ScienceWeek

THE NATURE OF ALZHEIMER'S DISEASE

IMAGING THE PROGRESSION OF ALZHEIMER PATHOLOGY THROUGH THE BRAIN

The following points are made by A. David Smith (Proc. Nat. Acad. Sci. 2002 99:4135):

1) Soon after the widespread availability of computerized x-ray tomography (CT) in clinical medicine in the 1970s, reports began to appear of the changes in the brain in patients with Alzheimer's disease (AD). Atrophy of brain tissue was a common finding, but a critical review in 1990 concluded that "at present there is little definite evidence for clear anatomic brain changes that accurately predict the cognitive dysfunction within a group of patients suffering with AD."(1) Since then, convincing evidence that selective atrophy of particular brain regions is highly correlated with cognitive deficits characteristic of AD has been obtained. What has caused this revolution?

2) First, it has been recognized that the diagnosis of AD was not sufficiently accurate in many early neuroimaging studies. Second, until pioneering studies from New York University (2), most early work did not examine the medial temporal lobe (MTL), the part of the brain with the highest density of AD histopathological markers (amyloid plaques and neurofibrillary tangles). In 1992 a CT study of patients with AD, whose diagnosis was later confirmed by histopathology, showed marked atrophy of the MTL (3). Third, there were few longitudinal studies to reveal changes in the same patients over time. One of these, however, showed rapid enlargement of the fluid-filled ventricles in the brain in patients with AD (4). Enlargement of the ventricles is usually caused by loss of brain tissue. A dramatic loss of tissue from the MTL, part of which shrunk at a rate of 15% per year, was found in serial CT studies on patients with AD (5). Because the MTL in controls only shrunk at one-tenth of this rate, it was concluded that AD cannot be the result of an acceleration of normal aging, but must be the consequence of a disease process. Scahill et al. (Proc. Nat. Acad. Sci. 2002 99:4703) took the story into a new chapter by using serial MRI scans in patients with AD to show how the disease process, revealed by regional atrophy, spreads in a highly specific way from the MTL to other parts of the brain.

3) How do we know that the atrophy revealed by the structural neuroimaging reflects the progression of the disease process? AD is defined by its histopathology, so it might be assumed that the only way to track the spread of pathology would be devise a way of revealing the plaques and tangles in the living brain by neuroimaging. However, the clinical symptoms are not directly caused by the deposition of amyloid or the formation of intracellular tangles, but rather by the loss of neurons and, in particular, loss of their connections with other neurons made through synapses. We can follow a trail back from the symptoms, through regional atrophy, through loss of neurons and fibers, and finally to the histopathological markers of AD. Cognitive deficits, in particular of memory, are associated with atrophy of the MTL in AD as revealed by CT or MRI. This association is specific because deficits in verbal memory correlate with atrophy of the left hippocampus and deficits in the nonverbal memory correlate with atrophy of the right hippocampus. Atrophy of brain tissue can be caused by shrinkage or death of neurons, loss of the neuropil (the axons and dendrites of neurons), or shrinkage of tracts of nerve fibers. All of these have been implicated in the atrophy of the MTL that occurs in AD.

References (abridged):

1. DeCarli, C., Kaye, J. A., Horwitz, B. & Rapoport, S. I. (1990) Neurology 40, 872-883

2. De Leon, M. J., George, A. E., Stylopoulos, L. A., Smith, G. & Miller, D. C. (1989) Lancet ii, 672-673

3. Jobst, K. A., Smith, A. D., Szatmari, M., Molyneux, A., Esiri, M. M., King, E., Smith, A., Jaskowski, A., McDonald, B. & Wald, N. (1992) Lancet 340, 1179-1183

4. Luxenberg, J. S., Haxby, J. V., Creasey, H., Sundaram, M. & Rapoport, S. I. (1987) Neurology 37, 1135-1140

5. Jobst, K. A., Smith, A. D., Szatmari, M., Esiri, M. M., Jaskowski, A., Hindley, N., McDonald, B. & Molyneux, A. J. (1994) Lancet 343, 829-830

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ON THE SECRETASES AND ALZHEIMER'S DISEASE

The following points are made by Mark P. Mattson (Nature 2003 422:385):

1) Scientific discoveries often originate in surprising places. Some years ago, for instance, researchers looking at how the brain develops received help from an unexpected quarter: studies of patients with Alzheimer's disease. This disease is characterized in part by the abnormal accumulation, in the brain, of a protein called amyloid-beta peptide (A-beta), which is a fragment of a larger protein, the amyloid precursor protein (APP), that sits across the outer membrane of nerve cells. Two enzymatic activities are involved in precisely snipping APP to produce A-beta, which is then shed into the brain. Curiously, one of these activities -- dubbed gamma-secretase(1) -- was later discovered also to cleave Notch, a receptor protein that lies on the cell surface, and thereby to affect the way in which Notch regulates gene expression during normal development(2). Takasugi et al(3) add to our understanding of how APP and Notch are processed: Using genes and cells from flies and humans, and the powerful new technology of RNA interference, these authors establish specific roles for four different proteins underlying gamma-secretase activity.

2) For many years, much of the research into Alzheimer's disease has concentrated on identifying and characterizing the protein (or proteins) that generate A-beta. In the first step of this process, APP is cleaved at a specific point by a so-called beta-secretase activity; the protein responsible for this activity was identified some four years ago. Cleavage by the gamma-secretase activity then produces A-beta -- but here the molecules at fault have been harder to pin down. An early hint came from the finding that mutations in a gene encoding the presenilin-1 protein occur in several families with inherited Alzheimer's disease; it was quickly shown that these mutations cause increased cleavage of APP to produce A-beta. So presenilin-1 was assumed to be the gamma-secretase.

3) A surprising link to brain development was then discovered when researchers knocked out the presenilin-1 gene in mice. The animals died as embryos, and had severe defects in brain development that were indistinguishable from the defects in mice lacking Notch. This is because presenilin-1 is required not only to cleave APP and generate A-beta, but also to cleave Notch after Notch has detected and bound a partner protein. An intracellular fragment of Notch is then released, and regulates gene expression in the neuronal nucleus. It has been suggested4 that an intracellular fragment of APP, generated by gamma-secretase, likewise moves to the nucleus and regulates gene expression.

4) But it soon became clear that presenilin-1 cannot work alone to cleave APP and Notch, and a search began for other proteins that might be involved. APP and Notch have been highly conserved during evolution, which not only attests to their physiological importance, but also means that molecular-genetic analyses of fruit flies and worms can be used to investigate their cleavage. Such studies have found that four proteins seem to contribute to gamma-secretase activity; these are presenilin-1, nicastrin, APH-1 and PEN-2(5). It has now been shown that gamma-secretase activity can be fully reconstituted with only these four proteins.

References (abridged):

1. Haass, C. & De Strooper, B. Science 286, 916-919 (1999)

2. Selkoe, D. J. Curr. Opin. Neurobiol. 10, 50-57 (2000)

3. Takasugi, N. et al. Nature 422, 438-441 (2003)

4. Leissring, M. A. et al. Proc. Natl Acad. Sci. USA 99, 4697-4702 (2002)

5. Yu, G. et al. Nature 407, 48-54 (2000)

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ON ALZHEIMER SECRETASES

The following points are made by W.P. Esler and M.S. Wolfe (Science 2001 293:1449):

1) We are now in an age when we can truly appreciate molecular relations between entities and processes that at first glance appear unconnected. Indeed, recent discoveries in such seemingly disparate areas of inquiry as neurodegenerative disease, developmental biology, and lipid biochemistry have coalesced to paint a portrait of nature more intricate than we could have imagined, each aspect explaining and enhancing the other. At the same time, these discoveries have illuminated important therapeutic targets for Alzheimer's disease (AD).

2) This disease is characterized pathologically by cerebral plaques containing the amyloid beta-peptide (A-beta), a proteolytic product derived from the A-beta precursor protein (APP). The search for the proteases responsible for processing APP has unexpectedly revealed proteins that are also involved in a signaling pathway essential for proper cell differentiation during embryonic development. And one of these proteins appears to be a member of an emerging class of polytopic membrane proteases that includes an unusual metalloprotease involved in cholesterol biosynthesis.

3) First described by Alois Alzheimer (1864-1915) in 1906, the disease that bears his name largely remained an enigma until the twilight of the 20th century. Along with descriptions of progressive loss of memory and general cognitive decline, Alzheimer noted the presence of intraneuronal tangles and extracellular "amyloid" plaques in the diseased-damaged brain, but he could not decipher whether the tangles or plaques were causative or merely markers of the disease. In 1991, the search for genetic linkages yielded a major clue: Missense mutations in APP caused autosomal dominant, early-onset (familial) AD, and these mutations occurred in and around the A-beta region of the precursor protein (1-3). These findings, together with observations that A-beta readily forms neurotoxic, threadlike structures called fibrils (4,5), bolstered the view that the accumulation and deposition of A-beta in the brain over decades leads to neuronal dysfunction and eventually clinical manifestation of the disease (the amyloid hypothesis).

4) In summary: The amyloid beta-peptide (A-beta) is a principal component of the cerebral plaques found in the brains of patients with Alzheimer's disease (AD). This insoluble 40- to 42-amino acid peptide is formed by the cleavage of the A-beta precursor protein (APP). The three proteases that cleave APP, alpha-, beta-, and gamma-secretases, have been implicated in the etiology of AD. Beta-Secretase is a membrane-anchored protein with clear homology to soluble aspartyl proteases, and alpha-secretase displays characteristics of certain membrane-tethered metalloproteases. Gamma-Secretase is apparently an oligomeric complex that includes the presenilins, which may be the catalytic component of this protease. Identification of the alpha-, beta-, and gamma-secretases provides potential targets for designing new drugs to treat AD.

References (abridged):

1. A. Goate, et al., Nature 349, 704 (1991)

2. M. C. Chartier-Harlin, et al., Nature 353, 844 (1991)

3. J. Murrell, M. Farlow, B. Ghetti, M. D. Benson, Science 254, 97 (1991)

4. C. Hilbich, B. Kisters-Woike, J. Reed, C. L. Masters, K. Beyreuther, J. Mol. Biol. 218, 149 (1991)

5. J. T. Jarrett, E. P. Berger, P. T. Lansbury Jr., Biochemistry 32, 4693 (1993)

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COMMON STRUCTURE OF SOLUBLE AMYLOID OLIGOMERS IMPLIES COMMON MECHANISM OF PATHOGENESIS

The following points are made by R. Kayed et al (Science 2003 300:486):

1) Recent reports suggest that the toxicity of amyloid-beta (A-beta) and other amyloidogenic proteins lies not in the insoluble fibrils that accumulate but rather in the soluble oligomeric intermediates (1). These soluble oligomers include spherical particles of 2.7 to 4.2 nm in diameter and curvilinear structures called "protofibrils" that appear to represent strings of the spherical particles (2). The oligomers have also been referred to as A-beta-derived diffusible ligands or ADDLs (3). The soluble A-beta oligomers represent protein micelles, because A-beta is an amphipathic surface-active peptide, oligomer formation displays a critical concentration dependence, and their formation is correlated with the appearance of a hydrophobic environment (4–5).

2) Soluble A-beta oligomers are also found in human Alzheimer's disease (AD) cerebrospinal fluid, and the soluble A-beta content of human brain is better correlated with the severity of the disease than are plaques. Taken together, these results indicate that the soluble oligomers may be more important pathologically than are the fibrillar amyloid deposits, but there is no direct evidence that they actually exist in human AD brain.

3) In summary: Soluble oligomers are common to most amyloids and may represent the primary toxic species of amyloids, like the A-beta peptide in Alzheimer's disease (AD). The authors demonstrate that all of the soluble oligomers tested display a common conformation-dependent structure that is unique to soluble oligomers regardless of sequence. The in vitro toxicity of soluble oligomers is inhibited by oligomer-specific antibody. Soluble oligomers have a unique distribution in human AD brain that is distinct from fibrillar amyloid. The authors suggest these results indicate that different types of soluble amyloid oligomers have a common structure and may share a common mechanism of toxicity.

References (abridged):

1. J. Hardy, D. J. Selkoe, Science 297, 353 (2002)

2. D. M. Hartley et al., J. Neurosci. 19, 8876 (1999)

3. M. P. Lambert et al., Proc. Natl. Acad. Sci. U.S.A. 95, 6448 (1998)

4. B. Soreghan, J. Kosmoski, C. Glabe, J. Biol. Chem. 269, 28551 (1994)

5. L. O. Tjernberg et al., Chem. Biol. 6, 53 (1999)

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THE PRESENILINS IN ALZHEIMER'S DISEASE

The following points are made by C. Haass and B. De Strooper (Science 1999 286:916):

1) Worldwide, about 20 million people suffer from age-related dementia caused by Alzheimer's disease (AD). A very small fraction of AD cases are caused by autosomal dominant mutations in the genes encoding presenilin (PS) proteins 1 and 2 and the amyloid precursor protein (APP). Study of familial AD cases has illuminated the pathological mechanisms involved in the major, sporadic form of the disease. Disease-linked mutations in PS1, PS2 and APP result in an increase in the production of the 42-amino acid peptide form of amyloid-beta (A-beta), which is a major component of the amyloid plaques deposited in the brains of AD patients. Three enzymes, alpha-, beta- and gamma-secretase, cleave the transmembrane APP into A-beta fragments of different sizes.

2) Recent research demonstrates the involvement of presenilins in the formation of A-beta through their effects on gamma-secretase, and connects them to the signaling pathway mediated by the Notch receptor. These findings define presenilins and gamma-secretases as molecular targets for developing drugs to combat AD and hint at the potential side effects that could be associated with such drugs. Curiously, AD research links diverse fields such as developmental biology and neurobiology through genetic and biochemical studies in fish, flies, and worms.

3) The presenilins are serpentine integral membrane proteins. By using the indices of Kyte and Doolittle, ten hydrophobic regions, linked by short hydrophilic sequences, can be identified (1). The presenilins do not contain a signal peptide, and the hydrophilic amino-terminal domain protrudes into the cytoplasm. A second hydrophilic domain, between transmembrane domains (TM) 6 and 7, and the relatively hydrophobic carboxyl-terminal tail also protrude into the cytoplasm (2,3). Although the proposed structure implies eight transmembrane domains (3,4), alternative models for the insertion of presenilin into biological membranes are possible (5). Studies of endogenous presenilins are required to answer this important question more definitively because transient overexpression of presenilins may lead to abnormal membrane insertion.

4) Presenilin proteins have been localized to the endoplasmic reticulum (ER) and the Golgi subcellular compartments (2). The finding of overexpressed presenilin proteins within Golgi compartments should, however, be interpreted with caution, because recent evidence indicates that membrane proteins with many transmembrane domains (such as the presenilins and the cystic fibrosis transmembrane regulator) can accumulate in structures called aggresomes. These cytoplasmic structures merely reflect cell stress and overloading of the proteasome compartment. They accumulate at the microtubule organizing center, which is located in many cells near the nucleus and close to the Golgi apparatus. Endogenous presenilins, in contrast, have a relatively limited subcellular distribution; they are found in the early compartments of the biosynthetic pathway. Confocal and electron microscopy, combined with subcellular fractionation experiments, show that presenilins in neurons reside in the smooth and rough ER, the ER-Golgi intermediate compartment (ERGIC), and, to a limited extent, in the cis-Golgi, but not beyond.

5) In summary: Alzheimer's disease (AD) research has shown that patients with an inherited form of the disease carry mutations in the presenilin proteins or the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid-beta (the primary component of the amyloid deposits found in AD brains). However, it is not clear how the presenilins contribute to this increase. New findings now show that the presenilins affect APP processing through their effects on gamma-secretase, an enzyme that cleaves APP. Also, it is known that the presenilins are involved in the cleavage of the Notch receptor, hinting that they either directly regulate gamma-secretase activity or themselves are protease enzymes. The authors suggest these findings indicate that the presenilins may prove to be valuable molecular targets for the development of drugs to combat AD.

References (abridged):

1. R. Sherrington, et al., Nature 375, 754 (1995); E. Levy-Lahad et al., Science 269, 973 (1995); E. I. Rogaev et al., Nature 376, 775 (1995)

2. B. De Strooper et al., J. Biol. Chem. 272, 3590 (1997)

3. A. Doan et al., Neuron 17, 1023 (1996); X. Li and I. Greenwald, Neuron 17, 1015 (1996)

4. X. Li and I. Greenwald, Proc. Natl. Acad. Sci. U.S.A. 95, 7109 (1998)

5. S. Lehmann, R. Chiesa, D. A. Harris, J. Biol. Chem. 272, 12047 (1997)

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TOXIC PROTEINS IN NEURODEGENERATIVE DISEASE

The following points are made by J.P Taylor et al (Science 2002 296:1991):

1) Neurodegenerative disorders as diverse as Alzheimer's disease, Parkinson's disease, prion diseases, Huntington's disease, frontotemporal dementia, and motor neuron disease all share a conspicuous common feature -- aggregation and deposition of abnormal protein. Expression of mutant proteins in transgenic animal models recapitulates features of these diseases (1). Neurons are particularly vulnerable to the toxic effects of mutant or misfolded protein. The common characteristics of these neurodegenerative disorders suggest parallel approaches to treatment, based on an understanding of the normal cellular mechanisms for disposing of unwanted and potentially noxious proteins.

2) Correct folding requires proteins to assume one particular structure from a constellation of possible but incorrect conformations. The failure of polypeptides to adopt their proper structure is a major threat to cell function and viability. Consequently, elaborate systems have evolved to protect cells from the deleterious effects of misfolded proteins. The first line of defense against misfolded protein is the molecular chaperones, which associate with nascent polypeptides as they emerge from the ribosome, promoting correct folding and preventing harmful interactions. A large fraction of newly translated proteins nonetheless fails to fold correctly, generating a substantial burden of defective polypeptide (2). These proteins are degraded primarily by the ubiquitin-proteasome system (UPS), a multicomponent system that identifies and degrades unwanted proteins (3). In addition to its role in clearing defective proteins, the UPS carries out selective degradation of many short-lived normal proteins, thereby contributing to the regulation of numerous cellular processes. Failure to detect and eliminate misfolded proteins may contribute to the pathogenesis of neurodegenerative disease. Conversely, it has been suggested that the UPS itself may be a target for toxic proteins (4).

3) Under some circumstances, misfolded proteins may evade the quality control systems designed to promote correct folding and eliminate faulty proteins. When they accumulate in sufficient quantity, misfolded proteins are prone to aggregation. Insoluble aggregates of disease-related proteins may be deposited in microscopically visible inclusions or plaques, the characteristics of which are often disease specific.

4) It has been widely assumed that the formation of intracellular inclusions is a passive process driven by mass-action chemistry, with self-assembly of misfolded monomers into a single growing aggregate. However, this assumption has been challenged by evidence that some intracellular inclusions are formed as part of a physiological response to excess misfolded protein. For example, some mutant proteins are delivered to inclusion bodies by dynein-dependent retrograde transport on microtubules (5). These actively formed inclusions have been designated "aggresomes." Mutant superoxide dismutase, found in some patients with familial amyotrophic lateral sclerosis, and polyglutamine-containing protein, such as generated in Huntington's disease, have been shown to form aggresomes in vitro (4). Inclusion formation by some mutant proteins is regulated by corticosteroids and by the activity of the stress kinase MEKK1, providing further evidence of an active process.

5) In summary: A broad range of neurodegenerative disorders is characterized by neuronal damage that may be caused by toxic, aggregation-prone proteins. As genes are identified for these disorders and cell culture and animal models are developed, it has become clear that a major effect of mutations in these genes is the abnormal processing and accumulation of misfolded protein in neuronal inclusions and plaques. Increased understanding of the cellular mechanisms for disposal of abnormal proteins and of the effects of toxic protein accumulation on neuronal survival may allow the development of rational, effective treatment for these disorders.

References (abridged):

1. A. Aguzzi and A. J. Raeber, Brain Pathol. 8, 695 (1998)

2. U. Schubert, et al., Nature 404, 770 (2000)

3. A. Hershko and A. Ciechanover, Cell 79, 13 (1997)

4. N. F. Bence, R. M. Sampat, R. R. Kopito, Science 292, 1552 (2001)

5. R. R. Kopito, Trends Cell Biol. 10, 524 (2000)

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AMYLOID BETA PROTEIN AND LONG-TERM POTENTIATION

The following points are made by D.M. Walsh et al (Nature 2002 416:535):

1) Although extensive data support a central pathogenic role for amyloid beta protein in Alzheimer's disease(1), the amyloid hypothesis remains controversial, in part because a specific neurotoxic species of beta amyloid protein and the nature of its effects on synaptic function have not been defined in vivo.

2) The authors report that natural oligomers of human beta amyloid protein are formed soon after generation of the peptide within specific intracellular vesicles and are subsequently secreted from the cell. Cerebral microinjection of cell medium containing these oligomers and abundant beta amyloid protein monomers but no amyloid fibrils markedly inhibited hippocampal long-term potentiation (LTP) in rats in vivo. Immunodepletion from the medium of all beta amyloid protein species completely abrogated this effect. Pretreatment of the medium with insulin-degrading enzyme, which degrades beta amyloid protein monomers but not oligomers, did not prevent the inhibition of LTP. Therefore, beta amyloid protein oligomers, in the absence of monomers and amyloid fibrils, disrupted synaptic plasticity in vivo at concentrations found in human brain and cerebrospinal fluid. Finally, treatment of cells with gamma-secretase inhibitors prevented oligomer formation at doses that allowed appreciable monomer production, and such medium no longer disrupted LTP, indicating that synaptotoxic beta amyloid protein oligomers can be targeted therapeutically.

3) An attractive therapeutic approach to Alzheimer's disease would be to reduce selectively the levels of potentially synaptotoxic beta amyloid protein oligomers. The authors suggest that because stable oligomers can potentially arise from a large variety of proteins, both those already implicated in disease and those that are not, the prevention of oligomer formation by reducing monomer concentrations could have wide relevance to the treatment of protein-folding disorders.(2-5)

References (abridged):

1. Selkoe, D. J. Alzheimer's disease: genes, proteins and therapies. Physiol. Rev. 81, 742-761 (2001)

2. Pike, C. J. Walencewicz, A. J., Glabe, C. G. & Cotman, C. W. In vitro aging of -amyloid protein causes peptide aggregation and neurotoxicity. Brain Res. 563, 311-314 (1991)

3. Lorenzo, A. & Yankner, B. A. Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. Proc. Natl Acad. Sci. USA 91, 12243-12247 (1994)

4. Terry, R. D. et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30, 572-580 (1991)

5. Dickson, D. W. et al. Correlations of synaptic and pathological markers with cognition of the elderly. Neurobiol. Aging 16, 285-298 (1995)

Related Brief:

BETA-AMYLOID NEUROTOXICITY REQUIRES FIBRIL FORMATION AND IS INHIBITED BY CONGO RED. Beta-amyloid (beta A) is normally produced as a nontoxic soluble peptide. In Alzheimer disease, beta A aggregates and accumulates in the brain as inert diffuse plaques or compact plaques associated with neurodegenerative changes. To determine the relationship of neurotoxicity to the physical state of beta A, the authors created (a) nonamyloidogenic amorphous aggregates of beta A [amorphous beta A (Am-beta A)] analogous to diffuse plaques and (b) amyloidogenic fibrils of beta A [fibrillar beta A (Fib-beta A)] analogous to compact plaques. In primary rat hippocampal culture, Fib-beta A was neurotoxic, whereas Am-beta A was not toxic. Fib-beta A caused significant loss of synapses in viable neurons, while Am-beta A had no effect on synapse number. The amyloid fibril-binding dye Congo red inhibited Fib-beta A neurotoxicity by inhibiting fibril formation or by binding to preformed fibrils. Congo red also inhibited the pancreatic islet cell toxicity of diabetes-associated amylin, another type of amyloid fibril. The authors suggest these results indicate that beta A neurotoxicity requires fibril formation. These findings and the previous demonstration that amylin fibrils are toxic suggest that a common cytopathic effect of amyloid fibrils may contribute to the pathogenesis of Alzheimer disease and other amyloidoses. Lorenzo A, Yankner: Proc. Nat. Acad. Sci. 1994 91:12243

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PHYSICAL BASIS OF COGNITIVE ALTERATIONS IN ALZHEIMER'S DISEASE: SYNAPSE LOSS IS THE MAJOR CORRELATE OF COGNITIVE IMPAIRMENT. The authors present both linear regressions and multivariate analyses correlating three global neuropsychological tests with a number of structural and neurochemical measurements performed on a prospective series of 15 patients with Alzheimer's disease and 9 neuropathologically normal subjects. The statistical data show only weak correlations between psychometric indices and plaques and tangles, but the density of neocortical synapses measured by a new immunocytochemical densitometric technique reveals very powerful correlations with all three psychological assays. Multivariate analysis by stepwise regression produced a model including midfrontal and inferior parietal synapse density, plus inferior parietal plaque counts with a correlation coefficient of 0.96 for Mattis's Dementia Rating Scale. Plaque density contributed only 26% of that strength. R.D. Terry et al: Ann Neurol 1991 30:572

ON NEUROPSYCHIATRIC SYMPTOMS IN DEMENTIA AND COGNITIVE IMPAIRMENT

The following points are made by C.G. Lyketsos et al (J. Am. Med. Assoc. 2002 288:1475):

1) Dementia is a serious public health problem with an increasing prevalence because of the aging of the population.(1) Dementia is characterized by global cognitive decline sufficient to affect functioning.(2) It is a chronic illness with seriously disabling effects for patients, their families, and society.(2) Mild cognitive impairment (MCI) describes cognitive impairment in elderly persons not of sufficient severity to qualify for a diagnosis of dementia.(3) Individuals with MCI have complaints of impairment in memory or other areas of cognitive functioning usually noticeable to those around them. In addition, their performance on memory and cognitive tests is below that expected for their age and education. However, their day-to-day functioning is generally preserved. Several operational definitions for MCI have been proposed.(3,4) Mild cognitive impairment is a chronic condition and may be a precursor to Alzheimer-type dementia.(4) Mild cognitive impairment is often worrisome to patients and families, and is increasingly a presenting complaint for care.

2) Neuropsychiatric symptoms are a common accompaniment of dementia.(5) These include agitation, depression, apathy, delusions, hallucinations, and sleep impairment. In some cases, they cluster into syndromes, leading to the proposal of operational criteria for specific dementia-associated psychotic or mood disturbances. These symptoms have serious adverse consequences for patients and caregivers, such as greater impairment in activities of daily living, more rapid cognitive decline, worse quality of life, earlier institutionalization, and greater caregiver depression. Thus, the neuropsychiatric accompaniments of dementia are serious conditions that are increasingly becoming a focus of attention.

3) The authors report a population-based study to estimate the prevalence of neuropsychiatric symptoms in dementia and MCI. A total of 3608 participants were cognitively evaluated using data collected longitudinally over 10 years and additional data collected in 1999-2000 in 4 US counties. Dementia and MCI were classified using clinical criteria and adjudicated by committee review by expert neurologists and psychiatrists. A total of 824 individuals completed the Neuropsychiatric Inventory (NPI); 362 were classified as having dementia, 320 as having MCI; and 142 did not meet criteria for MCI or dementia. From their results, the authors conclude: Neuropsychiatric symptoms occur in the majority of persons with dementia over the course of the disease. These are the first population-based estimates for neuropsychiatric symptoms in MCI, indicating a high prevalence associated with this condition as well. The authors suggest these symptoms have serious adverse consequences and should be inquired about and treated as necessary.

References (abridged):

1. Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Am J Public Health. 1998;88:1337-1342.

2. Rabins PV, Lyketsos CG, Steele C. Practical Dementia Care. New York, NY: Oxford University Press; 1999.

3. Petersen RC, Stevens JC, Ganguli M, et al. Practice parameter: Early detection of dementia: mild cognitive impairment (an evidence-based review). Neurology. 2001;56:1133-1142.

4. Morris JC, Storandt M, Miller JP, et al. Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol. 2001;58:397-405.

5. Finkel SI, Costa e Silva J, Cohen G, et al. Behavioral and psychological signs and symptoms of dementia. Int Psychogeriatr. 1996;8(suppl 3):497-500.

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