Ihe two terms are related but not synonymous. AD is the disease process that ultimately results in Alzheimer's dementia. Alzheimer's dementia has a characteristic cognitive pattern. Early in a patient's course, AD may cause memory loss of insufficient severity to warrant the designation of dementia. Other patients with AD may follow an atypical course with progressive aphasia or progressive apraxia rather than a typical Alzheimer's dementia. Most of the time, however, AD causes Alzheimer's dementia.
Pathogenesis and Pathophysiology. AD is characterized by generalized cerebral cortical atrophy ( Figr...3.3:.1.. ) with widespread cortical neuritic (or senile) plaques
(NP) and neurofibrillary tangles (NFT) (..Fig 33-2 ). Other typical pathological findings include neuropil threads, granulo- vacuolar degeneration, lipochrome accumulation, and Hirano bodies. NPs are composed of an amyloid core surrounded by dystophic neurites, whereas paired helical filaments are the major constituent in NFIs, neuropil threads, and dystrophic neurites. None of these histological findings individually are entirely specific for AD, because NPs can be seen in clinically nondemented patients,^] and NFIs can occur in other neurodegenerative and prion disorders. Although recently debated, current neuropathological criteria for the diagnosis of AD requires that an adequate number of NPs be present within a specified age range in a clinically demented patient. y
Synapse loss appears to be the most important correlate of dementia severity, y but the number of NPs and NFIs and the density of beta-amyloid load have each been associated
Figure 12-1 Alzheimer's disease. Note the generalized cerebral cortical atrop\(Courtesy J. E. Parisi, Mayo Clinic, Rochester, Minnesota.)
with dementia severity. Mesial temporal structures, particularly the hippocampal formation, are involved early in AD, and this accounts for the amnestic syndrome in these patients. AD produces a lamina-specific pattern of damage to the entorhinal cortex that disrupts cortical input to the hippocampal formation from association and limbic cortices, and disrupts hippocampal outflow from the cornu Ammonis (CA) sectors and subiculum to the association cortices, diencephalon, basal forebrain, and amygdala. Hence, AD effectively disconnects the hippocampus from its major input and output pathways. [4
Ihe plaque core in AD in isolation or occurring with Down's syndrome is composed of insoluble beta amyloid, y and the gene for amyloid beta precursor protein (betaAPP) has been mapped to chromosome 21. Ihe betaAPP is normally expressed in multiple cells of neural and non-neural origin and has several putative cellular functions. Ihe betaAPP can be processed by nonamyloidogenic and amyloidogenic pathways. Ihe fragment of betaAPP formed by the latter pathway, termed B-amyloid or Abeta, is a soluble secretory product composed of 39 to 43 residues. This pathway may generate Abeta at the cell surface, in the lysosomes, or in the Golgi apparatus, and the precise mechanism of Abeta processing may be cell-type specific. [6 Ihe form secreted in highest quantity is Abeta1-40, with lesser amounts being in the Abeta1-42 form. Each form is secreted in varying amounts in cognitively normal and abnormal individuals, and levels of each can be measured in both plasma and CSF. Ihe insoluble Abeta1-42 form is contained in plaques. Additional amyloid-associated proteins are believed to interact with Abeta, which can also promote amyloid fibril formation and deposition as plaques.
Plaques, in which amyloid deposition is diffuse and distended neurites are absent, have been termed diffuse non- NPs. Ihese plaques are present in nondemented aged and Down's syndrome patients. With the appearance of distended neurites, the plaques are then classified as diffuse NPs. Insoluble amyloid fibrils surrounded by distended neurites constitute a dense-core NP, which is equivalent
Figure 12-2 Photomicrograph of entorhinal cortex in Alzheimer's disease. Ihe neuritic plaque is composed of an amyloid core surrounded by dystrophic neurites. Ihe dark flame-shaped fibrillar structures are neurofibrillary tangles, which are chiefly made up of paired helical filamentsfBielschowsfcy silver stain; 200*; courtesy J. E. Parisi, Mayo Clinic, Rochester, Minnesota.)
to the classic NP. A "burnt-out" plaque is a dense core of amyloid without the surrounding distended neurites. Ihe amyloid cascade hypothesis states that the initial abnormality in AD pathogenesis is amyloid deposition in the neuropil (forming plaques) and cerebral vessels (forming amyloid angiopathy). y , M This deposition is neurotoxic, leading to cytoskeletal derangement with neurofibrillary tangle formation, leading, in turn, to neuronal degeneration. Studies from several laboratories suggest that Abeta1-42 is the crucial form of Abeta involved in this cascade. Abeta1-42 has been shown to form insoluble amyloid fibrils faster than Abeta1-40 in vitro. This form is deposited in the diffuse plaques of Down's syndrome patients far in advance of Abeta1-40, and this peptide is the primary form of Abeta deposition in the NPs of sporadic AD. Plasma Abeta1-42 is elevated in approximately 12 percent of patients, and CSF Abeta1-42 is reduced in patients with clinically diagnosed AD. [8 Ihe reduction of Abeta1-42 presumably reflects diminished clearance and subsequent deposition. It is hoped that interfering with Abeta1-42 formation or deposition may impact AD pathogenesis.
Ihe six human isoforms of the microtubule-associated protein tau are derived from a single gene on chromosome 17. Iau normally binds to microtubules when dephosphorylated or only partially phosphorylated. Hyperphosphorylated tau is the major component of paired helical filaments, which are the major constituents of neurofibrillary tangles, neuropil threads, and dystrophic neurites. Accumulated paired helical filaments or microtubule destabilization, or both, may disrupt axonal transport and lead to NFT formation and neuronal death. In AD, tau concentration is elevated in the CSF. y
Ihe association between the type 4 allele of apolipoprotein E (ApoE epsilon-4) and late-onset familial  , y and sporadic AD[1j] was recognized in 1993. An increased risk of developing sporadic AD and a decreased age of onset has been associated with the ApoE epsilon-4 allele, whereas risk decreases and age of onset increases with the ApoE epsilon-2 allele. y However, ApoE epsilon-4 does not directly cause AD because it can occur in the absence of even one copy of the ApoE epsilon-4 allele, and two copies of this allele have been documented in cognitively and neuropathologically normal individuals. Disease progression does not appear to be associated with ApoE status.
ApoE is found in the NPs, vascular amyloid, and NFIs of AD. Amyloid deposition in NPs and blood vessels has correlated with ApoE epsilon-4 dosage (that is, whether there is one or two copies of the ApoE epsilon-4 allele), whereas the frequency of NFIs has not. y ApoE promotes amyloid filament formation in vitro Jij ApoE epsilon-3, but not ApoE epsilon-4, binds to microtubule-associated protein tau, which may slow the rate of tau phosphorylation and self-assembly into parahelical filaments (PHF).
Ihere are four types of ApoE receptors in the brain. One type, the low-density lipoprotein receptor-related protein (LRP) is found in hippocampal pyramidal cells and dentate granule cells. It is a highly conserved protein found also in nematodes, and it functions in membrane maintenance. LRP binds and internalizes not only ApoE but also several other ligands, all of which have been associated with NP. LRP internalization of its associated ligands may be impaired in AD, thus resulting in Abeta-ApoE complex aggregation and NP formation.^ Ihe specific interactions between the various ligands and ApoE isoforms remain to be determined, but the potential may exist for developing therapeutic interventions that manipulate these interactions.
Limited pathological, clinical, and epidemiological studies have supported a role for immunological activation as an intrinsic component of the neurodegenerative process.^ Ihe number of activated microglia is high in diffuse plaques and higher in diffuse NPs, but there are fewer microglia in more mature plaques with amyloid cores, suggesting that the inflammatory response may have a primary role in the early steps of plaque formation.
Chronic aluminum exposure was once thought to play a role in AD mainly due to encephalopathy occurring in dialysis patients who were exposed to toxic levels of aluminum. Ihe possible mechanisms by which aluminum could lead to AD histopathology include promoting hyperphosphorylation of tau and subsequent formation of NFIs, altering processing of the betaAPP, which would lead to the formation of NPs, and initiating the inflammatory response. 
However, at present, aluminum exposure is not thought to be a major risk factor for AD.
The oxidative stress hypothesis of neurodegeneration holds that free radical generation from metabolism is neurotoxic, and there is some evidence that Abeta may promote free radical formation.^1 This has led some to propose the use of antioxidants clinically and in experimental trials in patients with clinically diagnosed AD. y
Levels of acetylcholine, noradrenaline, serotonin, gamma-aminobutyric acid (GABA), glutamate, somatostatin, neuropeptide Y, and substance P have all been documented to be reduced in the brains of AD patients. However, reductions in acetylcholine and choline acetyltransferase are the most profound, and therefore they have been thought to be the most important. Such reductions are due to neuronal loss in the basal forebrain, which is the major region from which cholinergic projections originate.y Only modest improvement in cognitive functions have been achieved with cholinergic agonists, presumably due to neuronal loss in the cortical targets that receive cholinergic input.
Pathological variants of AD include limbic AD, plaque- only AD (usually the Lewy body variant of AD y ), and the Lewy body variant (LBV) of AD. The pathophysiological relationship between LBV and AD and the appropriate nomenclature are still under debate (see diffuse Lewy body disease section).
There are four genetic variants of AD. AD1 results from a mutation in the APP gene on chromosome 21, resulting in increased amyloid formation and deposition in the brain, resulting, in turn, in late onset familial AD, as well as cerebral vasculature with consequent amyloid angiopathy. AD2 is another genetic subtype of late-onset familial AD reflecting the type 4 allele of apolipoprotein E located on chromosome 19. y AD3 is a form of early-onset familial AD resulting from mutation of an integral membrane protein (presenilin-1) gene located on chromosome 14. Mutations in this gene may be responsible for more than 75 percent of cases of early onset familial AD with a mean onset before age 50.y Finally, AD4 is another early-onset familial form of AD related to a mutation of another transmembrane protein (presenilin-2) located on chromosome 1 in seven related families of Volga German ancestry (and one Italian kindred) with autosomal dominant AD. y
Alzheimer's pathology has also been found in some patients with non-Alzheimer-type patterns of dementia, including frontotemporal, aphasic, and perceptual-motor syndromes (see ACDS, later).
Epidemiology and Risk Factors. AD is the most common cause of dementia overall, accounting for more than half of all cases, and it increases in frequency with advancing age. Epidemiological age-specific estimates of incidence and prevalence vary by region and study due to differences in diagnostic criteria and population demographics. Figurei33-3 and Fig.uieiii,3.,3.-4. ) show the incidence and prevalence rates for dementia (all causes) and AD in particular in Olmsted County, Minnesota. y There is an exponential increase in both with advancing age at least through the ninth decade. Whether this trend continues into the tenth decade is presently unknown. The prevalence of severe dementia over the age of 60 is estimated at 5 percent, and over the age of 85, between 20 and 50 percent.
Figure 12-3 Incidence rates of dementia (all causes) and Alzheimer's disease in Olmsted County, Minnesota, by age for five quinquennial periods (1960 to 1984). pyrs = person (Fram Kokmen E, Beard CM, O'Brien PC, Kurland LT: Epidemiology of dementia in Rochester, Minnesota. Maya Clin Prac 1996;71:275-282.)
Figure 12-4 Prevalence rates of dementia (all causes) and Alzheimer's disease in Olmsted County, Minnesota, by age for two prevalence dates: January 1, 1975, and January 1, 1980. pyrs = persorfFrem Kokmen E, Beard CM, O'Brien PC, KurlandLT: Epidemiology of dementia in Rochester, Minnesota. Mayo Clin Proc 1996;71:275-282.)
The lifetime risk of developing AD is estimated to be between 12 and 17 percent. y , y
Following age, apolipoprotein E (ApoE) status is the second most important risk factor. In both familial late- onset y and sporadicy cases, the ApoE epsilon-4 allele increases risk and the epsilon-2 allele decreases risk. y The lifetime risk of AD in people without a family history increases from 9 percent without an ApoE epsilon-4 allele to 29 percent with one copy of the ApoE epsilon-4 allele. y ApoE epsilon-4 homozygotes make up roughly 2 percent of the population, but approximately 83 percent are estimated to develop AD in their lifetime, y similar to the 91 percent reported in familial late-onset cases. y , y In limited populations, other genetic factors play a determining role including Down's syndrome (trisomy 21), y1 familial early-onset Alzheimer's kindreds (chromosome 14), [211 and the Volga German kindreds of familial early onset AD (chromosome 1). y
Other purported risk factors are weaker and some are more controversial in that not all well-controlled epidemiological studies have found them to be significant. These risk factors include limited education, depression, gender, estrogen replacement therapy, use of vitamin E, head trauma, use of anti-inflammatory drugs, and a history of thyroid disease.
Clinical Features and Associated Disorders. AD has been considered the paradigm of a cortical dementia syndrome. The hallmarks of cortical dementia include not only memory loss, which is common to many dementia syndromes, but also elements of aphasia, apraxia, and agnosia. Further, in general, there is an absence of subcortical features such as parkinsonism. Some patients with pathologically proven AD, however, also exhibit features of mild parkinsonism, emphasizing that diagnostic boundaries are relative, not absolute. Tables.^-.!., shows the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) Work Group's diagnostic criteria for AD. y1 Definite AD is defined by tissue confirmation. Probable AD is defined by the clinical picture of dementia in the absence of certain atypical features such as focal neurological abnormalities and for which another cause cannot be found. Possible AD is defined by the clinical picture of dementia, but with either atypical features in the course of the illness or with a second potentially contributory disease not believed to be the primary cause. In the absence of histological confirmation, therefore, the clinical picture of dementia is the most important diagnostic feature.
Dementia is not a homogeneous clinical syndrome. It is defined as disabling impairment of multiple cognitive domains. Hence, memory loss alone does not equal dementia, even though it may be the heralding symptom of a dementing illness and is the most commonly impaired cognitive domain among all dementia syndromes (cortical and subcortical). Degenerative dementia further implies disease progression over time. The pattern and evolution of cognitive deficits defines the syndrome of Alzheimer's dementia, even though pathologically defined AD may rarely not present in this way. Nonetheless, the overall clinical-pathological correlation of Alzheimer's dementia with AD is now approximately 87 percent. y
Most clinical studies agree that the earliest clinical sign
_TABLE 12-1 -- NINCDS-ADRDA CRITERIA FOR THE DIAGNOSIS OF ALZHEIMER'S DISEASE*
I. Clinical Diagnosis of Probable Alzheimer's Disease
1. Dementia established by clinical examination and mental status testing and confirmed by neuropsychological testing
2. Deficits in at least two cognitive domains
3. Progressive cognitive decline, including memory
4. Normal level of consciousness
5. Onset between ages 40 and 90 (most common aiter 65) years
6. No other possible medical or neurological explanation II. Probable Alzheimer's Disease Diagnosis Supported by
1. Progressive aphasia, apraxia, and agnosia
2. Impaired activities of daily living
3. Family history of similar disorder
4. Brain atrophy on CT/MRI, especially if progressive
5. Normal CSF, EEG (or nonspecifically abnormal)
III.Other Clinical Features Consistent with Probable Alzheimer'.s Disease
2. Associated symptoms: depression; insomnia; incontinence; illusions; hallucinations, catastrophic verbal, emotional, or physical outbursts; sexual disorders; weight loss; during more advanced stages increased muscle tone, myoclonus, and abnormal gait
3. Seizures in advanced disease
4. CT normal for age
IV. Features that Make Alzheimer's Disease Uncertain or Unlikely
1. Acute onset
2. Focal sensorimotor signs
3. Seizures or gait disorder early in course
V. Clinical Diagnosis of Possible Alzheimer's Disease
1. Dementia with atypical onset or course in the absence of another medical/neuropsychiatric explanation
2. Dementia with another disease not felt otherwise to be the cause of dementia
3. For research purposes, a progressive focal cognitive deficit
VI. Definite Alzheimer's Disease
1. Meets clinical criteria for probable Alzheimer's disease
2. Tissue confirmation (autopsy or brain biopsy)
VII.Research Classification of Alzheimer's Disease Should Specify
2. Early onset (before age 65)?
3. Down's syndrome (trisomy 21)?
4. Coexistent other neurodegenerative disease (e.g., Parkinson's disease) ?
*National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association Work Group's report summarizing the criteria for a diagnosis of Alzheimer's disease.
CSF, Cerebrospinal fluid; CT, computed tomography; EEG, electroencephalogram; MRI, magnetic resonance imaging study.
Reprinted from Mckhann G, Drachman D, Folstein M, et al; Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force of Alzheimer'.s Disease Neurology 1984;34:939-944. By permission of Little. Brown and Company (Inc.).
of AD is memory loss, which precedes the actual dementia. Abnormal cerebral metabolism, demonstrated by positron emission tomography (PET), may precede even mild memory loss.^ A few studies have correlated other relative cognitive inefficiencies occurring much earlier in life with the subsequent development of dementia, although interpretation of these findings has been a source of controversy.
Recent memory is easier to assess reliably than remote memory and is thought to be disproportionately severely involved. Nonetheless, remote memory is also abnormal, and there is a gradient effect regarding recall over a retrograde time interval: The oldest memories appear to be the best preserved, with proportionately greater forgetting as the retrograde interval shortens. y In contrast, procedural memory appears to be relatively spared. Alzheimer's patients are able to learn simple skills as easily as normal controls and better than patients with subcortical patterns of dementia or patients with various types of sensorimotor deficits. y Although apraxia is one of the defining features of cortical dementia, it is rarely severe in mild to moderate stages of AD and can be very difficult to distinguish from impaired comprehension in these patients. One very important skill that needs to be addressed clinically is driving. Despite the relative preservation of procedural memory, patients with mild Alzheimer's dementia have a higher rate of collisions and moving violations than age-matched controls, y although estimates of risk vary, especially during the first 2 years of the disease. Whether this actually results from impaired procedural memory, attentional factors, other cognitive aspects, or a combination is unclear, although visual tracking, memory, and Mini-Mental State score all correlate with a laboratory-based driving score. y
Memory loss is a cardinal feature of Alzheimer's dementia but it is not the only abnormality in most patients. However, a subset of patients present with a circumscribed, slowly progressive amnesic syndrome, which is sometimes referred to as "age-associated memory impairment" (AAMI).y Despite the disarming terminology, memory loss in these patients should be distinguished from the milder memory problems of normal aging. AAMI has the same profile of risk factors as AD, including advanced age and ApoE,y and patients who have come to autopsy often prove to have AD. Such patients also have radiologically demonstrable hippocampal atrophy. Roughly half of patients who present with AAMI develop features of dementia over a 4- to 5-year period. y
Aphasia, apraxia, and agnosia are the other categories of cognitive impairment that typically occur in cortical dementia syndromes and particularly in AD. In Alzheimer's dementia, these aspects do not dominate the clinical picture. A patient with a predominant aphasic syndrome (progressive aphasia) should not be assumed to have AD, though some do (see Asymmetrical Cortical Degeneration Syndromes). Rather, these aspects of cognitive pathology occur in discrete apportionments that define the dementia syndrome as typical Alzheimer's dementia. In patients with such an apportionment, clinicopathological correlation rates are high.y In mild to moderate stages of dementia, anomia is prominent and readily detectable with neuropsychological testing using a variety of naming tests (see Chapter..27. ). Patients are, however, fluent and may have relatively good comprehension, so clinical detection is not always easy. As the disease progresses, the predominantly anomic aphasia gives way to a more fluent, or Wernicke's, type of aphasia with impaired comprehension. Nonfluent aphasia does not generally occur in AD, although preterminally patients become mute (see Chagter.6 ). This should not be the case in a patient who is still ambulatory, however.
Apraxia can be confused with impaired comprehension in mild to moderate stages of Alzheimer's dementia. Patients have difficulty performing tasks at which they were previously adept, such as repairing a household appliance or doing carpentry work. They also have difficulty learning
new procedures such as operating a new car, new appliance, or remote control device. They have some difficulty pantomiming gestures in the office setting but also have constructional apraxia. In moderately advanced stages, patients have trouble dressing and performing other activities of daily living. Patients with clinically evident apraxia typically also have significant perceptual difficulties (see later) and definitely should not be driving a motor vehicle.
Anosognosia, the failure to recognize illness, is a cardinal feature of Alzheimer's dementia and is typically present, even in mild stages of the disease. It is a useful sign to distinguish progressive amnesic syndromes from Alzheimer's dementia. A typical patient with AD is brought or sent for evaluation rather than coming of his or her own accord. He or she may deny significant memory problems and will actively try to explain away the observations of concerned family members and friends, even to the point of becoming hostile and accusative. This is one of the most difficult aspects of the disease because such patients often should not be driving or managing their own finances but will do so anyway, sometimes to their detriment.
In moderate to advanced stages, patients exhibit other so-called agnosic types of disturbances. Arguably, the difficulty such patients have in recognizing familiar people reflects prosopagnosia, save that they are not reliably benefited by voice recognition either. Difficulty finding their way could be compared with atopographagnosia, another visual agnosic syndrome, but again this is not occurring in the pure form given the wealth of other cognitive problems accompanying it. Rarely, patients with histologically documented AD present with a disabling, primarily visual syndrome termed asimultanagnosia, in which there is an inability to view all parts of a complex visual scene in a single coherent time-space frame. Such patients fail to see a target object that is right in front of them, especially if it is surrounded by potentially distracting stray objects. y Strictly speaking, this is not an agnosic disorder, but another type of complex visual disturbance that resembles agnosia and can occur in this setting. It is rarely the presenting feature. More commonly, it is a mild accompanying feature.
Psychiatric symptoms include both affective and psychotic disturbances. Depression interferes with a person's functional status and an accurate cognitive assessment, erroneously leading to the diagnosis of dementia; such is the nature of pseudodementia, which has been estimated to account for 4 to 5 percent of dementia cases.y More commonly, depression may complicate the course of AD and other dementing illnesses. Antidepressant therapy should be strongly considered in such patients. Psychotic symptoms most commonly involve paranoid delusions and, less commonly, hallucinations. AD should be in the differential diagnosis of an elderly patient presenting de novo with an organic delusional syndrome or hallucinosis. Common paranoid themes involve infidelity and stealing. Hallucinations are generally complex, involving people (familiar or unfamiliar), animals, or both. The combination of anosognosia, paranoid delusions, and mild cognitive decline is potentially dangerous and very difficult to manage, especially if such individuals live alone, yet a significant minority of Alzheimer's patients have exactly that combination.
Two common vegetative groups of symptoms regard sleep disturbances and incontinence. Sleep-wake cycle disturbances are common and may be present even during relatively mild stages of the illness. They become more common and more severe during moderately severe stages. There are two aspects to the sleep-wake cycle disturbance. The first is the so-called sundowning effect, which means that the patient becomes more confused, agitated, and difficult to manage during the evening hours. The second regards either not sleeping at night, waking up during very early hours, or going to sleep very early in the evening. Sleep becomes fractionated into shorter segments throughout the 24-hour period. As the disease progresses to more advanced stages, patients may become generally less active, sleep more, and eventually, in terminal stages, are bedbound with little apparent conscious activity. Weight loss is common during the latter stages, as well. Incontinence (both urinary and fecal) is uncommon in mild stages but becomes increasingly frequent as the disease progresses and is universal in late stages. Early on, it may inadvertently result from voiding in the "wrong place" rather than actual sphincter control problems, but in later stages, sphincter control is lost.
Late and preterminal stage AD ensues after roughly a 5- to 10-year course but is highly variable and can be shorter or longer. In very advanced stages, patients are no longer ambulatory, become mute and incontinent, and are totally dependent on their caregiver or nursing attendant. Eventually dysphagia signals the terminal phase, and unless a feeding tube is placed, patients eventually die from inanition or aspiration, or both. Few patients live to these stages, with death resulting from intercurrent illnesses in most.
Down's syndrome has a strong association with AD. If a patient with Down's syndrome (trisomy 21) lives beyond the age of 40 years, it is a near certainty that there will be neuropathological evidence of AD at autopsy. y Clinical dementia increases with age and peaks at roughly 40-75% over the age of 60. y Analysis of the amyloid plaques has shown that trisomy 21 predisposes to larger plaques, presumably reflecting increased production of Abeta, in contrast to ApoE epsilon-4, which leads to greater numbers of plaques presumably reflecting increased probability of senile plaque initiation. y
Not all neuropathologically defined cases of AD present with Alzheimer's dementia, as is elaborated in the discussion of ACDS. Patients with the syndromes of progressive aphasia, progressive apraxia (and other motor syndromes), and progressive asimultanagnosia have all been reported, on occasion, to have Alzheimer-type pathology. Such cases raise questions regarding the nosology of degenerative cortical syndromes.
Differential Diagnosis. AD is one disease among many, both degenerative and nondegenerative, that can produce the categorical syndrome of a chronic progressive encephalopathy. All-encompassing, indiscriminant differential diagnostic inclusion of a hundred conditions encompassed by this broad category is inefficient and impractical. So, too, is the reflex assumption that memory loss in an elderly individual equals dementia equals AD. Simply determining that a disease is degenerative already accomplishes the most important goal of excluding any possible or more effectively treated etiology. Reversible forms of dementia are truly chronic encephalopathies and often cause one or several of the following: hypersomnolence, acute or subacute deterioration, fluctuating
severity, severe electroencephalographic abnormalities, visual hallucinations, tremulousness, or unsteadiness, or it may be accompanied by non-neurological symptoms as well. Such symptoms may occur within the context of another disease process known to cause neurological problems sometimes, such as hypothyroidism, or may occur under specific circumstances such as immunosuppression. Irreversible forms of dementia are generally more slowly progressive (more than a year or two), fluctuate much less, do not occur within the context of another potentially causative disease, have recognizable clinical and cognitive profiles, and are not accompanied by many of the aforementioned clues of a reversible chronic encephalopathy. When analyzed in this way, a more realistic differential diagnosis of AD includes (1) other degenerative diseases, such as Pick's disease, nonspecific degeneration (progressive subcortical gliosis), and diffuse Lewy body disease; and (2) vascular dementia resulting from small vessel disease due either to atherosclerotic small vessel disease or amyloid angiopathy. In mild to moderate stages, clinical cognitive patterns can be very helpful in distinguishing various dementing illnesses. In late stages, however, patients are more diffusely impaired both cognitively and somatically, making it difficult to tell one degenerative brain disease from another.
Evaluation. Because the recognition of distinctive clinical cognitive patterns can be difficult, a practical approach must take into account some of the chronic encephalopathic causes as well as degenerative and related causes. Neuroimaging is essential. Magnetic resonance imaging (MRI) is preferred, if possible, but computed tomography (CT) is generally adequate. Structural processes such as chronic (or subacute) subdural hematomas, tumors (frontal lobe meningiomas and temporal lobe gliomas in particular), cerebrovascular lesions, prior traumatic encephalomalacia, relevant focal atrophy (see ACDS section), and meningeal enhancement are among the many important diagnostic clues that mitigate against a diagnosis of AD. Bilateral medial temporal or more generalized atrophy may be discernible, but this is nonspecific and in the absence of quantitation, it is difficult to use for diagnostic purposes. Physiological neuroimaging is not recommended for routine evaluation of patients suspected of having AD but may be helpful in ACDS (see later). Nonetheless, single photon emission computed tomography (SPECT) and PET have shown bilateral temporoparietal and posterior cingulate hypometabolism and hypoperfusion in AD.
Cognitive examination is essential, but whether formal neuropsychological assessment is required depends on the examining physician's skill in clinical cognitive assessment. In general, neuropsychological assessment is highly desirable in mild to moderate stages of dementia for both qualitative description of the dementia pattern (which has diagnostic significance) and quantitative estimation of cognitive disability. Although variable, a typical neuropsychological profile will show reduced performance IQ relative to verbal IQ, severe learning and memory impairment, and anomia. Frequently, there is also evidence of impaired aural comprehension, a generally reliable indicator of significant cognitive disability. Psychomotor speed is generally preserved, although with longitudinal assessment, it also declines.
Basic laboratory and general health measures are also essential. Cognitive decline has very different implications in a smoker with active lung cancer, severe anemia, or disseminated intravascular coagulation, for example, than in a previously healthy octogenarian. Recent chest x-ray study, electrocardiogram, urinalysis, complete blood counts, and a chemistry profile (which should include electrolytes, calcium, fasting blood glucose, and renal and liver function tests) are not specifically neurological but can be very relevant if they disclose a severe abnormality. Thyroid function tests and vitamin B 12 should be assessed. The actual frequency of B12 deficiency-related dementia is questionable, however. In patients with severe vitamin B 12 deficiencies, anemia and combined systems disease with prominent myelopathic features seem to predominate. Cognitive decline in such a setting should certainly prompt consideration of B 12 deficiency, but in cases of mild B12 deficiency without accompanying features, its significance is doubtful (see Chagtei.4.0 ). CNS syphilis has become rare, but again should be screened with rapid plasma reagin or other syphilitic serological tests. The erythrocyte sedimentation rate is an arguably useful screening test for a variety of diseases that result in a systemic inflammatory response, and when the rate is highly elevated, it may be an important diagnostic clue.
The above-mentioned laboratory measures are the core tests to consider in essentially all patients. Additional tests that may not be necessary in every patient include EEG, spinal fluid examination, overnight oximetry, psychiatric evaluation, small bowel biopsy, Lyme disease serology, human immunodeficiency virus serology, various connective tissue disease serologies, and paraneoplastic serologies. Ultimately, invasive testing including cerebral angiography and meningeal or brain biopsy also have their place in the diagnostic armamentarium for chronic progressive encephalopathy but not when AD is the leading diagnostic consideration.
Degenerative diseases and depression are rarely accompanied by severe EEG disturbances. In contrast, EEG abnormalities are often severe (and usually nonspecific) in toxic, metabolic, inflammatory, infectious, and neoplastic encephalopathies. Complex partial status epilepticus and Creutzfeldt-Jakob disease may produce pathognomonic patterns. When in doubt, an EEG is a simple, noninvasive screening test for a wide variety of diseases, many of which are reversible. Patients suspected of having a chronic encephalopathy, perhaps reinforced by a severely abnormal EEG, should undergo spinal fluid examination, and tests should include immunological indices such as IgG index, IgG synthesis rate, and oligoclonal bands. Although these tests are nonspecific, they are markers of intrathecal inflammation, which does not generally occur in AD or any other degenerative neurological diseases. Other tests including cytology, cultures for fungi and mycobacteria, and routine tests such as total protein, glucose, cell count, and syphilis serology should also be obtained when a spinal tap is performed. Opening pressure should be recorded, especially in patients suspected of having communicating, normal pressure hydrocephalus.
Overnight oximetry is a useful screening test for obstructive sleep apnea, a common cause of hypersomnolence with secondary inattentiveness and mild memory impairment.
Psychiatric evaluation should be considered if depression is suspected, and if psychotic symptoms complicate the clinical picture. Small bowel biopsy should be considered if CNS Whipple's disease is suspected. Various serological tests should be considered for specific infectious diseases (such as Lyme disease, particularly if a patient is from an endemic area), autoimmune diseases (including Sjogren's syndrome), and paraneoplastic conditions in patients with prior or known provocative malignancies (especially oat cell lung cancer and ovarian cancer).
Management. There is no known way to entirely protect against AD, but some beneficial trends have been noted among people who take vitamin E supplements (and possibly other anti-oxidants), take anti-inflammatory drugs, and have a highly educated background, although many college graduates and accomplished professionals who take anti-inflammatory drugs for arthritis and vitamin E to stay young still develop AD. Some studies have suggested that among postmenopausal women, there is a slight protective effect with estrogen replacement. On the other hand, more women than men have AD and gender has itself been suggested as a risk factor.
There are few so-called memory tonics available to patients and physicians. At present, the only drug with possible cognitive enhancing effects in AD is tacrine, a centrally acting acetylcholinesterase inhibitor that is thought to partially reverse the decline in cortically projected acetylcholine that results from degeneration of the cholinergic basal forebrain. y The effects of the drug are modest and side effects are significant, particularly when given at higher doses, which tend to be the more effective dosages (typically 30 or 40 ml, four times daily). Unfortunately, only about a fourth of patients tolerate those dosage levels, with nausea, diarrhea, and elevated liver enzymes often being the treatment-limiting side effects. Nonetheless, it can result in functionally important gains in some patients and should be considered in patients with mild to moderate stages of the disease. It should either not be used or be used with great caution in patients with cardiac conduction defects, liver disease, or seizures. A sudden decline in cognitive status or other neurological function, such as ambulation, in a patient with AD generally implies a secondary disease process, often one that is non-neurological such as a urinary tract infection, pneumonia, and fluid and electrolyte disturbances. Medication side effects (particularly those associated with tricyclic antidepressants, benzodiazepines, and narcotic analgesics) or complications from improper medication administration should be sought, especially if the patient has continued to administer his or her own medications without adequate supervision. Common neurological causes include subdural hematoma, stroke, and complex partial seizures. The differential diagnosis is extensive and is that of an acute encephalopathy.
Although it is disabling and characteristic of AD, cognitive loss is not the greatest obstacle posed by patients to their caregivers. Paranoid delusions and other psychotic symptoms are disruptive, pose extraordinary obstacles to effective caregiving, and are probably the most common reasons patients are sent to nursing homes. Small doses of neuroleptic medications may produce sufficient relief as to permit caregivers to continue to keep the patient at home, and these medications should be part of the therapeutic armamentarium. Haloperidol at doses ranging from 0.5 mg to 2 mg a day is often sufficient, but sometimes higher doses are required. Extrapyramidal side effects, however, can become dose-limiting problems. Risperadone is a newer neuroleptic agent with additional effects on serotonergic systems and may be associated with fewer extrapyramidal side effects at equivalent doses of haloperidol.
Antidepressants with anticholinergic side effects, including all the tricyclic antidepressants, often exacerbate the confusion in these patients and are generally not recommended. Rather, serotonin reuptake inhibitors (SRIs), such as fluoxetine, sertraline, and paroxetine, can enhance energy levels (and possibly attentiveness as a result in some patients) and have antidepressant effects without the risk of anticholinergic side effects. They should not be used, however, in agitated patients or in patients with psychotic symptoms because SRIs can exacerbate these behaviors. For anxiety, buspirone, although it is generally less effective than benzodiazepines, has much less risk of paradoxical agitation and should be tried first. Neuroleptic agents can also be considered for anxiety in some patients, especially if there are accompanying psychotic symptoms.
Sedative hypnotic agents can be used in patients in whom sleep-wake disturbances are disrupting their home care. Agents that have few side effects or risks of exacerbating confusion and agitation include diphenhydramine, chloral hydrate, and zolpidem. Many patients fall asleep without difficulty but awaken at an early hour. In such instances, it is important that the sleeping aid be given when they waken. These medications help patients fall asleep, but they will not reliably keep them asleep for prolonged periods, which is in part why they are more advisable than longer acting agents.
Treatment of the patient with AD ultimately means ensuring that their needs are met. Depending on what the patients cannot do for themselves, these things need to be done for them, or they need assistance with them. That includes dressing, cooking, bathing, eating, exercise (such as walking), and those problems listed earlier. The caregiver becomes an integral part of the patient's life and is vulnerable to depression, burn-out, and associated problems. Support groups are important for caregivers, as is respite care to give the caregiver time away from the patient. Adult day care should be considered for patients at mild to moderate stages as a way to provide not only respite care for the caregiver but a supervised social outlet for the patient, too.
Prognosis and Future Perspectives. AD, like all degenerative neurological diseases, is relentlessly progressive. Because the patients are elderly, and susceptible to a variety of other disease processes, AD itself is not the most common cause of death. However, if no other disease process supervenes, death usually ensues over roughly 6 to 10 years (there is great variability) after onset.
Increasing emphasis has been placed on early diagnosis in anticipation of preventive or retardant therapy. At the extreme of this approach is the fact that those individuals destined for AD have measurable differences throughout their lives, y and one such study correlated certain aspects of verbal skills at the mean age of 22 years with the subsequent development of AD 50 to 60 years later. y Other studies, however, still envision AD as a disease that begins in later life, but that various types of cognitive and
metabolicy derangements can be measured at least several years in advance of clinically evident cognitive decline. Possible strategies for preventive and retardant therapy include interfering with a critical step in the amyloid/tau/ApoE pathway that results in plaque formation, or in the pathway that results in the hyperphosphorylation of tau leading to cytoskeletal disruption administration of ApoE epsilon-2 or analog to promote whatever salutary effect it appears to have in preventing AD
use of a large family of growth factor compounds that normally function during embryogenesis, some of which promote neuronal growth and retard neuronal death use of antioxidants to interfere with the generation of free radicals that cause cellular damage. Strategies for symptomatic therapy include the use of tacrine-like drugs that enhance cortical acetylcholine levels yet with less toxicity than tacrine.
use of neurochemical cocktails that act on multiple neurochemical projection systems.
the use of antipsychotic agents that provide greater antipsychotic effect with less extrapyramidal side effects.
Unless a very effective treatment or cure is found, the most important agenda item for the future lies not in the realm of science or medicine but in public policy. How to deal with the burgeoning elderly population and the growing number of Alzheimer's patients, many of whom require expensive chronic institutional care, will be issues of increasing societal and political focus.
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