In: advances in the diagnosis and treatment of alzheimer's disease




НазваниеIn: advances in the diagnosis and treatment of alzheimer's disease
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In: ADVANCES IN THE DIAGNOSIS AND TREATMENT OF ALZHEIMER'S DISEASE


V. Kumar and C. Eisdorfer, Editors


Advances in the Diagnosis and Treatment of Alzheimer's Disease.


Springer Publishing Company: New York, 1998.


NEUROBIOLOGICAL SYSTEMS DISRUPTED BY ALZHEIMER'S DISEASE AND MOLECULAR BIOLOGICAL THEORIES OF VULNERABILITY


Chapter 3, pages 53-89


J. Wesson Ashford, M.D., Ph.D.

Mark Mattson, Ph.D.

Vinod Kumar, M.D.


J. Wesson Ashford, M.D., Ph.D.

Associate professor of Psychiatry and Neurology and

the Sanders-Brown Center on Aging and

the Alzheimer's Disease Research Center,

University of Kentucky

and

Staff Psychiatrist, VA Medical Center, Lexington


Mark P. Mattson, Ph.D.

Associate professor of Anatomy and Neurobiology and

the Sanders-Brown Center on Aging and

the Alzheimer's Disease Research Center,

University of Kentucky


Vinod Kumar, M.D.

Professor of Psychiatry

University of Miami


SUPPORT:

NIH, AG05144 (Drs. Ashford & Mattson)

NS30583, Alzheimer's Association, Metropolitan Life Foundation (Dr. Mattson)


INTRODUCTION


Alzheimer's disease (AD) is a neuropathological process which progressively and relentlessly devastates the brains of its victims. The AD pathology produces progressively more severe deficits in cognition, behavior, and activities of daily living over a time course of deterioration averaging 8 years (Ashford et al., 1995). Most of the studies of AD pathology have examined the composition and distribution of the neurofibrillary tangles and senile plaques first described by Alois Alzheimer in 1907 (see Greenson and Jarvik, 1989). However, Alzheimer's first comments on this disease referred to the psychosocial disruptions which he found in his patient. To solve this disease, the psychosocial clinical problems and the neurobiological system dysfunctions must be defined to the point that they indicate what neuromolecular mechanisms are attacked by the AD process.


The AD process has no direct effects on most functions of the body and is restricted in its attack on the brain. Investigations into the biology of AD have yet to reveal the basis of this process. Clearly the most important factor associated with the development of AD is age (Friedlich & Butcher, 1994), with AD changes appearing in many individuals at a young age and developing in a majority of individuals as age progresses past 60 years (Ohm et al., 1995). Studies of family constellations, DNA polymorphisms, and genetic mechanisms have revealed that genetic factors play a significant role in predisposing some individuals to developing AD (Roses, 1994; the genetic aspects of AD are discussed in the chapter by Matsuyama in this volume). Certain environmental factors, including a possible contribution by aluminum (Bertholf, 1987; Lovell et al., 1993; Harrington et al., 1994; Forbes et al., 1994), may also influence the onset of the disease. However, a major concern is understanding which neuronal systems in the brain are affected by the AD process, and how their unique physiological processes may predispose them to allow the progressive development of this disease process. The affected neurobiological systems seem to be those which underlie learning, and the AD process appears to attack mechanisms for storing new information from molecular biological machinery, to specific neurotransmitter systems to macroscopic anatomical structures of the cerebrum (Ashford & Jarvik, 1985; see Table 1). Through more complete understanding of the attack of the AD process, it is hoped that approaches can be developed to prevent or slow the development of AD.

TABLE 1 - BIOPSYCHOSOCIAL SYSTEMS AFFECTED BY AD

(MNEMONIC FUNCTION AT EACH LEVEL IS ATTACKED BY AD)


SOCIAL SYSTEMS

DYSFUNCTION IN INSTRUMENTAL BEHAVIORS (EARLY AD)

(REMEMBERING A GROCERY LIST OR PHONE NUMBER)

DYSFUNCTION IN PERSONAL CARE (LATE AD)

(REMEMBERING HOW TO DRESS OR BATHE)


PSYCHOLOGICAL SYSTEMS

PRIMARY LOSS OF ABILITY TO LEARN NEW INFORMATION

INCLUDING INABILITY TO KNOW OF THIS DEFICIT

SECONDARY LOSS OF PREVIOUSLY LEARNED INFORMATION

LATER LOSS OF LEARNED PERCEPTUAL AND MOTOR SKILLS

(APHASIA, AGNOSIA, APRAXIA)


CORTICAL SYSTEMS

- ENTORHINAL CORTEX (MEMORY NETWORK) (EARLY AD)

- HIPPOCAMPUS (ARCHICORTEX) - LOCATIONAL MEMORY

- AMYGDALA (PALEOCORTEX) - EMOTIONAL MEMORY

- TEMPORO-PARIETAL CORTEX (NEOCORTEX) (MIDDLE AD)

SENSORY ANALYSIS AND PERCEPTION STORAGE

- FRONTAL CORTEX - EXECUTIVE FUNCTION (MID-LATE AD)

- PRIMARY CORTEX - PRIMARY SENSORY/MOTOR ANALYSIS (LATE)


CORTICAL NEUROTRANSMITTER SYSTEMS

- GLUTAMATE (INFORMATION STORAGE MEDIATION)

- GABA-SOMATOSTATIN (UNKNOWN MNEMONIC FUNCTION)


SUBCORTICAL NEUROCHEMICAL SYSTEMS PROJECTING TO CORTEX

- NUCLEUS BASALIS OF MEYNERT - ACETYLCHOLINE

(MEMORY; CLASSICAL CONDITIONING)

- ROSTRAL RAPHE NUCLEI - SEROTONIN

(SENSITIZATION CONDITIONING)

- LOCUS COERULEUS - NOREPINEPHRINE

(REWARD-RELATED CONDITIONING)


NEURONAL SYSTEMS (PRIMARILY CORTICAL)

- MICROTUBULE ASSOCIATED PROTEIN - TAU

(PROCESS GROWTH FOR ESTABLISHING NEW SYNAPSES)

NEUROFIBRILLARY TANGLES, NEURITIC PLAQUES

- AMYLOID PRE-PROTEIN (APP)

(POSSIBLE INVOLVEMENT IN FORMATION OF NEW SYNAPSES)

β-AMYLOID IN SENILE PLAQUES, AMYLOID ANGIOPATHY

PSYCHOSOCIAL SYSTEMS AFFECTED BY AD


In the study of AD, the first principle is that investigations of pathology must be linked to clinical dysfunctions. In AD, there is a progressive development of complex psychological and social symptoms. However, it is important to decipher these complex changes into simple psychological precepts which can be meaningfully related to the underlying organic disease. Though the psychological and social difficulties of the AD patients seem diverse, there may be a common thread in the signs and symptoms which is the failure of memory (Ashford et al., 1989; Carlesino & Oscar-Berman, 1992), and more specifically, the disruption of the fundamental mechanism for storing new information.


In most cases, the first reported symptoms of AD patients are failures of memory for recent events (Oppenheim, 1994). Tests of the most mildly affected patients indicate that the earliest difficulties involve the storage of new information into memory, that is, learning (Ashford et al., 1989a; 1995; Welsh et al., 1991; Fillenbaum et al., 1994; Masur et al., 1994). Even various psychiatric symptoms found in AD patients (Oppenheim, 1994; Cohen et al., 1993) can be linked to the failure of learning mechanisms. For example, claims of "stolen keys" usually turn out to be keys which were placed consciously, but the placement not retained. "Unfaithful spouses" are in fact spouses whose whereabouts the night before is not available for recall, though they were within the patient's view the entire time. Thus, the primary symptoms of AD seem to relate to difficulties with the neural mechanism for storing new information.


As AD progresses into more moderate phases, patients begin to lose the ability to recall information which had been learned prior to the onset of the disease. Neurological signs and symptoms such as aphasia, agnosia, and apraxia, which develop insidiously during the middle course of the disease, bear no resemblance to the failures seen after such critical brain injuries as stroke, but rather relate to the associative failure to recall a word, the purpose of an object, or how to perform a specific task. Consequently, the middle phase psychosocial symptoms of AD point to a disruption of neural connections related to the long-term storage memory mechanisms.


As AD progresses into late phases, a host of diverse symptoms develop, including disruption of activities of daily living. Yet, with careful consideration, each of the symptoms can be traced to failures of cortical information retention.


The logical leap in making the connection between memory mechanisms and such diverse symptoms as inability to shop, bathe, or toilette, lies in understanding that information is stored in the brain in a distributed fashion (Ashford & Fuster, 1985; McLelland & Rummelhart, 1989; Fuster, 1995). As new information is stored, it is placed (as a vector convolution; B.B. Murdock, 1982; Lewandowsky & Murdock, 1989) on top of the information which is already in place (Fuster, 1995; Ungerleider, 1995). If the mechanism for storing the new information disrupts neuronal structure, then slowly, old information and habits will be lost as well. Consequently, the psychosocial symptoms and their progression point to a neuropathological process which attacks the mechanism for learning or storing information. This brain mechanism which is so vulnerable to the AD process is presumed to be neuroplasticity (Ashford & Jarvik, 1985; Horwitz, 1988; Repressa et al., 1988; Butcher & Woolf, 1989; Woolf & Butcher, 1990; Di Patre, 1991; Geddes & Cotman, 1991; Larner, 1995).


NEUROBIOLOGIC SYSTEMS AFFECTED BY ALZHEIMER PATHOLOGY


AD is known as a neurodegenerative disorder. The major signs of the disorder are dystrophic neurites, neurofibrillary tangles (NFT's) and neuritic amyloid plaques (NAP's). The dystrophic neurites and the NFT's are composed of paired helical filaments (PHF's) which are primarily abnormally phosphorylated microtubule associate protein-tau (Trojanowski & Lee, 1995). The PHF's clog the dendrites of the neurons and coalesce to form the NFT's in the neuronal cell bodies. They appear to reside indefinitely in situ after the neuron has died. NAP's are complex structures which contain a core of beta-amyloid (Aâ) and activated microglia (Itagaki et al., 1989; Streit & Kincaid-Colton, 1995), with reactive astrocytes (Sadowski et al., 1995) and invading neurites (Geddes et al., 1986), which contain PHF's. The distribution of these changes is not random, preferentially occurring in particular regions of the cortex (Brun & Englund, 1981) and subcortical nucleii projecting to those cortical regions (German et al., 1987). The process disrupts memory presumably by causing loss of synapses and the death of neurons.


1) Telencephalic Systems Affected by AD


Alzheimer pathology is most concentrated in the structures of the temporal lobe, particularly the amygdala, the hippocampus, the entorhinal cortex, and the amygdala (Hirano et al., 1962; Hyman et al., 1984). In the development of AD, the AD process makes its initial appearance in the transitional entorhinal cortex, then spreads to entorhinal cortex, then selective regions of the hippocampus (Braak & Braak, 1991). At a later stage, about the time that there is a transition from mild memory deficits to significant functional impairment, pathology begins to develop in the convexity of the temporal lobe (Bancher et al., 1993). In some cases, dementia develops without significant pathology in the medial temporal lobe structures, but still in association with the lateral distribution. Development of pathology in the neocortex also follows a progression, with successive appearance of disease occurring in the parietal cortex, frontal cortex, and late in the primary cortical regions. Even the occipital cortex, containing the primary and secondary visual cortical regions, shows a gradient of pathological involvement, increasing from the primary visual area 17 to areas 18 and then 19 (Lewis et al., 1987). However, considerable variation occurs between individual cases. Alzheimer pathology can disproportionately affect one side of the brain or one lobe more in one case than another.


The degree of clinically relevant AD pathology in specific regions of the cortex is indicated most clearly by the concentration of neurofibrillary tangles (Arriagada et al., 1992; Hyman, 1994; Nagy et al., 1995), while plaques, diffuse or neuritic types, are less clearly associated with the severity of the pathology (Braak & Braak, 1991). However, the cortical change most closely associated with cognitive dysfunction is the loss of synapses (Davies et al., 1987), occurring in the temporal (Scheff & Price, 1993), frontal (DeKosky and Scheff, 1990; Scheff et al., 1990; DeKosky et al., 1992), and parietal regions (Terry et al., 1991). Yet, it is not clear whether this association is based on the critical role of these cortical regions in functions which are most clearly measured by cognitive testing in the middle phases of the disease, rather than directly reflecting the global advance of the disease process. In another analysis, atrophy of the hippocampal formation subdivisions corresponds closely to stage (Bobinski et al., 1995) and duration (Jobst et al., 1994) of AD. Since dementia symptoms are highly dependent on premorbid factors such as education and occupational attainment (Stern et al., 1994), and probably numerous other factors, including variation in pathology between cases and in presentation, variability can be expected in the relationship between pathology and function. In the clarification of these relationships, it is important to analyze the time-course of development of the pathological factors (Ashford et al., 1995).


The sequence of appearance of Alzheimer pathology in macroscopic structures is generally consistent with the concept that the principle target of the underlying process of Alzheimer pathology is a neuroplastic mechanism. The hippocampus has been long associated with memory formation (O'Keefe & Nadel, 1978; Squire & Zola-Morgan, 1991; Grady et al., 1995), and the amygdala also plays an important role in learning (Mishkin, 1982). However, the reason why the entorhinal cortex would be the primary site of attack of the Alzheimer process is unclear. Part of the explanation could be that this region is the critical pathway connecting the neocortex to the hippocampus (VanHoesen et al., 1975; Rosene & VanHoesen, 1987) for consolidation of information into long term memory. An important concept in this regard is that information is processed in the neocortex while connections with the medial temporal lobe (in particular, the hippocampus and amygdala) serve to coordinate the encoding of that information in the neocortex (Coburn et al., 1990; Ungerleider, 1995). Thus, processed information is not actually transferred form associative cortical regions to the medial temporal lobe, but reciprocal connections with the medial temporal lobe through the entorhinal cortex serve to initiate and foster the consolidation of information bearing connections in those regions of the convexity of the brain. Accordingly, the transitional region of the entorhinal cortex serves as the critical bridge between the medial and lateral structures during memory consolidation. The major burden of this role potentially explains why the AD process makes its initial appearance in this site. The evolutionary association of the olfactory system with the cortex, especially the medial temporal regions involved in memory, may further explain this vulnerability (see below). As AD progresses and information storage continues to be attempted in broadly distributed cortical regions, those regions which are burdened with relatively more storage requirements can be supposed to be affected earlier in the disease course than areas which have lower storage demands.


An important recent development is the field of brain imaging. New techniques are being used to define and track the macroscopic development of AD pathology in the brains of living patients. As noted above, atrophy of the hippocampus (Bobinski et al., 1995; Jobst et al., 1994) accompanies the progression of AD. Loss of metabolism in the temporo-parietal cortex also develops with respect to disease severity (Kuhl et al., 1985). Further, metabolic losses can be traced over time from the temporal to parietal to frontal regions (Jagust et al., 1988; Jagust, 1994). Metabolic loss could be related to a variety of different factors including local loss of neurons to loss of activation by projecting fibers. However, the most parsimonious explanation of loss of local metabolic activity is loss of synapses. Synapse quantity is an indicator of the volume of the neuropil of a cortical region, and maintenance of membrane polarization of axonal and dendritic fibers in the neuropil is the major metabolic demand in the cortex. Loss of neuropil substance will result in a loss of metabolic activity and a resulting loss of blood flow. While not directly reflecting metabolism, the pattern of loss of cerebral blood flow in AD patients resembles the loss of glucose metabolism (Jagust et al., 1990) and does appear similar to the reported distribution of AD pathology in the brain (Figure 1). Both metabolism and blood flow changes can be quantified over time in the living patient. It is now important to link the temporal relationships of the development of pathology in the living patients with the concentration or rate of development of particular components of the cellular pathology, such as neurofibrillary tangles or senile plaques. The development of special ligands applicable for use in living patients for these primary pathologic microscopic structures would help to trace the time-course of their appearance.


FIGURE 1: Cerebral Blood Flow in a Severe AD Patient's Brain


These images of cerebral blood flow were produced from SPECT (Single Photon Emission Computed Tomography) of a 75 year old male with severe Alzheimer's disease (Mini-Mental State Score = 0) who was still able to walk and state his name (testing performed by Cathy Cool, R.N., M.S.N., VA Medical Center, Lexington). The SPECT images were obtained with Neurolite (ECD - ethylene cysteine dimer) which was injected intravenously. The patient was scanned after 30 minutes of resting in a dimly lit room. Scanning was performed with a 3-headed Picker Prism camera for 20 minutes (horizontal detectors every 2mm, 120 angles of acquisition; full-width, half-maximum resolution of 6.7 mm at 10 cm for the technetium tracer). Image data was back projected into a three-dimensional array with voxels 2 mm on a side. (The data array was provided by Dr. Wei-Jen Shih, VA Medical Center, Lexington.) The external surface images were constructed by directing lateral rays toward the brain, thresholding out non-brain structures and seeking local maxima across 3 voxels. The anterior and posterior aspects of the left and right side views were justified with the anterior and posterior images so that these two images (only) did not show tangential diminution of cerebral blood flow activity. (Three-dimensional analysis and imaging program by J.W. Ashford.) The color images on the left show blood flow with red being normal relative to the cerebellum and purple representing severe diminishment of flow. The black and white images on the right are three-dimensionally shaded reconstructions indicating the locations of the cerebral blood flow pixels. The top images represent the left and right lateral views. The bottom row shows the inferior and superior views.


Note that the medial and inferior aspects of the anterior temporal lobe shows the most diminution of blood flow with less decline spreading out over the lateral temporal and parietal lobes. A unique finding in this demonstration is the severe involvement of the entire limbic lobe, including the cingulate and basal frontal cortex. By contrast, aged matched normals show only slight decrease of flow in the limbic structures. Three-dimensional display characterizes the distribution of blood flow more clearly than cross-sectional images using SPECT or PET (Burdette et al., 1995). Further, the distribution of the blood flow decline demonstrated here clearly corresponds to the distribution of pathology seen at autopsy (Brun & Englund, 1981; Braak & Braak, 1991; 1995). This approach provides a means to stage Alzheimer pathology in the living patient.


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