5 Steps to Reverse Dementia

All About Alzheimers

All About Alzheimers

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

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Secretase Inhibitors as Therapeutics for Alzheimers Disease

Introduction - Alzheimer's disease (AD), the most common form of dementia, was the 12th leading cause of death in the U.S. in 1998, claiming 22,824 individuals (1). The disease affects 7-10 of those over 65 years of age the prevalence among those 80 years of age or older may be > 40 (2-5). Beginning with mild cognitive impairment, the clinical course proceeds through significant, then profound dementia, loss of motor function, and death (6,7). In addition to the devastating impact on individuals and families, the financial burden of this protracted illness has been estimated at over 100 billion in the U.S. each year (8). In view of the aging population, the societal burden of AD is likely to increase significantly. Alzheimer's disease is defined by the co-occurrence of two histologic lesions in brain - extracellular deposits (senile plaques) whose principal component is a fibrillar form of a predominantly 40-42 amino acid peptide known as p-amyloid (AP), and intracellular tangles of...

Emerging Themes in Alzheimers Disease Research Paradigm Shift in Drug Discovery

Introduction - This year marks the 95th anniversary of the first published case of Alzheimer's disease (AD), a disease currently afflicting more than 12 million people worldwide. Over the past 15 years, the pace of AD research has accelerated dramatically, and the discovery focus has moved from cholinergic enhancement medicines to drugs that interfere with amyloid. Recent results have emerged to challenge the core dogma of the prevailing amyloid cascade hypothesis which invokes amyloid plaque deposition as the cause of AD. The present report examines this central hypothesis, highlighting recent results that implicate non-fibrillar AO oligomers rather than fibrils as the molecular pathogens in AD, and evaluating those drug discovery approaches that are poised to capitalize on these new findings.

Dementia With Lewy Bodies

Although it has long been recognized that a significant proportion of PD patients develop dementia (12), the pathological substrate for this cognitive dysfunction remained uncertain. In 1961, Okazaki reported finding LBs in the cerebral cortex of two patients with PD and atypical dementia (27). Although subsequent cases of diffuse Lewy body disease (DLBD) were published, the condition was initially considered rare. In the late 1980s, with greater awareness of cortical LBs and the development of more sensitive staining methods, several groups reported finding cortical LBs in 15-25 of elderly demented patients, both with and without parkinsonism (28,29). It has recently been proposed that dementia associated with Lewy bodies (DLB) represents a recognizable clinicopathological syndrome that may be distinguishable during life from other causes of dementia (30). The proposed diagnostic criteria are purely clinical however, and recommendations as to how to quantitate LBs are only designed...

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,...

Changes of cortical cholinergic innervation in aging and Alzheimers disease

A loss of cortical cholinergic innervation in Alzheimer's disease has been reported in more than 30 papers (Geula and Mesulam, 1994). We find that this depletion is severe (76-85 ) in inferotemporal, midtemporal and entorhinal cortex and in parts of the amygdala modest (40-67 ) in prefrontal, posterior parietal, peristriate, orbitofrontal, insular, posterior cingulate, primary auditory and hippocam-pal cortex and light (4-28 ) in primary visual, primary somatosensory, primary motor, premotor, and anterior cingulate cortex (Emre et al., 1993 Geula and Mesulam, 1994). In general, the choliner-gic depletion tends to be the most accentuated within the temporal lobe, including its limbic, paralimbic and association components. Even in very advanced stages of Alzheimer's disease, and even in areas with a severe depletion of cholinergic innervation, the cerebral cortex still contains some cholinergic axons. The regional densities of these residual cholinergic axons appear to reflect...

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...

Cerebrovascular dysfunctions in Alzheimers disease

Perfusion deficits have been characterized in specific cortical subdivisions of the cerebral cortex in Alzheimer's disease, most particularly in the temporal and parietal cortex (Johnson et al., 1998). These have been partially mimicked in the cortex of rats with a selective lesion of basal forebrain ACh neurons (Waite et al., 1999). Moreover, CBF (Niwa et al., 2002) or ACh-mediated cerebral dilations (Iadecola et al., 1999) are greatly reduced in transgenic mice that over-express the amyloid- precursor protein. An intrinsic microvascular pathology (amyloid deposition, endothelial cell thinning, smooth muscle cell and pericyte degeneration, and thickening of the basal lamina) is apparent in the vast majority of Alzheimer patients (Vinters et al., 1994) and could partly account for these deficits. However, we recently found that cortical microvessels and NO-synthesizing interneurons in neuropathologically confirmed cases of Alzheimer's disease exhibit a severe cholinergic denervation...

Differential diagnosis and stages in Alzheimers disease

Traditionally, (neuro)psychologists working in a psychiatric setting are frequently asked to assess whether a particular patient is dementing or not. It appears very difficult to differentiate early stages of senile dementia from depression. In the first place, early stages in dementia are very frequently accompanied by a depressed mood (Jolles and Hijman, 1983 Strub and Black, 1981). This depression is most probably a secondary consequence of the subjective feeling that there is cognitive deterioration (see for instance Strub and Black, 1981). There is evidence to suggest that the major catecholaminergic pathways that are involved in depression (Van Praag, 1982) are also involved in the pathogenesis of AD (Rossor, 1982). There may thus be a common cerebral substrate in both depression and dementia. Secondly, profoundly depressed patients frequently display overt signs of dementia such as slowness, general inertia, disorientation and memory disturbances. The differentiation of...

Searching for Alzheimers Disease Therapies In Your Medicine Cabinet The Epidemiological and Mechanistic Case For NSAIDs

Introduction - Alzheimer's disease (AD) is a chronic neurodegenerative disorder that progressively robs its victims of their intellect, memory, and personality. With the demographic aging of the population, AD is becoming an ever-larger public health burden. There are, unfortunately, no approved therapies for AD able to block progression of the disease. The current pharmacological arsenal against AD includes only the cholinesterase inhibitors, which seek to ameliorate the symptoms of AD by augmenting activity of compromised cholinergic neurons.

Lack of correlation between NP load and dementia

One of the early findings used to argue against a pathological role for NPs in the pathogenesis of AD was the lack of correlation between extent of Ap plaque deposition and degree of dementia measured using standard clinical scales 28 . One source of confusion in many of these studies was a failure to distinguish different types of Ap immunoreactivity. Plaque deposition as defined by Ap immunoreactivity occurs as large diffuse areas of staining that show minimal to no perturbation of neuropil associated with it. While NPs are also labeled by Ap antibodies, the total area of this labeling is a small fraction of the total area of diffuse Ap immunoreactiv-ity. Thus, these studies sought to correlate dementia with a form of Ap that seems to have little effect on associated neuropil. These studies, not surprisingly, were for the most part negative. Other studies have restricted their analysis to fibrillar forms of Ap that are relevant to NPs and have been more equivocal in their reporting...

Genetics of Alzheimer Disease

Alzheimer disease is a complicated genetic disorder. Only about 10 of cases occur as well-defined, fully penetrant autosomal dominant inheritance. In these families, the onset of the disease is between 55 and 60 years of age, which is considered early for a condition that usually affects much older people. The original patient examined by Alois Alzheimer was only 51 years old when she first had serious problems with memory and geographic orientation. Because of the relatively young age of occurrence of these symptoms, the condition was originally designated as presenile dementia. Patients with early-onset AD (EOAD) show the same clinical and neuropathological features as those with late-onset AD (LOAD), that is, > 65 years, except that the time course of EOAD is usually more rapid than LOAD.

Genetic Risk Factor for Alzheimer Disease

Other than AD, APOE*4 is not significantly associated with any neurological disorder. However, the presence of an APOE*4 allele exacerbates nervous tissue damage from head injuries such as concussions by increasing the severity of the response and lengthening the recovery period and, in the long term, increases the likelihood that presenile dementia of the Alzheimer type will occur. Table 14.3 Odds ratios for developing Alzheimer disease with APOE genotypes in different populations. Table 14.3 Odds ratios for developing Alzheimer disease with APOE genotypes in different populations.

Possible causes of cell loss in Alzheimers disease

The causes of neuronal loss in Alzheimer's disease are, of course, still unknown, but a number of possibilities can be suggested. Clearly, inheritance must play a role, especially in view of the fact that 5 or 10 of Alzheimer patients come from families with the dominant inheritance pattern, and another 30 to 50 , or perhaps more, have more affected relatives than statistically expected, although not in any simple Mendelian pattern (Heston et al., 1981 Breitner and Folstein, 1984). Nevertheless, it has to be admitted that studies of DNA to date have failed to reveal abnormalities in affected specimens (Spector and Kornberg, 1985). An endogenous neurotoxin such as a neurotransmitter analog might be formed by some error in synthesis but analog transmitters have not been reported. Immunologic abnormalities have been suggested, but have not been demonstrated to be cytopathic (Miller et al., 1981). The suggestion of a deficient trophic factor (Appel, 1981) begs this question as to cause,...

Microscopic lesions in Alzheimers disease

The dendritic arbor of pyramidal cells has been reported to be markedly deficient in hippocampal and neocortical areas in Alzheimer's disease (Scheibel, 1978). This shrinkage of the arbor involves not only the dendrites themselves, but also their spines. On the other hand, in normal aging the arbor is actually increased according to some reports (Buell and Coleman, 1979), and decreased in others (Scheibel, 1978). It is not at all impossible that both processes are going on simultaneously even in adjacent cells in the course of normal aging. At any rate, dendritic shrinkage might well be a step toward cell death, and certainly reduces synaptic contacts. characteristic of Alzheimer's disease, the first two being essential to the diagnosis. First is the neurofibrillary tangle, made up of paired helical filaments (PHF) (Kidd, 1963), and found in large and medium size neurons especially in neocortex, hippocampus, parahippocampus, amygdaloid, in-nominata, septum, and mesencephalic raphe....

Agerelated changes in Down syndrome brain and the cellular pathology of Alzheimer disease

In DS precocious age-related degenerative changes of the skin, hair and lens of the eye are encountered commonly. Mortality studies in institutionalized populations demonstrate a higher rate of deaths for DS cases over the age of 50 years than for retarded individuals without DS (Richards and Sylvester, 1969). In 1929, Struwe noted that the youngest case in his collection of brains with cortical neuritic plaques (NP), associated presumably with Alzheimer disease (AD), was a 37-year-old person with DS. Many subsequent studies have confirmed that the neuropathological changes characteristic of AD (viz. NP, neurofibrillary tangles NFT composed of paired helical filaments and granulovacuolar change) are present by the fourth decade in virtually all cases of DS, and increase in severity with advancing age (Ropper and Williams, 1980 Price et al., 1982). functioning near the time of death. A recent decline in self-help, communication or vocational skills a striking change in mood, social...

Predictors of Alzheimers disease

How important is an early detection of MCI patients How important is it to initiate drug treatment in MCI patients before they may convert to AD Is there any possibility of predicting which MCI patients are likely to convert to AD MCI is considered as an intermediate in the continuum from normalcy to dementia (Almkvist et al., 1998). The most commonly used criteria for MCI include memory complaints and memory impairment, but normal general cognitive function and daily living (Petersen et al., 1999). In a four year follow-up of 76 subjects selected for MCI, the annual conversion rate to AD was 12 compared to 1 in normal subjects (Petersen et al., 1999), whereas in a two year follow-up study, it was estimated to be 25 (Flicker et al., 1991). It has recently been estimated that, among subjects with MCI, the rate of progression to dementia or AD is 6-c25 per year (Petersen et al., 2001). We followed

Clinical issues in dementia and related conditions

It is possible that more effective approaches will be developed for the treatment of dementias based on our increasing understanding of the role of acetyl-choline in cerebral cortex. Currently, much energy is being spent on the prevention of AD and related dementias. In order to prevent the condition, one needs to identify people at risk for becoming demented. Currently, the concept of Mild Cognitive Impairment (MCI) is attracting attention in this regard. People with MCI have features of AD but not severely enough to warrant the diagnosis of dementia. Logically, all degenerative dementias must pass through a preclinical phase where the symptoms are present but subtle enough to escape attention or of insufficient magnitude to warrant a diagnosis of dementia. However, clinically this label is problematic. If someone is labeled as having MCI does it mean that he (she) has AD, does not have AD or may get AD Thus, although this concept may be helpful for research, it has significant...

Alzheimer and Parkinson Diseases

Subthalamic Nucleus Anatomy

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...

With a Focus on Alzheimers Disease

The loss of synapses in selected regions in Alzheimer's disease (AD) has been documented by stereological counting at the ultrastructural level (11,12). Frontal cortical (13) and hippocampal synaptophysin loss has been correlated with clinical decline (8,14,15). Postsynaptic (16) and multiple presynaptic marker loss has been documented in AD hippocampus (17). The most egregious presynaptic pathology is represented by dystrophic presyn-aptic neurites with upregulated, lysosomally derived organelles suggestive of the type of autophagy associated with axonal retraction (synapse elimination by process 2 above). On the postsynaptic side, dendritic pathology includes Hirano bodies and neurofibril-lary tangle-related tau immunoreactive curly fibers. Tangle-bearing cells have reduced synaptophysin message consistent with some relationship between tangles and synapse loss (18). There is also evidence that tangle-bearing neurons have DNA strand breaks, showing upregulation of pro- and...

Case Study 2 Pre Clinical Development of CDD0102A for the Treatment of Alzheimers Disease William S Messer PhD

Summary Muscarinic agonists have the potential to treat memory and cognitive deficits associated with Alzheimer's disease, and the potential to slow or stop the disease process. CDD-0102A, a small molecule, was discovered at The University of Toledo, and was characterized as a selective muscarinic agonist. It displayed promising biochemical activity, functional selectivity, in vivo efficacy, and was well tolerated at doses that improve memory function in animal models. NIH-RAID contributed to the development of CDD-0102A by preparation of GMP bulk drug, development of a clinical formulation, and manufacture of Phase 1 clinical supplies. These Chemistry and Manufacturing Controls (CMC) tasks were part of a larger full-development program carried out by the investigator and was supported through several funding mechanisms. An INDA was submitted for CDD-0102A and allowed by the FDA in 2009. The clinical development has been partnered with a biotech company, Mithridion, Inc. The agent...

The neuropsychology of aging and dementia

Neuropsychological research in aging and dementia has primarily focussed on memory processes although it is obvious that other cognitive functions are impaired as well. The quantity of research on memory may thus give the wrong impression that memory is the major function involved. There is an obvious need for further studies of information processing, language, perception and planning organization coding processes. There exists a parallel with biological research on aging and dementia, which focusses on the structure and function of the hippocampus (involved in memory function Newcombe, 1980). The emphasis on memory and hippocampus tends to obscure the fact that other cognitive functions (information processing, language, perception, problem solving) and other brain areas (other neocortical and limbic subcortical) are involved as well. The neuropsychological knowledge discussed so far does not provide any indication that there is more than a gradual difference between 'normal' aging...

Cognitive functions in aging and dementia

Some perceptual deficits have been demonstrated in demented patients (Willanger and Klee, 1966). Visuospatial functions deteriorate as deduced from observations in visuoconstructive tasks in which the patient is required to copy drawings. These tasks are among the tests frequently used in the assessment of dementing patients (Strub and Black, 1981). Patients with senile dementia have difficulty in solving paper and pencil mazes they also have an impaired appreciation of reflected space (such as mirrorview) (Botwinnick, 1981). Demented subjects may also experience a disintegration of the body scheme and they are impaired in tasks that require the subjects to fit together pictures of different parts of the human body (Miller, 1981). Data are scarce with respect to the question whether deficits in simple sensory functions exist in dementia. Some studies suggest that elementary perceptual functions might stay intact longer than more complex functions in Alzheimer-type dementia...

Neuropathology of Alzheimers disease

In Alzheimer's disease, there is an additive significant loss of brain tissue, and this involves both neocortex and cerebral white matter, septum, amygdaloid, and hippocampus. The weight loss, however, does not regress as a function of age, with which there is no correlation. Brain weight correlates significantly with the concentration of plaques in the neocortex if normals are included. Counting neuroectodermal cells in three areas of the neocortex revealed population changes which are distinctly different from those of normal aging. Comparing groups of age-matched normal specimens with 70- to 90-year-old specimens of senile dementia of the Alzheimer type (SDAT), we found in the latter a major loss of large neurons in all three areas, but no change of small neurons in temporal or parietal areas (Terry et al., 1981), and a barely significant decrement in the midfrontal region (Terry, unpublished data). The number of glial cells did not change, but there was an increased proportion of...

Alzheimer Disease

Dementia is the deterioration of intellectual capabilities, memory, judgment, and personality to the extent that daily functioning and quality of life are seriously impaired. Generally, dementia affects the elderly but is not confined to this age group. A number of different circumstances including Alzheimer disease (AD), Huntington disease (HD), Parkinson disease (PD), Pick disease, Creutzfeldt-Jakob disease (CJD), adrenoleukodystrophy, head injury, multiple strokes (multi-infarct dementia), boxing (dementia pugilistica), alcoholism, and viral infections impair brain function and cause dementia.


Epidemiological studies have suggested that statin treatment in man may be beneficial in the treatment of dementia 115-119 . This has been extensively reviewed in previous years 120 . As with all epidemiological data which relies on historical data, the answer is not clear-cut and a number of prospective studies are now underway. An added complexity for analysing trial data for a role of statins in treating dementia is their variable penetration across the blood brain barrier. The etiology of Alzheimers-type dementia is complex but recognised to be associated with an accumulation of the amyloid b peptide (Ab) which is neurotoxic. Ab is formed through the cleavage of the amyloid precursor protein (APP) by b- and g-secretases. An issue relating to the retrospective studies for efficacy of statins in modifying disease progression for dementia is that the pathophysiology leading to dementia can vary enormously and statins can act through different mechanisms dependent on the nature of the...

Section III Etiological Factors and Animal Models

DNA damage, DNA repair and the genetic basis of Alzheimer's disease aging of the mammalian brain and in Alzheimer's disease C. A. Marotta, R. E. Majocha, J. F. Coughlin, H. J. Manz, P. Davies, M. Ventosa-Michelman, W.-G. Chou, S. B. Zain and E. M. Sajdel-Sulkowska (Belmont, MA, Boston, MA, Washington, DC, Bronx, NY and Rochester, NY, 303 20. Cell-specific pathology in neural systems of the temporal lobe in Alzheimer's 21. The old animal as a model in research on brain aging and Alzheimer's disease senile dementia of the Alzheimer type implications and possible relevance to understanding or treating Alzheimer's disease encoded by cellular genes an animal model for human dementia J. Goudsmit and F. W. Van der Waals (Amsterdam, The Netherlands) 391 26. Clinical strategies in the treatment of Alzheimer's disease 27. Neuropeptides and the treatment of cognitive deficits in aging and dementia 28. Environmental influences on brain and behavior in aging and Alzheimer's 30. The striatal...

To Deliver Peptides into Single Neurons

Microinjection of intracellular peptides in neurons can also allow the study of suspect peptides resulting from abnormal protein metabolism such as the Alzheimer's disease amyloid P peptide (manuscript in preparation). Alternative methods to deliver pep-tides include delivery by a carrier peptide that is linked to the peptide of interest. The link, usually made by disulfide bonds, is cleaved

Microinjection of Recombinant Active Caspases in Primary Neurons

Here, we describe the microinjection of recombinant active cas-pases into primary cultures of human neurons and astrocytes as an example for a protein injection. It has been well defined that caspases play an important role in neuronal apoptosis and are possibly crucial to neuronal loss in neurodegenerative diseases, such as Alzheimer's disease (reviewed in refs. 23 and 24). Our initial studies in the identification of caspases in human neuronal cell death had unexpectedly shown that caspase-6, but not caspase-3, was activated in serum deprived primary cultures of human neurons (25). To address whether caspase-6 was directly responsible for cell death or whether the activation of caspase-6 was only one of many possible events that occurs during neuronal apopto-sis, we choose to microinject the recombinant active caspases in these neurons in the absence of any other insults. The microinjections determined that caspase-6, but not caspase-3, -7, or -8, induced human neuronal apoptosis...

Microinjection of Peptides into Neurons

The importance of peptides such as Alzheimer's disease amyloid P peptide (AP) or the caspase-generated C-terminal amyloid precursor protein fragments (25,27-30) in the pathophysiology of neurodegenerative diseases can require testing the toxicity of these peptides inside neurons. Microinjections can also be used to assess the intracellular toxicity of these or other peptides. The microinjection of peptides has the same advantages outlined above for the protein microinjection. Here we describe techniques developed in our laboratory to test the effect of such peptides in neurons.

Summary and conclusions

The dementia syndrome has many causes, some of which are treatable. In the diagnosis of dementia three questions should be answered (1) Does this patient have dementia or not If yes (2) Does this patient have other neurological signs These may provide clues to (3) What is the aetiology single or multiple of dementia in this patient The emphasis should be on detecting treatable causes. Clinical history and examination, including mental status examination, are all-important in the differential diagnosis, which includes normal aging, depression, delirium, amnesic syndromes and focal neurological dysfunction. The concept 'subcortical' dementia appears useful in the analysis of patients with dementia, as most treatable forms of dementia belong to this group. Ancillary investigations should not be used indiscriminately neither 'minimax' nor purely 'probabilistic' strategies are permissible or feasible in dementia. The principle of decision analysis should be applied 'maximisation of...

Michael Tucker and Steven Estus

The use of DNA arrays offers the promise of semiquantitative analysis of large numbers of genes simultaneously. Here, we report our efforts at applying this technology to an issue of potentially high relevance to current research in Alzheimer's Disease (AD). The AD field is in strong need of biomarkers suitable for the diagnosis of AD prior to symptomology. Amyloid-beta (AP) deposition in the brain is a hallmark of AD, and amino acid racemization studies suggest that AP deposition occurs well before symptomology (1). Hence, approaches that provide an indirect indication of AP burden may be useful in early AD diagnosis. A mouse model of AP deposition resulting from overexpression of the AP protein precursor has proven utility as a model of AD. Although such mice do not have the striking neuronal loss seen in AD, these mice manifest many of the other attributes of AD including fibrillar and nonfibrillar AP deposits, neuritic plaques, decreased synapse density and gliosis, and behavior...

Biological Aspects of AD Pathogenesis

In AD, the main cause of dementia is assumed to result from the progressive loss of synapse and the neuronal degeneration 11 . The neuropathologic hallmarks of neurofibrillary tangles (NFTs) and senile plaques were originally described by Alois Alzheimer, a German psychiatrist, at the beginning of the last century. Both the senile plaques and the NFTs, although not individually unique to AD, have a characteristic spreading and density in this disease 12 . Although the etiology of AD is still largely unknown, increasing evidence indicates that the conversion of the A 3 peptide to amyloid is central to the pathogenesis of AD 17, 18 . The amyloid hypothesis states that neuronal dysfunction and death, neurofibrillary degeneration, microglia activation and the full manifestations of Alzheimer pathology are initiated by A deposition 19 . The most compelling evidence for the amyloid hypothesis comes from the recognition that the known mutations for autosomal AD in the APP (chromosome 21),...

Biological Markers and Early Diagnosis of AD

The search of relevant biomarkers of AD in living patients has been an active part of clinical research for the last few decades. The assumption of such an enterprise is that a biomarker provides at least an indirect link to the disease process or, ideally, directly relates to the primary mechanism of the disease. It is in this context that, along with the progress in the understanding of the pathogenetic mechanisms of AD, there has been an increasing interest in discovering both central and peripheral markers that may be closely linked to the pathophysiology of the disease. With the advent of symptomatic treatment and the prospect of stabilizing therapies for AD, the race for reliable disease and progression markers has picked up speed, and standardized criteria have been developed. According to a recent consensus report 61 , an ideal biomarker for AD should fulfill the following criteria detect a fundamental feature of the neuropathology be validated in neuropathologically confirmed...

Future Approaches in Preclinical Diagnosis of AD

Clinical diagnosis of AD is not difficult once the disease is established, but early diagnosis before dementia becomes overt is far from perfect, although it is likely that many therapies will be most effective in the early stages of AD. Thus, there is a great need for techniques to detect AD in the preclinical stages.

Methods for early assessment of ageassociated cognitive decline

Generally, standardized tests have increased our knowledge of the development of deficits in normal aging and dementia. Unfortunately, this knowledge has been obtained from groups of elderly subjects and patients as a whole but psychometric tests appear not sensitive and reliable enough to be used in early assessment of individual subjects (e.g. Russell, 1981). Psychometric tests have a number of advantages they are standardized and published norms are generally available. In addition, they are easy to administer and there is usually a good reliability. A drawback of the psychometric approach is that the use of test scores as such does not allow the identification of cognitive deficits that underly the performance changes. The traditionally used tests allow only a fairly crude Apart from the use of standardized test batteries (HRNTB, WAIS, the Nebraska battery), several more specific psychometric tests are used for the determination of deficits in aging and dementia. This applies...

Neuropathology of normal aging

At this time of the century in the United States, it is quite difficult to collect a large series of normal autopsy specimens from patients who had been thoroughly tested and found to be cognitively intact on all counts. What one can say in this regard about the series to be described is that the great majority had been so tested, while some individuals were accepted on faith since they came from independent community situations and had no historical evidence of any level of dementia. Most of these untested subjects were below age 50. Furthermore, all specimens were histologically intact with only a few lesions (plaques and tangles) in the hippocampus and entorhinal areas and far fewer plaques and no tangles in the neocortex.

Of Postmortem Human Synaptosomes

Synaptosomes may be prepared from cryopreserved postmortem human tissue (66), and this preparation has been used to demonstrate amyloid-B toxicity to ion-motive ATPases (69). Experiments in our laboratory show that approximately 70 of human synaptosomes are viable, e.g., calcein-AM positive (unpublished observations). This compares to 90 integrity observed in freshly prepared synaptosomes from rat brain (65). Preliminary flow cytometry studies indicate that a postsynaptic marker, PSD-95, is decreased in AD brain compared to control brain, and that antibodies directed against P-amyloid show increased labeling in nerve terminals from Alzheimer's brain, suggesting that analysis of human synaptosomes may provide unique insights into AD-related mechanisms of terminal degeneration.

Practical Clinical Applications

Review of the current applications beyond the scope of this chapter. Instead, a few remarkable examples demonstrating the breadth of possibilities are presented, including cancer and infectious diseases reviewed in 49, 74, 75 . Other topics of interest that are not covered include evaluating drug toxic-ities 76, 77 profiling of neuropsychiatric disorders such as schizophrenia, Alzheimer disease, and Parkinson disease reviewed in 78 immunopheno-typing of leukemias with a long-term goal of monitoring minimal residual disease 79 , and characterizing human spermatozoa surface antigens in relation to immunological infertility 25 .

Association of Kallikreins with Human Diseases

Many kallikreins seem to play important physiological roles in the CNS. In mouse, neuropsin appears to have an important role in neural plasticity, and the amount of neuropsin mRNA is related to memory retention after a chemically induced ischemic insult 191 . The human neuropsin gene (hK8) was first isolated from the hippocampus. Recent reports describe the association of hK8 expression with diseases of the CNS, including epilepsy 192, 193 . In addition, an 11.5-fold increase in KLK8 mRNA levels in Alzheimer's disease (AD) hippocampus compared to controls was recently reported 194 . The same study showed that KLK1, KLK4, KLK5, KLK6, KLK7, KLK8, KLK10, KLK11, KLK13, and KLK14 are expressed in both the cerebral cortex and hippocampus, whereas KLK9 is expressed in the cortex but not the hippocampus 194 . Another kallikrein, KLK6, was shown to have amyloidogenic activity in the AD brain 107, 195 , indicating that it may play a role in AD development (107). KLK6 was also found to be...

The Relationships Between Lipid Profile Levels Depression and Suicide Attempts

Alzheimer disease (AD) is characterized by the presence of senile plaques, neurofibrillary tangles, and neuronal cell loss associated with membrane cholesterol release. 24S-hydroxycholesterol (24S-OH-Chol) is an enzy-matically oxidized product of cholesterol mainly synthesized in the brain. Lutjohann et al. found that the concentration of 24S-OH-Chol in AD and non-AD demented patients was significantly higher than in healthy controls and in depressed patients 55 . However, there was not a significant difference in the concentrations of 24S-OH-Chol between depressed patients and healthy controls, or between AD and non-AD demented patients. The researchers speculated that 24S-OH-Chol plasma levels may potentially be used as an early biochemical marker for an altered cholesterol homeostasis in the central nervous system 55 . Even though it is known that apolipoprotein E is deeply involved in major age-related disorders such as atherosclerosis or AD 56 , the control of cell-specific...

Clinical Phenotypes in Depression and Molecular Levels

55 Lutjohann D, Papassotiropoulos A, Bjorkhem I, et al. Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients. J Lipid Res 2000 41 195-198. 58 Teunissen CE, de Vente J, Steinbusch HW, De Bruijn C. Biochemical markers related to Alzheimer's dementia in serum and cerebrospinal fluid. Neurobiol Aging 2002 23 485-508.


In the individual patient with possible dementia, the clinician should ask himself three questions (1) Does this patient have dementia or not If yes (3) What is the aetiology single or multiple of dementia in this patient The emphasis should be on detecting treatable causes of dementia. The conventional clinical approach, i.e. history and examination, followed by ancillary investigations, is applicable in dementia, but with special attention to mental status examination and observation of behaviour. family history of dementia. The history and the way the patient presents it may reveal disturbance of memory and impairment of cognition, and thus contribute to diagnosing the dementia syndrome (cf. question 1). Moreover, the history may provide clues as to its possible cause (cf. question 3). For example, gradual progression of dementia with intact personality is compatible with Alzheimer's disease stepwise progression and a history of hypertension and or strokes with MID headache and or...


The search for treatable causes of dementia is a comparatively recent development and has been stimulated by the description of normal pressure hydrocephalus (Adams et al., 1965). Some of the most important are listed in Table III. Depression may present as dementia, especially in the elderly ('pseudo-dementia') and is therefore usually included in this category. It may of course coexist with dementia, and cause further clinical deterioration (Reding et al., 1985). The same applies to the factors called 'secondary' in Table III, and these are stressed here to avoid overemphasis on distinguishing reversible from irreversible dementia (Larson et al., 1984). All clinicians

Clinical research

It has been argued in this paper that clinical performance in dementia leaves little room for complacency. Diagnosis is unreliable, and treatment disappointing. Therefore, research including clinical research becomes all the more important. This will remain true also if progress is made at a more fundamental level. To quote Wulff (1981) At present there is a need for more research which directly concerns the clinical decision process (assessment of diagnostic tests, therapeutic trials and studies of the natural history of Examples of areas where clinicians, working together with other disciplines, could make useful contributions to the problem of dementia are improvement and quantification of diagnostic methods development of a positive test for the diagnosis of Alzheimer's disease would be important further analysis of the pathophysiology of vascular dementia, and the relation with the site of the causative infarcts better description of clinical pictures and their variation valid...


Walstra for our fruitful discussions about dementia. Albert, M. L Feldman, R. G. and Willis, A. L. (1974) The 'subcortical dementia' of progressive supranuclear palsy. J. Neurol. Neurosurg. Psychiat., 37 121-130. Albert, M., Naeser, M. A., Levine, H. L. and Garvey, A. J. (1984) Ventricular size in patients with presenile dementia of the Alzheimer's type. Arch. Neurol., 41 1258-1263. Barclay, L. L., Zemcov, A., Blass, J. P. and Sansone, J. (1985) Survival in Alzheimer's disease and vascular dementias. Neurology, 35 834-840. Bradshaw, J. R Thomson, J. L. G. and Campbell, M. J. (1983) Computed tomography in the investigation of dementia. Br. Med. J., 286 277-280. Brown, R. G. and Marsden, C. D. (1984) How common is dementia in Parkinson's disease The Lancet, ii 1262-1265. Brust, J. C. M. (1983) Vascular dementia still overdiagnosed. Stroke, 14 298-300. Cummings, J. L. and Benson, D. F. (1983) Dementia a Clinical Approach, Butterworths, London. Damasio, H.,...

Diagnostic Issues

Available evidence indicates that mild dementia is rarely diagnosed, and even moderately severe dementia is under-recognized in clinical practice 51 . Thus, diagnostic accuracy is much lower at the earlier clinical, and especially presymptomatic, stages of the disease. Up to a few years ago, with no medical treatment of dementia, the need for an accurate diagnosis was of little importance. Today, with existing and emerging therapeutic strategies, the clinical involvement has dramatically changed, and there is a need for a reliable diagnosis. The transition from normal cognitive functioning to dementia is gradual, and most if not all patients with AD experience a subtle cognitive decline before reaching the clinical threshold for the diagnosis of clinically probable DAT. During the preclinical phase of AD the neuronal degeneration proceeds, and the amount of plaques and tangles increases, and at a certain threshold the first symptoms, most often including impairment of episodic memory,...

Conclusive Remarks

1 von Strauss E, Viitanen M, De Ronchi D, Winblad B, Fratiglioni L. Aging and the occurrence of dementia Findings from a population-based cohort with a large sample of nonagenarians. Arch Neurol 1999 56(5) 587-592. 2 Di Carlo A, Baldereschi M, Amaducci L, et al. Incidence of dementia, Alzheimer's disease, and vascular dementia in Italy. The ILSA Study. J Am Geriatr Soc 2002 50(1) 41-48. 3 Ghiso J, Frangione B. Amyloidosis and Alzheimer's disease. Adv Drug Deliv Rev 2002 54(12) 1539-1551. 4 Petersen RC, Smith GE, Ivnik RJ, et al. Apolipoprotein E status as a predictor of the development of Alzheimer's disease in memory-impaired individuals. JAMA 1995 273(16) 1274-1278. 5 Ritchie K, Lovestone S. The dementias. Lancet 2002 360(9347) 1759-1766. 6 Cummings JL, Cole G. Alzheimer disease. JAMA 2002 287(18) 2335-2338. 8 Frisoni GB, Padovani A, Wahlund LO. The predementia diagnosis of Alzheimer disease. Alzheimer Dis Assoc Disord 2004 18(2) 51-53. 9 Nestor PJ, Scheltens P, Hodges JR. Advances...

Oxidative Damage

One probable mechanism promoting caspase activity in neuro-degenerative conditions is oxidative damage to the mitochondria leading to cytochrome-c release and other events initiating caspase activation. Oxidative damage is implicated in ischemia reperfu-sion, Parkinson's disease, Alzheimer's disease, and aging (79). In AD, oxidative damage may play a critical role (80). If this damage is initiated in synaptic compartments, it could lead to synaptosis. This would be consistent with mitochondria as both the primary source of free radical generation and initiation of apoptosis (81). Free iron, a potent pro-oxidant molecule, appeared to stimulate apoptotic events in synaptosomes (48). Similarly, like free iron, Ap induces both oxidative damage to mitochondria in synapto-somes (82) and apoptotic events (49).

Series Editors Introduction

Since the original classic description of Parkinson's disease, there have been swings in concept from a unitary disease with characteristic clinical features and unique neuropathologic changes to that of a more variable disorder with multiple etiologies owing to a spectrum of pathological processes. Originally, the terms paralysis agitans and Parkinson's disease first used in the 19th century implied a unitary disease. The concept of parkinsonism as a special disease entity was supported by the stereotyped features of akinesia, rigidity, tremor, and postural instability. The appearance of postencephalitic parkinsonism and later the recognition of arteriosclerotic parkinsonism led to the realization that there must be multiple forms of the disease. Idiopathic Parkinson's disease finally became anchored by identification of the Lewy body, which provided the necessary objective marker for what, at least temporarily, quite remarkably came to be called Lewy body disease. However, the later...

Acquired immunodeficiency syndrome

Generally the most severe but neurological problems such as dementia resulting from HIV infection of the brain cells can also occur. The disease is almost always fatal. It is generally transmitted through blood and body fluids, usually through unprotected sexual intercourse, but vertical and or perinatal transmission is also very common. AIDS is prevalent among injecting drug addicts and in patients receiving blood transfusions. It can be partly controlled by antiretroviral drugs such as AZT (azidothymidine) or non-nucleoside reverse transcriptase inhibitors such as nevirapine combined with protease inhibitors (See HAART therapy), but the side-effects of the drugs are not negligible.

Miscellaneous chemotypes 961 Furopyrimdines

1 2009 Alzheimer's Disease Facts and Figures. Alzheimer's & Dementia, 2009, 5, 30. 3 J. Hardy, J. Alzheimer's Dis., 2006, 9(Suppl. 3), 151. 17 J. B. Standridge and E. M. Welsh (eds), Trends in Alzheimer's Disease Research, Nova Science Publishers, Hauppauge, NY, 2006, pp. 53-96. 19 A. Lorenzo and B. A. Yankner, Ann. N.Y. Acad. Sci., 1996, 777, 89, Neurobiology of Alzheimers Disease. 23 K. Iqbal and I. Grundke-Iqbal, J. Alzheimer's Dis., 2006, 9(Suppl. 3), 219. 25 M. A. Glicksman, G. D. Cuny, M. Liu, B. Dobson, K. Auerbach, R. L. Stein and K. S. Kosik, Curr. Alzheimer Res., 2007, 4, 547.

What Is Disease Mapping

To answer the question 'What is disease mapping ' we must first consider some definitions. The disease in disease mapping refers to the geographical distribution of a disease within a population. A suitable study for example would be the addresses of people who have Alzheimer's disease in a community. Another example, which has more environmental resonance, would be the geographical distribution of the cases of childhood leukaemia within an area around a nuclear power station. Geographical distribution can be expressed as residential addresses but more commonly, because of confidentiality, the addresses of individuals are not available directly.

Corticobasal Degeneration

With the advent of cognitive neurology as a subspecialization of neurology, historical research efforts related to corticobasal degeneration have focused on descriptions of cases with signs of cortical dysfunction rather than motor. The clinical disorder of the celebrated composer, Maurice Ravel, has been retrospectively diagnosed as corticobasal degeneration, focal dementia, and progressive aphasia without dementia (27,28). These analyses provide interesting reading, but, because the medical information is incomplete and no autopsy material has been identified, they do not substantially advance historical understanding of corticobasal degeneration.

Biological Characterization And Interpretation

Levels of BACE mRNA and protein expression are reported to be higher in the brains of sporadic AD patients after death, and there is also a correlation of this upregulation with the levels of Ap1-x and Ap1-42, suggesting that elevation of BACE may lead to increased Ap production and enhanced deposition of amyloid plaques in the sporadic AD brain 25,26 . There is also increased expression of BACE in rats following transient ischemia, suggesting that BACE inhibitors may prove beneficial for the prevention of dementia following a stroke 27 . Although the BACE mouse knock-out showed only mild phenotypic changes 28 , subsequent analysis revealed subtle behavioral changes characteristic of neurotransmitter modulation 29 . Importantly, when the BACE knock-out was incorporated in a mouse model of APP overexpression (Tg2576) not only were cerebral Ap1-40 and Ap1-42 levels lower but the behavioral deficits found in the Tg2576 mice were dramatically absent. This

PNKourounakis and EARekka

Despite the advances in medical and pharmaceutical sciences, there are still many diseases which are incurable or can only be treated symptomatically, and at a great economic and social cost owing to only moderately effective or even to the lack of appropriate therapeutic agents. Of the 30000 or so diseases or disorders currently known, only one-third can somehow be treated with drugs. Furthermore, there are incurable maladies, like viral diseases (influenza, AIDS), CNS disorders (Alzheimer's disease), cancer and autoimmune disorders, which can be fatal or cause great suffering and disability 3 . Therefore, there is still a great need for more and better drugs more active and selective, drugs with fewer undesired or toxic side-effects, agents useful in prophylaxis and drugs which will cause as little as possible harmful contamination in the already polluted environment. This volume covers topics such as drug discovery and physicochemical properties, structure-activity relationships,...

Dual action iNOS inhibitors

Studies have shown that iNOS and peroxisome proliferator-activated receptor g (PPARg) play important roles in neuroinflammation. For instance, the PPARg agonists Rosiglitazone and Pioglitazone, which are approved for the treatment of diabetes, preserve cognitive function in early Alzheimer's patients and attenuate learning and memory deficits in transgenic Alzheimer mouse models. In a rat spinal cord injury model, treatment of rats with thiazolidinedione PPARg agonists prevented neuronal damage, motor dysfunction, myelin loss, and the development of neuropathic pain 84 . Similarly, increased iNOS function is important in neuroinflammation and pain. A series of 2-phenyl-ethenesulfonic acid phenyl esters were synthesized and shown to suppress NO production in LPS interferon g-stimulated RAW 264.7 cells and activate PPARg in a cell-based transactivation assay 85 . Compound 37 inhibits iNOS activity (IC50 1.8 mM) in a whole cell assay and binds competitively to the PPARg receptor (IC50...

Ab aggregation and neurotoxic oligomers

Since the elucidation of the Ab sequences 10-12 , investigators have used synthetic Ab to examine aggregation and its effects on physiology. Many in vitro studies have suggested that aggregation of Ab is essential for toxicity, but characterization of the Ab species that formed was limited. However, amyloid plaque number does not correlate well with severity of dementia 13-15 , and instead, there is a stronger link between soluble Ab levels and the extent of synaptic loss and the severity of cognitive impairment 16-18 . Therefore, more recent studies have focused on various soluble forms of synthetic Ab1-40 and Ab1-42, ranging from monomeric to protofibrils 19 .

Ionotropic Gaba Receptors And Memory Disorders

Bis(7)-Tacrine (14, is a potential Alzheimer's disease drug on the basis of its superior acetylcholinesterase inhibition and memory-enhancing potency relative to tacrine. It is a potent competitive GABAA receptor antagonist (IC50 6 mM), some 18 times more potent than tacrine on these receptors, suggesting that its GABAA receptor antagonist activity may contribute to its memory-enhancing properties 64 .

Prevalence of PSP and MSA

It is possible that this clinical iceberg phenomenon is less important for PSP and MSA because their symptoms and disease progression make them less likely to be undetected. However, studies aimed at parkinsonism may underestimate rates of MSA since cases with predominantly cerebellar features may be undetected. Similarly, excluding patients who became demented before the onset of parkinsonism (14) will assist in the exclusion of dementia with Lewy bodies, in which a supranuclear gaze palsy may occur, but may also exclude cases of PSP.

Clinical evaluation of gsecretase inhibitors

Clinical evaluation of azepinone 32 (LY-450,139) in Alzheimer's patients has been reported. Rises in plasma Ap, but no significant effects on CSF Ap, were observed. Similar effects on plasma Ap were observed in guinea pigs treated with 32 86-88 . Clinical testing for g-secretase inhibitors GSI-953 and MK-0752 (structures undisclosed) has been initiated 89-91 . Significant reductions in CSF Ap40 (35 at 12 h) after treatment with MK-0752 have been observed. Based on the role of Notch signaling in tumorigenesis, g-secretase inhibitors are being evaluated as potential cancer therapeutics 92,93 . The development of g-secretase inhibitors for this indication may provide important clinical information on the relationship between g-secretase-mediated Ap reduction and side effects due to Notch inhibition.

Fraunhofer solar spectrum

Exclusion criteria for ENNR All patients with acute brain lesions and suffering from neurological and or mental cognitive impairments of higher cerebral functioning are eligible for referral to an ENNR department provided they are no longer on the ventilator, sufficiently stable in terms of circulation and breathing, without increased intracranial pressure, and not suffering from severe infection or progressive malignancy nor from progressive cerebral diseases such as M. Alzheimer or Chorea Huntington. All team members meet in weekly rounds to discuss and assess the patients' individual status. Diagnostic findings are presented with comments

Taihung Duong PhD Chap 6 Cellular Communication

Taihung (Peter) Duong is Associate Professor of Anatomy and Cell Biology at the Indiana University School of Medicine, Terre Haute, and Director of the Terre Haute Center. He received a B.A. degree in Biology from Whittier College in 1977 and a Ph.D. degree in Anatomy from the University of California at Los Angeles (UCLA) in 1989. He completed 2 years in a postdoctoral fellowship in neuroanatomy at the UCLA Mental Retardation Research Center before joining the faculty at the Indiana University School of Medicine in 1991. His research interests are brain aging and Alzheimer disease.

Idiopathic Parkinsons Disease

External examination of the brain is generally unremarkable, although PD patients who develop dementia may have mild to moderate cerebral atrophy. On cut sections, there is usually loss of pigment from the substantia nigra and locus ceruleus (Fig. 1A). The caudate, putamen, globus pallidus, thalamus, and other brainstem structures appear normal.

Historical Background

In 1907, Bavarian psychiatrist Alois Alzheimer described pathology and symptoms of a 51 year-old woman, Auguste D., who had suffered progressive cognitive decline, learning and memory deficits, and paranoid and delusional behavior (1). Alzheimer used a silver stain on cortical tissue samples to reveal prevalent and highly unusual lesions that he called neurofibrillary tangles and senile plaques, and these lesions remain the basis for definitive post-mortem diagnosis of Alzheimer's disease (AD). Alzheimer's initial report did not discuss any definitive cause for AD, but he did observe (his italics) Plaques are not the cause of senile dementia, but only an accompanying feature of senile involution of the central nervous system (2). Alzheimer's early exoneration of amyloid plaques apparently escaped most AD researchers, including Glenner and Wong, who in 1984 identified the 39-43 residue amyloid (3 peptide as the major plaque component (3). Shortly thereafter, synthetic Ap peptides were...

Second Messenger Systems

Phosphoinositide turnover is closely connected to the modulation of synaptic function and studies have demonstrated the incorporation of l- 11C butyryl-2-palmitoyl-glycerol ( 11C DAG) into the downstream components of the rat PI system, including phosphatidic acid and phosphotidylinositol 121 . This radiotracer has been utilized in imaging studies in normal control human subjects, as well as in Parkinson's disease, Alzheimer's disease, and stroke subjects 122 . 11C DAG has also been utilized for the evaluation of PI turnover in ischemic brain using PET 123 . However, the relatively high lipophilicity of the radioligand resulted in high non-specific binding and relatively slow pharmacokinetics in the brain.

The Role Of Ab And The Amyloid Cascade Hypothesis

Based on these observations, and because fibrillar Ap preparations were neurotoxic to cultured neurons, it was postulated the fibrillization of Ap into these amyloid plaques caused AD-related dementia (the amyloid cascade hypothesis). However, careful AD neuropathology studies have not been able to correlate the density of neuritic amyloid plaques and neurodegeneration or clinical dementia (52,53). Recent studies demonstrate that the severity of neurodegeneration correlates with small, stable oligomers of Ap (54,55). In addition, recent studies in APP transgenic mice suggest that amyloid plaque deposition is not required for synaptic toss or learning memory deficits (20,56). Thus, the classical amyloid cascade hypothesis needs to be re-evaluated.

H3 antagonists with a dual mechanism

Activity was reported for a series of tacrine analogs to treat the cognitive deficits in Alzheimer's disease 82 . Compound 34 (FUB833) (hH3 K 0.33 nM) had an IC5o of 2.6 nM for AChE. The series also showed activity for BuChE and HNMT, the main histamine metabolizing enzyme in brain. A series of compounds with dual H3 antagonist HNMT activity was reported 83 . Compound 35 had sub-nanomolar affinity for H3 and an IC50 of 51 nM for HNMT. Schering-Plough reported dual H H3 antagonists prepared by linking chloropheniramine with imidazole alkyl amines for allergic rhinitis 84 .

The Spectrum Of Lb Disorders

There is striking clinical and pathological overlap between PD and DLB. Up to one-third of patients with a clinical diagnosis of PD will develop dementia (9,12,42) and most (but not all) patients with DLB display some degree of parkinsonism (30). LBs are the defining histopathological feature of both conditions. In PD, LBs are most numerous in subcortical nuclei and it is the associated loss of dopaminergic neurons that is largely responsible for the characteristic extrapyramidal features. However, small numbers of cortical LBs may be found in virtually all cases of PD, even in the absence of dementia (31). In DLB, cortical LBs are usually more numerous and some studies have shown a

Progressive Supranuclear Palsy

In the original description of this disease entity, patients with supranuclear ophthalmoplegia, pseudobulbar palsy, dysarthria, rigidity, and mild cognitive deficits were found to have abundant NFTs in subcortical nuclei (91). The clinical phenotype is now recognized to be much more variable and includes both pure parkinsonism and frontotemporal dementia with no movement abnormality (1,2,4,5,71).

Other Neurodegenerative Conditions

Many other common idiopathic neurodegenerative conditions have parkinsonism as an inconsistent or minor clinical feature. Extrapyramidal symptoms are very common in AD and may take the form of true parkinsonism (135-137). Many patients with a clinical diagnosis of AD and parkin-sonism are found to have coexisting LB pathology at autopsy, either restricted to subcortical structures or also involving the cerebral cortex (35,136,138). The correct terminology for these cases is uncertain, because of the lack of universally accepted neuropathological diagnostic criteria for both AD and DLB (see subheading Dementia with Lewy Bodies). Interpretation is further complicated by recent reports of LBs as a common incidental finding in AD patients, even in the absence of extrapyramidal features (139). However, parkinsonism also occurs in some AD patients who have only SP and NFT pathology (136,138,140). SPs are a consistent finding in the striatum and are occasionally seen in the substantia nigra...

M1 is the major postsynaptic mAChR in the hippocampus

MAChRs expressed in the hippocampus, play a role in learning and memory (Jerusalinsky et al., 1997), and degeneration of cholinergic projections to the hippocampus has been implicated in Alzheimer's disease (Bartus et al., 1982 Gallagher and Colombo, 1995). Therefore, much research has focused on identifying the cellular mechanisms by which mAChR activation might contribute to learning and memory. One of the effects of mAChR activation in the hippocampus is potentiation of current through the NMDA glutamate ion channel, a major component of synaptic plasticity. Identifying the mAChR subtype responsible for potentiation of NMDA current has previously been difficult because of the lack of subtype selective mAChR antagonists. The highly selective M1 antagonist, M1-toxin (Max et al., 1993a,b), allows the investigation of the role the M1 mAChR plays in regulating hippocampal excitability. Application of NMDA causes an increase in inward current in CA1 pyramidal cells. Treatment with the...

Posttraumatic Parkinsonism

Parkinsomism immediately following a single episode of acute head injury is rare (180) but has been reported with direct penetrating lesions of the midbrain (181) and with subdural hematoma (182). Epidemiologic studies have shown a history of remote head trauma to be a risk factor for PD, however the mechanism is unclear (183-184). Repeated head injury may result in a syndrome that includes psychiatric symptoms, memory loss, and or parkinsonism (dementia pugilistica, punch-drunk syndrome). This most often occurs in professional and amateur boxers, with the onset of symptoms occurring several years after the end of their athletic career. Pathological studies have shown loss of pigmented neurons in the substantia nigra and the presence of widespread AD-like pathology, with numerous tau-immunoreactive NFTs and amyloid p (Ap) containing SPs (185,186). A direct link between these pathological changes and preceding trauma is supported by studies showing Ap deposits in the brains of...

MAChR trafficking following acute stimulation

M2 mAChR trafficking has been examined by electron microscopy in cholinergic interneurons of the striatum (Bernard et al., 1998). Following oxotre-morine treatment, M2 shows decreased cell surface localization and enhanced localization to endosomes and multivesicular bodies. M2 expressed in cell bodies of the medial septum also shows internalization following cholinergic stimulation. Immunofluo-rescence reveals that M2 shows a linear, continuous distribution along the cell surface in saline treated rats (Fig. 4). Forty minutes after intraperitoneal injection of oxotremorine, its distribution is mostly intracellular and punctate. Overall, these experiments suggest that mAChR internalization and intracellular trafficking is an important component of receptor regulation in the brain. The effects of chronic cholinergic stimulation on muscarinic receptor subtype regulation will be critical, given the widespread use of cholinesterase inhibitors for the treatment of Alzheimer's disease....

Mice Expressing Transgenes That Alter Tau Kinase Or Phosphatase Activity

The filamentous tau lesions observed in human neurodegenerative disease invariably contain tau that is hyperphosphorylated at specific residues (10). As a result, there has been much speculation about the role of abnormal tau phosphorylation in the development of neurofibrillary pathology in Alzheimer's disease (AD) and the tauopathies. To examine this question, several groups have generated mice that overexpress transgenes designed to upregulate tau phosphorylation.

Biology of Aging and its Clinical Implications

Underlying loss of entropy and fractality is a chronic and progressive inflammation that represents the biologic hallmark of aging (11). Seemingly, this inflammation originates from the interaction of individual genetics, diseases, and environment. Increased concentrations of inflammatory cytokines, especially interleukin-6 (IL-6) have been associated with increased mortality, functional dependence, and with a number of geriatric syndromes including dementia and osteoporosis (10, 11). In this perspective, it is not far-fetched to hypothesize that anemia may be both a consequence and a cause of aging (Fig. 2.1). Correction of anemia may break this vicious circle and delay the complications of aging. Geriatric syndromes are conditions that are typical, albeit not unique, of aging. Approximately 20 of cancer patients aged 70 and older had some form of early dementia or sub-clinical depression when screened for these conditions (18). Early detection of dementia may allow prompt...

Intracellular Quality Control

Although the accumulation of protein aggregates and autophagic vacuoles is a hallmark of many neurodegenerative diseases such as Alzheimer's disease (Okamoto et al. 1991 Cataldo et al. 1996), polyglutamine (CAG) repeat diseases (Petersen et al. 2001 Ravikumar et al. 2002), and Parkinson's disease (Anglade et al. 1997), it remains unknown whether autophagy is indeed involved in the pathogenesis of these diseases. In some familial neurodegenerative diseases such as amyotrophic lateral sclerosis-like motor disease and frontotemporal dementia, the causative mutations in dynein and CHMP2B do indeed affect autophagosome-lysosome fusions, which should impair autophagic clearance of abnormal proteins (Ravikumar et al. 2005 Filimonenko et al. 2007 Lee et al. 2007). Irrespective of whether the autophagy defect is the direct cause or not, autophagy could be a good therapeutic target in these neurodegenerative diseases (Rubinsztein 2006). Inhibitors of Tor, a potent endogenous suppressor of...

Topography and distribution of cortical cholinergic projections

In the monkey brain, individual cortical areas receive their major cholinergic input from different sectors of the nucleus basalis-Ch4 complex. Thus, Ch4am provides the major source of cholinergic input to medial cortical areas including the cingulate gyrus Ch4al to frontoparietal cortex, opercular regions, and the amygdaloid nuclei Ch4i to laterodorsal frontoparietal, peristriate and mid-temporal regions and Ch4p to the superior temporal and temporopolar areas (Mesulam et al., 1983a). The experimental methods that are needed to reveal this topographic arrangement cannot be used in the human brain. However, indirect evidence for the existence of a similar topographical arrangement can be gathered from patients with Alzheimer's disease. We described two patients in whom extensive loss of cholinergic fibers in temporopolar but not frontal opercular cortex was associated with marked cell loss in the posterior (Ch4p) but not the anterior (Ch4am + Ch4al) sectors of Ch4 (Mesulam and Geula,...

Neurodegenerative Disorders

Hyperactivity of central excitatory amino acid (EAA) neuronal pathways, where glutamic acid (Glu) is the major neurotransmitter, has been associated with the aetiology of certain neurodegenerative diseases, such as status epilepticus, Huntington's chorea and senile dementia of Alzheimer type (SDAT) 1, 2 . In Alzheimer patients a regional degeneration of neurones, notably cholinergic (see subsequent section) and serotonergic neurones (Fig. 1) is observed 3 . In addition, loss of glutamatergic neurones is seen in the progression of Alzheimer's disease (AD) 2 (Fig. 2). Thus, hyperactive as well as hypoactive EAA neuronal mechanisms may be operative in AD. The neuronal degeneration observed after ischaemia, including stroke, hypoxia and hypoglycaemia, may also be due to prolonged and excessive stimulation of EAA receptors 2 . There is some evidence that hypoactivity of the central EAA system(s) may be a key factor in schizophrenia 4 .

Disability And Handicap After aSAH

Handicap is often confused with disability, but it refers specifically to loss of interpersonal or societal role function, due to either an impairment or disability. For example, a person may be impaired due to moderate memory loss and dysarthria, which may result in instrumental disability due to loss of independence for traveling outside the house and taking care of personal finances. These problems, in turn, can result in handicap in terms of fulfilling one's role as a husband, father, and wage earner. Handicap is common after aSAH. Even among good-grade patients, only 50 return to the same level of work prior to their hemorrhage (30 ), and significant strains are often placed on interpersonal relationships, primarily due to behavioral changes, such as irritability, apathy, and impulsivity (31).

Cholinergic Dysfunctions And Senile Disorders

Neurochemical examination of biopsy and autopsy brain material from Alzheimer patients has revealed loss of the presynaptic marker enzymes acetyl coenzyme A (acetyl-CoA), choline O-acetyltransferase and acetylcholinesterase (AChE), and of muscarinic receptor sites of the M2 subtype correlating with dementia score and severity of neurohistopathology 8 . These alterations do, to some extent, reflect the well-documented neuronal cell loss in the nucleus of Meynert in presenile dementia and AD. Lesions of this brain nucleus in rats, a limited model for the cholinergic deficit of AD, result in marked reductions in the levels of cholinergic enzyme markers in the neocortex accompanied by great decreases in the total muscarinic receptor levels 9, 10 . SYNAPTIC MECHANISMS AS THERAPEUTIC TARGETS IN ALZHEIMER'S DISEASE

Bone Resorption Inhibitors

Because the decline in estrogen levels following menopause is a major cause of osteoporosis, estrogen therapy is a logical treatment. Estrogen is most often combined with progesterone in this regimen to reduce the risk of uterine cancer associated with unopposed estrogen. This combination therapy was shown to increase bone mineral density (BMD) but the effect on fracture rate was initially unclear 4,5 . The recently released results of the large, five year, multi-center Women's Health Initiative estrogen plus progesterone (E + P) study indicated that the most commonly prescribed HRT therapy reduces fractures in postmenopausal women by 24 overall, and 33 in the hip 6 . These positive results were tempered by the findings of increased incidences of dementia and ovarian cancer in the same study. Increased caution is thus now recommended when considering the use of HRT for the prevention and treatment of post-menopausal osteoporosis.

The 3 and 4R Tauopathies

We turn now to a set of disorders in which tau protein that makes up the inclusions is a various mix of 3R and 4R isoforms. Alzheimer's disease belongs to that category and because of its frequency is the first disorder to be considered in this chapter. Alzheimer's Disease Alzheimer's-type pathology is the only detectable lesion in a significant proportion of cases in which the diagnosis of IPD has been made premortem (20,164,165). This observation raises the possibility that Alzheimer's disease, in the absence of dementia, causes the parkinsonian symptoms by a direct involvement of the nigrostriatal pathway (165). It is not the place to review here the pathology of Alzheimer's disease suffice it to say that extracellular deposition of Ap peptide and intracellular accumulation of both 3R and 4R tau isoforms are the principal lesions. Tau accumulates in three compartments the neuronal cell body (NFT), the dendrites (neuropil threads), and the axonal component of the corona of the...

Creutzfeldt Jakob disease CJD One of

The subacute spongiform encephalo-pathies a progressive degeneration of the CNS in humans, with dementia in the early stages. There may be myoclonus and typical EEG changes. Onset usually between 50 and 65 years. Occurs sporadically all over the world with an annual incidence of 1 per million population, but small clusters of cases are reported. Some cases have familial history. Has been transmitted in humans by corneal graft when the incubation period was 18 months, and by contaminated human pituitary-derived growth hormone with incubation periods of 10-30 years. The mode of natural transmission in humans is not known. There is no evidence of increased risk of developing the disease in health care workers. However, post-mortems should be conducted with extreme care. Disease can be transmitted to Old World and New World monkeys, cats, hamsters, guinea pigs and mice. The disease is caused by a prion, which has a very small size indicated by extreme resistance to irradiation. Very...

Subcortical High Intensity Lesions on Brain MRI

Brain MRI in aPL patients with ischemic stroke typically shows cortical abnormalities consistent with large vessel occlusion. However small sub-cortical white matter high-density lesions on brain MRI are frequently found in patients with aPL, and also in SLE patients with or without overt neuropsychiatric manifestations (Fig. 7.3). The finding of these lesions may represent a diagnostic and therapeutic dilemma especially in young patients. The significance of these lesions is not completely understood. They are often defined as consistent with the presence of small vessel disease by the neuroradiologists. It has been suggested that they may be due to multiple small infarcts. There is evidence that the presence of similar lesions is associated with a higher risk for stroke, seizures, psychiatric disturbances, dementia, and cognitive disorders.

Other Genetic Diseases Occasionally Presenting With Atypical Parkinsonism

Huntington's disease (HD) is an autosomal-dominantly inherited disorder, usually characterized by a hyperkinetic movement disorder, personality changes, and dementia. It is caused by the pathologic expansion of a CAG-trinucleotide repeat sequence in the gene for Huntingtin on chromosome 4 (94). The fact that particularly cases of early onset frequently present with dystonia and parkinsonism, rather than with chorea, has long been recognized (95). In addition, the widespread use of molecular diagnosis for HD has shown that the phenotypic spectrum may even include late-onset levodopa-responsive parkinsonism (96) and atypical parkinsonian syndromes (97).

Historical Perspective Early Work On nAChR Modulators At Abbott Laboratories

In 1989, Mike Williams joined the Neuroscience Discovery group at Abbott with the challenge of refocusing research activities toward a more aggressive drug discovery mode. His initial effort involved redirection of an existing effort in Alzheimer's disease that was, like many others, focused on muscarinic agonists as a palliative therapy. Many other companies were targeting the same approach, and compounds active at muscarinic receptors are highly prone to unacceptable side-effect liabilities. Therefore, it was felt that Abbott could be more competitive by focusing in the area of nicotinic receptor agonists, whereby two acute, albeit limited, human trials had shown beneficial action of nicotine in improving cognitive function in Alzheimer's patients. The decision was somewhat risky, inasmuch as there were few programs of this type in the industry, inevitably raising questions regarding what others knew that we did not, and vice versa. Moreover, the word nicotine immediately conjured...

Definition And Identification Of Key Neuropsychiatry Symptoms

The definition of psychotic symptoms (i.e., delusions, delusional misidentification, and hallucinations) requires particular consideration as these symptoms are very frequent in some parkinsonian disorders, particularly in patients with dementia. In addition, as they are phenomenologically different from psychotic symptoms occurring in patients with functional psychoses and cannot be reliably observed or inferred from behavior, a specific method is required to identify these symptoms in patients with cognitive impairments. According to Burns, delusions are defined as false, unshakable ideas or beliefs that are held with extraordinary conviction and subjective certainty (3). To minimize overlap with confabulation and delirium, they should be reiterated on at least two occasions more than 1 wk apart. Hallucinations are described as percepts in the absence of a stimulus, reported directly by either the patient or indirectly via an informant, and may occur in any modality. Typically,...

Measuring Psychiatric Symptoms

A number of different instruments have been used to measure neuropsychiatry symptoms in patients with parkinsonian disorders. These can be divided into clinical interviews that focus upon a broad range of symptoms or more focused scales. Examples of the first group include the Present Behavioural Examination (PBE) (6), Neuropsychiatric Inventory (NPI) (7), and Brief Psychiatric Rating Scale (BPRS) (8). The PBE is a lengthy interview with a detailed assessment of behavior in patients with dementia, and requires a trained observer. The NPI is a highly structured, caregiver-based interview, which can be completed in a relatively short time depending on the amount of disturbances (see below). The BPRS was constructed essentially for schizophrenic states, and requires a trained rater. Examples of scales that assess specific syndromes in more detail are the Hamilton Depression Rating Scale (HAM-D) (9) and self-rating scales completed by the patients themselves (i.e., Beck Depression...

Neurobiological Theories Of Adhd

Animal models also support a dopaminergic hypothesis in ADHD. Mice without a functioning dopamine transporter (DAT1 knockout KO mice) have high extracellular striatal dopamine levels, a doubling of the rate of dopamine synthesis (15), decreased dopamine and tyrosine hydroxylase in striatum (16), and a nearly complete loss of functioning of dopamine autoreceptors (17). They display markedly increased locomotor and stereotypic activity compared to normal (wild-type) mice (15,18). The reduced striatal dopamine may be most relevant to a hypodopaminergic theory of ADHD. Also, selective destruction of dopamine neurons by 6-hydroxydopamine results in hyperactivity and learning difficulties in mice (19). The spontaneously hypertensive rat (SHR) has also been used as an animal model of ADHD because of the SHR's locomotor hyperactivity and impaired discriminative performance. Russell (20) showed that the altered presynaptic regulation of dopamine in SHR led to the downreg-ulation of the...

The Neuropsychiatry Of The Basal Ganglia

Cummings proposed an integrating hypothesis linking observations from molecular biologic, neu-ropathologic, and neurochemical studies in neurodegenerative disorders to neuropsychiatric manifestations of these disorders. According to this model, proteinopathies, such as tauopathies and alpha-synucleinopathies, are associated with a distinct anatomic pattern of degeneration. Cell death in specific brain nuclei responsible for transmitter synthesis leads to deficits in a variety of transmitter systems. Specifically, a-synuclein disturbances, such as PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), mainly involve substantia nigra, brainstem, and limbic system neurons, whereas frontal and basal ganglionic neurons are predominantly affected in tau metabolism disturbances, such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), resulting in frontal and subcortical abnormalities (22). These differential regional and transmitter involvements may...

Biological Functions of Intracellular Regulators of Apoptosis

Recent studies have indicated that the activated caspases play a role in the formation of apoptotic morphology by proteolytic cleavages of a set of key proteins (Table 4). Although the exact mechanism whereby the degradation of these proteins results in apoptotic morphology remains unknown, many target proteins of caspases participate in the formation and regulation of the membrane-associated cortical microfilament cytoskeleton, which is an important determinant of the cell shape (Table 4). Insufficient apoptosis because of caspase inactivation may promote oncogenesis by allowing cell accumulation (M5). On the other hand, caspase overreactivity promotes cellular suicide, and this may be the basis for degenerative conditions such as Huntington's disease and Alzheimer's disease (G2, W8). Further investigation of the caspase system will provide a biochemical basis for the treatment of apoptosis-related diseases in the future.

Epidemiology And Implications Of Neuropsychiatric Features In Parkinsonian Disorders

There are few epidemiological studies of neuropsychiatric symptoms in parkinsonian disorders. In one study of a relatively large, representative community-based sample of patients with PD, 61 had a positive score on at least one NPI item, and 45 had a positive score on at least two items. Patients in nursing homes, with more advanced parkinsonism, and with dementia had more frequent and severe neuropsychiatry symptoms (12). Studies of patients with atypical parkinsonian disorders have typically involved small convenience samples from highly specialized movement disorder clinics, and thus may not necessarily be representative of the general population. The exception is DLB, and two studies, both including 98 patients with DLB, showed a high prevalence of neuropsychiatric symptoms (23,24). In one study, 98 had at least one positive symptom as measured by the NPI (24) demonstrating the importance of neuropsychiatric symptoms in this common disorder, which affects 5 of the elderly aged 75...

The Role Of Neuropsychiatric Assessment In Diagnosis Of Parkinsonian Disorders

Neuropsychiatric symptoms are common, and their prevalence, phenomenology, and clinical implications have been extensively studied during the last decade. The majority of PD patients develop dementia with cortical and subcortical features when disease duration exceeds 10 yr (41). Depression is the most common psychiatric symptom in PD (12,50), and may occur in up to 40 of patients (51). Different studies report wide variations in prevalence rates, however, and population-based studies suggest that major depression according to the DSM system is uncommon, occurring in less than 10 of cases (52,53). Visual hallucinations are also common in PD, and typically involve people of normal size and configuration who do not communicate with the patient. A substantial proportion of patients report vague feelings of a presence (57). The patients may or may not be aware of the abnormality of the experience, and the visions usually do not cause emotional disturbance. However, more severe psychotic...

Confocal microscopy of muscarinic receptors on dendritic spines

It is clear that most of the M1 receptors in the brain are co-localized with glutamate receptors at the tips of dendritic spines in the cortex, hippocampus and striatum, that M1-activation potentiates excitatory NMDA currents, and that M1-knockout causes severe cortical-hippocampal memory deficits and hyperactivity. Thus M1-rich spines are crucial for normal cognition and movement. We have begun to examine the specific characteristics of these spines in the rat hippocampus and striatum with fluorescent m1-toxin1 and confocal microscopy (McCollum et al., 2003). So far it is clear that the fluorescent toxin saturates M1 receptors in vivo, that toxin-receptor complexes are stable in perfusion-fixed tissue, and that M1-rich dendritic spines are beautifully imaged by confocal microscopy. We intend to use this approach to address the following questions. How does the administration of donepezil (an esterase inhibitor used to treat dementia) (Barnes et al., 2000), or atropine (a common...

Pharmacological Treatment Of

Few trials of neuropsychiatric symptoms have been reported in PSP. In a recent placebo-controlled trial, the cholinesterase inhibitor donepezil did not improve neuropsychiatric symptoms. A slight improvement in memory was noted, but because of worsening of motor symptoms, a worsening of ADL was found in patients receiving donepezil (116). Similarly, a small placebo-controlled trial with RS-86, a cholinergic agonist, did not improve cognition or mood in PSP patients with dementia (115). In a clinical survey, it was reported that some PSP patients responded to antidepressive drugs (77). In a chart review, 7 of 12 autopsy-diagnosed PSP patients responded to a dopaminergic drugs, and 1 of 3 to a tricyclic antidepressant. None of the patients responded markedly, however. The serotonergic agent trazodone, but not the neuroleptic drug thiotixine or carbamazepine, improved agitation in patients with PSP (130). Another case report suggested that electroconvulsive therapy (ECT) could improve...

Types Of Limb Apraxia

Ideational apraxia was traditionally allocated to the left parieto-occipital and parieto-temporal regions (2,17), although frontal and frontotemporal lesions may also cause CA (32). Nevertheless, semantic or conceptual errors are particularly observed in patients with temporal lobe pathology (e.g., semantic dementia) these patients are impaired in the use of objects for which they have lost conceptual knowledge (34).

Distribution Of The Apraxias In Other Body Parts

Truncal or whole body apraxia is a disorder of axial movements neither attributable to elementary motor (e.g., extrapyramidal) or sensory deficit nor to dementia. Patients have difficulties dancing or turning around and may be unable to adapt the body to the furniture patients have difficulty sitting down in a chair, showing hesitation, sitting in a wrong position (e.g., on the edge of the chair) and in incorrect directions (e.g., facing the back of the chair). When lying in bed, their body is not aligned parallel to the major axis of the bed and they place the pillow in an unusual position. Patients may have minimal or no difficulty in standing or getting up, in contrast to features of some basal ganglion disorders such as parkinsonism. Truncal apraxia is seen with bilateral hemispheric damage involving the parietal or parieto-temporal cortex or affecting parietofrontal connections (55,56). CBD patients may not only exhibit spatiotemporal errors when handling objects but in addition...

Apraxia In Other Atypical Parkinsonian Disorders

Limb apraxia is not observed (13), or exceptionally found with MSA (15) and has not been systematically studied in patients with demential Lewy bodies (DLB). However, we have found IMA with predominantly imitative deficits in three patients with mild to moderate DLB as clinically diagnosed by McKeith et al. criteria (72) (see also Abeleyra et al., in preparation) (videotape 5). Limb apraxic deficits in PSP seem to correlate with low MMSE, whereas in PD they appear to correlate with neuropsychological tests reflecting frontal lobe dysfunction and visuospatial cognitive deficits (13). Since focal lesions restricted to the basal ganglia only rarely cause apraxia and patients with MSA, which is characterized by severe basal ganglion and slight cortical involvement, fail to exhibit praxic deficits, we suggested that apraxia in PSP and PD reflect combined corticostriatal dysfunction (13). Cortical degeneration is now recognized to be common in PSP and identified mainly in the cingulate,...

Potential concerns with targeting CCR2

Two independent papers have highlighted the toxic effects of cellular products normally cleared by CCR2-dependent processes. In the first, it was shown that both CCR2_ _ and MCP-1_ mice begin to exhibit retinal degeneration after 9 months of age 53 . The authors hypothesized that impaired clearance of C5a and IgG enabled complement activation and immune complex deposition. In the second study, it was demonstrated that both CCR2_ _ and CCR2_ + mice exhibit enhanced mortality in an aggressive transgenic model of Alzheimer's disease 54 . The authors hypothesized that efficient clearance of Ap by microglial cells is a CCR2-dependent function.

Visuospatial Disorders In Parkinson Disease

Since degeneration of dopaminergic neurons constitutes the main biochemical abnormality found in PD, dopamine depletion has been considered to account for most of the symptoms, including behavioral abnormalities and cognitive deficits (89). If striatal dopamine deficiency plays a role in PD patients' cognitive deficit, specialized hemispheric functions contralateral to the motor symptoms should be altered in patients with hemiparkinsonism, providing a unique opportunity to study the effect of asymmetrical subcortical degeneration on cognitive functions (108). Yet, the results of these studies have been controversial. A number of studies were not able to demonstrate a specific pattern of difference between patients with predominantly left and right symptoms (9,109-111). However, a number of more recent studies (43,44) did find a specific directional bias related to the side of the predominant symptoms. On the other hand, Pillon et al. (112) demonstrated that cognitive impairment is...