5 Steps to Reverse Dementia

Unraveling Alzheimers Disease

Unraveling Alzheimers Disease

I leave absolutely nothing out! Everything that I learned about Alzheimer’s I share with you. This is the most comprehensive report on Alzheimer’s you will ever read. No stone is left unturned in this comprehensive report.

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Diagnosing Very Mild Cases Of Dementia In Epidemiological Studies

Most of the prevalence studies cited have used either Mini-Mental State Examination (MMSE) scores of 24 or lower or equivalent scores on related tests as a screening tool. East Boston used a sophisticated delayed recall task for screening patients (Evans et al., 1989). This indicated a higher rate of dementia prevalence, a rate considered an 'outlier' by some (see Figure 2.1). Today we often diagnose clinical AD and dementia in less impaired individuals with a fair degree of accuracy. Can this be done in the briefer evaluations required for epidemiological studies Inclusion of cases of dementia at a very early stage in the course of the illness is now recognized as important, but raises the issue of the accuracy of diagnoses in very mild dementia and also the issue of the accuracy of the differential diagnosis in dementia in the setting of an epidemiological study, where autopsy follow-up is unlikely. This is a circumstance in which the need for readily obtained objective markers is...

Dementia As A Major Cause Of Mortality

That AD and vascular dementia are as powerful predictors of mortality as cancer has been shown in the Shanghai study (Katzman et al., 1994) and in the Italian longitudinal study (Baldereschi et al., 1999). Mortality data from the East Boston study led Ewbank (1999) to estimate that the number of

One hundred years of Alzheimer research

Jacqueline Mervaillie

Few medical or scientific addresses have so unmistakeably made history as the presentation delivered by Alois Alzheimer on November 4,1906 in T bingen. The one-hundred year anniversary of that event has been marked on several occasions in 2006, most notably at the very site of the original lecture, namely the Institute of Psychiatry of the University of T bingen in Germany on November 2-5,2006. The celebratory event, Alzheimer 100 Years and Beyond organized on the initiation of the Alzheimer community in Germany and worldwide, in collaboration with the Fondation Ipsen, was the highlight of the Year of Alzheimer. However, beyond these few months of tributes, the centennial offers a unique opportunity to assess both the progress achieved and the uncertainties remaining. This volume, a collection comprised mainly of articles by the invited speakers and also of a few other prominent researchers, is meant to be a record of those events. Over the last century of Alzheimer research...

Incidence Of Dementia

During the past decade new cases of dementia developing during the follow-up of non-demented individuals from earlier prevalence studies or based on longitudinal studies of normal volunteers, have provided data concerning the incidence of AD and dementia, i.e. the number of new cases per year (Figure 2.2). An exponential increase with age (Jorm and Jolley, 1998) is apparent in this semi-log plot, again with doubling of incidence, prompting the question of what happens to the incidence of dementia after age 95. The regression line in this figure is based upon the values from the Canadian Study of Health and Aging (2000) and values from a Eurodem meta-analysis of four studies (Letenneur et al., 2000). Figure 2.2 also includes data from additional incidence studies (Copeland et al., 1992 Gussekloo et al., 1995 Fichter et al., 1996). There is some variability between sites, which may reflect the smaller numbers of new cases observed in incident studies as compared to prevalent cases....

Alzheimer joins Kraepelin

Friedrich Lewy

In 1903, after 14 years in Frankfurt, Alzheimer left the Frankfurt institution. Emil Kraepelin (Fig. 4), one of the most influential psychiatrists of his time, had offered him a position as scientific assistant at his clinic in Heidelberg. Alzheimer's close friend, Franz Nissl, who had previously also moved to Heidelberg, persuaded Alzheimer to join them. Alzheimer's stay in Heidelberg, however, was to be short. Only six months after he had taken up his new position, in the autumn of 1903, Kraepelin moved to Munich to head the Royal Psychiatric Clinic (Nissl 1916). Alzheimer went with Kraepelin to Munich and took over the clinic's large anatomical laboratory. Under Alzheimer, the laboratory quickly filled with students and guest scientists from various countries (Fig. 5). These included Friedrich H. Lewy, famous today for the Lewy bodies named after him, as well as Hans-Gerhard Creutzfeld and Alfons Maria Jakob, who in the early 1920s would be the first to describe the disease that...

Auguste D the first patient diagnosed with Alzheimers disease

Alzheimer Handwriting

On the November 26, 1901, Alzheimer examined Auguste D. for the first time. The entry into her case file revealed that, eight months earlier, Auguste D. had developed increasing signs of a change in her personality (Maurer et al. 1997, 2000, 2003). Her memory failed her. More and more, she neglected her household chores and began hiding objects. When preparing food, she made mistakes and spoiled the dishes. She became agitated and aimlessly paced around her apartment. Frequently, she was lost in familiar situations and developed a fear of people well acquainted to her. She became paranoid and unduly jealous of her husband. At times she even believed that someone wanted to kill her and began to shout wildly. At the time, Auguste D. was 51 years of age. She had never been afflicted by any serious illnesses and, apart from being underweight, her physique was normal. When examined upon admission at the Frankfurt clinic by the institution's personnel, Auguste D. was diagnosed as being...

Alois Alzheimer and the myth of the pioneer

From a historical point of view, what can be referred to as the myth of the pioneer finds expression in a two-way contradictory process. On the one hand, there is a tendency, from a hagiographical viewpoint, to give the creator full credit for the discovery. Meanwhile, others, taking an anti-establishment standpoint, endeavour to demonstrate how small the creator's contribution was, since it is in fact always possible to find forerunners of the greatest of pioneers. Alois Alzheimer is no exception. What, therefore, is his actual contribution

How did the eponym Alzheimers Disease came into being

The year 2006 marks the centenary of Alois Alzheimer's remarkable presentation on A Characteristic Disease of the Cerebral Cortex. Alzheimer read this paper during an afternoon session of the 37th Assembly of Southwest German Psychiatrists in T bingen. Eighty-eight physicians and researchers were present including Binswanger, Curschmann, D derlein, Levi, Merzbacher, Nissl and Romberg. Besides Alzheimer Binswanger and Levi were to become well know eponymists. Carl Gustav Jung from the Burgh lzli Hospital in Z rich was also present. He later developed analytic psychology. The paper read by Alzheimer was the 11th contribution and published in the same year 1906 as abstract in the Neurologische Centralblatt with the title ber einen eigenartigen schweren Erkrankungsprozess der Hirnrinde (Neurologisches Centralblatt 1906 23 1129-36). One year later, in 1907, the Allgemeine Zeitschrift f r Psychiatrie und PsychischGerichtliche Medizin (General Journal of Psychiatry and Psycho-Forensic...

Dementia With Lewy Bodies

DLB has not been examined as extensively with PET and SPECT as other atypical parkinsonian disorders. Albin and colleagues have reported the 18FDG PET findings of six demented individuals with pathologically verified diffuse Lewy body disease (71), three of whom had had pure DLB and three combined DLB and Alzheimer's disease (DLB-AD) pathology. These patients showed hypome-tabolism in association cortices with relative sparing of subcortical structures and primary somatomotor cortex, a pattern reported previously in AD. The main difference in comparison to patients with AD was the more pronounced hypometabolism in the occipital association cortex and primary visual cortex, indicating the presence of diffuse cortical abnormalities in DLB and suggesting that FDG-PET may possibly be useful in discriminating DLB from AD antemortem (Fig. 4). The presynaptic system has been characterized in DLB using both PET and SPECT. Using 18F dopa PET, Hu and colleagues (75) described a reduction of...

Overview of Vascular Dementia

The concept that atherosclerosis and impaired cerebral blood were the causes of dementia dates back to the late nineteenth century (Blass et al., 1991). Our modern understanding of dementia was greatly influenced by Tomlinson et al. (1968, 1970) who clarified that Alzheimer's disease (AD) was the most common cause of dementing disorders. They also showed that there was a relationship between the volume of infarcted tissue and dementia, supporting the idea that cerebrovascular dementia was due to brain destruction and not to a gradual reduction of neurons due to diminished blood flow. Subsequently, it has been shown that a broad spectrum of cerebrovascular lesions can result in cognitive function decline. These disorders have been referred to as multi-infarct dementia (Hachinski et al., 1974), vascular dementia, vascular cognitive impairment (Hachinski and Bowler, 1993), and, more recently, dementia associated with stroke (Gorelick, 1997). Although Hachinski and colleagues provide...

Evaluating CNS Biomarkers for Alzheimers Disease

There are more than 50 medical, neurological, and psychiatric diseases considered in the differential diagnosis of dementia (Mayeux et al., 1993). Alzheimer's disease (AD) is by far the most common cause of dementia DSM-IV and ICD-10 criteria follow closely on the NINCDS-ADRDA guidelines first published in 1984 (McKhann et al., 1984). Because of these common standards, diagnostic procedures for AD are remarkably uniform throughout the world. In a survey I conducted of 26 centers specialized for AD care in the US, Europe, and Japan, 6 items out of a menu of 16 procedures were specified as essential steps in the diagnosis of AD. These procedures were history of illness, generally obtained from a spouse, caregiver, or other knowledgeable informant physical examination, including a neurological examination and psychiatric assessment as indicated laboratory blood tests to exclude underlying medical or metabolic conditions that can masquerade as dementia a mental status test psychometric...

Inflammation And Alzheimers Disease

A large number of epidemiological studies have addressed the possible protective effect of antiinflammatory drug use with regard to Alzheimer's disease (AD) (McGeer et al., 1996). The most convincing of these studies the Baltimore Longitudinal Study of Aging utilized data collected prospectively, thereby minimizing recall bias issues. Corroborated by related studies, their results indicated a protective effect from the use of non-steroidal antiinflammatory drugs (NSAIDs) (Stewart et al., 1997). Available intervention studies support the beneficial efficacy of NSAIDs in AD. One small controlled trial of the NSAID indomethacin suggested that the drug slowed cognitive deterioration (Rogers et al., 1993). Recently, a small controlled trial of diclofenac showed similar results (although not statistically significant because of a high drop-out rate) (Scharf et al., 1999).

From the amyloid protein A4 to isolation of the first Alzheimers disease gene amyloid A4 precursor protein APP

As life expectancy continues to increase, so will the prevalence and incidence of Alzheimer's disease (AD) in our elderly population by 2050, as many as 14 million AD cases are expected in the USA, alone. AD is characterized by global cognitive decline in association with specific brain pathological lesions, neuronal loss, and synaptic pruning. The disease takes its name from Dr. Alois Alzheimer, a German psychiatrist who in the fall of 1906 suggested that specific physical aberrations in the brain were driving dementia in his female patient, Auguste D (Alzheimer 1907a). Alzheimer had been treating Auguste D since she was first admitted at age 51 to the Hospital for the Mentally Ill and Epileptics in Frankfurt for frenzied delirium. Shortly after the patient's death at age 56, Alzheimer presented the results of his post-mortem examination of her brain at a meeting in Tubingen. He wisely took advantage of Camillo Golgi's new silver staining technique to examine the neurons in his...

Alzheimer Actualits 20 years and nearly 200 issues

In 1986, the French medical and scientific community's need for information about Alzheimer's disease was unmistakable research findings from international teams were just beginning to build, yet the means of circulating them were not the same as with today's information technologies. This monthly newsletter, very widely circulated in French-speaking countries, was designed, from the outset, to highlight, summarize and, if possible, clarify research findings just as they were unveiled in the world's premier publications. For scientists eager for the latest news, reading through the monthly newsletter's concisely worded pages quickly became a habit. Today, curious minds with the leisure to do so can easily flip through each issue in the collection and see the history of Alzheimer's disease flash before their eyes, with two decades of hopes, doubts, disillusionment and, more rarely, certainties confirmed. (Fig. 4)

Olfactory Function In Alzheimers Disease

Neuropathological changes in olfactory areas of the brain in patients with AD suggest the theoretical importance and potential diagnostic utility of investigating functional changes in olfaction in these patients. A series of investigations utilizing psychophysical, neuropsychological, and electrophysio-logical techniques have been conducted to assess olfaction function in both patients with AD and those at risk for the disease. Both Alzheimer's patients and those at risk for AD show significant impairment in olfactory threshold sensitivity, odor identification, and odor memory, with some measures showing more impairment than others in the early stages of the disease process (Murphy, 1999). Functional testing in AD revealed deficits in olfactory threshold (Murphy et al., 1990 Nordin and Murphy, 1996 Bacon

Development of Extramural Research Program on Alzheimer NIANIH

The other categorical institutes at NIH, which had responsibilities for specific disease e.g., cancer, diabetes, heart, stroke etc. In 1977, this author was recruited to translate NIA's broad legislative directive into 'a blue-print for action'. The NIA strategic plan for a national program of research on the neurobiology of aging and Alzheimer's disease outlined the details of the scientific content, organizational structure, mechanisms of support, resources and infrastructure needs, and professional judgment budget estimates for a comprehensive program. In 1978, however, the task of implementing NIA's broad legislative mandate, i.e., solving 'the problems and diseases of aging' faced a number of difficult hurdles e.g., lack of funds, little or no academic interest in the topic, small cadre of investigators, the absence of a compelling scientific story, the lack of scientific credibility and inadequate resources infrastructure . Although NIA continued to share an interest in...

Challenges to the enigma of ysecretase and to Alzheimers disease

Our interest in Alzheimer's disease (AD) and in y-secretase, a mysterious and fascinating machinery for the production of amyloid p peptides (Ap), was aroused by the in vitro demonstration that Ap ending at position 42 (Ap42) forms amyloid fibrils much faster than Ap40 (Jarrett et al. 1993), the latter being the predominant Ap species produced by cells. Owing much to the groundbreaking invention by Drs. Nobu Suzuki and Asano Asami of the monoclonal antibodies that discriminate the C-terminal clip-site structures of Ap40 and Ap42 (Suzuki et al. 1994), we were able to visualize these different Ap species in the brain tissues of patients with AD and Down's syndrome, showing that Ap42 deposition, typically as diffuse plaques, is one of the earliest changes in the Alzheimerization of human brains (Fig. 1 Iwatsubo et al. 1994). Fig. 1. Deposition of Ap42 precedes that of Ap40 in Alzheimerization of human brains. Sections from frontal cortices from patients with Down's syndrome at young 31...

Ap immunotherapy prevents and Reverses Alzheimers disease neuropathology

By the late 1990s, research into the role of beta amyloid peptide (Ap) in Alzheimer's disease uncovered a number of important findings. It was a key pathological feature of the disease and nearly all known familial forms of the disorder appeared to either directly or indirectly increase levels of the more amyloidogenic Ap 42 in the brain tissue of affected individuals. The precise details of the Ap generating proteases, beta and gamma secretase, were not yet understood, but their existence was fairly certain. Most importantly, a few transgenic mouse models finally existed that demonstrated fairly robust progressive amyloidosis. A immunotherapy prevents and Reverses Alzheimer's disease neuropathology 421 Perhaps the most important question underlying A immunotherapy is determining its potential clinical utility. The first clinical test of the potential of immunization of A as a possible treatment for AD used a synthetic version of A 42 termed AN 1792. This agent was used in a number of...

Assessment of Alzheimers Type Dementia

Dementia is characterized by the development of multiple cognitive deficits, with the essential fea- ture of this syndrome being memory impairment along with one or more additional disturbances in cognitive functions (APA, 1994). These other affected functions may include orientation, abstraction, and problem solving, judgment, visual-spatial performance, and language, in addition to changes in personality (Nixon, 1996). In Alzhe-imer's-type Dementia, the most common form of dementia, there is a gradual deterioration in cognitive functioning (American Psychiatric Association, 1994). In order to diagnose Alzheimer's-type Dementia, all other causes of the symptoms must first be ruled out because it is technically not diagnosed until an autopsy is conducted to identify neuritic plaques and neurofibrillary tangles. Thus, the primary purpose of intelligence and memory testing in individuals with suspected Alzheimer's is to track the level of deterioration against one's premorbid level of...

Misregulation of Tau Alternative Splicing in Neurodegeneration and Dementia

Tau is a microtubule-associated protein that fulfills several functions critical for neuronal formation and health. Tau discharges its functions by producing multiple isoforms via intricately regulated alternative splicing. These isoforms modulate tau function in normal brain by altering the domains of the protein, thereby influencing its conformation and post-translational modifications and hence its affinity for microtubules and other ligands. Disturbances in tau expression result in disruption of the neuronal cytoskeleton and formation of pathological tau structures (neurofibrillary tangles) found in brains of dementia sufferers. More specifically, aberrations in tau splicing regulation directly cause several neurodegenerative diseases that lead to dementia. This review briefly presents our cumulative knowledge of tau splicing regulation in connection with the alterations in tau splicing seen in neurodegeneration.

Frequency Of Vascular Dementia

For example, the prevalence of VaD evaluated in a memory disorders clinic, such as occurs in many AD centers, might be much lower than that from a vascular disease clinic. In addition, it is difficult to compare the prevalence of VaD in clinical studies with recent autopsy studies of dementia patients where a low rate is present. Evaluation of 11 pooled European population-based clinical studies of persons 65 years and older revealed an age-standardized prevalence of 6.4 for all causes of dementia, 4.4 for AD, and 1.6 for VaD (Lobo et al., 2000). VaD accounted for 15.8 of all dementia cases. The prevalence of VaD ranged from 0.0 to 0.8 at ages 65 to 69 and from 2 to 8.3 in the 90 and older age group in the different countries. In a Canadian clinical study of 603 dementia patients, 12.1 had VaD and 12.6 had mixed AD VaD (Rockwood et al., 2000). In Asian countries, VaD may be more common than AD. Studies from Japan revealed that the prevalence of VaD was more...

HIVassociated dementia complex AIDS dementia complex or HIV dementia

This complication occurs in 15 of AIDS patients usually in patients with a CD4 count below 200 mms. The early reports of evidence of cognitive abnormalities in HIV positive asymptomatic individuals have been discounted by large cohort studies using clinical, neuropsychological, MRI and neurophysiological methods of assessment. The clinical picture is of a variably progressive dementia with psychomotor slowing and impairment of memory. The diagnosis is one of exclusion of other infective or neoplastic aetiologies by brain imaging and CSF examination. Although there is a correlation between the CSF HIV RNA viral load and the severity of dementia, there is too much overlap for use as a diagnostic test. A neuropsychological assessment is also helpful. MRI shows cortical atrophy and diffuse or patchy white matter high signal on T2-weighted images. Since the introduction of zidovudine and subsequently HAART the incidence of HIV-associated dementia has progressively declined. However, more...

Early Neuropathology In Alzheimers Disease

The initial event in AD is the appearance of neurofibrillary tangles in the transentorhinal and entorhinal areas of the brain (Braak and Braak, 1994, 1997). Degeneration then proceeds to other temporal lobe structures, which include the hippocampus. Also affected relatively early in the disease is the frontal cortex, including the orbital frontal area. All of these areas are involved in processing of olfactory information. Price et al. (1991) also described tangles in these areas which mediate olfactory function, particularly the anterior olfactory nucleus, entorhinal cortex, and amygdala, even in AD patients with mild dementia. The most severe lesions are in the entorhinal cortex and perirhinal cortex, hippocampus, amygdala, and the association cortices. The prevalence of lesions in the entorhinal cortex, which forms the primary projection to the hippocampus, suggests the mechanism for the impairment in hippocampal function that gives rise to memory dysfunction. Braak and Braak...

Mild Cognitive Impairment and Alzheimers Disease

Mild cognitive impairment (MCI) is characterized by memory complaints and impairments on formal testing. Amnestic MCI (aMCI) is usually regarded as a transitional stage between normal aging and early AD (eAD Markesbery et al. 2006 Petersen et al. 2006 Jicha et al. 2006). Patients with AD show progressive difficulties with memory and other cognitive functions (Cummings 2004), leading in the late stages to profound dementia.

Alzheimer genetics out of limbo

Another factor was the serendipitous realization that a large family with 12 persons affected with early-onset AD that had been described in the US by Feldman et al. (1963) was linked with family N. The authors did not give any indication about the origin of the family they described, but they mentioned an official with a surname I knew from my studies in Calabria. This clue, together with the identity of the clinical picture and of the ultrastructural neuropathology in both families (Krigman et al. 1965), led me to contact Professor Feldman, who generously gave me access to his data. I could thus establish that his patient 1.1 (known by history) was a daughter of the couple 18-17 in my data base they lived in the first half of the nineteenth century and were ancestors of all the affected people known at the time in Calabria. Professor Feldman had a collaboration with Dr. Polinsky, a neuropharmacologist with an interest in familial AD (FAD Nee et al. 1983) at NIH-NINCDS, in the...

Alois Alzheimers Life

Creutzfeldt Hans Gerhard

Alois Alzheimer was born on June 14,1864, in Marktbreit, a small town in lower Fran-conia on the Main river in Bavaria, southern Germany. His father was a Royal Bavarian * From Concepts of Alzheimer Diseasae, Biological, Clinical and Cultural Perspectives Eds. Peter J. Whithehouse, Konrad Maurer, Jesse Ballenger (2000) The John Hopkins University Press Baltimore and London. pp 5-29 Alzheimer 100 Years and Beyond Springer-Verlag Berlin Heidelberg 2006 Fig. 1. Alois Alzheimer 1884 as a member of the Franconia fraternity in W rzburg Notary. When he graduated from high school in the district capital of Aschaffenburg, Alzheimer's teachers certified that he was excellent in the sciences. Science was also his hobby. Alzheimer studied medicine in Berlin, W rzburg, and T bingen. He returned to W rzburg, where he graduated in 1888 after writing a doctoral dissertation, On the Ceruminal Glands of the Ear. His doctoral adviser was the famous swiss-born physiologist Albert Koelliker. Alzheimer...

Tau and Alzheimer paired helical filaments

Tau Structure

The molecular structure of PHFs is still unknown but determining it represents one of the major goals in the field, since this would greatly aid in the development of methods and drugs to prevent pathological aggregation. From a structural point of view, there was a long gap between Alzheimer's discovery of neurofibrillary tangles (Alzheimer 1907a) and the identification of PHFs as their basic elements, made possible by the advances in electron microscopy (Kidd 1963 Terry 1963). Another two decades passed with attempts to find suitable conditions for the isolation and characterization of PHFs (e.g., Ihara et al. 1983 Wisniewski et al. 1984). One important outcome was the reconstruction of PHFs from negatively stained electron micrographs, which showed each half of a PHF to be composed of three protein densities, with overall dimensions of 8 nm x 20 nm (Crowther and Wischik 1985) Subsequent work showed an analogous doubly tripartite structure for straight filaments, a minor variant of...

Synaptic activity amyloidp and Alzheimers disease

Eeg Pathway

An unsolved mystery for most neurodegenerative disorders, including Alzheimer's disease (AD), is why the underlying pathology that occurs is region-specific. In other words, why are some brain regions vulnerable and others not Several interesting findings and events have come together over the last six years that have led us to hypothesize that one of the reasons that the amyloid-p (Ap) peptide deposits in aregion-specific fashion in AD is related to the overall synaptic activity that occurs over many years in areas vulnerable to Ap deposition. If this assumption is correct, it has important implications for both AD pathogenesis and potentially for future therapies. Dept. of Neurology1, Psychiatry2, Molecular Biology & Pharmacology3, the Hope Center for Neurological Disorders4, and Alzheimer's Disease Research Center5, Washington University School of Medicine, St. Louis, MO 63110 Acknowledgements. This work was supportedby National Institutes of Health grants AG13956, AG11355...

Molecular and cellular pathways towards and away from Alzheimers disease

Alzheimer Disease Biological Pathways

The findings from my laboratory during the past three decades that have contributed to an understanding of the pathogenesis of Alzheimer's disease (AD), and to its prevention and treatment. The findings described below help to place key discoveries in other laboratories in the areas of genetics, amyloid and tau biology (Selkoe and Schenk 2003 Forman et al. 2004 Hardy 2004 Dermaut et al. 2005) within the broader context of mechanisms of aging, neuronal plasticity and cell death (Mattson 2004). Molecular and cellular pathways towards and away from Alzheimer's disease 373 We have been working to identify dietary factors that may affect the risk of AD. We found that dietary restriction can increase the resistance of neurons in the brain to dysfunction and degeneration in animal models of relevance to the pathogenesis of Alzheimer's, Parkinson's and Huntington's diseases and stroke (Bruce-Keller et al. 1999 Duan et al. 2003 Maswood et al. 2004 Mattson 2005). The underlying mechanism was...

Fondation Ipsen and Alzheimers disease a 20year relationship

Shortly after its founding in 1983, Fondation Ipsen's destiny became intertwined with that of alzheimerology and although its activities extend to fields as diverse as endocrinology, oncology, neuroscience and cardiovascular pathologies, the foundation is most often associated with its focus on Alzheimer's disease. Chance, rather than strategy, was the main engineer at work. As the foundation published the first issue of Alzheimer Actualit s Alzheimer News in June 1986, and later organized its first Colloque M decine et Recherche on Alzheimer's disease on September 14, 1987, the importance that the theme was to take on was only occasionally visible. Little known to the medical community, particularly in France, and often considered a pathology more or less on a par with cognitive aging, the disease's neuropsychological signs had elicited only a limited number of studies while on the research side, the molecular lesions were not yet identified. Conference speakers broaching the topic...

Of stains and brains a brief account of how microscopic and clinical observations contributed to the understanding of

Max Bielschowsky

At the eve of the 20th century, when Max Bielschowsky, using chemicals common in photography, described the silver technique to which his name is now attached, he believed that he had discovered a reliable way of staining the so-called neurofibrils (Bielschowsky 1902, 1903). Neurofibrils, described by Remak in 1838, make up a visible network of thin intracellular structures visible in the cell body and the processes (mainly the axon) of neurons. It is no wonder that Alzheimer, using Bielschowsky's method, described the abnormal accumulation of argyrophilic material seen in his first cases as Fibrillenveranderung (Alzheimer, 1911). He indeed believed that the neurofibrils of Remak were altered (Fig. 1). But what were these neurofibrils, seen with light microscopy using Bielschowsky's method This has been a matter of debate since the advent of electron microscopy, with some authors stating that silver was deposited both on neurofilaments and on neurotubules and others believing that...

Tau focused drug discovery for Alzheimers disease and related Neurodegenerative Tauopathies

Tau Phosphorylation Kinase

Alzheimer's disease (AD), like most neurodegenerative disorders, results from the aggregation of misfolded proteins that deposit as fibrillar amyloid lesions in the central nervous system (CNS), where they are thought to be toxic and compromise brain function (reviewed in Forman et al. 2004 Skovronsky et al. 2006). For example, neurofibrillary tangles (NFTs) and senile plaques (SPs) were first recognized by Alois Alzheimer at the beginning of the 20th century as the diagnostic hallmark lesions of AD it is now known that NFTs are formed by abnormal tau filaments in neurons whereas SPs are composed of extracellular deposits of fibrillar Ap (Forman et al. 2004 Skovronsky et al. 2006). Although the discovery of pathogenic mutations in the genes encoding tau and the Ap precursor protein in familial neurodegenerative disorders definitively implicated these proteins in disease pathogenesis, the mechanisms whereby brain degeneration results from NFTs and SPs still are not entirely clear....

Targeting ySecretase for Alzheimers Disease

Y-Secretase is responsible for the final proteolysis that produces the amyloid p-peptide (Ap) from its precursor, amyloid precursor protein (APP), and has been considered a potential therapeutic target for Alzheimer's disease (AD) since the early 1990s, even before anything was known about its character or identity. This protease activity, which takes place within the transmembrane domain of APP, generates heterogeneity at the C-terminus of Ap peptides, forming longer, minor variants, especially the 42-residue variant (Ap42), which is highly prone to aggregation and represents the major species of Ap found deposited in the characteristic cerebral plaques of AD (Hardy and Selkoe 2002). The first hint to the identity of Y-secretase was the discovery that AD-associated missense mutations in the presenilin genes, presenilin-1 and presenilin-2, cause increases in the ratio of Ap42 to the less aggregation prone 40-residue variant (Citron et al. 1997 Duff et al. 1996 Lemere et al. 1996...

Segregation of a missense mutation in the amyloid protein precursor gene with familial Alzheimers disease

Swedish Mutation

In 1991, little was known about the pathogenesis of Alzheimer's disease (AD). Earlier studies had demonstrated that plaques contain amyloid p (Ap) and that neurofibril-lary tangles were composed of paired-helical filaments of hyperphosphorylated tau (Glenner and Wong 1984a Masters et al. 1985a Grundke-Iqbal et al. 1986a). However, a major impediment to a more detailed understanding of AD was the absence of cellular or animal models of disease. It has been known for more than 50 years that families exist in which AD has an early onset (< 60 years) and is inherited as an autosomal dominant trait (Familial Alzheimer's disease (FAD) Lowenberg and Waggoner 1934), but the techniques of molecular genetics only made analysis of these families feasible in the late 1980s. Initial studies of FAD focused on chromosome 21 because individuals with Down Syndrome all develop AD and Ap is derived from a precursor, p-amyloid protein precursor (APP), that is encoded by a gene on chromosome 21...

Alzheimers final years

Alzheimer was a passionate scientist. He worked very long hours andrarely took time off for a holiday. In Munich, he worked without a salary for years and even paid a large part of the cost incurred by his research from his private funds. In 1909, his commitment was honored and he was appointed as extraordinarius (assistant professor) at the University of Munich. His scientific merits are reflected by his appointment as editor of a newly established psychiatric journal in 1910, at a time when the eponym Alzheimer's disease was becoming increasingly recognized by psychiatrists worldwide. Over time, however, his hard work began to exhaust him. Nonetheless, when in 1912 he received an offer to become a full professor and director of the Psychiatric and Neurological Clinic at the Silesian Friedrich-Wilhelm-University in Breslau, he rapidly accepted. The clinic was a prestigious institution at the time. Alzheimer succeeded scientists such as Heinrich Neumann, Carl Wernicke and most...

How did the eponym Alzheimers disease come into being

Auguste Neurofibrils

In the autumn of 1903, Alois Alzheimer left Frankfurt. Following a short stay in Heidelberg, he moved to Munich to continue his scientific and medical activities at the Royal Psychiatric Clinic under director Emil Kraepelin. After Auguste D. died on April 8, 1906, Alzheimer asked that the record and the brain be sent to Munich. He immediately did a report on the admission formulas used in Munich at this time and wrote a full-page epicrisis. After this he made an entry to the autopsy book of the clinic under the number 181, dated 28 April 1906, Frankfurt, followed by the last name D. and the source of the tissue as Frankfurt (Graeber et al. 1998). This proves that the brain had been analyzed in his famous neuropathologic laboratory. Within six months, on November 3,1906, he presented his findings at the thirty-seventh meeting of the Southwest German Psychiatrists in T bingen. In 1907 the lecture was published in Allgemeine Zeitschrift f r Psychiatrie und Psychisch-Gerichtliche Medizin...

Alzheimer and Parkinson Diseases

Inflammatory Tangle

Alzheimer and Parkinson diseases are degenerative disorders of the brain associated with neurotransmitter deficiencies. Alzheimer29disease (AD) may begin before the age of 50 with symptoms so slight and ambiguous that early diagnosis is difficult. One of its first symptoms is memory loss, especially for recent events. A person with AD may ask the same questions repeatedly, show a reduced attention span, and become disoriented and lost in previously familiar places. Family members often feel helpless and confused as they watch their loved one's personality gradually deteriorate beyond recognition. The AD patient may become moody, confused, paranoid, combative, or hallucinatory he or she may ask irrational questions such as, Why is the room full of snakes The patient may eventually lose even the ability to read, write, talk, walk, and eat. Death ensues from pneumonia or other complications of confinement and immobility. Diagnosis of AD is confirmed on autopsy. There is atrophy of some...

Alzheimers case report

Auguste Deter

A full transcription of Alzheimer's questions and Auguste D.'s answers appears in previous publications as well as in a biography of Alzheimer (Maurer and Maurer 1998), and will not be printed here in their entirety. Alzheimer's notes in the file begin on November 26,1901. He asked very simple questions and wrote down the dialogues systematically. His questioning continues on four handwritten pages, dated through November 30,1901 (Fig. 9). Alzheimer's note She sat on her bed with helpless expression. Alzheimer What is your name Auguste D. Auguste. Alzheimer Last name Auguste D. Auguste. Alzheimer What is your husband's name Auguste D. Auguste, I think. Alzheimer Your husband Alzheimer Are you married Alzheimer Mrs. D. Alzheimer How long have you been here She seems to be trying to remember. Auguste D. Three weeks. Alzheimer What ist his I showed her a pencil. Auguste D. A pen. Alzheimer's note A purse, a key, a diary, a cigar are named correctly. At lunch she eats cauliflower and...

Imaging the pathology of Alzheimers disease Building on a centuryOld blueprint

Alzheimer Pathology

Alois Alzheimer carefully described the clinical and histological findings of an unusual case of pre-senile dementia in his benchmark presentation in T bingen, Germany, in 1906. He meticulously documented the presence of tangled bundle s of fibrils and miliary foci of a peculiar substance. With this description of neurofibrillary tangles and amyloid-beta (A ) plaques, the basis for the characteristic neuropathology that still defines Alzheimer's disease (AD) 100 years later was born. In recent efforts to image this pathology in living patients, we had several advantages over Alzheimer most importantly, he had told us exactly what pathology to target. Although it took almost 100 years to develop an effective in vivo tool to image this pathology, Alzheimer had effectively laid out the blueprint in his classic paper published in 1907 (Alzheimer 1907a). The answer to this very difficult issue may bring us back to Dr. Alzheimer's very first patient, Auguste D., who had an early-onset form...

Apolipoprotein E and Alzheimers disease A brief retrospective

The past 14 years from 1992 to 2006 provide an interesting perspective for the application of genetic methods to Alzheimer's disease (AD) research. In the science of genetics, these years saw the beginning of linkage analyses for the identification of inherited disease mutations as well as susceptibility genes for complex diseases. This was followed in 1999-2001 with maps of single nucleotide polymorphisms (SNPs) across the now-sequenced genome, ushering in the latest era of whole genome association studies of sporadic patients with complex diseases. For our AD studies, clinical collection of patients from families in which there were two or more AD patients started in 1981. The hypothesis was that AD was a complex disease with multiple contributing genetic influences that could possibly be identified by a new method of genetic research linkage analysis using a growing number of genetic variants distributed across the genome. At that time, few authorities considered AD to be a genetic...

The Potamkin prize for research in Picks Alzheimers and related diseases

According to the American Academy of Neurology, the Potamkin Prize is regarded by many as the Nobel Prize of dementia research. It has become the bellwether for progress in international research into Alzheimer's and related diseases. The Potamkin familyworked with leading neurologists to create this 100 000 annual award sponsored by the American Academy Neurology. The first Potamkin prize was established in 1988 at a time when very little was known about what happened in the brain during the course of Alzheimer's disease, not to mention its causes and cure.

Alzheimers early years and medical studies

Aloysius (Alois) Alzheimer (Fig. 1) wasborn on June 14,1864, to the royal notary Eduard Alzheimer and his second wife, Therese, in the small Bavarian town of Marktbreit.2 Early on in school, he showed a vivid interest in the natural sciences. His school leaving certificate remarked on his academic achievements This student shows outstanding knowledge of the Natural Sciences, which he has studied with particular predilection throughout his time at high school. In the autumn of 1883, after having left school, Alzheimer followed this interest and began to study medicine at the University of Berlin, a hub for the medical and biological sciences at the time. In Berlin, Alzheimer was introduced to novel approaches regarding the study of brain pathology as an important tool in psychiatric investigations. Scientists increasingly tried to find anatomical causes, particularly damage to the brain, to explain mental disorders. But despite the great opportunities Berlin offered to the young...

Epidemiology of Dementia in Downs Syndrome

Epidemiology Alzheimer Disease 2015

Neuropathological changes consistent with a diagnosis of Alzheimer's disease (AD) have been found in virtually all individuals with Down's syndrome (DS) over the age of 40, including deposition of p-amyloid (Ap) in diffuse and neuritic plaques (Mann, 1988 Wisniewski et al., 1994). Most adults with DS will develop dementia by the time they are 70 years of age, and it has been suggested that the identification of processes which contribute to a high risk of AD can serve as a model for the role of genetics in the etiology of AD (Lai and Williams, 1989). The neuropathological manifestations of AD in DS have been attributed to triplication and overexpression of the gene for Ap precursor protein (pAPP), located on chromosome 21, and the increased risk of AD may be mediated by an increased substrate for cellular production of Ap peptides. Before age 50, diffuse plaques are the most prevalent lesion seen in DS, while after age 50, neuritic plaques, containing fibrilized Ap peptides,...

Pathways to the discovery of the neuronal origin and proteolytic biogenesis of Ap amyloid of Alzheimers disease

Our contributions in the 1980s (Kang et al. 1987 Martins et al. 1986 Masters et al. 1985a,b) to the purification and N-terminal sequencing of the amyloid plaque cores (APC) of Alzheimer's disease (AD) and the discovery of its biogenesis from a neuronal precursor (the amyloid protein precursor - APP) by proteolytic cleavages (the P- and y- secretases) need to be seen against the background of many years of prior research activity from a diverse range of individuals and groups. Address for correspondence Colin L Masters, Department of Pathology, The University of Melbourne, Victoria 3010, Australia * This is an abbreviated version of a longer article written for the Alzheimer 100 Special Issue of the Journal of Alzheimer's Disease edited by G. Perry, J. Avila, J. Kinoshita and M. Smith. the enzymatic activity specific for acetylcholinesterase. This observation eventually developed into the cholinergic theory of AD and the current class of cholinesterase inhibitors that are useful in the...

Genetics molecular biology and animal modeling of Alzheimers disease

Christine Van Broeckhoven

Our group at the Center for Research in Neurodegenerative Disease, at the University of Toronto, first became interested in several aspects of the biology of Alzheimer's disease (AD) during the early 1980s. The relative homogeneity of the clinical and neuropathological features of (AD) had led to the prevailing assumption that AD was likely to be a single homogeneous disorder. At that time, standard biochemical methods were being applied to dissect the protein composition of both the amyloid plaque and the neurofibrillary tangle (NFT). While these biochemical studies were on the edge of providing important clues to the biochemical pathogenesis of AD, mechanistic insights into the disease remained elusive. One notable exception was the observation that AD clustered in some families and was often inherited as an autosomal dominant trait. This observation alone, however, was insufficient to provide much traction. Indeed, some early attempts to define the chromosomal location of the...

Mixed Vascular Dementia And Alzheimers Disease

'Mixed dementia' can refer to the presence of two or more causes of dementia however, it generally refers to the coexistence of the clinical and pathologic alterations of both AD and VaD. Tomlinson et al. (1968, 1970) first called attention to this disorder when they suggested that the combined effects of AD histopathologic lesions and cerebral infarctions might lead to intellectual decline. Criteria for the diagnosis of mixed AD VaD have not been developed thus, the true frequency is not known. A recent review of autopsy studies found the prevalence of mixed VaD AD to range from 3.7 to 36 in different autopsy series (Markesbery, 1998). The mean of these studies was 17.7 . The Canadian Consortium for the Investigation of Vascular Impairment of Cognition found that out of 603 dementia patients, 149 had VaD and, of these, 76 had mixed AD VaD (Rockwood et al., 2000). Cohen et al. (1997) reviewed different approaches to the clinical diagnosis of mixed dementia. Characteristics of AD by...

Staging of cortical neurofibrillary inclusions of the Alzheimers type

Alzheimer's disease (AD) is the most widespread degenerative illness of the human central nervous system. It is progressive and is not subject to remission. Central to the pathological process that underlies this disorder is the formation of proteinaceous inclusions in selectively vulnerable neuronal types (Goedert 1993 Goedert et al. 1997 Jellinger 1998 Dickson 1999 Trojanowski and Lee 2000). The pathological inclusions consist, for the most part, of abnormal tau protein and appear as pre-tangle material, somatic neurofibrillary tangles (NFTs), dendritic neuropil threads (NTs), and abnormal material in dystrophic neurites of plaques (NPs Braak and Braak 1991 Braak et al. 1994).

Alzheimers Disease at midCentury 19271977 and a little more

In 1959, when Saul Korey and I began to think about planning a study of Alzheimer's disease (AD), the situation seemed quite simple and straightforward. It was widely accepted that AD was exclusively a rare pre-senile disorder, that it was entirely different from senile dementia, that it had a simple dominant genetic inheritance, and that there had been little or no work related to the problem for several decades. All of these ideas soon showed themselves to be at least partially wrong. Nevertheless, we did have a few advantages Saul was the head of the Department of Neurology at the Albert Einstein College ofMedicine and was also a well-trained (for 1959) neurochemist, and I, a neuropathologist, was asssigned a new Siemens electron microscope, much different from my previous RCA. The combination of chemist plus electron microscopist was a promising, but untried collaboration. A world-class neurosurgeon, Leo Davidoff, had agreed to do the brain biopsies. It now seems remarkable how...

The genetic Alzheimerfrontotemporal dementia spectrum

Neurodegenerative brain diseases, including dementias, are common diseases among elderly people, and their population frequency is increasing rapidly because people are living longer due to high quality health care systems. Predictions indicate that in 2030 at least one in four people in Western European countries will be 65 years or older. In this age group, people are at high risk for neurodegenerative dementias such as Alzheimer's disease (AD), with risk increasing with age to as high as 20 for those 85 years. Neurodegenerative brain diseases or cerebral prote(in)opathies have in common the presence of inclusion bodies containing abnormal protein aggregates. These protein depositions in specified brain regions occur within neurons or in the brain parenchyma and are commonly used as pathological hallmarks in morphological diagnosis of demented patients at autopsy. In AD, the major protein aggregates are found in parenchymal senile plaques and intraneuronal neurofibrillary tangles....

Anatomical changes underlying dementia in Alzheimers disease

The severity of the clinical problem of Alzheimer's disease (AD) is astounding the Alzheimer's Association estimates that 1 in 10 Americans is affected by someone with AD in their family. Despite decades of research and advances in the cell biology and genetics of AD, current medications provide only subtle symptomatic benefits. Studies of the natural history of the illness present an even more worrisome image the pathologic changes of AD begin years prior to the emergence of overt clinical symptoms. New imaging modalities (PIB amyloid PET scans, quantitative MRI scans, etc.) and more sensitive clinical instruments are pushing the diagnosis of AD earlier in the course, leading to an explosion of recognition of the illness in its earliest stages that makes the need for disease-modifying interventions even more pressing. The key to successful prevention and treatment is understanding what causes dementia. The major theme of this chapter is to examine ideas about the pathological...

Distinguishing Schizophrenia from Dementia

While the onset of schizophrenia typically occurs in adolescence or young adulthood, schizophrenia may also occur in late life. Schizophrenia with a late life onset is often called paraphrenia, and may occur in individuals who have a history of eccentricity and are socially isolated. However, dementia can also produce hallucinations and delusions, and thus, like depression, it is important to distinguish between the two conditions.

Depression and Pseudodementia

Assessment tool in diagnosing depression however, they can be useful to this end. For instance, many individuals with learning disabilities also have major depression (APA, 1994 Culbertson & Edmonds, 1996). Additionally, it can be difficult, particularly in elderly persons, to determine whether cognitive symptoms are due to dementia or to a major depressive episode (APA, 1994). In fact, the literature suggests that the cognitive symptoms associated with depression are the most common type of pseudodementia and the most easily misdiagnosed (Lishman, 1987). Thus, neu-ropsychological testing and other tests assessing cognitive abilities can be helpful in the differential diagnosis of depression versus other disorders. TABLE 13.15 Hypothesized KAIT results for clients with Alzheimer's-type dementia

Inflammation And The Clinical Progression Of Alzheimers Disease Dementia

Complications Alzheimer Disease

Recent evidence suggests that different indices of classical inflammatory cascades may have distinct associations with different phases of the clinical progression of AD, as reflected in the clinical dementia rating (CDR) (Luterman et al., 2000). For example, COX-2 (but not COX-1) expression in the neurons of the hippocampal formation, a brain region at risk for AD neurodegeneration, may be a predictor of progression of early AD before neurodegeneration occurs (Ho et al., 2001, in press). Surprisingly, and in contrast to COX-2, other classical markers of inflammatory neurodegeneration, such as interleukin-6 (IL-6) and transforming growth factor p1 (TGFp1) (Luterman et al., 2000), HLA-DR immunopositive reactive microglia, and complement components gene expression (Xiang and Pasinetti, 2000) showed increased expression, but only at the latest stages of AD dementia (Figure 35.1). The evidence showing elevation of COX-2 protein content in neurons of the hippocampal formation early in AD...

Reanalysis of the first described cases of Alzheimers disease

The diagnosis of Auguste D. has since been confirmed by a re-examination of Alzheimer's original histological slides (Graeber et al. 1998 Graeber and Mehraein 1999). These analyses verified the loss of neurons in various areas of the cortex, the accompanying gliosis, as well as the presence of large numbers of typical neurofibrillary tangles and amyloid plaques in her cerebral cortex, precisely as had been described and depicted by Alzheimer. Moreover, the studies proved the absence of any significant changes to the brain's vessels or any changes suggestive of a metachromatic leukodystrophy (both pathologies had variously been suggested as the real causes of Auguste D.'s affliction (see Graeber et al. 1998 and references therein). Combined with Auguste D.'s clinical symptoms (Alzheimer 1907a Maurer et al. 1997), these data confirm this first case of Alzheimer's disease as being a typical example of the disease now bearing Alzheimer's name. Isolation of DNA has recently also been...

The cholinergic deficit in Alzheimers disease

In the period immediately prior to publication of the first reports of cholinergic markers in the brains of patients with Alzheimer's disease, there was very little hard science going on in this field. This was before the recognition that Alzheimer's disease was the most common cause of dementia in the elderly, and it was generally thought to be a rather rare, pre-senile dementia. Having spent some time trying to do neurochemical analyses on the brains of schizophrenics, I became disillusioned by the subjectivity of the diagnostic criteria and looked around for a brain disease that was reasonably common and one in which objective, neuropathological diagnosis was possible. The late AJF Maloney convinced me that Alzheimer's disease would be a relatively easy problem to tackle, and so my systematic biochemical studies were undertaken in 1975. I was not aware at that time that two other groups in Great Britain were doing almost exactly the same things as I was, and the discovery of the...

Mild Cognitive Impairment Transition from Aging to Alzheimers Disease

Early identification of persons who might be developing a cognitive impairment which may lead to Alzheimer's disease (AD) has become an increasingly popular topic for investigation. At the previous meetings of what is now the World Alzheimer's Congress, the concept of mild cognitive impairment received scant attention. However, this year there are numerous presentations and scientific studies involving this condition.

Differentiating Depression from Dementia

Some depressive symptoms mimic cognitive impairment, especially in the elderly. In particular, psycho-motor retardation and memory lapses in the elderly are usually attributed to dementing processes, but actually may reflect depression. Pseudodementias can result from a wide variety of disorders, including nutritional deficiencies, prescribed medications, alcohol and substance abuse, and surgical procedures. Thus, assessment of the occurrence of problems of this type may be an important component in elders presenting with cognitive impairment. In turn, dementia is often associated with difficulty concentrating, loss of en In 1992, Newman and Sweet identified a number of different features which may distinguish depression from dementia. Depression often has a rapid onset while dementia often has a gradual one. In addition, there may be differences in both patient and familial awareness of the problems, with recognition greater in depression-related cognitive impairment than in problems...

Psychiatric Aspects Of Dementia With Lewy Bodies

DLB is characterized clinically by dementia, visual hallucinations, and fluctuating consciousness in addition to parkinsonism. Neuropathological characteristics include alpha-synucleinopathy, such as Lewy bodies and Lewy neurites in the brainstem, particularly the substantia nigra, subcortical structures, limbic cortex, and neocortex. Some amyloid deposition is also found in most patients. Neurochemically marked cholinergic deficits are reported in addition to a moderate nigro-striatal dopaminergic, and monoaminergic deficits have also been reported. It is estimated that at least 80 of DLB patients experience some form of neuropsychiatric symptoms (23), such as visual hallucinations, auditory hallucinations, delusions, delusional misidentification, and depression. These visual hallucinations are consistently reported to be more frequent in DLB than in AD, also in samples diagnosed at autopsy, and constitute one of the key diagnostic features of the disorder. Although rates vary from...

Alsparkinsonism Dementia Complex Of Guam

A high incidence of neurodegenerative disease is found within the Chamorro population of the Western Pacific island of Guam, and includes parkinsonism, dementia, and amyotrophic lateral sclerosis (ALS), each of which may occur in isolation but are more commonly combined (121). The cause is unknown but a toxic or viral etiology has been postulated (122-124). The histopathology is dominated by the presence of numerous NFTs (125,126), with similar immunohistochemical, biochemical, and ultrastructural features as those seen in AD (127,128), but usually in the absence of SP (Fig. 6A,B). The anatomical distribution of NFTs is different from AD (129) and more similar to that seen in PSP and postencephalitic parkinsonism (PEP) (130,131). Chronic degenerative changes including neuronal loss and gliosis are found in regions where NFTs are numerous, including the frontotem-poral neocortex, hippocampus, entorhinal cortex, nucleus basalis, basal ganglia, thalamus, subthalamus, substantia nigra,...

Magic bullets shotguns or cocktails to treat or prevent Alzheimers disease

The molecular dissection of the pathogenic cascades that result in Alzheimer's disease (AD) has led to the identification of multiple potential AD therapeutic targets that appear druggable (Golde 2003, 2005 Hardy and Selkoe 2002). Based on results from proof of concept preclinical studies in amyloid precursor protein (APP) and tau transgenic mouse models, a degree of cautious optimism is warranted with respect to a number of magic bullet therapies for prevention of AD. Less optimism is warranted with respect to such magic bullets showing marked efficacy in patients with AD. Pharmacologic or immunologic treatment of AD mouse models initiated when the mice show limited pathology can significantly attenuate the development of additional AD-like pathologies (Schenk et al. 1999) however, the same treatments initiated when the mice have more robust pathology typically show limited efficacy (Das et al. 2001). Though it is imperative that we test single target therapies for AD in the clinic,...

Detecting Early Stage Alzheimers Disease in MCI and PreMCI The value of informants

In the century since Alzheimer's seminal presentation of the original patient with Alzheimer's disease (AD Alzheimer et al. 1987), emphasis now is being given to the recognition of early-stage AD in comparison to nondemented aging. As a consequence, there is intense interest in mild cognitive impairment (MCI). The concept of MCI was introduced to characterize older individuals with cognitive deficits that, although abnormal for age, fell short of overt dementia (Flicker et al. 1991). Related terms such as age-associated memory impairment (Crook and Bartus 1986) and age-associated cognitive decline (Levy 1994) were proposed as variants of normal cognitive aging, and cognitive impairment, no dementia (Graham et al. 1997) overlaps MCI but may characterize a broader array of cognitive dysfunction. The MCI construct was further developed by Petersen and colleagues to feature memory deficits (amnestic MCI) this group proposed MCI as a transitional state between the cognitive changes of...

The Transition from Normal Functioning to Dementia in the Aging Population

During the last few decades a substantial effort has been made to understand better the etiology and natural history of dementia, which has led to significant results. However, only in recent years has the availability of follow-up data from several community-based studies provided us with the opportunity to explore what happens just before the manifestation of the first dementia symptoms and before the diagnosis of dementia. Most of the studies focused on Alzheimer's disease (AD). The preclinical phase of AD may be considered as the transition from normal aging to dementia. Alzheimer's Disease Advances in Etiology, Pathogenesis and Therapeutics. Edited by K. Iqbal, S. S. Sisodia & B. Winblad. 2001 John Wiley & Sons, Ltd. TIME BEFORE DEMENTIA DIAGNOSIS Due to the insidious onset of AD, the time of diagnosis is the only definite point in the initial phase of the disease. The time of diagnosis may be defined as the time when diagnostic criteria for dementia and AD are fulfilled....

Immunotherapy of Alzheimers disease

Immunotherapy For Alzheimer

Early in April 1906, Auguste Deter's brain was obtained by autopsy after four and a half years of progressive dementia that ultimately led to her death. Her doctor, Alois Alzheimer, who had cared for her, examined and photographed her since the initial admission in November 1901, stained microscopic sections of her brain by using his colleague's Franz Nissl newly established protocols. Besides profound neuron loss and fibrillar tangles, he found multiple deposits of a peculiar substance -amyloid. Several months later, in November 1906, he reported this finding at a meeting in T bingen (Alzheimer 1907a), and in the 1910 edition of his psychiatry textbook, Alzheimer's mentor, Emil Kraepelin, coined the term, Alzheimer's disease, for the discovery (Kraepelin 1910). Today, 100 years after the initial report, -amyloid has become the most promising target for curing the disease, and it appears as if immunotherapy can remove this peculiar substance from the brain (Weiner and Frenkel 2006)....

Neuronal loss and neurofibrillary tangles correlate with degree of dementia

The AD brain contains innumerable plaques, tangles, neuronal loss and gliosis. The idea that neuronal loss and synaptic loss are associated with impaired neural system function seems straightforward. Clinical-pathological correlation data support the idea that these lesions, as well as neurofibrillary tangle formation, correlate relatively well with dementia severity or duration (Arriagada et al. 1992a,b Gomez-Isla et al. 1997 Ingelsson et al. 2004 Masliah et al. 1994 Terry et al. 1991). Indeed, neurofibrillary tangles and neuronal loss parallel one another and occur predominantly in parts of the brain that appear to be most affected clinically, such as the medial temporal lobe memory-related neural systems.

Alzheimers Disease Pathogenesis Models and Experimental Therapeutics

Alzheimer's Disease (AD) is associated with progressive impairments of memory and cognition, genetic causes risk factors, characteristic neuropathology and biochemistry, and dysfunction death of specific subsets of neurons in certain brain regions neural circuits. Disease-defining pathology biochemistry include the presence of extracellular toxic Ap42 peptides (oligomers) and intracellular protein aggregates of tau. Over the past several decades, investigators have taken advantage of advances in knowledge of the disease to design therapies for AD. For example, the demonstration of abnormalities of basal forebrain neurons (with cholinergic deficits in the cortex and hippocampus) led to the introduction of cholinesterase inhibitors for symptomatic treatments. Similarly, when information about involvement of glutamatergic systems in ventral-medial temporal lobes in AD was coupled with knowledge of roles of glutamate in excitotoxi-city, glutamate antagonists were tried as treatments....

Alois Alzheimer

Alois Alzheimer 3 The history of Alois Alzheimer's first case Auguste D. Alois Alzheimer and the beginnings of research into Alzheimer's disease RalfDahm 37 Alois Alzheimer and the myth of the pioneer Alzheimer's Disease at mid-Century (1927-1977) and a little more A chapter in the development on Alzheimer's disease research Anatomical changes underlying dementia in Alzheimer's disease Staging of cortical neurofibrillary inclusions of the Alzheimer's type observations contributed to the understanding of Alzheimer's disease Presenile forms of Alzheimer's disease in 2006

Alzheimers Disease

As the population ages, Alzheimer's disease has emerged as a major health problem. After the age of 65 years, the prevalence of dementia and Alzheimer's disease doubles every 5 years 30 to 50 percent of women older than 83 years may suffer from dementia of some sort. Laboratory studies suggest that estrogen may affect Alzheimer's disease through several mechanisms. Estrogen has been shown to improve regional cerebral blood flow and to increase glucose utilization. It can also stimulate neurite growth and synapse formation in vitro. Under some circumstances, estrogen may modify neural sensitivity to neurotrophin and play a role in the reparative neuronal response to injury. One key histologic feature of Alzheimer's disease is the deposition of beta-amyloid protein in cores of neuritic plaques. Estrogen may promote the breakdown of the amyloid precursor protein to fragments less likely to accumulate as beta amyloid. Acetyl-choline is a key neurotransmitter in learning and memory....

Auguste Ds dementia

In addition to Alzheimer disease, other hypothetical diagnoses of Auguste D.'s disease have been put forward, especially arteriosclerosis and, astonishingly, metachromatic leukodystrophy. Many postmortem diagnoses listed arteriosclerosis at this time. In Auguste D.'s file, Alzheimer himself noted Arteriosklerotische Gehirnatrophie. The question mark is interesting and also appeared in the autopsy report Arteriosklerose der kleinen Hirngef e. However, the histopathologic details in the 1907 and 1909 publications always pointed to vessels without arteriosclerosis Perusini found that the large vessels, the arterial circle of Willis, and the Sylvian arteries showed no significant sign of arteriosclerosis only some regressive alterations of the arterial walls were described. In both papers the presence of the neuritic plaques and neurofibrillary tangles was confirmed. There are a number of convincing arguments against the assumption of a metachromatic leukodystrophy in Auguste D.'s case,...

Less Developed Countries

The Alzheimer Disease International convened a group headed by Dr. Prince of the London School of Hygiene, calling themselves the 10 66 Group, Dementia prevalence has been intensively studied in developed countries, especially in Japan and in Europe, somewhat less in North America. In Asia, it has also been intensively studied in Taiwan and along the East coast of China, but with few studies in Western China, India, smaller South Asian countries, and Africa, areas with over two billion people. Only a small number of studies have been carried out in South America. One hopes that initiatives by the 10 66 Group to rectify this situation will be successful. The age-specific prevalence rates in developing countries tend to be somewhat, but not significantly, lower than those in the developed world. However, as shown in Figure 2.1, very low rates have been reported in Ibadan, Nigeria, compared to those in African Americans in Indianapolis, Indiana, in a study carried out jointly by...

Education As A Protective Factor

In the Shanghai survey of dementia, the 27 of the subjects in the sample of 5500 who had received no formal education had approximately twice the Figure 2.2. Incidence of age-specific dementia (as log of incidence of age-defined population per annum) plotted against age. The regression line is calculated from data from the Eurodem incidence analysis (Launer et al., 1999) and the Canadian Study of Health and Aging (2000). Sites of other studies include Baltimore (Kawas et al., 2000) Bronx (Aronson et al., 1991) Cambridge, England (Paykel et al., 1994) East Boston, Massachusetts (Hebert et al., 1995) Hisayama, Japan (Yoshitake et al., 1995) Mannheim, Germany (Bickel and Cooper, 1994), Monongahela, Pennsylvania (Ganguli et al., 2000) North London (Boothby et al., 1994) Nottingham (Morgan et al., 1992) Rochester, Minnesota (Rocca et al., 1998) and Shanghai, China (E. Yu, in preparation, based upon Zhang et al., 1998). (Updated from Katzman and Kawas, 1999, reproduced by permission of...

Apolipoprotein E In Downs Syndrome

In adults with DS, all studies have consistently found that the presence of the apoE-e2 allele increases longevity and reduces risk of dementia (Hardy et al., 1994 Royston et al., 1994 Schupf et al., 1996 Tyrrell et al., 1998 Sekijima et al., 1998 Lai et al., 1999). In two studies employing survival analysis, the presence of an apoE-e4 allele was associated with earlier onset of AD (Schupf et al., 1996 Lai et al., 1999) (Figure 3.2). Negative findings have been reported in studies with small sample sizes and, importantly, failure to consider differences in the age at onset of dementia among those with and without an e4 allele. Since the effect of the e4 allele is not expressed until midlife, inclusion of sufficient numbers of adults over 50 years of age and analysis using survival methods that can adjust for age and years of follow-up are important methodological considerations. In sum, in DS, as in the general population, the presence of the e2 allele is protective, while the...

Summary And Conclusions

Factors that increase the formation of Ap or accelerate its deposition, such as the presence of apoE e4 allele, estrogen deficiency, and high levels of Ap1-42 peptides, are associated with earlier onset of dementia in DS, while factors that decrease the formation of Ap, such as the apoE e2 allele or atypical karyotypes that reduce APP gene dose, are associated with improved survival and reduced risk of dementia. Since 95 of persons with DS have triplication of pAPP associated with free trisomy, overexpression of APP alone cannot account for the differences in age at onset of dementia within this population. An important task for future work will be to identify the sources of individual variation in premorbid Ap levels which contribute to risk. These are likely to include the joint effects of factors reviewed here and others not yet identified.

Commentary on Correlative memory deficits Ap elevation and amyloid plaques in transgenic mice

The Tg2576 mouse model was developed to study the molecular basis of memory loss in Alzheimer's disease (Hsiao 1996). The descriptions of the memory impairments, neuropathological abnormalities and biochemical analyses in Tg2576 mice were first presented in Chicago at IBC's 5th Annual Conference on Alzheimer's disease in June 1996. At that time the PDAPP mouse model had been shown to develop Congophilic Ap deposits (Games 1995). Age-related behavioral and memory deficits had been demonstrated in several lines oftransgenic mice that did not form Congophilic plaques (Moran 1995 Hsiao 1995), but little was known about memory function in mice that produced bona fide plaques. Because plaques that stain with Congo red dye are one of the neuropathological hallmarks of Alzheimer's disease, the demonstration that age-related memory impairment correlated roughly with the appearance of Congophilic plaques was hailed as a major advance in the field. Ironically, the Congophilic plaques that were...

Mileposts in Characterizing Behavioral Clinical Phenotypes

In the era between Alzheimer's initial report in 1907 and 1960s, the primary focus of scholarship on dementia was the epistemology of the disease and the struggle for consensus on the clinical definitions (Dillmann 2000) Progress in understanding the relationships between the behavioral expression and pathological phenotypes of dementia was relatively slow during this period due to two impediments first, the lack of objective clinical assessment tools, and second, uncertainty in the definition of the clinical phenomenon. In the 1960s, arguably the start of the modern era of dementia research, clinical studies on dementia faced several challenges concerning the precise clinical characterization, definition and objective measures of the phenomena. Among these the most critical questions was 'whether Alzheimer changes were simply an accentuation of normal senescence'. The landmark investigations by the Blessed, Tomlinson and Roth in the mid-1960s (Blessed et al. 1968) began to address...

Both a posthumous achievement and a retraction

Since the work of Thomas Kuhn, the history of science cannot be approached without an attempt to tease out the paradigm shifts that mark out the major stages in the development of a scientific discipline. How can the evolution of Alzheimerology be analyzed from this standpoint It seems clear that a major change took place around the middle of this century. Those who contributed to the development of medicine at the turn of the 19th century were, in some respects, inclined towards taxonomy. They sought out the rare in the same way that zoologists went in search of mysterious and as yet undiscovered animals. This resulted in the impressive list of diseases and syndromes that we know today Pick's disease, Alzheimer's disease, Creutzfeldt-Jakob disease, etc. (Beighton and Beighton 1986). From this point of view, it is not without reason that Emil Kraepelin was described as the Linnaeus of psychiatry his disposition towards classification made his work the basis for the future, successive...

Case Study of Public Policies on the Development Funding of Research Program

Although Alzheimer's disease, as a clinical-neuropathologic entity, was described one hundred years ago by Alois Alzheimer, the preponderance of knowledge on the disease was accumulated since the 1970s. The dramatic research advances during the last three decades propelled the disease from near obscurity to the forefront of modern biomedical science. The remarkable transformation of this field of study is reflected by the exponential increase in the numbers investigators, publications and funded projects. The current preeminence of dementia research is largely due to the increasing numbers and quality of significant breakthroughs in understanding the molecular neurobiology of the disease. Multiple promising leads now have created an atmosphere of optimism about the prospects of discovering effective interventions to delay the progression of the disease. Some of the key factors that influenced the pace of progress and helped to change the 'status' of dementia research were a)...

Results And Discussion

AD, Alzheimer's disease FTD, frontotemporal lobe dementia DLB, dementia with Lewy bodies 'Parkinson-related conditions' includes Parkinson's disease without dementia (n 15), multiple system atrophy (n 16), and progressive supranuclear palsy (n 15) CI, confidence interval. AD, Alzheimer's disease FTD, frontotemporal lobe dementia DLB, dementia with Lewy bodies 'Parkinson-related conditions' includes Parkinson's disease without dementia (n 15), multiple system atrophy (n 16), and progressive supranuclear palsy (n 15). AD, Alzheimer's disease FTD, frontotemporal lobe dementia DLB, dementia with Lewy bodies 'Parkinson-related conditions' includes Parkinson's disease without dementia (n 15), multiple system atrophy (n 16), and progressive supranuclear palsy (n 15).

Clinical Diagnosis Of VaD

More recently, several diagnostic criteria have been developed in an attempt to widen the concept of VaD. The criteria of the state of California Alzheimer's Disease Diagnostic and Treatment Centers (California ADDTC) (Chui et al., 1992) include dementia evidence of two or more ischemic strokes by history, neurologic signs or neuroimaging studies the occurrence of a single stroke with temporal relationship to the onset of dementia and evidence of at least one infarct outside the cerebellum by neuroimaging. The criteria of the National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) (Roman et al., 1993) used the presence of dementia, presence of cerebrovascular disease defined by the presence of focal neurologic signs consistent with stroke and verified by brain imaging, and a causal relationship between these two criteria. Gold et al. (1997), using autopsied subjects, compared the...

Csf Biomarkers In Clinical Practice

Numerous scientific papers have evaluated the diagnostic potential of CSF-tau and CSF-Ap42, revealing high sensitivity and specificity figures. However, most of these studies have been performed in research centers, with selected patient samples and CSF analyses run on one occasion, i.e. under conditions providing figures on the optimal sensitivity and specificity of these analyses. However, two studies have been performed on prospective consecutive patient samples from one clinic, with ELISAs run each week in the clinical neurochemical routine, which may give figures closer to the true performance of CSF-tau and CSF-Ap42. The analytical variation and stability (analyzed over the course of one year) for these CSF analyses were adequate. In these studies, too, the ability of CSF-tau (Andreasen et al., 1999a) and the combination of CSF-tau and CSF-Ap42 (Andreasen et al., 2000a) to differentiate AD from normal aging, depression, and Parkinson's disease was high, while its specificity...

Materials And Methods

AD, Alzheimer's disease FTD, fronto temp oral dementia DLB, dementia with Lewy bodies PD, Parkinson's disease MSA, multiple system atrophy PSP, progressive supranuclear palsy CBD, corticobasal degeneration MMSE, Mini-Mental State Examination p25, lower quartile p75, upper quartile. * Significantly different from controls (p< 0.001 Kruskal-Wallis test with Dunn's multiple comparison test). **Significantly different from controls (p< 0.05). ***Significantly different from AD (p< 0.001). AD, Alzheimer's disease FTD, fronto temp oral dementia DLB, dementia with Lewy bodies PD, Parkinson's disease MSA, multiple system atrophy PSP, progressive supranuclear palsy CBD, corticobasal degeneration MMSE, Mini-Mental State Examination p25, lower quartile p75, upper quartile. * Significantly different from controls (p< 0.001 Kruskal-Wallis test with Dunn's multiple comparison test). **Significantly different from controls (p< 0.05). ***Significantly different from AD (p< 0.001).

Summary and Future Directions

From Alois Alzheimer's clinicopathological assessment of Auguste D to the discovery of the amyloid protein (A4, A ) to the cloning of the AD field's first molecular drug target, APP, to the identification of the pathogenic mutations causing FAD, the amyloid hypothesis has continued to gather momentum. Moreover, functional studies of FAD mutations in APP and the presenilins in cell- and animal-based model systems have continued to lend strong support to the amyloid hypothesis. One updated version of the amyloid hypothesis, called the amyloid cascade hypothesis, posits that all AD pathology begins with excessive accumulation of Ap in brain (Hardy and Higgins 1992). When one considers how Ap accumulates in the brains of early-onset FAD patients, the common molecular phenotype for the vast majority of known early-onset FAD gene mutations does not involve increased production of Ap but an increase in the ratio of Ap42 Ap40 (reviewed in Price et al. 1998). Ap42 is the more amyloidogenic and...

Encouraging research through awards and scholarships

Every year from 1986 to 2000, a jury of specialists handed out both awards and scholarships, under the aegis of Fondation Ipsen. The awards offered recognition for outstanding contributions to Alzheimer research (K. Beyreuther, J. Hardy, J.-F. Foncin, C. Duyckaerts and A. Delacourte, to mention only a few) while the scholarships were intended to encourage the work of young researchers. More than 60 people have benefited from them in various capacities. (Fig. 3) Fig. 2. The proceedings of all 20 Alzheimer meetings have been published by Springer (Heidelberg) in a Fondation Ipsen series Research and Perspectives in Alzheimer's Disease Fig. 2. The proceedings of all 20 Alzheimer meetings have been published by Springer (Heidelberg) in a Fondation Ipsen series Research and Perspectives in Alzheimer's Disease

Cholinergic Ch4 Cell Preservation In Mild Cognitive Impairment And Early Ad

The groups for this analysis consisted of 33 subjects meeting the criteria for no cognitive impairment (NCI n 11), mild cognitive impairment (MCI n 11), or mild AD (n 11). No individuals had a co-existing condition judged to be contributing to cognitive performance. In the first experiment, unbiased stereological counting methods were used to estimate the number of ChAT- and VAChT-immunoreactive (-ir) neurons within the nucleus basalis of individuals from these three groups. Of the 33 cases, complete series of sections were available from 22 cases (6 NCI, 7 MCI, and 9 AD), making them suitable for stereological evaluation. Intensely stained ChAT-ir and VAChT-ir neurons were seen within the nucleus basalis neurons in all three groups. Individuals without cognitive decline (NCI) displayed on average 210 540+15 240 ChAT-ir and 174 000+12 773 VAChT-ir nucleus basalis neurons. Individuals with MCI displayed 167 879+17 903 ChAT-ir and 192 637 + 34 737 VAChT-ir nucleus basalis neurons, a...

The Ethical Dimension Rights And Wrongs

In 1995 the Fairhill Guidelines on Ethics of the Care of People with AD were published in the United States (Post and Whitehouse, 1995). These guidelines were drawn up by a focus group of professionals working in the field of dementia after a series of meetings with family caregivers and individuals with mild dementia of the Alzheimer's type. The main recommendation of the group was that physicians should inform affected individuals and their families about the diagnosis of probable AD. If a family In most memory clinics around the world, trials are ongoing of cognition-enhancing drugs that may halt the progression of AD. Doctors are obliged to obtain informed consent in order to recruit subjects into any trials or research projects. A survey of researchers at the 15 federally funded US Alzheimer's Disease Research Centers, however, found a significant lack of uniformity on the assessment of subjects to consent for research, proxy informed consent usually supplied informally by family...

Serving families and caretakers

Very quickly, it became clear that the quest for information was one that also involved patients' families and the general practitioners called upon to answer their harried questions. Since 1986, a film has been available to them -La Maladie d'Alzheimer-in which Professor Jean-Louis Signoret (H pital de la Salp tri re, Paris) and Michel Maladie a Alzheimer Fig. 3. Posters advertising some of the Fondation Ipsen prizes in Alzheimer's disease Fig. 3. Posters advertising some of the Fondation Ipsen prizes in Alzheimer's disease Fig. 4. Nearly 200 issues of the Alzheimer Actualit s newsletter have been published since 1986 Almost at the same time, Fondation Ipsen began to widely circulate tens of thousands of copies of a translated, adapted version of Caring (New York City Alzheimer's Resource Center), which turned out to be virtually as successful as the original document. Later came two other brochures, also intended for families Pour les Aider (How to Help Them. 1987) and Pour D fendre...

Colloques Mdecine et Recherche to help communicate knowledge

Since that day and in a pioneering spirit, Fondation Ipsen has strived to bring to light new developments in science's understanding of Alzheimer's disease, detecting the promising topics and devoting to them, in many cases, some of the leading international conferences available to researchers. On each occasion, it has chosen to bring together Alzheimer specialists and researchers from various fields, with the aim ofsparking new ideas and enhancing debate. Twenty Colloques M decine et Recherche (Table 1) have since been held, each another opportunity to focus on the best teams and the most promising research avenues. Following every conference, a publication was issued and the series Research and Perspectives in Alzheimer's Disease (Springer) is now a valued part of any university library's collection, each volume a reference point in the advancement of Alzheimer research (Fig. 2). The speakers include the vast majority of those who have made or are still making Alzheimer history....

Challenges Barriers to Program Development

In 1978, task of launching a national initiative on neurobiology of aging and Alzheimer research faced a number of daunting hurdles. The process of program development involved the interaction of several variables and required inertia work to overcome impediments the relationship of the key components is very similar to that in a chemical reaction. The raison d' tre of NIA's efforts to mobilize the scientific enterprise was the acquisition of new knowledge to solve a looming public health problem. The ultimate product of the program was the discovery of a cure for Alzheimer's disease. However, the start of the process required Energy in form of massive funds to support research. Any large-scale national enterprise of discovery could not be initiated, maintained or, expected to make progress without the appropriate level of resources. Certainly the funding of any particular project alone could not assure discovery of a cure, however inadequate funds was, and still is, a virtual...

The paired helical filament

In the 1960s, electron microscopy of tissue sections was used to investigate the fine structure of neurofibrillary tangles in the Alzheimer's disease (AD) brain. Bundles of abnormal cytoplasmic filaments were observed in nerve cell bodies and their processes (Kidd 1963, 1964 Terry 1963 Terry et al. 1964). In 1963, Michael Kidd described the characteristic paired helical nature of the majority of filaments. He named the paired helical filament (PHF) because it appears to consist of two filaments wound helically around one another, with a longitudinal spacing between crossovers of about 80 nm and a width of 30 nm at the widest point and 15 nm at the narrowest (Fig. 1). There was discussion about the molecular nature of the PHF, with some arguing that it was made of neurofilaments (Terry 1963 Terry et al. 1964), and Kidd himself favoring the view that it was unrelated to the normal cytoskeleton (Kidd 1963, 1964). Also found in the neurofibrillary tangles of AD, as a minority species, is...

Introduction The nonamyloidogenic asecretase pathway

In the non-amyloidogenic pathway, the amyloid precursor protein (APP) is cleaved by an a-secretase within the Ap sequence, thus precluding Ap peptide generation. Following a-secretase cleavage, the C-terminal APP fragment undergoes y-cleavage, leading to the generation of the p3 peptide, which is generally not found in the amyloid plaques characteristic for Alzheimer's disease (AD). The a-secretase cleavage releases the N-terminal ectodomain of APP (APPsa), which has neurotrophic and neuroprotective properties. Therefore, activation of the non-amyloidogenic pathway provides a logical alternative strategy to p- or y-secretase inhibition for treatment of AD. Although cleavage by a-secretase was the first proteolytic pathway of APP to be characterized in detail, this idea remained almost forgotten as long as the a-secretase had not been identified.

Pathogen or Protector

Viewing amyloid-p and tau as antioxidants provides an explanation for the in vitro oxidative effects of amyloid-p (since all antioxidants are, by definition, also prooxidants dependent on environment) as well as the in vivo antioxidant properties of amyloid-p. Therefore, as we celebrate the 100th anniversary of Alois Alzheimer's original paper describing the pathological lesions, we find ourselves at a crossroads, namely, is the pathology a harbinger of disease or a protective response to the disease The latter would represent a major paradigm shift but, after 100 years, is it not about time

The neuronal origin hypothesis of cerebral amyloid angiopathy

With the rapid evolution of mouse genetics 20 years ago, murine models have gained increased attention in the neurobiology of aging. The genetic contribution of age-related traits as well as specific mechanistic hypotheses underlying brain aging and age-related neurodegenerative diseases could be assessed by using genetically selected and genetically manipulated mice. At that time I was a postdoc with Dr. Donald Ingram at the National Institute on Aging, NIH, Baltimore, USA, where I started to examine age-related alterations in the brain among a variety of mouse strains (Jucker and Ingram 1997). At that time, we noticed hippocampal deposits of fibrillary material (inclusion bodies) in the normal aged C57BL 6J mouse brain. At the same time, others reported on identical inclusion bodies in amyloid precursor protein (APP) transgenic mice, then believed to be the first mouse model of Alzheimer's disease (AD). Subsequently we showed that these apparent lesions in this AD mouse model have...

What have we learned from mouse models of CAA

I want to thank Donald Ingram and Matthias Staufenbiel for their great support. It was the enthusiasm of Donald Ingram that shaped my interest in brain aging, and it was the support of Matthias Staufenbiel that helped me to step into the field of Alzheimer's disease. Over all these years, Konrad Beyreuther greatly supported my work. I also want to thank the many talented students and postdocs in my laboratory for their tremendous contributions and the late-night discoveries.

Tau phosphorylation and aggregation

The two most noticeable changes of Alzheimer tau are its aggregation and extensive phosphorylation. Therefore, it is of great interest to test how these properties are related, and in particular, whether the phosphorylation of tau promotes the aggregation. The issue has been addressed by various authors using tau phosphorylated by different kinases and or using pseudophosphorylated forms of tau, where certain residues were

Who Are Our Members and What Are They Saying

Many of our scientific advisory board members (all very busy researchers and clinicians) visit the website around one to three times per week. Alzforum is the local newspaper for Alzheimer research, writes John Hardy, Director of the Laboratory of Neurogenetics at the National Institutes of Aging. I visit it one to two times a week just to see what's going on to check up on recent papers, .to see who's hiring people and so on. I read people's comments on papers, and I go from there to PubMed for anything I've missed. I think pretty much everyone in the field uses it in the same way, and I have often seen my informal reviews on the site cited.

Initial immunocytochemical analysis of PHF

At about the same time, several groups investigated the antigenic composition of PHF. This approach was taken either by generating antibodies to isolated PHF and studying their cross-reactivity with normal brain proteins or by generating antibodies to normal proteins and studying their cross-reactivity with PHF. The antibodies raised to PHF preparations were found to react strongly with NFT in light microscopy (Ihara et al. 1983) and in electron microscopy (Brion et al. 1985c). This labelling was absorbed by brain homogenates from Alzheimer patients but not by homogenates from control subjects or only with high concentrations of proteins (Brion et al. 1985b). Similarly, an anti-PHF serum was observed to react with none of the polypeptides of normal brain (Grundke-Iqbal et al. 1984). These results suggested that PHF contained highly modified proteins exhibiting antigens mainly present in AD brains.

Prevention of amyloidogenesis in an AD mouse model by the asecretase ADAM10

In a second step, we generated double-transgenic mice by crossing the ADAM10-overexpressing lines as well as the line expressing mutant ADAM10-dn with mice transgenic for human APP v7i7I . We found that even moderate neuronal overexpression of ADAM10 in mice transgenic for human APP V7i7I increased the release of APPsa, and reduced the formation of Ap40 and Ap42 by direct competition with the P-secretase BACE1, and prevented Ap deposition in plaques. Expression of the catalytically inactive ADAM10 led to an enhancement of the number and size of amyloid plaques in the brains of double-transgenic mice (Fig. 1). Most importantly, defects in long-term potentiation and cognition, which are evident in the AD mouse model before the formation of amyloid plaques, were alleviated by modest overexpression of ADAM10. While APP V717I transgenic mice showed defects in hippocampus-dependent spatial learning and memory, both learning and memory were nearly fully restored in mice moderately...

Biochemical characterization of Apdegrading enzymes in vivo

Nearly a decade ago, we hypothesized that down-regulation of amyloid p peptide (Ap) degradation may be a primary relevant cause for Ap accumulation in sporadic Alzheimer's disease (AD Saido et al. 1996 Saido 1998 Iwata et al. 2000). This hypothesis was made on the basis that there is little evidence supporting the up-regulation of Ap generation upon aging prior to Ap deposition in the brain, that sporadic AD patients seem to accumulate less Ap42 compared to Ap4o than familial AD patients (Lemere et al. 1996), and that aging generally accompanies down-regulation rather than up-regulation of enzyme activities (except for those associated with inflammation and other pathological processes).

Identification of ADAM10 as an asecretase in vitro and in cultured cells

The results were published in the Proceedings of the National Academy of Sciences in 2001 (Kojro,et al. 2001). In the same issue of the journal, Fassbender and colleagues reported that treatment of guinea pigs with high doses of simvastatin decreased Ap production (Fassbender et al. 2001). The two papers were accompanied by a comment by Benjamin Wolozin (2001). He expressedhis hope to develop medicines thattarget the brain lipids or lipid compartments that specifically regulate Ap production. This opens up new therapeutic approaches to Alzheimer's disease. In 2005, it was reported that simvastatin treatment of AD patients affected the brain cholesterol metabolism and favored the non-amyloidogenic pathway of APP processing (Hoglund et al. 2005).

Innate Immunity Autotoxicity and Degenerative Neurologies

The lesions of established Alzheimer's disease (AD) are characterized by the presence of a broad spectrum of inflammatory molecules (for review, see Neuroinflammation Working Group, 2000). They include complement proteins and their regulators, inflammatory cytokines, acute-phase reactants, and numerous proteases and protease inhibitors. Neurons, astrocytes and microglia participate in their production. Several of these inflammatory products are known to be toxic to neurons, providing a rational basis for the hypothesis that neuroinflammation is a major contributing factor to the pathogenesis of AD (McGeer and Rogers, 1992). CD Alzheimer-Clq Control-Clq Alzheimer-C9 CD Alzheimer-Clq Control-Clq Alzheimer-C9

Zinc Modulates Sod Neurotoxicity A Molecular Insult Linking Ad To Familial

Part of the appeal of this model to our laboratory is that it resonates with our own thinking about the possible pathogenic mechanism of Ap-mediated toxicity in Alzheimer's disease, which, as we have reported, is mediated by cell-free H2O2 production from O2 also dependent upon Cu2+ interaction (Huang et al., 1999b) and quenched by Zn2+ (Cuajungco et al., 2000). To test how far this mechanistic analogy can go, we have recently assayed SOD1 in its native and its 'zinc-less' Cu2+-loaded state, to determine whether, like Ap, it can produce H2O2 from O2. We have found that Cu-SOD but not Cu Zn-SOD or apo-SOD, does indeed produce H2O2 from O2 using ascorbate (or dopamine) as the electron donor. Interestingly, we also found that Ap loaded with Cu2+ also uses ascorbate (or dopamine) as a substrate for H2O2 production (Opazo et al., manuscript in preparation). Therefore, the reason why native SOD1 may not be able to rescue the phenotype induced by mutant SOD1 is because the lesion is not just...

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