Effective Diet for Alzheimer

Super Memory Formula

After the harsh reality that the doctor had to face his son ending his life, he suffered a major irreversible memory loss disease. This caused him to fall into depression and depend on the drugs from the pharma which was devasting for his mental and physical health and on so many other levels. After countless hours of research and experimentation, he realized that the root of all problems of memory loss was an enzyme that eats away the memory cells when the person gets older. This makes the person forget their loved ones, family and friends as if they have never met them. In some cases, they even forget about their past experiences, if they had children, how they came to the place they are in right now and who they are in the first place. This was exactly what the doctor had in his future if he did not make a decision. But he did and met with great people who helped him find the cure. This was a groundbreaking study that no one wanted to believe or endorse because it would go against the large pharma industry. However, the information is in there to protect yourself and your loved ones from such a devastating experience. You only need to follow the link and you will be guided to get the information downloaded to your device and follow the all-natural ways to get rid of memory loss. Continue reading...

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Key Molecules in the Alzheimers Pathology

Not much attention was paid to this disease for decades during which time this condition was often referred to as senile dementia. Great confusion existed as to whether the dementia often observed in old age and Alzheimer's disease were the same or different entities. It took nearly a century to define that the plaques were composed primarily of a specific peptide initially named A4 and today referred to as Ap (Glenner & Wong, 1984 Wong, Quaranta, & Glenner, 1985) and that tangles are composed primarily of hyperphosphorylated forms of tau, a microtubule-associated protein (Grundke-Iqbal, Iqbal, Quinlan, et al., 1986 Grundke-Iqbal, Iqbal, Tung, et al., 1986 Kosik, Joachim, & Selkoe, 1986 Wood, Mirra, Pollock, & Binder, 1986). Tau is a protein known to stabilize microtubules present primarily in axonal processes and involved in axonal transport of subcellular components. The abnormal phosphorylation of this microtubule-related protein leads to molecular protein structures called paired...

Tau Pathology in Alzheimers

As discussed above, in Alzheimer's disease, abnormally phosphorylated tau forms the so-called PHFs, which is the macromolecular assembly forming the core of the NFTs (Friedhoff, von, Mandelkow, & Mandelkow, 2000)(see also the chapter by Grundke-Iqbal in this book). NFTs invade the entirety of neurons forming fairly compacted and contorted filamentous structures that remain in the extracellular space after cell death. These NFTs have a clear-cut temporal and topographic distribution across brain areas as the disease progresses. The best staging of such structures has been provided by Braak and Braak (Braak & Braak, 1998). Interestingly, the earliest Braak stage is the occurrence of NFTs in the entorhinal cortex in the absence of an obvious deposition of Ap material in this brain region. This observation has been used as an argument to dissociate tau from Ap pathology in AD. The causal relation between these two molecular pathologies remains uncertain. However, relatively recent...

Additional Components of the Alzheimers Pathology

In an Alzheimer's diseased brain, the abnormalities of the key proteins Ap and tau result in a complex pathological cascade. The relative importance of the various components and the sequential evolution of this cascade is the subject of ongoing investigations. The simplified scheme of Fig. 3 attempts to highlight some of the most notable participants of this pathological cascade. Neurons possess APP molecules in their cell membrane and also in membranes of cell organelles (typically rough endoplasmic reticulum, Golgi complex, endosomes). In the cell surface the action of a-secretases (1) releases soluble APPa fragments which are regarded as neurotrophic molecules (Fig. 3). This is the APP nonamyloidogenic pathway, precluding the formation of Ap peptides. The APP amyloidogenic pathway (3) involves the sequential cleavage of APP in its p and y sites releasing Ap peptides. This process apparently involves an intracellular cycle and some of the Ap material accumulates abnormally in...

Clinical Evolution and Diagnosis of Alzheimers Disease a Synopsis

Alzheimer's disease is the main cause of dementia in the aged population. The earliest symptom is a gradual loss of memory, followed by increasing impairment of language abilities and other cognitive functions, such as mathematical abilities. AD sufferers develop impairments in naming objects and people, and have difficulty with word finding, often paraphrasing to define an object. At later stages, both verbal and written communication become compromised. Visual-spatial impairments result in objects being lost and to physical disorientation, for example, finding the way home. At advance stages, analytical capabilities are seriously compromised and one or more of the following behavioral symptoms, disinhibition, aggressiveness, agitation, delusions, hallucinations, or paranoia, are also exhibited. In the final stage, patients experience feeding difficulties, profound weight loss, ambulatory difficulties, motor dysfunction, and incontinence. There are a number of instruments to diagnose...

Synapses Neurotransmitters and Growth Factors in the Alzheimers Pathology

Besides the classical pathological hallmarks of NFTs and plaques, there is a widespread loss of synapses in AD. The point has been made that the extent of synaptic losses is a better correlation to AD cognitive impairments than plaques and tangles (Terry et al., 1991). There are molecules suspected of causing synaptic depletion, tau pathology by failing axonal transport, and creating conditions of synaptic starvation and the toxicity of Ap oligomers. Transgenic animal models have illustrated that the overexpression of Ap molecules per se is sufficient to provoke synaptic losses of which the cholinergic system appears as the most vulnerable in relation to glutamatergic and GABAergic synapses (Bell & Claudio, 2006 Bell et al., 2006). The choliner-gic vulnerability to the Ap burden is consistent with the preferential losses of cholinergic markers early noticed in AD brains by Davis and Maloney (1976) and Bowen and collaborators (1976) and with the apparent loss of cholinergic neurons of...

Instruments for assessing dementia and depression in the elderly

Epidemiological research on mental disorders in late life calls for specially built instruments to detect cognitive impairment, cognitive decline, depressive states, psychotic symptoms, and performance in the activities of daily living. All of the following have a section for assessing the elderly person and a separate section for an informant, who is usually a relative or close friend. The first to be developed was the Geriatric Mental State Examination ( GMS),(48) which has now been widely used. The second is CAMDEX,(49) which was intended as a clinician's instrument but can be used by laypersons after some training. A combination of parts of GMS and CAMDEX was used in a large United Kingdom study of cognitive impairment and dementia.(50) The third instrument is the Canberra Interview for the Elderly (CIE),(51) which is available in English, German, and French versions.(52) From CIE, Jorm and Mackinnon(53 developed the highly parsimonious Psychogeriatric Assessment Scales (PAS) to...

Changes in the concept of dementia

In the 1950s two important events occurred which led to new approaches to the concept of dementia. 1. Forms intermediate between senile dementia and the presenile dementia of Alzheimer were identified. Sj gren (24) described cases of dementia appearing at older ages than those reported for the presenile dementia of Alzheimer, without extrapyramidal signs, strokes, or signs of aphasia, agnosia, and apraxia, but with similar histopathology although the senile plaques and neurofibrillar tangles were less dense. Sj gren called this condition 'atrophia senilis cerebri'. During these years the Geneva School showed that patients with senile dementia could present, during the evolution of their disorder, with focal manifestations and lesions analogous to the those found in presenile dementia, in what they called 'Alzheimerized senile dementia'. This finding lead to a unifying thesis, so that parenchymatous dementias were usually referred to as 'senile dementia of Alzheimer type'. 2. Studies...

Studies of dementia in Parkinsons disease

Cases of dementia in Parkinson's disease have been reported for over a hundred years. Frequently, the relationship between dementia and this disease in reported cases is impossible to discern. A number of cross-sectional or prevalence studies of dementia in Parkinson's disease have been carried out. The frequency of dementia reported ranges from zero to 81 per cent. In a review of 17 studies Brown and Marsden found that, overall, 35 per cent of subjects were regarded as demented. (14 However, if more stringent criteria for dementia were applied then the proportions demented fell to between 15 and 20 per cent. The authors regarded these figures to be more realistic, and this Follow-up studies have great advantages in studying the frequency of dementia in Parkinson's disease they allow the diagnosis of Parkinson's disease to be checked repeated assessment reduces errors in the recognition of dementia the pattern of evolution of dementia may be followed the underestimation of dementia by...

Prediction of dementia in Parkinsons disease

There is a consensus from a number of studies as to which of those subjects with Parkinson's disease are most likely to suffer from dementia older people, patients with Parkinson's disease of longer duration, subjects who have a greater severity of motor symptoms and signs of Parkinson's disease, and those who show greater physical disability. M6 Some studies have shown that Parkinson's disease in men or of late onset is more likely to be associated with dementia. (,9) In parkinsonism, as distinct from Parkinson's disease, the likelihood of dementia is closely related to the pathological changes that underlie the symptoms of parkinsonism, which include diseases in which dementia is a leading feature, such as Alzheimer's disease. The explanation of an apparent association between the treatment of Parkinson's disease with levodopa and dementia is probably that successful treatment of the motor symptoms of Parkinson's disease prolongs life and thereby increases the risk of dementia.

The influence of dementia on mortality

Dementia of any origin is associated with an increased risk of premature death. A number of studies have shown an increased mortality in Parkinson's disease to be associated with age, late age of onset of this disease, cognitive impairment, dementia, and, in some studies, male sex. Certain medications have been associated with increased mortality. Many of the studies that have been carried out have been methodologically faulty, making comparisons between studies and the identification of the effect of particular factors, including dementia, problematic. A study, meeting most of the requirements for an accurate assessment of mortality, showed a hazard ratio for Parkinson's disease compared with controls of 1.64, in general, and of 1.94 for Parkinson's disease with dementia. (24 The occurrence of depression with Parkinson's disease led to increased mortality even more than dementia, with a hazard ratio of 2.66.

Clinical aspects of Parkinsons disease with dementia

The recognition of cognitive impairment in patients with Parkinson's disease has major implications for their management. Although prospective studies of patients with Parkinson's disease show that the illness usually follows a course extending over many years, dementia brings with it important changes in the care a patient will require and in their life expectancy. These needs will progressively increase and will place an increasing burden upon the patient's immediate family and carers. The timing of wills and other legal procedures may be affected. The most important step in the recognition of dementia in Parkinson's disease is to suspect its presence. There are many features of Parkinson's disease that tend to The clinical importance of dementia in Parkinson's disease is that there is a marked increase in disability, with problems arising in areas of functioning not previously affected by motor impairment alone. The development of drug treatments for dementia makes its recognition...

Cholinesterase Inhibitors for the Management of Noncognitive Symptoms in Dementia

The early studies of these treatments concentrated mainly, if not exclusively, on their ability to enhance cognition. However, it is important to consider their value in other aspects of dementia symptomatology. Neuropsychiatric symptoms and loss of functional ability are the main drivers for admission of a person with dementia to an institution, and the associated increase in cost of their care. They are also the main cause of stress in caregivers. Several reports have confirmed the benefits of ChEIs in modifying neuropsychiatric symptoms, (Levy, Cummings, & Kahn-Rose, 1999) (Francis, Palmer, Snape, & Wilcock, 1999 Trinh, Hoblyn, Mohanty, & Yaffe, 2003).

Memantine for the Treatment of Dementia Introduction

An early study (Winblad & Poritis, 1999) was the first to separate efficacy in AD and VaD. This was a relatively short, i.e., 12-week study of 166 patients with severe dementia, i.e., a mini-mental state examination (Folstein, Folstein, & McHugh, 1975) score of less than 10 30, of whom 49 had AD and 51 VaD. Memantine 10 mg, i.e., half the current maximum recommended daily dose, or placebo were compared on a number of outcome measures, including a clinical global impression of change scale and a functional scale. A positive outcome in favor of memantine was observed in both types of dementia. The tolerability of memantine has resulted in attempts to evaluate its potential for modifying difficult behavior in people with dementia, just as mentioned above, in relation to the ChEIs. Evidence in favor of this is beginning to emerge (Gauthier, Wirth, & Mobius, 2005) and it is beginning to be used off-license for this indication. There is, however, a suggestion that this requires caution in...

Memantine for the Treatment of Alzheimers Disease

Three of the other outcome measures showed changes in favor of memantine the severe impairment battery that measures cognitive impairment in advanced AD (Panisset, Roudier, Saxton, & Boller, 1994 Schmitt et al., 1997), the functional assessment staging scale (Sclan & Reisberg, 1992), and the resource utilization in dementia instrument assessing caregiver burden and AD-related health economic data (Wimo, Wetterholm, Mastey, & Winblad, 1998). In addition, memantine was well tolerated.

Dementias Classification

Alzheimer's Cerebrovascular Multi-infarct dementia Subcortical vascular Alzheimer's disease accounts for 60 of all dementias cerebrovascular disease 20 . It is important to investigate all patients with dementia as many causes are treatable in practice 10-15 can be reversed. Subdividing dementia depending upon the site of predominant clinical involvement is of questionable diagnostic value. However, many clinicians use this classification ALZHEIMER'S DISEASE AIDS DEMENTIA COMPLEX AIDS DEMENTIA COMPLEX e.g. ALZHEIMER'S DISEASE

Dementias specific diseases

MULTI-INFARCT (arteriosclerotic dementia) This is an overdiagnosed condition which accounts for less than 10 of cases of dementia. Dementia occurs 'stroke by stroke', with progressive focal loss of function. Clinical features of stroke profile - hypertension, diabetes, etc. - are present. Diagnosis is obtained from the history and confirmed by CT scan. This progressive condition accounts for 5 of all dementias. Usually sporadic, it more commonly affects women between 40 and 60 years. Frontal lobe dysfunction predominates with apathy, lack of initiative and personality changes. CT scan shows frontal atrophy. Blood flow studies (SPECT (HMPAO)) reveal anterior hypoperfusion. The disorder is characterised pathologically by argyrophilic inclusion bodies within the cytoplasm of cells of the frontotemporal cortex. There is no treatment, death occurring within 2-3 years of the onset. Dominant hemisphere perisylvian atrophy is associated with progressive disturbance of language which, after...

Dementia Diagnostic Approach

It is neither practical nor essential to perform all the screening tests in every patient with dementia. The presenting features should guide investigations. DEMENTIA Suspected cause Alzheimer's disease - Post-traumatic dementia - to diagnose early dementia - to separate true dementia from pseudodementia When the reason for dementia is unclear, comprehensive investigation is essential to ensure that treatable nutritional, infective, metabolic and structural causes are not overlooked.

Schizophrenia and Alzheimers disease

The belief that Alzheimer's disease is commoner in schizophrenia (independent of any cognitive impairment) originated in the 1930s. It received some recent support from three uncontrolled, retrospective studies, and tangentially from data suggesting that antipsychotic drugs promote neurofibrillary tangles. However, a meta-analysis shows that Alzheimer's disease is not more common, and may even be rarer, in schizophrenia. (29 This applies even in elderly schizophrenic patients with prospectively assessed severe dementia, who show no evidence of any other neurodegenerative disorder.(30) Nor is there good evidence that antipsychotic drugs cause Alzheimer-type changes. How, therefore, is the cognitive impairment of schizophrenia explained One possibility is that it is a more severe manifestation of whatever substrate underlies schizophrenia. Or, it may be that the brain in schizophrenia is more vulnerable to cognitive impairment in response to a normal age-related amount of...

Cholinergic Neurodegeneration in Alzheimers Disease

Abstract Neurotrophins play an important role in the survival, differentiation, and maintenance of neurons selectively involved in a number of disorders of the nervous system. Nerve growth factor (NGF) plays a vital role for basal forebrain cholinergic neurons (BFCNs), including the maintenance of the cholinergic phenotype in adults. Recognition of this role has suggested the use of NGF to ameliorate the loss of these neurons in Alzheimer's disease (AD). While clinical studies directed at supplying NGF to patients continue to be pursued, fundamental questions remain as to the relationship between selective vulnerability of cholinergic neurons and the actions of NGF. In this chapter, we review the structure and function of the basal forebrain cholinergic system, its role in higher cognitive functions, and the importance of NGF actions on these cells. Studies that link changes in NGF signaling to the degeneration of BFCNs are then discussed, as are current approaches to NGF-related...

Diagnostic Criteria for Delirium Dementia Alzheimers Disease and Vascular Dementia

A change in cognition or development of a perceptual disturbance is present and not explained by a preexisting, established or evolving dementia. Diagnostic criteria for dementia Cognitive impairment is present, as demonstrated by (1) memory loss and (2) Diagnostic criteria for Alzheimer's disease Dementia is present. History, physical and mental status examinations are consistent with Alzheimer's disease. Diagnostic criteria for vascular dementia Dementia is present. B. Testing a blood sample for apolipoprotein E may be used as an adjunct to other diagnostic procedures a positive test increases likelihood that the dementia is due to Alzheimer's disease. C. Physicians should rule out delirium and search for coexisting conditions that worsen dementia by reviewing medications, screening for depression, and ruling out nutritional deficiencies, diabetes mellitus, uremia, alterations in electrolytes and thyroid disease.

Frontal Temporal Dementia with Parkinsonism Linked to Chromosome

FTDP-17 is a heterogenous clinical pathologic entity that can now be defined by the presence of causative mutations in the tau gene (as described subsequently). As the name implies, the clinical picture is dominated by frontal-temporal dementia and parkinsonism. Different FTDP-17 syndromes have been described, and pheno-typic differences may reflect differences in regional distribution of tau pathology and degeneration in the brain (15).

Therapy of Alzheimers Disease

The discovery of the loss of the cholinergic neurons and acetylcholine in the brain of Alzheimer's disease patients led to the use of drugs that would enhance the actions of acetylcholine in the brain. Therapeutic agents approved for the treatment of Alzheimer's disease are the cholinesterase inhibitors, drugs that block the breakdown of acetylcholine and increase the availability of the neurotransmitter in synapses (see Chapter 12). These drugs are palliative only and do not cure or prevent neurodegeneration.

Future Directions in the Treatment of Alzheimers Disease

It is becoming clear that Alzheimer's disease is a multi-factorial syndrome and that unraveling its causes may be difficult. However, as knowledge of the mechanisms of degeneration are elucidated, this knowledge can be applied to the development of therapies to alleviate the symptoms and hopefully to prevent the disease or inhibit its progression.

The Rationale for an Immunological Approach to Alzheimers Therapeutics

Abstract Immunotherapy toward the AB peptide offers a unique therapeutic approach to the treatment of Alzheimer's disease. The rationale is that antibodies interacting with the Ap peptide will accelerate its clearance from the CNS, lead to less amyloid deposition, and reduce the other pathological features of Alzheimer's disease. Evidence from transgenic mouse models of amyloid deposition is highly supportive of both pathological and functional benefits of this approach. Data from human trials of active immunization (using a vaccine to stimulate generation of antibodies) led to several apparent cases of autoimmune CNS inflammation. However, some of the patients with high titers of brain-reactive antibodies have remained cognitively stable for up to 3 years after the vaccinations were halted. This has led to the investigation of passive immunotherapy, where monoclonal antibodies are injected directly on a monthly or bimonthly schedule, as a possibly safer, yet still effective approach...

Prevalence Neuropathology and Etiology of Alzheimers Disease

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder that currently affects 20-30 million individuals worldwide. With an increasing life expectancy, by 2050 the European region alone will harbor around 11.2 million prevalent AD cases (Wancata, Musalek, Alexandrowicz, & Krautgartner, 2003), a trend that could dramatically undermine the public health care system. The hallmark clinical symptom of the disease, cognitive decline leading to profound dementia, results at least in part from degeneration of cholinergic basal forebrain neurons that innervate the hippocampus and wide areas of the cortex (Whitehouse et al., 1982). Pathologically, AD is characterized by neuronal loss, neurofibrillary tangle (NFT) formation, and the extracellular deposition of amyloid-P (AP) plaques in susceptible brain regions. These lesions are accompanied by a chronic inflammatory response and extensive oxidative damage, which most likely occur in response to the amyloid pathology...

Cognitive Impairment and Dementia

The second theory is that the EDS contributes to the cognitive impairment found in patients with SDB. It is well known that one of the primary symptoms of SDB is EDS, and that EDS can impair cognitive functioning including auditory verbal learning (47), executive functioning, and working memory (48). It is also possible that the cognitive deficits found in SDB patients are a product of multiple factors, which may include both hypoxia and EDS. In addition, there is evidence that many of the progressive dementias involve degenerative pathologies in brainstem regions, areas that are responsible for regulating respiration and other autonomic functions relevant to sleep maintenance (49). Therefore, because many older adults suffer from dementia, it is possible that sleep disorders such as SDB may be more likely to occur in this group of patients. There are studies showing that the severity of the dementia is associated with the severity of the SDB (14,18). In institutionalized elderly,...

The Potential Application of Antioxidant Agents in Alzheimer Disease Therapeutics

Abstract Oxidative stress is a fundamental process contributing to the neuronal degeneration and death observed in Alzheimer disease, and many studies using markers of oxidative damage have provided evidence supporting this hypothesis. Consequently, antioxidants that prevent the detrimental consequences of oxidative stress are considered to be a promising approach to neuroprotection. While the clinical value of antioxidants for the prevention of AD is currently ambiguous, they still appear to be the most promising weapons that can be developed against disease progression.

Tau Pathology as a Target in Alzheimers Therapeutics

Keywords Abnormally hyperphosphorylated tau, Alzheimer disease, memantine, microtube-associated protein tau, microtubule assembly, neurofibrillary pathology, protein phosphatase-2A, tauopathies Abbreviations AD, Alzheimer disease PHF, paired helical filaments SF, straight filaments Abstract Alzheimer disease (AD) and related tauopathies are all characterized histopatho-logically by neurofibrillary degeneration of abnormally hyperphosphorylated tau. Unlike normal tau which promotes assembly and maintains structure of microtubules, the abnormal tau sequesters normal tau, MAP1, and MAP2, and causes disassembly of microtubules. This toxic behavior of the abnormal tau is solely due to its hyperphosphorylation because dephosphorylation restores it into a normal-like protein. The abnormal hyperphosphorylation also promotes the self-assembly of tau into paired helical filaments (PHF) straight filaments (SF) but, unlike the soluble abnormally hyperphosphorylated tau, the fibrillized protein is...

Alzheimers disease and other dementias Prevalence and incidence of dementia

The prevalence of dementia has been researched extensively and several meta-analyses have pooled data from a large number of studies. Figure.3 shows the prevalence of dementia by age group from three of these meta-analyses ,7,,8 and 9) The prevalence of dementia rises steeply with age, following approximately an exponential form up to the age of 90 years. There is dispute about what happens at older ages some authorities argue that the prevalence of dementia would eventually reach 100 per cent, whereas others believe that the rise in prevalence will eventually level off. However, the issue of what happens in extreme old age is best settled by incidence data, rather than prevalence, because any levelling off could be due to a shorter survival time after developing dementia. Fig. 3 Prevalence rates for dementia across age groups data from three meta-analyses. Of course, dementia is simply a syndrome caused by many different diseases. The prevalence of the underlying diseases is of more...

Risk factors for vascular dementia

Risk factors for vascular dementia have been investigated much less than those for Alzheimer's disease. The study of risk factors is complicated as there are several different types of vascular dementia, each of which is difficult to diagnose. The most common form is multi-infarct dementia, which is due to strokes. As might be expected, the risk factors for stroke also apply to this type of vascular dementia. The next most common form is subcortical vascular dementia in which there is vascular disease in the deep white matter of the cerebral hemispheres. Probable risk factors for vascular dementia are listed below. .i2 Old age as with Alzheimer's disease, the incidence of vascular dementia rises sharply with age. Family history first-degree relatives of individuals with vascular dementia or stroke have an increased risk of developing vascular dementia. ApoE genotype the e4 allele of the ApoE gene is a risk factor for vascular dementia as well as for Alzheimer's disease. Diabetes...

Synaptic Pathology In Dementia

Alzheimer's disease (AD) is a progressive cognitive disorder characterized by the accumulation of structural and biochemical changes that occur in association areas of the neocortex and the hippocampus. Recent work has demonstrated that synaptic loss provides an excellent correlation with cognitive ability and may provide the best correlate of dementia. The loss of synaptic connectivity in the brain of individuals with AD appears to occur early in the disease process and may represent a loss of brain plasticity. Decline in synaptic plasticity does not appear to be an inevitable consequence of the aging process but may be disease related. This chapter reviews and summarizes some of the morphological evidence for Alzheimer-related synaptic loss in the neocortex and hippocampus. Individuals with AD have a progressive decline in cognitive function. Although it is unclear what mechanisms are responsible for this cognitive demise, structural and biochemical changes in cortical and...

Evidence against cortical Lewy bodies as the sole cause of dementia

Recently, as few as 20 of cases with cortical a-synuclein pathology were retrospectively diagnosed in medical records as having PDD or DLB and this pathology was the ''sole cause'' for dementia in only 45 of those cases (Parkkinen et al., 2005). Alzheimer-type pathology has also been linked to the aetiopathogenesis of PDD. In one series, moderate to severe dementia was reported in 33 of 200 consecutive autopsied PD cases, with degree of cognitive impairment significantly correlated with AD pathology (Jellinger et al., 2002). AD lesions corresponding to CERAD B or C were seen in 84 of the demented PD cases. Regional NFT counts have also been correlated with dementia in PD. In one small series of PD cases, although there were no significant group differences in allocortical or neocorti-cal LB counts between demented and non-demented PD groups, mean entorhinal NFT severity ratings were more than twice those for non-demented cases (SantaCruz et al., 1999). Senile...

Possible drug effects on disease progression and dementia

Drugs currently used symptomatically in the management of PD and its complications may have adverse effects upon rate of cognitive decline. Thus, PD patients exposed to long term (defined as more than two years) anticholinergic medication have 2.5-fold higher cortical densities of SPs, compared to PD patients with short-term or no exposure to these drugs (Perry et al., 2003). In this study, NFT densities were also increased in the chronically treated PD group. These data raise the possibility that anticholinergic drugs, currently commonly used to treat bladder dysfunction, or tricyclic antidepressants with anticholinergic properties, may induce a pathological substrate for dementia in PD. Observational studies indicate that rate of cognitive decline is doubled in demented patients (not PD) taking typical antipsychotics. Most recently, the atypical antipsychotic, quetiapine, has been associated with a significantly more rapid rate of cognitive decline in Alzheimer disease patients...

Multifunctional Neuroprotective Drugs for the Treatment of Alzheimers Disease

Abstract The concept of targeting multiple disease etiologies that lead to cognitive impairment in the neurodegenerative disorder Alzheimer's disease (AD) is challenging the widely held assumption that silver bullet agents are superior to dirty drugs in drug therapy. Accumulating evidence in the literature suggests that a drug with two or more mechanisms of action targeted at multiple etiologies of the same disease may offer more therapeutic benefit in certain disorders than a drug that targets one disease etiology only. In addition, such multiple mechanism multifunctional drugs may exhibit a more favorable side effect profile than a polypharmaceutical combination of several drugs that individually target the same disease etiologies than those identified for a single multifunctional drug. In this chapter, we offer a synopsis of therapeutic strategies and novel investigative drugs, developed in our own and other laboratories, which modulate multiple disease targets associated with AD...

A key to memory loss oligomers ADDLs specifically target synapses

The identity of the hot-spots themselves may be the key to memory loss mechanisms. More than 90 of ADDL hot-spots co-localize with puncta of PSD-95 (Lacor et al. 2004a), a major component of post-synaptic densities that, in mature hippocampal cultures, is a reliable marker for post-synaptic terminals (Allison et al. 2000). Colo-calization of ADDLs with PSD-95 establishes that ADDLs are ligands that specifically target synapses. Roughly 50 of the synapses do not bind ADDLs, so specificity extends also to the nature of the synapses. The fact that ADDLs are ligands that directly and specifically attack synapses provides substantial strength to the hypothesis that memory loss could be an oligomer-induced failure of synaptic plasticity.

Neuropsychological Characteristics Of Dementia In Pd

In the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV),47 dementia is defined as the development of multiple cognitive deficits that affect memory and that result in aphasia, apraxia, agnosia, or executive dysfunction. Impairment must result in occupational or social dysfunction, must represent a decline from a previous level of ability, and must exist separate from delirium. Given that the bedside evaluation, the MiniMental State Examination,48 and other common screening measures may not be sensitive to the presence of dementia in PD, an in-depth cognitive evaluation is often essential. In many cases, neuropsychological evaluation can assist in determining whether cognitive impairment or dementia

Cognitive Dysfunction In The Absence Of Dementia

A proportion of individuals with PD will be spared clinically significant changes in cognition.49 However, it is widely recognized that mild cognitive dysfunction occurs in patients, even early in the course of the disease5051 and in the absence of frank dementia.5253 When dementia is absent, cognitive dysfunction tends to be rather circumscribed, and executive and language functions, memory, and visuospatial skills are most often affected.54 (Please refer to Table 33.1 for examples of tasks that assess these skill areas.)

Characteristics Of Dementia

If present, dementia often emerges late in the course of the illness.20 In addition, it is thought to be characterized by intellectual deterioration that is often less pronounced than that which accompanies AD and other cortical dementing illnesses.99 100 This has led some to suggest that the pattern of deterioration, which is often described as Subcortical dementing illnesses are typically characterized by slowed mentation (or bradyphrenia), alterations in personality and in mood, deficient manipulation of acquired knowledge, and forgetfulness or diminished retrieval of learned information. Frank amnesia, aphasia, apraxia, and agnosia, which are thought to be cardinal features of cortical illness, are often absent.101 While some investigators99 defend the use of this heuristic approach in characterizing the pattern of impairment that may accompany PD, others102,103 note that there is little evidence to support its continued use. Specifically, they point to postmortem investigations...

Ladostigil a novel multifunctional drug for the treatment of dementia comorbid with depression

Ladostigil is a novel drug that inhibits acetyl and butyrylcholinesterase, and monoamine oxidase (MAO) A and B selectively in the brain. It reverses memory deficits induced by chronic inhibition of cortical cytochrome oxidase in rats and has anxiolytic and antidepressant-like activity in prenatally-stressed rats. Ladostigil also prevents oxi-dative-nitrative stress induced in astrocytes in the hippocampal CA1 region following icv injection of STZ in rats which also impairs their episodic memory. The unique combination of ChE and MAO enzyme inhibition combined with neuroprotection makes lados-tigil a potentially useful drug for the treatment of dementia in subjects that also have extrapyramidal dysfunction and depression. Progressive neuronal loss resulting in deficits in cortical cholinergic transmission occurs in the three major forms of dementia, Alzheimer (AD) vascular (VD) and dementia with Lewy bodies (DLB). These deficits are strongly correlated with impairment of...

The amyloid cascade hypothesis revisited memory loss in early AD is a synaptic disease caused by soluble Ap oligomers

LTP is not memory but is widely recognized as a good experimental paradigm for the study of memory mechanisms. The rapid impact of oligomers on LTP thus is intuitively appealing in its relevance to AD, and in 1998 we proposed a new hypothesis that attributed early memory loss to oligomer-induced failure in synaptic plasticity (Lambert et al. 1998). The experimental foundation for this concept has been substantiated in multiple investigations (Chen et al. 2000 Vitolo et al. 2002 Klyubin et al. 2004, 2005 Wang et al. 2004a Costello et al. 2005 Nomura et al. 2005 Puzzo et al. 2005 Trommer et al. 2005 Walsh et al. 2005), with especially strong support found in a major study of LTP by Walsh, Selkoe and colleagues (Walsh et al. 2002). That group showed that oligomers found in medium conditioned by hAPP-transfected CHO cells are exceptionally potent inhibitors of LTP in vivo. Western blots indicate that the cell-derived oligomers comprise mostly small SDS-stable oligomers, free of structures...

Neuropsychological Prediction Of Incident Dementia

Is there a pattern of neuropsychological impairment that might predict the onset of dementia in PD Demographic risks (e.g., older age) have been identified, and risks related to the disease itself (e.g., motor symptom severity) have been acknowledged.18,33 Research has also begun to highlight the presence of a pattern of neuropsychological risk, and several authors71,94,95 have suggested that subtle executive dysfunction may precede the onset of dementia in PD. For example Jacobs et al.71 noted an association between poor baseline performance on measures of lexical and semantic fluency and the eventual occurrence of dementia. These authors suggest that executive dysfunction might underlie deficient task performance in this instance, as adequate performance on these measures likely requires the initiation of a systematic semantic memory search. Mahieux et al.96 also noted an association between deficient lexical fluency and the subsequent development of dementia in PD. In addition, the...

Natural History of Alzheimers Disease

Presymptomatic Prodromal Mild dementia Incident dementia Progression to dementia Cognition and global impression of change Conversion from aMCI to diagnosable dementia on care (Galasko, Edland, et al., 1995). For example, if the studies in aMCI using ChEI had demonstrated a sustained delay in progression to dementia, such patients would have been actively treated with these drugs worldwide. Delaying loss of autonomy for self-care and even death in moderate-to-severe stages of AD using a-tocopherol in only one study performed by the Alzheimer disease cooperative study group (Sano et al., 1997) has influenced clinical practice to use vitamin E in all stages of AD, at least in the USA, until a meta-analysis showed higher mortality associated with vitamin E at doses of 400 IU per day or higher (Miller & Pastor-Barriuso, 2005). Delaying the loss of autonomy for ADL or the emergence of some of the BPSD could reduce the burden of the caregiver and delay the need for nursing home placement....

Axial and diencephalic dementias

The Korsakoff syndrome is the prototype of the axial or diencephalic dementias. It is characterized by anterograde and retrograde amnesia, temporospatial disorientation, confabulation, false recognition, and occasionally euphoria. The main lesions are localized to the structures of the Papez system, especially the mamillary bodies, although there is always some frontal involvement. The amnesia is anterograde as well as retrograde, and it is reported that patients lack insight into it. (46 However, Shimamura and Squire(47 have reported that most patients with Korsakoff syndrome are aware of their amnesia and of their failures on tests. There is dissociation between explicit and implicit memories. The Korsakoff patient can learn, but is unable to remember the learning process, a fact described by Calparede in 1911.(48 For example, if a Korsakoff patient is pricked while shaking hands, he learns not to shake hands again although he is unable to explain why. The Korsakoff syndrome is...

Box 312 The 1066 Dementia Research Group key findings

People with dementia were heavy users of health services, and associated direct costs were high. Compensatory financial support was negligible few older people in developing countries receive government or occupational pensions, and virtually none of the people with dementia in the 10 66 study received disability pensions. Caregivers were commonly in paid employment, and almost none received any form of caring allowance. The combination of reduced family incomes and increased family expenditure on care is obviously particularly stressful in lower income countries where so many households exist at or near subsistence level. While health-care services are cheaper in low income countries, in relative terms families from the poorer countries spend a greater proportion of their income on health care for the person with dementia. They also appear to be more likely to use the more expensive services of private doctors, in preference to government-funded primary care, presumably because this...

Differential diagnosis of vascular dementia disease

Alzheimer's disease Typical Alzheimer's disease is characterized by insidious onset and slowly progressive intellectual deterioration, absence of symptoms and signs indicating focal brain damage, and absence of any other specific disease affecting the brain. (65 Alzheimer's disease has typical clinical stages ranging from early changes to profound dementia 6,67) When patients with vascular dementia have a clinical history, neurological examination, and brain imaging findings compatible with ischaemic changes of the brain, the differentiation from Alzheimer's disease can be made clinically. (25 Diagnostic problems arise when Alzheimer's disease is combined with cerebrovascular disease. Difficult clinical problems include stroke unmasking Alzheimer's disease in patients with post-stroke dementia, insidious onset, and or slow progressive course in vascular dementia patients, and cases where it is difficult to assess the role of white-matter lesions or of infarcts found on neuroimaging....

Dementia in motor neurone disease

The clinical picture of the dementia in motor neurone disease is similar to that in FLD with early changes of personality and behaviour, lack of insight, and signs of disinhibition such as restlessness, irritability, unrestrained sexuality, and hyperorality. (j Speech becomes stereotyped and perseverative, later developing into mutism. Receptive speech function, orientation and practicable abilities remain relatively untouched by the degenerative process. Emotional changes such as euphoria and apathy may appear and the face becomes expressionless. The mental changes may appear early in motor neurone disease and even precede development of typical neurological features.

Alzheimers Disease and Tauopathies

In Alzheimer's disease, Ap peptides (Ap42 and Ap40) are the principal components of extracellular amyloid plaques. These aggregation-prone peptides are generated in the secretory pathway by the sequential action of p- and y-secretase on the transmembrane Ap precursor protein (APP) (review in Walter et al. 2001). In a cell culture model it has been shown that the ER-resident Hsp70 homolog BiP Grp78 interacts with immature APP and decreases the secretion of Ap42 and Ap40 (Yang et al. 1998). Whether this decrease in Ap secretion is due to an impairment of APP processing or an intracellular retention of Ap was not addressed in this study. Using an inducible adenoviral-based system, Magrane et al. could show that targeted expression of Ap42 in the secretory pathway of primary neurons induces apoptotic cell death, which is suppressed by overexpression of Hsp70 (Magrane et al. 2004). Although no evidence for a physical interaction of Ap42 and Hsp70 is provided in this study, it is conceiv A...

Imaging Of Dementia In Pd

In the evaluation and management of PD, neuroimaging tends to occupy an ancillary position. Widely available imaging modalities, as currently utilized, primarily examine anatomy and effectively evaluate for the presence of space-occupying lesions (i.e., malignancy, ischemia, and so on). Magnetic resonance (MR) imaging has largely supplanted computed tomography as the method of choice for this application. Functional imaging with positron emission tomography (PET) and single-photon emission computed tomography (SPECT) is not readily available and is less often used for diagnostic purposes. Refinements in MRI technology are expanding its application beyond simple assessment of structure. Imaging is being increasingly utilized to characterize the diverse manifestations of PD, their progression, and to determine the impact of treatment on disease natural history. These insights will hopefully lead to improved differentiation of the parkinsonian syndromes as well as contrast PDD with other...

The methodology of studies of dementia in Parkinsons disease

Research to establish the status of dementia in Parkinson's disease has confronted a range of methodological issues. (H) A major problem in research on dementia in Parkinson's disease has been in the diagnosis of Parkinson's disease itself. The original description of paralysis agitans by Parkinson was, in fact, the identification of a syndrome rather than of a disease. The part played by such agents as heavy metals, infection, and vascular disease was recognized more than 50 years ago. More recently, the importance of drug-induced parkinsonism, where patients generally recover following withdrawal of the drug, has been recognized. The term Parkinson's disease had come to be regarded as synonymous with idiopathic Parkinson's disease and paralysis agitans, and to be a degenerative disease of unknown cause. In spite of the use of standardized methods of diagnosis, recent studies have shown that a substantial proportion of patients diagnosed as suffering from Parkinson's disease in life...

Behavioural and psychological symptoms of dementia

Depression, anxiety, emotional lability and incontinence, and other psychiatric symptoms are frequent in vascular dementia. Depression, abulia, emotional incontinence, and psychomotor retardation are especially frequent in subcortical vascular dementia disease. ( 36) Cardinal features of vascular dementia disease are incorporated in the Hachinski Ischaemia Score (5 ' (Ta.b.le,.5). In a recent neuropathological series, stepwise deterioration (odds ratio, 6.0), fluctuating course (odds ratio, 7.6), history of hypertension (odds ratio, 4.3), history of stroke (odds ratio, 4.3), and focal neurological symptoms (odds ratio, 4.4) differentiated patients with definite vascular dementia from those with definite Alzheimer's disease. (52 Nocturnal confusion and depression did not discriminate. However, the ischaemia score was unable to differentiate the Alzheimer's disease patients with cerebrovascular disease from those with vascular dementia.

Markers of Glutamate Neurotransmission in Alzheimers Disease

Pyramidal neuron loss is a feature of Alzheimer's disease (AD) (Francis et al., 1993 Morrison & Hof, 1997 Neary et al., 1986) and this can be seen reflected as atrophy and in loss of wet weight and total protein of cortical regions by gravimetric analysis (Najlerahim & Bowen, 1988a, 1988b). Glutamatergic neurons account for many of the neurons lost in the cerebral cortex and hippocampus in AD (Greenamyre, Maragos, Albin, Penney, & Young, 1988 Morrison & Hof). Accompanying loss of cells is a loss of synapses, and indeed this may precede overt cell loss (DeKosky & Scheff, 1990 Terry et al., 1991). Pyramidal neurons are also subject to tangle formation, which is likely to impair neuronal function, particularly protein synthesis and axonal transport (Chee et al., 2006 Mann et al., 1981 Mudher et al., 2004). On the postsynaptic side, a large decrease in glutamate receptors has been observed in the cortex (Greenamyre, Penney, D'Amato, & Young, 1985) and hippocampus (Greenamyre, Penney,...

Alois Alzheimers Realization of a Dementia Accompanied with a Defined Brain Pathology

The devastating neurological disorder known today as AD was first clinically recognized in 1901 by Alois Alzheimer, a German clinician working at a Frankfurt hospital. Alzheimer was interested in neurohistology and learned basic staining techniques from his colleague Nissl, around the time of the emergence of Cajal's neuronal theory. He examined a 51-year-old patient (Auguste D) who had difficulty naming familiar objects, writing complete sentences, and remembering words. She repeated I have lost myself, was strongly jealous toward her husband, and experienced increasing memory impairments and disorientation. She carried around various objects and hid them, and occasionally felt that someone wanted to kill her and sometimes screamed out loudly. Alois Alzheimer followed the progress of this patient even after he moved to Munich. Auguste D died in 1906, several years after her dementia was diagnosed. Alois Alzheimer performed a postmortem examination of the brain and applied...

Neurochemistry Of Dementia In Pd

Surprisingly, the neurochemical modifications that attend cognitive decline in PD have received limited direct exploration. Necropsy description of degeneration within select populations of neurons has provided the impetus to examine specific transmitter systems. While degeneration of dopaminergic neurons in the substantia nigra compacta (SNc) is the pathologic hallmark of PD, depletion within the lateral compartment, projecting to the putamen, accounts for characteristic motor dysfunction. Degeneration within the medial SNc, with projections primarily to the caudate nucleus, correlates with cognitive disturbance measured by a global scale.144 In addition, diminished binding to the D1 subtype of dopamine receptor in the caudate nucleus also correlates with the magnitude of cognitive dysfunction.145 Cholinergic dysfunction, prominently involved in AD, is also observed in PDD. This is indicated by the finding that the affinity with which 3H quinuclidinylbenzilate (QNB) binds to...

Frontotemporal Dementia And Enhanced Creativity

Frontotemporal dementia (FID) is a rare form of dementia specific to the frontal and temporal lobes, that accounts for as much as 25 of the presenile dementias (Miller et al., 1998). A number of studies have now documented the bizarre finding that in relation to the temporal lobe variant of FTD, enhanced artistic ability often emerges amidst an otherwise progressive cognitive decline. In the temporal lobe variant of FTD, the anterior temporal and basal frontal lobes atrophy slowly while dorsolateral frontal areas remain intact (Miller et al., 1998). Miller, Ponton, Benson, Cummings and Mena (1996) describe a 56-year-old businessman with the temporal lobe variant of FTD who began painting for the first time, despite no previous interest in art. The subjective experience described by the patient was one of heightened visual awareness, whereby lights and sounds were experienced as either intensely painful or as producing a euphoria that enhanced creativity. Even more unusual was the...

Neurological disorders and sleepwake disturbances Neurodegenerative disorders Alzheimers disease

Sleep disturbances in Alzheimer's disease may be related to the severity of dementia and possibly to the associated periodic limb movements in sleep ( PLMS) or sleep-related respiratory dysrhythmias. The presenting complaints include insomnia, inversion of sleep rhythm, and in some cases, excessive daytime sleepiness. 'Sundowning' is a major problem, characterized by episodes of confusion accompanied by partial or complete inversion of sleep rhythm with increased wakefulness at night and excessive daytime sleepiness. Mechanisms of sleep disturbances in Alzheimer's disease include degeneration of the neurones of the suprachiasmatic nuclei. Other factors include associated depression, PLMS, general medical disorders, medication effects, and environmental factors. Sleep disruption in Parkinson's disease can also be caused by depression, dementia, sleep apnoea, restless legs syndrome, REM behaviour disorder (see Chapter 4,14,4), other parasomnias (sleep walking, sleep talking), and...

Alzheimers Disease

Alzheimer's disease is a slowly developing neurodegen-erative disease that produces a progress loss of memory and cognitive function, that is, dementia. These functional changes appear to result primarily from the loss of cholinergic transmission in the neocortex. The four cholinesterase inhibitors that have been approved for use in the palliative treatment of Alzheimer's disease are tacrine, donepezil, rivastigmine, and galanthamine. These agents can cross the blood-brain barrier to produce a reversible inhibition of AChE in the CNS. These compounds produce modest but significant improvement in the cognitive function of patients with mild to moderate Alzheimer's disease, but they do not delay progression of the disease. Donepezil, rivastigmine, and galanthamine are as effective as tacrine in increasing cognitive performance but do not share tacrine's hepa-totoxic effects.


The term 'dementia' refers to patients with chronic brain damage and severe deterioration of intellectual processes. Frequently, psychotic symptoms (hallucinations and delusions) and affective symptoms are also present. This syndrome has a long history in antiquity it had a meaning similar to that understood today when used in a medical context (Celsus, 150 BC). The term 'dementia' was recognized by Pinel,(8) and Esquirol(9) distinguished acute dementia (later called mental confusion) and chronic dementia. Georget(l subdivided the latter into primary dementias, so called because the intellectual disorder appeared first, and secondary dementias, in which other mental manifestations (e.g. mania and dementia praecox) preceded the intellectual disorder. There are two periods in the subsequent history of dementia. In the first and longest, from the beginning of psychiatry to the 1970s, dementia was considered as an illness. Since then, dementia has been considered to be a syndrome. The...

Dementia Pugilistica

Dementia pugilistica is a form of chronic traumatic brain injury associated with boxing and clinically characterized by motor, cognitive, and or behavioral impairments that typically become clinically evident after the cessation of a boxing career (50). Early motor impairments may include mild dysarthria and difficulty with balance progressing to ataxia, spasticity, impaired coordination, and parkinsonism (50). Pathologically, the disease is characterized by deposition of abundant neurofibrillary tangles and amyloid plaques, similar to those seen in AD (51-53). In addition, glial tau pathology is frequently seen in dementia pugilistica. Just as in AD and ALS PDC Guam, the hyperphosphorylated tau pathology in dementia pugilistica comprises all six brain tau isoforms, suggesting that recurrent brain injury may cause dementia pugilistica by similar mechanisms as seen in AD and other neurodegenerative diseases (51).

Alzheimer disease

After NGF, pro-NGF is the predominant form of NGF in mouse, rat and human brain tissues. Not only is NGF protein increased in Alzheimer diseased brains, but also pro-NGF is increased in Alzheimer's diseased parietal cortex, indicating that it is the precursor form, pro-NGF, that accumulates in Alzheimer's disease. This increase may reflect either a role for biologically active pro-NGF or posttranslational disturbances in NGF biosynthesis that decrease the processing of pro-NGF to mature NGF in Alzheimer's disease.

Cortical dementias

Cortical dementias are classified into frontotemporal dementias, temporoparietal dementias, and occipital dementias. Frontotemporal dementias Frontotemporal dementias are characterized not by a loss of function but by an inability to act. There is apathy, indifference, or in contrast lack of inhibition, and the patient fails to make plans to change from one activity to another, and to select the actions needed to solve a problem. This syndrome is not necessarily due to lesions of the frontal lobe, but may arise from lesions in the frontal projection system and from other subcortical diseases, including Korsakoff's syndrome. 3. anterior cingulate syndrome which is characterized by apathy and reduction of initiative, which in extreme cases manifests as akinetic mutism. Temporoparietal dementia Temporoparietal dementia includes Alzheimer's disease. In a series of studies, the Geneva School(3,40 have found that this disease is characterized by a disintegration of psychological functions...


Dementia may occur at any age but is more common in the elderly, accounting for 40 of long-term psychiatric in-patients over the age of 65 years. A recent study shows an annual incidence rate of 187 100 000 persons. Dementia is a symptom of disease rather than a single disease entity. When occurring under the age of 65 years it is labelled 'presenile' dementia. This term is artificial and does not suggest a specific aetiology. The duration of history helps establish the cause of dementia Alzheimer's disease is slowly progressive over years, whereas encephalitis may be rapid over weeks. Dementia due to cerebrovascular disease appears to occur 'stroke by stroke'. All dementias show a tendency to be accelerated by change of environment, intercurrent infection or surgical procedures. This initial phase of dementia may be inseparable from the pseudodementia of depressive illness.

The pace of scientific advance

Advances in genetics and in the neurosciences have already increased knowledge of the basic mechanisms of the brain and are beginning to uncover the neurobiological mechanisms involved in psychiatric disorder. Striking progress has been achieved in the understanding of Alzheimer's disease, for example, and there are indications that similar progress will follow in uncovering the causes of mood disorder, schizophrenia, and autism. Knowledge of genetics and the neurosciences is so extensive and the pace of change is so rapid that it is difficult to present a complete account within the limited space available in a textbook of clinical psychiatry. We have selected aspects of these sciences that seem, to us and the authors, to have contributed significantly to psychiatry or to be likely to do so before long.

The burden of mental illness

Using the DALY as the basic statistic, the World Development Report(2) concludes that mental health problems make up 8.1 per cent of the total GBD. Of that 8.1 per cent, the largest contributors are depressive disorders, self-inflicted injuries. Alzheimer's disease and other dementia, and alcohol dependence, followed by epilepsy, psychoses, drug dependence, and post-traumatic stress disorder. Depressive and anxiety disorders account for between one-quarter and one-third of all primary-health-care visits worldwide.(3,,4) When appropriately diagnosed and treated, suffering is alleviated, disability prevented, and function restored when ignored, major losses persist.(5) By the year 2025, three-quarters of all elderly persons with dementia (about 80 million) will live in low-income societies. Mental retardation and epilepsy rates are three to five times higher in low-income societies compared with industrialized countries. In some Asian and African countries, up to 90 per cent of patients...

Contemporary Neuroscience

Mattson, 1998 Clinical Pharmacology of Cerebral Ischemia, edited by Gert J. Ter Horst and Jakob Korf, 1997 Molecular Mechanisms of Dementia, edited by Wilma Wasco and Rudolph E. Tanzi, 1997 Neurotransmitter Transporters Structure, Function, and Regulation, edited by Maarten E. A. Reith, 1997 Motor Activity and Movement Disorders Research Issues and Applications, edited by Paul R. Sanberg, Klaus-Peter Ossenkopp, and Martin Kavaliers, 1996 Neurotherapeutics Emerging Strategies, edited by Linda M. Pullan and Jitendra Patel, 1996 Neuron-Glia Interrelations During Phylogeny II. Plasticity and Regeneration, edited by Antonia Vernadakis and Betty I. Roots, 1995

The social aspects of psychiatry and the asylum system

The legal code promulgated by Napoleon in 1810 stipulated that 'no crime or delict exists if commited in a state of dementia', with the old term dementia being used as a synonym of Pinel's mental alienation. This legal provision, introduced in similar forms in other countries, opened an important domain of activity to the medical profession of psychiatrist. Because of their now recognized specialized knowledge, the alienists were to help the judges in determining whether the mental state of an individual convicted of a 'crime or delict' was normal or pathological, with decisive consequences on the subsequent decision. The title of Esquirol's Treatise mentions explicitely that it describes the mental diseases 'in their medical, hygienic and medico-legal aspects'. The conflict (which still exists) between the judges, usually supported by public opinion, who took a restrictive view of the concept of mental disease, and the psychiatrists, who tended to expand it to include new types of...

Neuroradiology And Ultrasound

PET and SPECT are used to create cross-sectional functional images of the brain. SPECT, which is available in all nuclear medicine departments, can be used to study changes in regional blood flow in the brain. It has been used in the investigation of dementia, where changes in regional blood flow can differentiate between multi-infarction dementia and Alzheimer's disease. It is helpful when considering surgery for intractable complex partial seizure disorder, giving further weight to structural information concerning mesial temporal sclerosis seen on MRI.

Advances in Neuroacanthocytosis

The collaborations initiated at this meeting led to the second Neuroacanthocytosis Symposium (Montreal Neurological Institute, Montreal, Canada, April 2005) and the third symposium, a satellite meeting of the 10th International Congress of Parkinson's disease and Movement Disorders, organised by the Movement Disorder Society, in Kyoto, Japan, October 2006 (Figs. 1 and 2 of the Foreword). An interim meeting was convened at the Third International Congress on Vascular Dementia in Prague, Czech Republic, October 2003 27 .

From complaints to formulation

The second box indicates that the complaints need to be sorted out into symptoms and impairments (an impairment in this sense is interference with a normal physiological or psychological function, as explained below). Some complaints are both symptoms and impairments symptoms because it is known that they can contribute towards the recognition of an underlying diagnosis or towards the identification of a disorder, and impairments because they indicate measurable interference with the function of a part of the body or of a particular organ. For instance, inability to remember the time of the day is a symptom (disorientation in time) that may contribute towards a diagnosis of some kind of dementia. It is also an impairment of cognitive functioning that is likely to interfere with the performance of everyday activities such as getting up and going to bed at the correct time, and organizing housework.

NAA and Magnetic Resonance Spectroscopy

Finally, it is important to note that there are two distinct NAA research communities one group involved in basic research into the neurochemistry of NAA, and another group which employs MRS techniques for the non-invasive analysis of NAA levels in the brain with respect to clinical applications. NAA levels measured by MRS have been shown to be changed in a number of neurological disorders. These studies have mostly detected decreases in NAA, with the exception of Canavan disease which involves accumulation of NAA in the brain.37 The diseases and disorders in which NAA levels are decreased include stroke,38 Alzheimer's disease,39 epilepsy,40 brain cancer,41 multiple sclerosis42 and AIDS dementia complex.43 Earlier, the decreases in NAA were interpreted to represent irreversible loss of neurons. However, more recent evidence indicates that these decreases also could represent reversible mitochondrial dysfunction.23,24 In support of this view, some evidence has been presented showing...

Tests of cognitive and neuropsychological functioning General ability and intelligence

A very useful broad screening test, especially when it is suspected that mental functions are severely compromised, is the Mini-Mental State Examination. (5,6,) It is brief, to the point, and can be repeated over time to gauge change. It measures general orientation in time and place, basic naming, language and memory functions, and basic non-verbal skills, and has good norms for a middle age range, especially the elderly, with appropriate adjustment for age. The maximum score is 30, and a score of 24 or less raises the possibility of dementia in older persons, especially if they have had 9 or more years of education (a score of 24 is at about the 10th percentile for people aged 65 and older).

Degenerative Diseases

So far, the authors have found it rare to have the final diagnosis be an unexpected degenerative disease. Neurosurgeons may be asked by neurologists to perform a biopsy for suspected neuronal storage diseases and leukodystrophies of different types, Creutzfeld-Jakob disease (CJD), Alzheimer's disease and Pick's disease, as well as for patients who show progressive deteriora

Genes Causing Parkinsonism

Golbe and his colleagues first reported a large family with an autosomal dominant form of parkinsonism in 1990 (20). Beginning with patients living in New Jersey, United States. the ancestry of this family was traced to a single couple in the village of Contursi, in the Campania region near Salerno in the south of Italy. Members of this family had immigrated to the United States around the turn of the 20th century and more than 60 family members over five generations had been diagnosed with disease. The disease described in this family ranged from a relatively typical PD to a disorder more reminiscent of diffuse Lewy body disease. The mean age at onset is early (mean 45.6, SD 13-48) and patients often develop dementia (21). In 2003, our group identified a genomic triplication of the SNCA locus, including the entire a-synculein gene and 1.5 megabases of flanking genomic sequence, segregating with disease in a large family called the Iowan kindred (30). Similar to the kindreds described...

Comments On Metal Ions In Neurology

The brain utilizes metal ions for myriad biochemical reactions, and cortical neurons release ionically exchangeable copper 3 and zinc 4 during depolarization and neurotransmission. Abnormalities of metal ion biochemistry in neural tissue arise by two basic mechanisms (i) protein aggregation mediated by metal ions, e.g., zinc induction of Alzheimer's disease -amyloid (A ) deposits 5 and (ii) oxidative reactions catalyzed by redox-active metals. Figure 1. Reactive oxygen species generation by redox-active metals as the basis for 'oxidation disorders'. The vast majority of biochemical radicals and ROS arise from the redox chemistry of metals. Dissolved molecular oxygen (O2) is liable to react with redox active metals (Mx, representing Cu or Fe ions most commonly, but also occasionally Cd, Hg, and Pb which may indirectly participate in redox reactions). Cu and Fe ions in their reduced state (Mx-1) will reduce O2 to superoxide O-, which is then dismutated or disproportionated to H2O2,...

Changes in discharge rate

Traditional models of the pathophysiol-ogy of parkinsonism are strongly influenced by this anatomic arrangement (reviewed in Wichmann and DeLong, 2003 Albin et al., 1989), which suggests that the overall amount of movement is in some way inversely related to the magnitude of basal ganglia output. According to the scheme mentioned above, loss of striatal dopamine within the motor circuit would result in increased STN activity, and increased basal ganglia output, reduced thalamocortical activity and the development of parkinsonian motor signs, such as akinesia or bradykinesia. Conversely, dopamine-induced dyskinesias have been postulated to result from decreased basal ganglia output.

Genetic Variants Where Parkinsonism Is Part Of The Clinical Spectrum

Frontotemporal Dementia with Parkinsonism Linked To Chromosome 17 Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) is an autosomal dominant disease, characterized initially by behavioral and motor disturbances that, in the latter stage of the disease, are associated with cognitive impairment. This disorder was linked to chromosome 17q21 in several nonrelated families, and termed frontotemporal dementia with parkinsonism linked to chromosome 17 (96-98). In 1998, exonic and intronic mutations in the gene MAPT were reported to segregate with FTDP-17 (99,100). Subsequent to this discovery, in excess of 60 separate families carrying more than 25 different mutations in MAPT have been identified (101,102). The vast majority of MAPT mutations are missense, deletion, or silent mutations in the coding region (most of them within exon 10), or mutations located close to the splice-donor site of the intron that follows alternatively-spliced exon 10. Clinical presentation...

Modulation of cortical activation and the anatomy of the reticular activating system

Specific information to the cerebral cortex, for example relating to sensory stimuli in the periphery, is relayed via the main thalamic nuclei. The other, diffusely projecting, systems are most likely to be involved in the regulation of cortical responsivity. Such a role has been demonstrated electrophysiologically for the claustrum, and the pharmacology of the antihistamines indicates a role for this transmitter system in the regulation of cortical arousal. The cholinergic input from the basal forebrain is necessary for the proper functioning of the cortex, and its degeneration is associated with cognitive decline and memory impairment. The possible relationship of mesolimbic dopamine pathways to schizophrenia is well known. Similarly, the psychopharmacology of serotonin also implies a major role for this transmitter system in the proper functioning of the cortex. There are two routes by which these 'non-specific' pathways affect the cortex direct projections, and an indirect pathway...

Neurologic Examination

Multiple sclerosis, Parkinson's disease, dementia, minor cerebrovascular accidents, and numerous additional neurologic processes can have genitourinary dysfunction as the presenting symptom. Back trauma and surgery, spinal stenosis, peripheral neuropathy, and damage to pelvic nerves also predispose women to incontinence and prolapse. Ambulation and mobility problems may jeopardize an individual's ability to reach a toilet, and should be identified. During the examination, the patient's mental status should be assessed. Cognitive impairment is a major impediment to behavioral modification and other forms of therapy. Realistic expectations regarding the ability to achieve continence in a demented patient should be addressed with family members and care providers.

Aging as a Risk Factor

Cognitive deficits and unleashing the AD pathology (Seshadri, 2006 Smith, 2002). This issue remains unresolved, however, it is worth noting that epidemiological studies have shown elevations in plasma homocystein preceding the development of dementia and that the folate pathway is key to DNA methylation and therefore implicated in epigenetic mechanisms. As a result, the administration of complex B vitamins and homocysteine-lowering treatments have been recommended for the preservation of cognition in the early stages of MCI and AD (Seshadri, 2006). As aging is such a prominent AD risk factor, an obvious way to delay the aging process, such as low-calorie intake (Mattson, 2003), exercise, and sensory stimulation, can also delay the onset of AD.

The hypothalamicgrowth hormone axis

The secretion of growth hormone and the regulation of this axis are distinct from that of the other endocrine axes for several reasons. First, this is the one axis in which two hypothalamic-hypophysiotrophic hormones have unequivocally been shown to play a physiological role. The first discovered was somatostatin or growth hormone-inhibiting hormone, isolated from ovine hypothalamus in 19Z4. It is a tetradecapeptide, which contains a disulfide bridge linking the two cysteine residues. It is distributed in the CNS not only in cells of the periventricular nucleus of the hypothalamus, which projects to the median eminence, but in a variety of extrahypothalamic areas as well. Indeed, somatostatin is known to function as a CNS neurotransmitter and is of particular interest to psychiatrists because of its early involvement in the Alzheimer's disease process. Our group and others have documented the marked reduction in somatostatin concentrations in this dementing disorder.(28 In addition,...

High Plasma Cholesterol

In the early 1990s, high cholesterol was found to be associated with the presence of ApoE4 alleles in clinically diagnosed Alzheimer's disease (Czech et al., 1994). In particular, high levels of LDL cholesterol resulted in a higher risk of dementia and stroke and the question posed was whether the administration of statins could diminish the incidence of these conditions (Moroney et al., 1999). The influential epidemiologic study of Wolozin and collaborators (Wolozin, Kellman, Ruosseau, Celesia, & Siegel, 2000) demonstrated that the patients taking the cholesterol-lowering drugs, which act as inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, better known as statins, show a 60-73 lower prevalence of probable AD. These findings were followed by numerous studies regarding the impact of high cholesterol in creating favorable conditions for the generation of Ap peptides and further clinical investigations on the impact of statins (Sjogren & Blennow, 2005 Wolozin, 2004). This...

Imaging psychotropic drug action

Many studies have investigated the occupancy of striatal dopamine D1 and D2 and cortical serotonin 5-HT2 receptors by neuroleptic drugs. Farde's group first demonstrated that clinically efficacious doses of a variety of classical antipsychotics cause between 65 per cent and 89 per cent occupancy of central dopamine D 2

Data analysis Clinical analysis

Structural MRI is most often used in clinical practice to exclude non-psychiatric causes for psychopathology. For example, it is routine in many centres to obtain an MRI examination in all first episodes of psychotic illness to exclude tumours, arteriovenous malformations, or other rare (but surgically treatable) causes of psychosis. Clinical examination of these cases may also sometimes reveal abnormalities such as hippocampal sclerosis or callosal agenesis which suggest that psychopathology has been determined by birth injury or abnormal development. In assessment of a patient with dementia, MRI may usefully demonstrate signs of vascular disease (such as infarcts or periventricular white matter changes), or a focal pattern of grey matter atrophy suggestive of Pick's disease (frontal cortex) or Huntington's disease (caudate nucleus and frontal cortex). All of these abnormalities may be detected simply by skilled visual examination of the data. However, clinical diagnosis of the...

Classes of Variation Associated with Elevated Disease Risk

A more complex example of the relationship of genetic variation to disease is the CACNL1A4 gene. This gene encodes a protein localized in the cell membrane and has a role in the transport of calcium into the cell. In this case, three different types of DNA sequence changes in a single gene are responsible for high risk of three different neurological conditions, including a specific class of migraine headache (Ophoff et al., 1996 1998 2001). Each class of variation disrupts the protein structure differently, and thus has a different impact on the ability of the protein to transport calcium and the degree of normal cellular function. An even higher level of complexity in the relationship of genetic variation to disease is observed for Alzheimer disease, where a subset of variants in one of three different genes, b-amyloid precursor and presenilin 1 and 2, places an individual at high risk of disease (Saunders, 2001 Sorbi et al., 2001). In addition, individuals with a variant allele at...

Clinical and research uses

PET scanning is of particular value in elucidating the relationships between cerebral blood flow, oxygen utilisation and extraction in focal areas of ischaemia or infarction (page 237) and has been used to study patients with dementia, epilepsy and brain tumours. Identification of neurotransmitter and drug receptor sites has aided the understanding and management of psychiatric (schizophrenia) and movement disorders.

Experimental stress and immunity

Naturally occurring human life stresses, both acute (e.g. examinations) and chronic (e.g. caring for patients with Alzheimer's disease), adversely affect a wide array of immune measures ,31 These include T-cell function, NK cell activity, antibody response to immunization, macrophage function, and activation of latent viruses like herpes simplex (controlled by cellular not humoral immunity). Such effects are increasingly being shown to have health implications. Social support can ameliorate stress effects. Natural disasters can have prolonged effects on immunity. (32)

Influence of products of the immune system on the central nervous system

The immune system affects brain and behaviour, especially via the effects of immune cytokines on the central nervous system.(42) Although cytokines are relatively large molecules, some, particularly IL-1, can cross the blood-brain barrier via active transport. IL-1 is also produced in the brain by both microglia, which are macrophages resident in the central nervous system, and astrocytes. Peripheral IL-1 can affect the brain, including its production of cytokines, via stimulation of the vagus afferent fibres. There are cytokine receptors in the brain, including those for IL-1, IL-8, and interferon, on both glial cells and neurones. Cytokines play a role in the development and regeneration of myelin-producing oligodendrocytes. Brain cytokines play a role in immune effector mechanisms as regulated by the brain, including a role in brain infection and inflammation. Cytokines are relevant to the progression of multiple sclerosis, gliomas, HIV-associated dementia, brain injury, and...

Effects of psychosocial factors on the course of disease

Long-term survivors with clinical AIDS and those who remain asymptomatic for prolonged periods of time in the face of very low CD4 counts seem to be those who have good coping skills, lead meaningful lives, find new meanings as a result of illness, are relatively not distressed, and are emotionally expressive and assertive. HIV-associated dementia, which is reversible in its early stages, appears to be closely related to the action of proinflammatory cytokines, particularly tumour necrosis factor, on neurones. Psychiatric symptoms, as well as cognitive defects, probably also cytokine induced, also occur in conjunction with HIV infection (primarily of microglia) of the brain they include apathy, withdrawal, psychosis, and regressive behaviours.

Comparative Genomics

The availability of these genomic sequences is extremely useful in the effort to determine the function of genes with currently unknown function, as it is easier to conduct initial experiments in model organisms than in humans and the function of most genes is similar in different organisms. The availability of genomic sequences from multiple organisms also will facilitate identification of noncoding sequences exhibiting minimal variation over evolutionary time. These regions have been suggested to be elements or sequences involved in regulation of gene expression (Cliften et al., 2001). Other applications that stem from the extensive databases on different organisms include development of better experimental models for the study of human disease and design and testing of new drugs. The characterization of the genomes of multiple organisms, with concurrent increases in understanding of their biology, increases the utility of these experimental models for pharmacology and...

Chapter References

Levy-Lahad, E., Wijsman, E.M., Nemens, E., et al. (1995). A familial Alzheimer's-disease locus on chromosome-1. Science, 269, 970-3. 17. Levy-Lahad, E., Wasco, W., Poorkaj, P., et al. (1995). Candidate gene for the chromosome-1 familial Alzheimer's-disease locus. Science, 269, 973-7. 18. Sherrington, R., Rogaev, E.I., Liang, Y., et al. (1995). Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's-disease. Nature, 375, 754-60. 19. Goate, A., Chartierharlin, M.C., Mullan, M., et al. (1991). Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's-disease. Nature, 349, 704-6. 30. Rogaev, E.I., Sherrington, R., Rogaeva, E.A., et al. (1995). Familial Alzheimer's-disease in kindreds with missense mutations in a gene on chromosome-1 related to the Alzheimer's-disease type-3 gene. Nature, 376, 775-8. 32. Hardy, J., Duf, K., Hardy, K.G., Perez-Tur, J., and Hutton, M. (1998). Genetic dissection of Alzheimer's disease and...

Studies of Gene Expression

It is now possible to have chips with 10,000-50,000 different unique sequences attached to a surface of less than the area of a coin. With the advent of the chip technology, investigators are now routinely monitoring the relative level of expression of thousands of different genes simultaneously in cells and tissues under different conditions and disease states (Lockhart and Winzeler, 2001). Applications of this technology have included searches for markers for early detection of Alzheimer disease (Pasinetti, 2001), markers for differentiating among classes of tumors (Brenton et al., 2001 Liotta and Petricoin, 2000) and differences in the expression profile between breast cancers derived from BRCA1 and BRCA2 patients (Hedenfalk et al., 2001).

Improving learning in memoryimpaired people

Building on these two strands of research we posed the question, 'Do amnesic subjects learn better when prevented from making errors during the learning process ' In one group study and several single-case studies (29 it was demonstrated that people with severe memory disorders learn more successfully with an errorless learning strategy. Others have adapted this strategy with non-progressive amnesic patients, (2 and recently we have used errorless learning procedures with patients who have Alzheimer' disease 22' All patients benefited to a greater or lesser degree and were able to learn some useful everyday information.

Alternatively Folded Proteins Are Implicated in Slowly Developing Diseases

Some neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease in humans and transmissible spongiform encephalopathy ( mad cow disease) in cows EXPERIMENTAL FIGURE 3-14 Alzheimer's disease is characterized by the formation of insoluble plaques composed of amyloid protein. (a) At low resolution, an amyloid plaque in the brain of an Alzheimer's patient appears as a tangle of filaments. (b) The regular structure of filaments from plaques is revealed in the atomic force microscope. Proteolysis of the naturally occurring amyloid precursor protein yields a short fragment, called p-amyloid protein, that for unknown reasons changes from an a-helical to a p-sheet conformation. This alternative structure aggregates into the highly stable filaments (amyloid) found in plaques. Similar pathologic changes in other proteins cause other degenerative diseases. Courtesy of K. Kosik.

Approach to a Patient with Chorea

As discussed above, there are numerous causes of chorea. A clinical approach keeping in mind the type of onset, the age, presence of a family history, antecedent illness or drug exposure, the distribution of chorea (focal or generalized) and presence of associated features are the key points. Additional features may include other extrapyramidal and pyramidal signs or cerebellar signs. The presence of additional neuropsychiatric findings (cognitive decline, mood disturbance, behavioural

Conclusions And Outlook

Elucidating the structures and properties of disordered biopolymers is an extremely challenging endeavor that urgently needs the development of new experimental probes and new modes of analysis. The usual structure-determination tools (X-ray crystallography, NMR spectroscopy) provide little insight into the properties of dynamic and heterogeneous polypeptide ensembles. In one amyloid-forming polypeptide, a-synuclein, we have shown that analysis of fluorescence decay kinetics can provide probability distributions of DA distances. Measurements of the FET and ET kinetics of other amyloidogenic peptides and proteins will allow us to take nanosecond snapshots of structures as well as determine the conformational dynamics of soluble prefibrillar aggregates. These powerful photophysical methods also will be used to investigate the interactions of a-synuclein and Alzheimer's Ap peptides with metal ions and other ionic and molecular species. Of special interest will be the characterization of...

Treatment Of Parkinsons Disease By Severity Of Symptoms

For patients older than 70 years or those with any cognitive decline, employ levodopa therapy. Not only is there less need for a dopa-sparing strategy in these elderly patients, they are more susceptible to confusion, psychosis, or drowsiness from other antiparkinson drugs, including dopamine agonists. Levodopa provides the greatest benefit at the lowest risk of these adverse effects, compared to the others.

Nonignorable nonresponse

The other occasion when non-response is a problem is in longitudinal studies, where a sample is followed over several years. If a disorder with an increased mortality is the topic, such as dementia or schizophrenia, it is recognized that some cases will be lost at follow-up. This means that those who are successfully re-examined are a survival lite and are different in important ways from the original cohort. These distortions could lead to mistaken conclusions if the losses are not allowed for. Various techniques have been developed to handle these difficulties, including Bayesian methods which adjust final estimates on the basis of prior knowledge. (19

Inhibitors targeted at AChE in the CNS

Several inhibitors of AChE have been developed for use in treating Alzheimer's disease, which requires that the drugs readily enter the CNS. These inhibitors are structurally unrelated and vary in their mechanism of inhibition, although all are reversible inhibitors. Tacrine (Cognex) is a monoamine acridine. Donepezil (Aricept) is a piperidine derivative that is a relatively specific inhibitor of AChE in the brain, with little effect on pseudo-ChE in the periphery. Galanthamine (Reminyl) is a tertiary alkaloid and phenanthrene derivative extracted from daffodil bulbs that is a reversible competitive inhibitor of AChE it also acts on nicotinic receptors.

Nineteenth century psychiatry

Kraepelin's important differentiation of manic-depressive illness from dementia praecox (schizophrenia) did not begin to be defined until 1896. Asylums contained patients suffering from many varieties of psychiatric illness who had nothing in common with one another except their inability to comply with the standards of behaviour demanded by society.

Genetic Counseling The Discipline and the Provider

As our knowledge of genetic disorders and complex inheritance patterns has expanded, so have the options for molecular-based genetic testing. With this growth, complex ethical and social issues have come to the forefront, such as genetic discrimination. As medical research has advanced, we have come to appreciate the strong influence of genetics in common disorders, such as cancer, diabetes, Alzheimer disease, asthma, and hypercholesterolemia. The burden of passing on an abnormal gene or trait is not limited to individuals and families faced with rare disorders of Mendelian inheritance. It is a reality for everyone. Increasing anxiety about genetic risk for disease and concern about passing on abnormal genes to future generations for common conditions has expanded the need for genetic counseling. There are now subspecialties of genetic counseling, such as prenatal, pediatric, cancer, and neuro-genetics. Genetic counselors also are working in clinical molecular diagnostic laboratories...

Symptomatic Treatment Versus Disease Stabilization

The main thrust of therapeutic research in AD has so far been directed at improvement of symptoms, using cholinesterase inhibitors (ChEI) and the NMDA receptor antagonist memantine. The initial expectations were primarily a cognitive enhancement effect, but these drugs improve cognition only transiently, stabilize activities of daily living (ADL), and delay emergence or improve existing behavioral and psychological symptoms of dementia (BPSD), such as apathy, agitation, and hallucinations. Although the improvement above baseline is small, these results are clinically meaningful in a neurodegenerative condition that leads to death within 3-8 years after the onset of symptoms (Winblad et al., 2001). The current interest is in disease modification. A delay of progression from no or minimal symptoms to diagnosable dementia would have an obvious value from a public health point of view, and delaying progression from mild AD to more advanced stages would also be considered important, even...

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