.. re senile plaques (SP) and Neurofibrillary tangles (NFT). There are two types of SP, neuritic and diffuse, both plaques share antigenic determinants with the Beta amyloid 4 protein. Neuritic plaques can be distinguished by their abnormally thickened neurites ( i.e., axons or dendrites) arranged around a central core of amyloid (Mirra & Gearing, 1994). By contrast the diffuse plaques lack the thickened neurites and the amyloid core seen in the neuritic plaques (Mirra & Gearing, 1994). Plaques of both types are found in varying degrees in the neocortex, entorhinal cortex, hippocampus, and in the amygdala.
SP also occur in the brains of healthy people. It is only when they exceed a certain critical number that AD emerges. NFT are intraneuronal structures which occupy the cell body of the neuron. Usually NFT coexist with SP in the neocortex, but they may be absent there in up to 30% of AD patients (Mirra & Gearing, 1994). However, NFT are consistently found in the entorhinal cortex, hippocampus, amygdala, nucleus basalis of Meynert, and dorsal raphe nucleus (Mirra & Gearing, 1994). It is thought that the major antigenic component in NFT is the protein tau.
Neuronal Loss Neuronal loss is directly related to the degree of synaptic density, which has been found to be crucial in determining the severity of cognitive decline. It is greatest in the temporal lobes, but is also significant in the frontal and parietal lobes (Lezak, 1995). The strongest correlation with a global measure of dementia is the loss of functional synapses in the midfrontal and lower parietal areas which surround the temporal lobes (Lezak, 1995). The effect of this pattern of neuronal cortical loss is twofold. First it disconnects the temporal lobe structures from the rest of the cerebral cortex. This accounts for the prominence of memory impairments (Lezak, 1995).
Second this pattern also disconnects the prefrontal structures from the parietal ones. This accounts for the compromised capacity for attentional tasks (Lezak, 1995). It is thought that besides the effects of SP and NFT, neuronal loss is chiefly related to the depletion of the neurotransmitter acetylcholine (see treatment). Overall Picture In a study conducted by Brun and Gustafson (1978) [as cited by Cummings, 1988], the regional distribution of SP, NFT, and neuronal loss, was examined in AD patients. The results indicated that the most severely affected areas were the medial temporal and the temporo-parieto-occipital junction region (see figure 1).
Two positron emission tomography (PET) studies by Benson et al. (1983) and Foster et al. (1984) [as cited by Cummings, 1988] have confirmed this pattern. Cognitive Deficits General Intelligence A profile of declining IQ scores reliably discriminates normals from AD patients. However, the utility of IQ scores in other dementing diseases is unknown. In the early stages of the disease performance IQ tends to decline at a faster rate than Verbal IQ which remains relatively unimpaired.
Subsequently, as the disease progresses the decline is evident in both performance and verbal IQ (Schmitt & Sano, 1994). Memory Memory dysfunction is often considered to be the distinguishing clinical feature of AD. Therefore, it is unlikely that a diagnosis of AD will be assigned unless a memory deficit is present. Homs (1992) study [as cited by Schmitt & Sano, 1994] compared the verbal and visual memory of elderly demented patients with similarly aged normals, under two conditions, immediate and delayed recall. Memory performance in the immediate recall condition was 29% for verbal memory and 31% for visual memory, of the average performance of the normals. The deficit was even more pronounced in the delayed recall condition, where the figures were 11% for verbal recall and 6% for visual recall. Common examples of memory dysfunction in mild dementia include misplacement of items without independent retrieval, failure to recall details of re cent conversations or events, and frequent repetition of questions.
At a more advanced stage recent events are forgotten, and even knowledge of highly learned material erodes (Morris, 1994). It is thought that in AD, memory failure occurs as a result of improper encoding rather than due to retention failure (Schmitt & Sano, 1994). Orientation dysfunction usually co-occurs with a memory deficit. There are difficulties with dates, temporal sequencing, day/night distinction, and navigating through familiar places (Morris, 1994). With regards to the last deficit it seems that an underlying visuospatial impairment is the critical causal factor (see other cognitive impairments).
Language The most common language impairment in AD patients is dysnomia, the inability to name common objects. Dysnomia emerges early in the course of AD, later on expressive and receptive aphasia are often present (Schmitt & Sano, 1994). Table 3 illustrates the linguistic impairments seen in each of the three AD stages (mild, moderate, and severe dementia). Table 3. Progressive Changes in Linguistic abilities in AD Stage I 1. Dysnomia 2. Empty, fluent speech 3.
Poor word list generation 4. Mild anomia 5. Lack of spontaneously initiated conversation Stage II 1. Anomia 2. Paraphasia with increasingly little relation to target word 3. Impaired auditory comprehension 4.
Impaired comprehension of written language 5. Aphasic agraphia 6. Relative preservation of repetition and reading aloud 7. Poor engagement in conversation Stage III 1. Incoherent verbal output 2.
Echolalia, palilalia, logoclonia 3. Diminished articulatory agility 4. Terminal mutism 5. Mechanical agraphia Note: Modified from Cummings & Benson, 1983, Dementia: A clinical approach, Boston: Butterworths The typical AD linguistic impairment pattern includes poor auditory comprehension, poor naming with paraphasia, writing impairment, and poor reading comprehension (Cummings, 1988). According to Benson [as cited by Cummings, 1988] the pattern of verbal output seen in AD resembles transcortical sensory aphasia (which is associated with focal posterior left hemisphere damage). The difference is that in AD there is less paraphsia, echolalia, and the completion phenomenon, and more impairment of automatic speech production.
Other Cognitive impairments Several other cognitive impairments are commonly seen in AD patients. Constructional dyspraxia (impairment in constructional tasks) is often present. Additionally, many patients suffer from basic visuospatial impairment. It is quite common for patients to find themselves lost in familiar neighborhoods, or drive in the wrong direction on a one way road (Cummings, 1988). Also common are attentional deficits, and disturbances of abstraction, calculation, problem solving and judgment.
The latter cluster of deficits points to an underlying frontal lobe dysfunction (Morris, 1994). Model for Overall Cognitive Deficit Picture Cummings (1988) has proposed a model to explain the above deficit picture observed in AD. The following discussion summarizes the main points. The combination of all of the cognitive deficits in AD is greater than the sum of the individual losses. For instance a focal lesion which results in a memory defect has a small impact on verbal output, and an aphasic disorder does not effect memory . By contrast, the dysfunction seen in AD results from multiple defects which interact to produce additive abnormalities.
In AD a memory deficit directly contributes to impoverished linguistic output and the aphasia in turn magnifies the memory problems. Furthermore, other abnormalities such as visuospatial and calculation deficits are superimposed on these, and together they disable various integrative abilities such as insight, strategy formulation, and anticipatory planning. Taking into account these considerations, Cummings (1988) proposes a three-tired model of human intellectual activity which applies to AD. The most basic activities (i.e., arousal, attention, motivation) are mediated by subcortical structures. These fundamental functions are largely intact in AD. However, two other aspects of intellectual activity are damaged in AD.
First instrumental functions which are specific neuropsychological abilities (i.e., memory, language, calculation) mediated by the cerebral cortex are damaged. More importantly, the distinguishing feature of AD involves damage to supraordinant functions (integrative abilities). These functions are dependent upon a proper interaction between the fundamental and instrumental functions. Behavioral Problems and Psychopathology The gradual destruction of various brain structures, causes several maladaptive behavioral changes. Typically dementia is viewed as a collection of negative symptoms, but positive symptoms are present as well.
Tariot and Blazina (1994) suggest that these behavioral changes may be collectively present up to 90% of the time during the course of a given dementing illness. Furthermore, they have determined that certain behaviors occur at a particularly high rate. Table 4 shows the eight different categories which include these behaviors. During the early stages of the illness when the patient is only mildly impaired it is very common for individuals to avoid active participation in life. Patients tend to withdraw from social engagements, lack initiative, and overall behave in an indifferent and apathetic manner.
A possible explanation for this behavior is that these patients may be embarrassed by their cognitive deficits, and so they avoid interacting. As the illness progresses and the cognitive deficits increase patients may become more anxious and agitated. Patients with preexisting psychological problems are prone to experiencing hallucinations and delusions. In particular these patients exhibit paranoid delusions, for instance accusing the elderly spouse of being unfaithful. Misperceptions, such as the inability to distinguish real people from television images, are also common at this stage (Tariot & Blazina, 1994). Aggression, in particular verbal hostility tends to increase as accurate perception declines. According to Cohen-Mansfield et al. (1986) [as cited by Tariot & Blazina, 1994, P.
470] agitated and aggressive behaviors may represent adaptive efforts to obtain stimulation and certain verbal behaviors may be frustrated efforts to communicate or obtain assistance. Table 4. Schematic Summary of Reported Frequencies of Behavioral disturbances Associated with Dementia (% of patients) Behavioral Disturbance Range Median 1. Disturbed affect/mood 0-86 19 2. Disturbed ideation (Delusions) 10-73 33.5 3.
Altered perception Hallucinations 21-49 28 Misperceptions 1-49 23 4. Agitation Global 10-90 44 Wandering 1-49 23 5. Aggression Verbal 11-51 24 Physical 0-46 14.3 Resistive/uncooperative 27-65 14 6. Anxiety 0-50 31.8 7. Withdrawn/passive behavior 21-88 61 8. Vegetative behaviors Sleep 0-47 27 Diet/appetite 12.5-77 34 Note: Reproduced from Morris, 1994, Handbook of Dementing Illnesses, New York, Marcel Dekker Assessment Interview The initial diagnostic procedure used in the assessment of dementia is the interview. The purpose of the interview is twofold. First it is important for the clinician to gain an accurate picture of the case history. It is important to interview at least one significant other person, and if possible more, to gain an objective view.
Information should be collected about premorbid functioning, and about the nature, onset, and course of the symptoms. Second during the interview the clinician evaluates whether the individuals presenting complaints match the clinical profile for dementia. It is important to rule out other disorders that may mimic dementia. For instance self reported memory complaints correlate better with the presence of depression than with dementia ( Morris, 1994). Brief Mental Status Examination Alongside the interview, a brief mental status examination is often used. The exams purpose is to indicate whether any gross cognitive deficits are present.
According to Schmitt & Sano (1994, P. 94) the strengths of such an exam are: (1) the ability to rapidly screen a large number of people, and (2) the ability to measure progression in those who have been identified with dementia. The problem with these exams is that they are insensitive to mild dementia, particularly in highly educated individuals. Furthermore, they lack the ability to assess specific neuropsychological functions, and thus are of little value in specifying the type of dementia (Schmitt & Sano, 1994). Nevertheless, these brief exams can be very useful.
In practice many primary care physicians do not routinely administer these tests. For instance in a study by McCartney and Palmateer (1985) [as cited by Katzman et al. , 1988] it was found that these exams were carried out in only 4 out of 165 patients in the United States. As a result 50 patients with cognitive impairments were missed. The two mental status tests which are in widest use are the information-concentration-orientation test of Blessed et al.
and the mini-mental state exam of Folstein et al. The Blessed test is the most sensitive, and thus is used the most in very early cases. The mini-mental test is broader in that it also tests language, writing, and drawing. Both tests are inappropriate to use with mentally retarded individuals or those with a poor educational background. Also the tests should be adjusted for individuals who are not fluent in English or for those who have a different cultural background (Katzman et al.
, 1988). Another useful brief item is the dementia rating scale. It is utilized to estimate the severity of dementia. Neuropsychological Testing According to Morris (1994, P. 79) neuropsychological testing in demented patients serves three functions: (1) to provide objective documentation of impaired cognition and therefore support the clinical diagnosis of dementia (2) to assess cognitive changes longitudinally, and (3) to identify selective patterns of cognitive deficits for correlation with neuroimaging and postmortem findings. The shortest battery for discriminating dementia patients from normals is the Iowa screening battery for mental decline.
It consists of three neuropsychological tests, Temporal Orientation, Benton Visual Retention Test and the Controlled Oral Word Association Test. This battery is used to determine if further evaluation is necessary. If further evaluation is necessary usually the Consortium to Establish a Registry for Alzheimers disease (CERAD) battery is used. The battery consists of seven tests, some of which are slightly modified from their original form (Lezak, 1995). These tests include the Word List Memory Test and the Boston Naming Test, which test for memory and language respectively.
The word List Memory Test tests for memory by verifying how well a person can recall three lists of ten words. Whereas the Boston Naming Test tests for language by verifying how well the person can duplicate three lists of five words (Lezak, 1995). Sometimes it is useful to test for specific cognitive abilities. For instance the Wechsler Memory Scale-Revised is often used to see if a memory impairment is present. Table 5 illustrates some of the more common neuropsychological tests utilized in the assessment of dementia. Table 5.
Assessment of Neuropsychological Functions for Dementia Diagnosis Function(s) assessed Examples of useful clinical tests Global mental status Mini Mental State, Mattis Dementia Scale, Information-Memory Concentration Test, Syndrome Kurtz Test Premorbid functioning National Adult Reading Test, Wide-Range Achievement Test-Reading General intellectual functioning Wechseler Adult Intelligence Scale-Revised, Ravens Progressive Matrices, Test of Nonverbal Intelligence Memory Wechsler Memory Scale Revised, Benton Visual Retention Test, Rey-Osterreith Complex Figure, Rey Auditory Verbal Learning Test, Selective Reminding Test, California Verbal Learning Test, Rivermade Behavioral Memory Test Language (naming and fluency) Boston Diagnostic Aphasia Examination, Western Aphasia Battery, Holland Communicative Abilities in Daily Living, Halstead-Wepman Aphasia Screening Test, Boston Naming Test, Controlled Oral Word Association, Semantic Category Naming Problem solving (and executive functioning) Halstead-Reitan Category Test, Wisconsin Card Sorting Test, Trailmaking A & B, Stroop Praxis and constructional ability Rosen Drawing Test, Rey-Osterreith Complex Figure (copy), Benton 3-Dimensional Blocks, Beery Test of Visual Motor Integration, WAIS-R Block Design, BDAE Stick Test Motor Finger Oscillation, Grooved and Purdue Pegboards, Diadokinesis Attention/concentration WAIS-R Digit Span, Reaction Time Tests, Cancellation Tasks, Syndrome Kurtz Test Note: Reproduced from Morris, 1994, Handbook of Dementing Illnesses, New York: Marcel Dekker Clinical Diagnosis and Related Problems A definitive diagnosis of AD and many other dementing diseases can only be made either through cerebral biopsy, the surgical removal of a small piece of the cerebral cortex, or when the patient dies and an autopsy is performed. The two most widely used criteria for the diagnosis of dementia are the Diagnostic and Statistical Manual Third Edition-Revised (DSM-IIIR) and the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimers Disease and Related Disorders Association (NINCDS/ADRDA). DSM-IIIR is more often used for research purposes and the NINCDS/ADRDA for clinical purposes. There are several problems in diagnosing dementia, most notably differentiating dementia from normal aging and from depression. In general, the cerebral processing resources needed for attention demanding tasks and secondary memory functions are adversely affected by age (Morris, 1994). Clinically, these impairments result in limited attentional capacity and diminished speed of information processing and retrieval. But unlike in dementia these symptoms are largely nonprogressive, and do not interfere substantially with everyday life (Morris, 1994).
In patients with mild cognitive changes it is almost impossible to make an exact diagnosis even with the best neuropsychological tests. Only the likelihood of developing dementia can be estimated. There can be a great deal of symptom overlap between dementia and depression especially in the early stages of dementia. Depression presenting as dementia is often called pseudodementia. The term pseudodementia implies that the dementia is reversible, and is not caused by an organic disorder but rather it is caused by a psychiatric disorder (Clarfield, 1989). Currently there are no definitive tests to differentiate between dementia and depression. Clinical Subgroups of Alzheimers Disease Blenow, Wallin & Gttfries (1994) have proposed a model for clinical subgroups in AD based upon differential clinical symptomatology and neuropathology.
Their findings indicate that there are two distinct subtypes which they have termed Alzheimers disease type I and type II. Alzheimers disease type I is characterized by dominant temporoparietal symptoms, low frequency of vascular factors, normal blood-brain barrier function, low frequency of CT indicated leukoaraiosis (white matter lesions), and relatively younger age of onset. These characteristics correspond to the classic description of AD. Therefore AD type I appears to constitute classical or pure AD (Blenow et al. , 1994). Alzheimers disease type II is characterized by general cognitive symptoms, absence of or mild temporo- parietal symptoms, high frequency of confusional symptoms, relatively high frequency of vascular factors, mildly impaired blood-brain barrier function, high frequency of CT indicated leukoaraiosis, and relatively late age of onset. These characteristics suggest that vascular changes are responsible for the production of dementia symptoms in AD type II (Blenow et al.
, 1994). Markers Markers Reflecting Brain Changes Markers which belong to this category utilize cerebral spinal fluid (CSF) changes to reflect altered neurotransmitter levels or abnormal proteins (Katzman et al. , 1988). The enzyme Acetylcholinesterase (which regulates the neurotransmitter Achetylocholine, see treatment) is known to be decreased in the cerebral cortex of demented patients. Several investigators have found it decreased in the CSF, while others have failed to confirm this.
According to Thal (1985) [as cited by Katzman et al. , 1988] the apparent decrease in some studies may be a dilutional effect secondary to ventricular enlargement. Similarly Somatosatin and Norepinephrine are also reduced in the cerebral cortex of demented patients. However, in the CSF Somatosatin is only decreased in some patients, whereas Norepinephrine is actually increased in the CSF. A good area for future research is to investigate whether any of the abnormal proteins associated with AD can be found in the CSF (Katzman et al. , 1988). Peripheral Markers Peripheral markers are markers which reflect changes in the skin or blood cells (Katzman et al.
, 1988). Most of the findings in this category are either inconclusive or have not been replicated. For instance Diamond et al. (1983) [as cited by Katzman et al. , 1988] have found that the sodium-lithium counter- transport rates in red blood cells were elevated in AD patients, but this finding has not been replicated. Olfactory deficit Markers Several investigators have found that AD patients have olfactory recognition and threshold deficits. Peabody and Tinklenberg (1985) [as cited by Katzman et al.
, 1988] have found that 8 out of 18 AD patients had these deficits compared to only 1 out of 26 normals. Katzman et al. (1988) discuss increased carbon dioxide production, increased superoxide dismutase, and decreased calcium uptake as possible causes for these deficits in AD patients. Pharmacological Treatment Cholinergic Drugs There is no known cure for AD or many other dementing diseases. Several medications are available but their effectiveness is limited.
The most promising group of drugs work by potentiating the cholinergic systems in the brain. During the 1970s several studies have shown that demented patients have low levels of the neurotransmitter Acetylocholine (ACh). This has led to the development of the cholinergic hypothesis for dementia. It has since been established that the enzyme from which ACh is synthesized, Choline Acetyltransfearse (ChAT), is severely decreased in AD patients. There are three mechanisms by which these drugs work (1) precursor loading , (2) preventing the breakdown of ACh , and (3) the direct stimulation of the postsynaptic receptors. Precursor loading in AD is similar to Parkinsons disease (PD).
The difference is that instead of using the precursor L-dopa for dopamine in PD, the precursors choline and lecithin are used in AD to synthesize ACh. Generally this treatment when used alone fails to improve cognitive performance (Schneider, 1994). Preventing the breakdown of ACh involves inhibiting the enzyme Acetylocholinesterase (AChE). The principal drugs which utilize this mechanism are Physostigmine, Tacrine, and Valancrine. The problem with Physostigmine is that the duration of its therapeutic effect is very short, usually about one to two hours, whereas Tacrine and Valancrine have serious side effects (Schneider, 1994).
A second generation of cholinesterase inhibitors which are longer acting and more selective are currently being developed, and the initial results are encouraging. In AD the postsynaptic M-1 cholinergic receptors are relatively intact. It is the presynaptic M-2 cholinergic receptors which regulate ACh release that are damaged. Therefore, it makes sense to try to directly stimulate the postsynaptic receptors (Schneider, 1994). These cholinergic agonists include Bethanechol, Oxotremorine, Pilocrapine, RS-86, and Arecholine. When these drugs are given orally they are not very effective.
They are more effective when administered through an implant of an intracereroventricular pump. But the risks of such an implant are not insignificant. For instance in one trial out of 68 implants 16 resulted in surgical complications, including one death, two hemorrhages, and seven seizures (Schneider, 1994). Other Drugs There are several other drugs used in the treatment of dementia, although their therapeutic mechanisms are not understood very well. Hydergine is the longest used and most extensively studied antidementia drug. Hydergine is an ergoloid derivative which effects the alpha-adrenergic, dopaminergic, and sertoninergic receptors.
There have been conflicting reports about its efficacy, but overall it seems that it is only slightly better than a placebo in relieving symptoms (Schneider, 1994). Nootropics are a group of drugs derived from the neurotransmitter GABA. But instead of having GABA effects they have a neuroprotective effect on the central nervous system, and they may stimulate central cholinergic activity. Still, the specific mechanism of action relevant for dementia has not been established for these drugs. Overall results with Nootropics such as Piracetam, and Oxiracetam have not been very encouraging (Schneider, 1994). Summary As the human race marches forward into the new millennia, one of the challenges that will remained to be solved is the dementia epidemic. The continuous increase in life span means that the number of people which are afflicted with dementia will continue to grow.
Notwithstanding, we have come along way in our understanding of the dementia syndrome since the days of Pinel or even since the days of Alzheimer. We now know that dementia (senility) is not the natural outcome of aging, rather it is the result of a variety of possible abnormal brain processes. For instance in AD (the most important dementing disease) the formation of SP and NFT in the brain have been proven to be the main causal factors of the disease. Furthermore, in AD these processes have been shown to occur mainly in the cerebral cortex, and in particularly in the temporal lobes. The effects of these brain lesions are mainly manifested in various cognitive and behavioral impairments.
With regards to cognition, memory and language dysfunction are the most commonly encountered deficits in AD. In fact memory impairment is so crucial, that a diagnosis of AD will almost never be made unless it is present. With respect to behavior, anxiety disturbances tend to predominate in the earlier stages of AD, whereas aggression is encountered in the latter stages. Significant progress has also been made in the assessment of dementia. Standard interviewing methods are now used alongside brief mental status examinations. Although the mental status exams have a limited diagnostic usefulness (they are only used as initial screening devices), they are nevertheless important because of their relative low cost and quick administration time.
When further confirmation is required or more detail is desired neuropsychological testing is performed. Neuropsychological testing allows for the assessment of specific cognitive functions (i.e. memory, language, attention) thus discovering which brain areas are affected. This is useful because not only is it possible to judge if the person suffers from dementia, but with a high degree of accuracy it is possible to say which dementing disease is responsible. Notwithstanding, even the best neuropsychological tests may run into difficulties at times. For instance differentiating dementia from depression is extremely difficult since people who are depressed may display many of the clinical symptoms observed in dementia.