plaque and NFT formation by enhancing AP production and tau protein hyperphosphorylation, respectively. The alternative possibility worth considering is that impaired signal transduction occurs as a consequence of Alzheimer's disease pathology (e.g., as a result of the effects of AP). In this respect, it has been shown that AP exerts multiple effects on cellular calcium homeostasis, either by interactions with existing calcium channels or by de novo channel formation (for a review, see ref. 95). Studies in intact cells have shown that physiological levels of AP can stimulate PKC translocation and activity (96) and also enhance phosphoinositide hydrolysis by amplifying depolarization-induced calcium...

Accelerated Biomarker Development through Data Pooling

Given the emerging public health crisis caused by the age-related, exponential growth in the number of cases of dementia and their concomitant costs, an increasing number of worthwhile initiatives involving the cooperation of government, academia, foundations, and industry have arisen in recent years to maximize the availability of useful data for sharing. One well-known example is the National Institute of Aging's Alzheimer Disease Neuroimaging Initiative (ADNI). Data from this initiative, involving some 800 individuals followed for 3 years, have already become available through the ADNI (www.adni-info.org ) and Laboratory of Neuroimaging, UCLA (LONI www.loni.ucla.edu ADNI ) websites as of March 2008. The project has not only developed standardized neuroimaging and biochemical marker methods to be used in AD trials, but seeks to validate AD neuroimaging and biomarker findings by correlating them with neuropsychological and behavioural test data. Another example of standardization is...

From Single Analyte to Multi Analyte Testing

Diagnosis of AD is still based on probabilistic clinical exclusion criteria requiring a time-consuming and expensive diagnostic work-up. Studies evaluating diagnostic accuracy rates are based on follow-up periods of several years and have been performed in specialized clinical centers. Low average specificity levels of 48 for clinical diagnosis of possible AD are considered as a reflection of the overlap of clinical profiles between AD and non-AD dementias (Knopman et al. 2001). Should diagnostic errors occur, they most likely involve one of the other primary dementias, mixed pathologies that include a vascular component, or uncertainties associated with early diagnosis. Patients are often unaware of symptoms in the early phases or they believe that their memory loss forms an integral part of normal aging, resulting in a barrier for (early) clinical detection of the disease (Solomon and Murphy 2005).

No In Neurological Disorders

Neurotrophins, despite their general role in attenuating excitotoxic neuronal injury, were recently shown to increase the number of nNOS neurons in cortical culture grown on glial feeder layers and render neurons more sensitive to NMDA (88). This finding is consistent with a previous report by Choi and colleagues on the enhancement of excitotoxic neuronal injury by neurotrophins under certain conditions (90). However, when neurons are grown on a polyornithine matrix, neurotrophins failed to enhance the expression of nNOS and are neuroprotective, consistent with the neuroprotective role of neurotrophins in neurotoxicity studies in intact animals. Glutamate neurotoxicity also contributes in some degree to the pathogenesis of neurodegenerative diseases such as Huntington's disease and Alzheimer's disease (91), implicating NO in these disorders. Neuronal NOS neurons have garnered much attention from a neuro-pathological point of view because they are...

Evidence For Apoptosis In Sporadic Ad

Apoptosis is generally defined on the basis of strict morphological criteria the basic features include cell shrinkage, membrane blebbing, chromatin condensation, and nuclear fragmentation. Additionally, the cleavage of DNA into oligonucleosome-length fragments detectable by gel electrophoresis occurs in many, but not all models of apoptosis (15-18). The process of DNA degradation produces a series of oligonucleosome-length DNA fragments that have newly generated 3'-OH ends. These strand breaks can be labeled by methods such as terminal transferase-mediated dUTP nick-end labeling (TUNEL). We have recently reported that cells in the AD brain exhibit labeling for DNA-strand breaks using TUNEL, and that many TUNEL-labeled cells exhibit an apoptoticlike morphological distribution of DNA strand breaks, including granulated and marginated patterns of intense TUNEL labeling, shrunken, irregular cellular shape, and the presence of apoptoticlike bodies consistent with apoptosis (19,20). We...

Clinical Qualification of the xMAP Assay using Autopsy Confirmed Samples from demented Patients

A retrospective case-control study was set up consisting of healthy persons and subjects with a clinically determined dementia. All dementia patients were diagnosed according to strictly applied clinical diagnostic criteria. The inclusion criteria for the control group were (1) no neurological or psychiatric antecedents and (2) no organic disease involving the central nervous system following extensive clinical examination. For demented patients, a post-mortem dementia diagnosis was established. CSF, obtained by lumbar puncture at the L3 L4 or L4 L5 interspace during clinical work-up of the patient, was collected from all patients. The study was approved by the local ethics committee. More details are described in Engelborghs et al. (2008), including the reference papers for diagnosis of the different dementia types. A total of 100 CSF samples from demented patients with autopsy-confirmed pathological diagnoses were included. The majority of these patients had an AD diagnosis (n 65)...

Integration of the innobia Alz Bio3 in the usadni Program

The increase in the number of clinical trials studying potential disease-modifying therapies for AD is one of several driving forces behind the growing interest in AD biomarker development (Blennow et al. 2006 Shaw et al. 2007). Moreover, the focus of this interest is not only limited to patients with familial or sporadic AD, but extends also to those individuals at increased risk for AD such as subjects with mild cognitive impairment (MCI), or prodromal AD. Therefore, one might use AD biomarkers not only to establish a diagnosis of AD, but also to predict the onset of AD years before it becomes clinically manifest. Thus, it appears that amnestic MCI defines a group of individuals with cognitive impairment, but not overt dementia, who are at increased risk for developing AD. Subjects shown to meet criteria for amnestic MCI go on to show evidence of clinical AD at a rate of 10-15 per year such that within 5 years, 45 of individuals with MCI convert to AD. Indeed, there is growing...

Potential Mechanism of Nonconvulsive Stimulation with rTMS

It had been paradigmatic that, at least in ECT, a seizure was the necessary prerequisite for therapeutic effects (163,164). Although this may be the case for ECT, the emerging data suggest that this is not the case for rTMS. We have postulated that whereas seizures are necessary for the induction of the adaptive changes in ECT that are the therapeutic principles in depression, rTMS may be able to evoke some of these adaptive mechanisms more directly without the requirement of a seizure (157). Thus, it is well known that ECT in man (165,166) and electroconvulsive seizures (ECS) in animals (167,168) increases TRH mRNA and TRH protein, which has been postulated to at least partially relate to ECT's therapeutic effects (164,169). Perhaps alterations in TRH mRNA or the other critical neuroadaptive changes pertinent to the effects of ECT could eventually be induced by appropriate nonconvulsive brain stimulation parameters with rTMS. To the extent that this becomes possible, it would...

Biomarker Definitions

Historically the term biomarker was probably first mentioned in a study investigating extraterrestrial samples in 1973 32 . The first landmark paper in the field of neurodegenerative dementias is a consensus report of the working group on molecular and biochemical markers of Alzheimer's disease 33 . This paper originated from a literature research which resulted in contacting investigators who then were invited to submit a position paper on the antemortem diagnosis of AD. The ideal biomarker for AD should be able to detect a fundamental feature of AD pathology, validated in neuropathologically confirmed AD cases, precise, reliable, non-invasive, simple to perform and inexpensive. accumulation of irreversible morbidity and survival. 35 o Time-to-event outcome The time until a predefined event occurs, e.g. the time to reaching a certain score on the Alzheimer's Disease Assessment Scale-cognitive scale.

Amyloid beta Peptides The Protein

The 700 amino acid large amyloid precursor protein (APP) is cleaved at the P and y sites by secretases into amyloidp sequences of 40 43 residues (ABP). The numbers behind the ABP refer to the cleavage site of the protein fragment (e.g. ABP 1-42 is cleaved at the 42nd amino acid residue). The amyloid beta peptide (ABP) is important in the pathogenesis of Alzheimer's disease. ABP 1-42 has shown to aggregate more rapidly than ABP 1-40 and is the main AB peptide found in senile plaques 47 . Sequestration of ABP 1-42 into plaques is thought to be the reason for the decrease of CSF ABP 1-42 levels in AD. The central event in the amyloid cascade hypothesis is thought to be an imbalance between AB production (increased in familial cases) and clearance (decreased in sporadic cases) 4 . The formation of AB polymers may directly impair synaptic function. Aggregate formation then leads to the typical plaques which cause oxidative stress and local inflammation, further enhancing neurotransmitter...

The Complement System

No immunoglobulins or T-cell subsets can be detected within or around plaques of AD cases, which indicates that humoral or classical cellular immune-mediated responses are not involved in cerebral P-amyloid plaque formation or Ap plaque induced inflammatory events in AD 67 , unlike in other brain disorders such as multiple sclerosis 46 and HIV-dementia 199 . No (increased) expression of the most relevant intercellular adhesion molecules (ICAM-1, VCAM-1, E-selectin) is seen on endothelial cells of capillaries in AD brains 70 , whereas in MS and HIV dementia the expression of E-selectin and VCAM-1, necessary for adhesive interactions between leukocytes and endothelial cells of brain capillaries and for leukocyte recruitment to inflammatory foci in the neuropil, coincides with monocyte macrophage infiltration. In addition, many of the large variety of inflammatory mediators, including acute phase proteins, protease inhibitors, complement factors, cytokines, and chemokines seen in AD...

Early Diagnosis of ad

One of the problems encountered is, that pure AD is relatively uncommon, as was concluded from community based as well as clinico-neuropathological studies in which the diagnostic accuracy was neuropathologically confirmed 129,131,141,211 . In a retrospective clinico pathological study including 1050 elderly demented, 62.9 of the cases was clinically diagnosed as probable-possible AD, whereas at autopsy, 86 of the cases had AD related pathology, of which 42.8 were pure AD, 22.6 AD and vascular lesions and 10.8 AD with Lewy body pathology 129 . In a large longitudinal community-based study, at autopsy cerebral microinfarcts, followed by AD and neocortical Lewy bodies were found to be predominant pathological correlates of dementia in an US suburban and urban elderly population 256 . Similar findings were obtained in a community based study in which 34 amnestic MCI cases, that progressed to clinical dementia were followed up prospectively. At autopsy the majority appeared to have...

Csf Biomarkers for ad

In the NINCDS-ADRDA criteria which specify inclusion and exclusion criteria and three levels of confidence (possible, probable and, upon histopathological confirmation, definite) for diagnosis of AD, CSF examination was recommended to exclude vasculitis, other inflammatory diseases and demyelination as cause of dementia 178 . Because there is a considerable clinical and radiological overlap between early onset AD and FTLD, biomarkers may be useful for the differential diagnosis of early onset dementias, and of late onset dementias in an early stage. Midtemporal atrophy as seen on MRI and biomarkers are independently associated with the diagnosis AD, especially in young AD cases that have no signs of MTA 241 . Next to aid in the differential diagnosis, CSF analysis may also allow accurate, early diagnostics that enables the start of specific treatment or preventive measures before clinical signs become overt and irreversible damage is done. Alzheimer's Disease is a multistage process...

Existing Biomarkers Ap ttau and ptau

Was first investigated and specific tests detecting Ap1-42, total tau (t-tau) and hyperphosphorylated tau (p-tau) in CSF were developed. CSF levels of Ap and p-tau were shown to reflect the central pathogenic process of Ap accumulation in plaques and of tau related neurodegenerative changes. However, the use of such determinations suffers from a lack of specificity. Whereas Api-42 concentration in CSF of AD cases is low compared to controls, also decreased levels of Api-42 are seen in DLB, FTLD and vascular dementia cases. Raised t-tau levels are also not specific for AD. Tau levels can also be increased in DLB and FTLD, and are very high in CJD.

Search for new Biomarkers for AD

Mutations in the APP gene and in the presenilin 1 and 2 genes (APP, PSEN1, PSEN2), that are directly associated with the amyloid cascade, explain major part of the early onset AD families. Rare autosomal dominant mutations that are causative for early onset AD, are present in less than 5 of the Alzheimer's disease population. Polymorphism in Apolipoprotein E encoding gene (APOE) is up to now the only polymorphism that is highly replicably associated with the risk to develop LOAD. The epsilon4 allele of APOE represents a major risk factor for more than 40 of patients with dementia.

Which Neuroinflammation Related Factors can be detected in serum and plasma

Only a few studies on CRP in serum have been published 154 , whereas several studies regarding IL-6 and ACT have been performed, most of which demonstrate increased IL-6 or ACT levels in serum 9,112,153,157,158,249 . Recently, a few longitudinal population-based studies showed an association between the inflammatory markers CRP, IL-6 and ACT and cognitive decline, many years before onset of dementia 63,239,299 . Recent studies have indicated that possibly other serum markers can also be used for AD diagnostics and stageing. Cystatin C levels were found to be reduced in AD patients compared to controls 49 and complement factor H as well as A2M serum levels are raised in AD compared to controls 121 . Also, surfactant protein-D (SP-D) levels were found to correlate with development of dementia in a follow-up study 200 .

Postmortem Brain Studies

The reciprocal changes in the levels and activity of Gaq 11 in BD occipital cortex also appear to uniquely distinguish this disorder from Alzheimer's disease (79a), schizophrenia (44), alcoholism (44), and major depression (80), in which the activity of Gaq 11 is either increased or decreased in the absence of changes in Gaq 11 and PLC-P1levels. It is also noteworthy that the largest differences in Gas levels and forskolin-stimulated adenylyl cyclase activity were observed in the occipital cortex of BD subjects (10,11). Given the substantial evidence of crossregulation between cAMP and PPI signaling pathways, the possibility that the observed differences in Gaq 11 and PLC-p1 levels may reflect the consequences of relatively greater disturbances in cAMP signaling in this brain region in BD cannot be excluded.

Differential Diagnosis

The differential diagnosis of dementia is broad (DSM-IV, ICD10) and the diagnostic criteria keep evolving in order to improve sensitivity and specificity 2,118,119,120 . Subcortical dementia with prominent changes to the CSF analytical brain (striatum and thalamus) is distinguished from cortical dementias with prominent changes in the cortical association areas12. The spectrum of primary degenerative dementia includes AD, Down's syndrome, Pick's disease, primary progressive dysphasia, frontal lobe degeneration and frontal lobe dementia, Lewy body dementia and a number of miscellaneous degenerative dementias including the tauopathies listed in Table 1. In particular the genetic, pathological and clinical spectrum of the fronto-temporal lobe dementias continues to widen. Dementia is also a recognised feature of other neurodegenerative diseases such as Parkinson's disease, progressive supranuclear palsy, Huntington's disease, thalamic dementia, Prion disease, amyotrophic lateral...

Abstract

Mild Cognitive Impairment (MCI) was proposed as a nosological entity referring to elderly people with mild cognitive deficit but no dementia. In the first criteria for MCI, which were proposed by Petersen et al in 1997, the emphasis was on the compulsory presence of memory problems and memory disorders, implying that cases of MCI represented a fairly uniform group of subjects. The criteria for MCI are the following memory complaints of the subject, objective memory disorders considering age, absence of other cognitive disorders, intact basic activities of daily living, and absence of dementia. This concept of MCI made it possible to define a group of patients at high risk of developing dementia, particularly Alzheimer-type dementia, as 80 of MCI subjects converted to dementia within 5 years. Based on whether predominant memory impairment was present or not, two primary subtypes were delineated amnestic and non-amnestic MCI. Regarding MCI diagnosis, the most commonly used rating...

Horizontal Approach

The mechanism by which the first messenger triggers the appearance of the second messenger depends on the event that links the two (Table 1). In the case of the second messengers cAMP, cyclic guanosine monophosphate (cGMP), diacylglycerol (DAG), inositol triphosphate (IP3), and arachidonic acid (AA), the link between the activation of a receptor by the first messenger and the stimulation of a second messenger occurs via G-proteins. The G-proteins (Gs, Gi, Go, Gi,o, Gq) make up a complex family with many different combinations of the various a-, P-, and y-subunits (see Chapters 5 and 11 for G-protein changes in Alzheimer's disease and bipolar affective disorder, respectively). Stimulation of the Gs subfamily increases adenylate cyclase activity, inhibits Na+ channels, and opens Ca2+ channels, whereas Gi subfamily activation has the opposite effect and can also promote cGMP phosphodiesterase. Go protein activation closes Ca2+ channels, whereas Gio proteins inhibit adenylate cyclase and...

Epidemiology of mci

The prevalence of MCI and its subtypes varies greatly in different studies, ranging from 3 to 17 of people over 65 years 27 these data largely depend on the diagnostic criteria used and on the type of cohort studied (longitudinal follow-up of cohorts or memory clinic cohorts). First studies included only amnestic MCI, while more recent studies refer to the wider concept of MCI. Epidemiological studies also suggest that the progression of MCI is heterogeneous, and may be reversible, stable or progress to dementia 27-31 , usually of the AD type 32,33 .

Diagnosis of mci

The question as to how approach the diagnosis of MCI is very important. In 2001, the Quality Standard Subcommittee of the American Academy of Neurology recommended that, to make an effort to detect MCI early, screening instruments such as Mini Mental State Examination (MMSE) were found useful, as were neuropsychological batteries 34 , but at present there is no agreement on the recommended way to diagnose or screen for MCI according to literature, and no clear consensus exists in the literature for a specific diagnostic approach. In fact, making MCI diagnosis using cut-off scores on established neuropsychological scales, ignores the possibility that some subjects may have always performed poorly and have no cognitive deterioration, while other patients might perform well even in presence of significant deterioration, due to a high pre-morbid performance level. As in Petersen criteria 14 , it is clear that MCI diagnosis requires amnestic information, documenting a meaningful cognitive...

Pathway Divergence

Recently, PKG has been proposed to be part of a neuroprotective pathway triggered by a metabolite of P-amyloid precursor protein (PAPP), sAPP. sAPP formation prevents the release of amyloid P peptide (AP) because a cleavage occurs between aminoacids 16 and 17 of Ap. The latter protein forms senile plaques in Alzheimer's disease (see Chapter 5). sAPP acts through a putative receptor linked to a G-protein, which stimulates guanylate cyclase. cGMP, in turn, stimulates PKG, which could activate a protein phosphatase resulting in dephosphorylation of K+ channels producing hyperpolarization. The latter counteracts the depolarizing action of glutamate during excito-toxic sequelae (63,64). PKG may also activate the transcription factor NFkB, regulating expression of several neuroprotective gene products. NO may be involved in this process, as inhibition of NO synthase prevents NFkB activation (see ref. 65). This interaction may link this arm of the signaling pathway to the NO PKG pathway...

Research in Progress

The Alzheimer's Disease Neuroimaging Initiative (ADNI), launched in October 2004, and connecting many centres in United States and Canada. The ADNI is funded by the National Institute on Aging (NIA) and the National Institute of Biomedical Imaging and Bioengineering (NIBIB) of the National Institutes of Health (NIH), and also by several pharmaceutical companies and foundations (Mueller et al., 2005)

S Final Remarks

The paper by Knopman and colleagues reported an evidence-based review of the parameters for diagnosis of dementia they concluded that structural neuroimaging with either a noncontrast CT or MR scan in the initial evaluation of patients with dementia is appropriate, at the time of the initial dementia assessment to identify pathology such as brain neoplasms or subdural haematomas, and normal pressure hydrocephalus. Because of insufficient data on validity, no other imaging procedure is recommended, although both PET and SPECT imaging provided promising results, for diagnosis confirmation as well as differential diagnosis (Knopman et al., 2001). The last European Federation of Neurological Societies guidelines recommends the usage of structural imaging in the evaluation of every patient suspected of dementia non-contrast CT could help identifying surgically treatable lesions and vascular disease, and, to increase specificity, MRI (with a protocol including T1, T2 and FLAIR sequences)...

Biomarkers

In view of existing and emerging therapeutic compounds there is a great need for reliable biochemical diagnostic markers (biomarkers), allowing early and accurate diagnosis of dementia, particularly for AD. Cerebrospinal fluid (CSF) is in direct contact with the extracellular space of the brain, and thus biochemical changes in the brain are reflected in CSF. A diagnostic marker for AD should reflect a central pathogenic process of the disorder, such as the degeneration of neurons and their synapses and the defining lesions, naming, senile plaques, deriving from the aggregation of Ap, and NFTs, resulting from hyperphosphorylation of tau protein. A clinically useful diagnostic marker should have a sensitivity exceeding 80 and a specificity above 80 according to the statement of the Consensus Group for Biomarkers (The Ronald and Nancy Regan Research Institute of the Alzheimer's Association, 1998). The goals of this declaration were to define characteristics of an ideal biological marker,...

AP levels in CSF

Moderately low levels were also found in Lewy Body Dementia (LBD Kanemaru et al., 2000). A mild or moderate decrease in A 42 was found in a percentage of patients with Frontotemporal Dementia (FTD) and Vascular Dementia (VaD) (Sj gren et al., 2000), whereas normal A 42 were found in depression, Parkinson's disease and Progressive Supranuclear Palsy (PSP) (Holmberg et al., 2003).

Conclusions

This chapter has provided an overview of current knowledge as to the integrity of receptor-G-protein-mediated PLC PKC and AC PKA signaling in Alzheimer's disease brain. Given the involvement of these signaling pathways in APP metabolism and tau protein phosphorylation, together with evidence of the detrimental effects of AP peptides on certain components of these pathways, a number of workers have suggested scenarios whereby signal transduction abnormalities play a pivotal role in exacerbating the progressive neurodegeneration seen in Alzheimer's disease (10,54,104). One such scheme that attempts to incorporate some of the ideas discussed in this chapter is shown in Fig. 3. Although speculative, this scheme provides a basis by which disturbed neurotransmission via receptor-G-protein-medi-ated signaling pathways could contribute to APP mismetabolism and tau protein hyperphosphorylation. The subsequent increase in AP production and breakdown of the cytoskeleton would, in turn, undermine...

Dynamic Range

Concentrations are only reported for values within the concentration ranges of the calibrator series. For the xMAP assay, as well as for the single-analyte ELISAs, the concentration range for each analyte covers the concentration range distribution for healthy subjects and AD patients (Figure 11). The concentration range for T-tau, phosphorylated tau, and ABi-42 in a set of CSF samples (n 200, obtained from autopsy-confirmed dementia subjects and healthy controls) are shown in Figure 11.

Conclusion

Over the life-span, it appears that the brain uses apoptosis to control cell fate. This has long been accepted as a principle in the development of the nervous system. Recently, as discussed in this chapter, we and others have suggested that this mechanism is applicable throughout life and may play a major role in aging and AD pathogenesis. As the brain ages, multiple risk factors that can contribute to apoptotic cell death accumulate. This is a particular challenge to neurons, which are differentiated postmitotic cells with extremely limited capacity for renewal. We suggest that neurons have special mechanisms embedded in a complex array of signal transduction pathways to counteract apoptotic processes, overcome cellular injury, and delay or prevent apoptosis. In fact, cell-cycle checkpoint proteins and anti-apop-totic markers are evident in the aging and AD brain. In this light, it can be hypothesized that neurons may re-enter the cell cycle to use checkpoint molecules for damage...

Acknowledgements

We thank our colleagues for their contributions to the work summarized here. In the U.S., this work was supported by grants from the NIH (P01 AG09215, P30 AG10124, P01 AG11542, P01 AG14382, P01 AG14449, P01 AG17586, PO1 AG19724, P01 NS-044233, UO1 AG24904), and the Marian S. Ware Alzheimer Program. We are especially indebted to our patients and their families whose commitment to research has made our work possible. This research was also supported by the Special Research Fund of the University of Antwerp, the Institute Born-Bunge, the central Biobank facility of the Institute Born-Bunge -University of Antwerp, the agreement between the Institute Born-Bunge and the University of Antwerp, International Alzheimer Research Foundation (Stichting voor Alzheimer Onderzoek), Medical Research Foundation Antwerp, Neurosearch Antwerp, the Thomas Riellaerts Research Fund, the Research Foundation - Flanders (FWO-F grant no G.0127.07), the Institute for Promotion of Innovation through Science and...

CSF Spaces

The majority of the CSF flows from the choroid plexi2 through the lateral, 3rd and 4th ventricles down into the lumbar sac from where it can be sampled by a lumbar puncture as described below. Importantly, not all the CSF reaches the lumbar sac. This may be important for CSF analysis in dementia because most of the CSF passing the gyri of the hemispheres where degenerating neurons are located is absorbed by the arachnoid villi. In contrast the lumbar CSF reflects proteins released by the following brain structures

Biomarker Overview

Loss of cortical neurons is a key pathological feature of the degenerative dementias. Following neuronal death and axonal degeneration, proteins present in the neuro-axonal compartment will be released into the interstitial fluid and diffuse into the cerebrospinal fluid (CSF). At present the most promising CSF biomarker thought to be related to axonal degeneration in dementia is tau protein.

The Protein

Phosphorylation of tau plays an important role in the pathophysiology of dementias and other neurodegenerative diseases (Table 1). The more extensively tau is phosphorylated the more likely it is to form aggregates. Phosphotau aggregates further promote self-assembly into filaments 39 . Tau filaments are likely to result from toxicity causing progressive neurodegeneration. Phosphorylation of the tau protein mainly occurs at the amino acids serine and threonine. In the longest CNS tau isoform (Figure 5) there are 79 phosphorylation sites. Some of these phosphorylation sites have attracted particular interest. For example the binding to microtubule is reduced after phosphorylation of Ser-262 (by 35 ), Thr-231 ( 25 ) and Ser-235 ( 10 ) 39 . Critical sites for converting normal to toxic tau are Table 1. Alzheimer's disease is part of a large spectrum of diseases in which tau deposits are described (list extended from reference 38 ) Alzheimer's disease Amyotrophic lateral sclerosis...

Clinical Studies

At present the most promising CSF biomarker thought to be related to axonal degeneration in dementia is tau protein 3,40-44 . For quantification of total tau most laboratories now use the hTau ELISA from Innogenetics (Ghent, Belgium). developing AD 46 . This exciting research will be discussed in more detail in the chapter by Venturelli et al. on Predicting Alzheimer's disease in mild cognitive impairment the role of CSF markers.

Treatment Trials

Many key molecular mechanisms leading to Alzheimer's disease continue to be unravelled. The recognition of the pathological role of amyloid and tau has been translated into experimental therapeutic approaches and clinical trials. However, treatment trials may have been biased by the inclusion of non-AD subjects because of the low diagnostic sensitivity (46-88 ) and specificity (37-90 ) of the inclusion criteria for patients with prodromal AD 2,141 . CSF protein biomarkers may be used as inclusion criteria for such trials in order to increase specificity. They may also be used for monitoring of the treatment trial. Some of the hypotheses to be tested in future treatment trials are

Chemokines

The number of CCR1-positive plaque-like structures in the hippocampus and entorhinal cortex highly correlated with the clinical dementia state. CCR1 is rarely seen in nondemented control brain, and not in other types of dementia, unless Ap42-positive plaques are also present. Therefore, neuronal CCR1 seems to be part of the neuroimmune response to Ap in Ap42-positive neuritic plaques, and CCR1 may be a specific marker for this process instead of being a generalized marker of neurodegeneration. 105 .