American Journal of Alzheimer's Disease and Other Dementias

http://aja.sagepub.com Alzheimer's disease and other dementias: A review

Shannon Rogan and Carol F. Lippa Am J Alzheimers Dis Other Demen 2002; 17; 11 DOI: 10.1177/153331750201700106 The online version of this article can be found at: http://aja.sagepub.com/cgi/content/abstract/17/1/11

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Alzheimers disease and other dementias: A review

Shannon Rogan, BS Carol F. Lippa, MD

Abstract
Dementia and its associated diseases are important causes of disability and morbidity in developed countries, especially in the aged population. As the babyboomers arrive at retirement and individuals over 100 are one of the fastest growing segments of our nations population, we may realize the substantial cost these diseases bring to society. Dementia is characterized by a significant loss of cognitive function and should be clinically distinguished from an acute delirium or decreased arousal. Its manifestations cause anguish to millions of caregivers and family members, who are pressed to cope with their loved ones unfortunate decline in multiple cognitive domains, functioning, and behavior. Early detection and management may prevent overuse of costly medical resources and allow patients and family members time to prepare for future medical, financial, and emotional challenges. Diagnostic clues to the etiology of the patients dementia can be found in a medical workup in which the neurologic history and examination (including mental status examination) are essential and neuroimaging is indicated. Herein, the concept of central nervous system (CNS) degenerative diseases as disorders of specific proteins is introduced. This review is intended to summarize clinical, biological, and genetic features of the common subtypes of dementia, and bring light to potential benefits of early and accurate diagnoses to optimize treatment. Details of the various diseases remain only partially uncovered, raising extensive prospects for future research and therapy for patients with dementia.
Shannon Rogan, BS, Department of Neurology, MCP-Hahnemann University, Philadelphia, Pennsylvania. Carol F. Lippa, MD, Department of Neurology, MCP-Hahnemann University, Philadelphia, Pennsylvania.

Key words: Alzheimers disease, dementia, dementia with Lewy bodies, frontotemporal dementia, Picks disease

Introduction
In the past, central nervous system (CNS) degenerative diseases were classified as motor disorders, cognitive disorders, or combined disorders, according to the symptoms patients experienced. This classification system was fraught with difficulty due to overlapping symptoms between diseases and because many patients show complicated presentations that do not fall into one obvious disease category. More recent research has determined that degenerative diseases of the CNS are often caused by abnormalities in specific proteins. Most degenerative dementias are now identified as abnormalities of three proteins, the amyloid precursor protein (APP), tau, and =-synuclein. Thus, degenerative diseases of the brain are now being reclassified according to associated protein abnormalities. Although this classification does not necessarily facilitate diagnosis, developing strategies for disease treatment and prevention may be focused on normalizing the underlying biological changes that these proteins undergo for each disease. In this review, we discuss common subtypes of dementia according to the underlying pathological protein. In addition to discussing typical symptoms, we attempt to link each disease with its pathogenesis so that a rationale for current and future therapies might be more clearly understood. Alzheimers disease (AD), the most common form of degenerative dementia, is a disorder of the APP. The frontotemporal dementia (FTD) syndromes and some extrapyramidal dementias (corticobasal degeneration and progressive supranuclear palsy) are now associated with abnormalities of the microtubule-associated protein, tau. Other degenerative diseases, including multiple system atrophy, Parkinsons disease (PD) and dementia
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with Lewy bodies (DLB), are associated with the abnormal aggregation of =-synuclein. Since efforts at developing preventive measures or treatments for these diseases target the underlying pathologic proteins, this review will be organized according to the disordered protein.

Disorders of the APP and A>

Alzheimers disease is characterized by an insidious onset and progressive decline in cognition with the sparing of motor and sensory modalities until the later stages. Patients rarely become symptomatic before 50 years of age and the average course of AD is approximately a decade,1 although the rate of progression is variable among patients. Memory impairment present in the earliest stages of the disease correlates with pathology and degeneration seen in the entorhinal cortex, hippocampus, and neocortex, confirming a functional importance of these areas in memory and higher cortical functioning. Cellular losses in the cholinergic nucleus basalis of Meynert also contribute to attentional and cognitive deficits in AD. Patients with AD have difficulty retaining newly learned information for more than a few minutes, as clinically ascertained in a Mini-Mental Status Examination (MMSE)2 or other testing of mental functioning. The ability to learn is increasingly compromised with disease progression. Access to distant memories may be lost as a late feature, while aphasia, apraxia, disorientation, visuospatial dysfunction, impaired judgment, and impaired executive functioning may occur in early stages of the disease.1 Although the disease is considered progressive and irreversible, symptomatic treatments of cognitive and the associated behavioral problems hold potential to improve quality of life.1 Two of the most notable neuropathologic hallmarks, neurofibrillary tangles and beta-amyloid (A>)-laden senile plaques in the brain (see Figure 1), have been described since 1907, while the degree to which the lesions constitute normal aging versus actually signifying a clinical dementia has been controversial. The current consensus is that these changes are pathological, abnormal, and diagnostic for the disease in subjects with dementia.3 Other microscopic features that have since been visualized are gliosis, granulovacular degeneration, Hirano bodies, and cerebral deposition of A>-containing intracerebral blood vessels. Patients with Down syndrome often develop identical imaging and pathological abnormalities earlier in life, probably due to the extra copy of the APP gene on chromosome 21.4 Although probable clinical diagnostic criteria are available,5 pathologic examination of brain tissue remains the gold standard for a definitive diagnosis of AD. The primary risk factors for AD are age and family
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history.1 Most cases are of nondominant inheritance or sporadic with still mysterious nutritional or environmental etiologies. Molecular geneticists have made considerable advances in identifying foci of significance that play a role in the development of the genetically heterogeneous AD. Five to 10 percent of AD cases are attributable to an identifiable genetic mutation.6 Mutations in at least three genes have been determined fully penetrant to the development of AD in patients younger than 60 years: the APP gene on chromosome 21, the presenilin 1 gene on chromosome 14, and the presenilin 2 gene on chromosome 1. Together, they account for about half of the cases of the early-onset form of the disease. The epsilon-4 (A-4) allele of the gene encoding apolipoprotein E-4 (APOE) on chromosome 19, has been strongly associated with the more prevalent late-onset AD.4 One copy of this allele doubles or triples a subjects risk of acquiring the disease.7 Thus, an increased concern among those with a family history of AD is warranted and should be anticipated by practitioners. Since at least half of individuals with AD do not have the APOE A-4 allele and half of subjects with AD do not carry it, routine genetic testing for this is not recommended.7 No genetic abnormality has been easily adapted for modern use as a diagnostic or predictive test for the clinical disease. Future research entails searching for additional genes, especially for those involving the late-onset type, and elucidating the mechanisms of action as part of a gradual effort to develop more effective therapeutic and preventive strategies. The primary goals of treating patients with AD are to improve quality of life and maximize functional performance by enhancing cognition, mood, and behavior. A comprehensive system of care for patients with dementia requires consideration of psychosocial strategies to enhance quality of life. These include emotion-oriented psychotherapy and stimulation-oriented treatment, including art and other expressive recreational or social therapies, exercise, and dance.8 Support groups for patients with mild impairment are encouraged and may help establish a constructive environment to help mobilize cognitive and behavioral resources.1 Evidence from a recent study of nuns suggests that those who have had a positive outlook will have improved outcomes.9 Despite a paucity of well-controlled data, preliminary studies and clinical practice suggest that these interventions may decrease behavioral problems and improve mood in patients and family alike. Within the past 20 years, there has been continual progress in our understanding of the brains neurotransmitter deficits associated with AD and other neurodegenerative conditions. The strategy of cholinergic treatment in response to a deficit in acetylcholine was developed on the
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Table 1. Dementias and their symptomatic, biologic, therapeutic, and clinical indications
Diagnosis Symptoms Insidious onset and progressive decline in cognition; remarkable memory loss Visual hallucinations, spontaneous Parkinsonism, alterations of alertness and attention Personality change, language impairment, memory deficit Vertical supranuclear palsy, postural instability Asymmetric akineticrigidity, gait disturbance, jerky limb dystonia, and early cognitive symptoms, including ideomotor apraxia Acute dysfunction of cognitive domains, focal neurologic signs, hyperrelexia, gait abnormalities Protein involved Mainstay of treatment Pharmacologic cholinergic enhancers, disease modifying agents, psychotherapy Cholinergic enhancers Clinical notes Genetic risk factors identified; anticipate concern from family members Neuroleptic sensitivity; paradoxical responses to various pharmacological agents Cholinergic enhancers not proven effective Cholinergic enhancers not proven effective

Alzheimers disease

APP, A>

Dementia with Lewy bodies Frontotemporal dementia (Picks disease) Progressive supranuclear palsy

=-synuclein

tau

None currently available None currently available

tau

Corticobasal degeneration

tau

None currently available

Cholinergic enhancers not proven effective

Vascular dementia

Not applicable

Identify and modify risk factors, physical therapy, gait analysis

Neuroimaging might aid diagnosis

basis of the successes of dopaminergic therapy with levodopa in the treatment of Parkinsons disease, another progressive age-related neurodegenerative disorder, but one characterized by a deficit in dopamine. Acetylcholinesterase inhibitors such as tacrine, donepezil, rivastigmine, and galantamine reduce degradation of acetylcholine at the synapse, thereby offering the potential for improved memory and cognition. Cholinergic side effects, most commonly gastrointestinal distress (all agents), and hepatoxicity (tacrine) are clinically significant and require careful monitoring. Most medical groups have suggested starting cholinergic treatment of persons with mild to moderate disease symptoms (MMSE score, 10-24). Improving central cholinergic neurotransmission is the mainstay of current treatment available for the cognitive impairment of AD. There is considerable interest in the so-called diseasemodifying agents that are best viewed as neuroprotective in persons predisposed to AD or with early signs of AD.
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A> is a peptide metabolite of the larger APP that occurs when alternate cleavage pathways are utilized. In normal individuals, APP processing often involves the =-cleavage pathway. This enzymatic pathway results in APP breakdown without formation of A>. Evidence suggests that alterations in the processing of APP, using a >-secretase and then C-secretase pathway results in formation of A>. Increased use of the latter pathway leads to increased A> in the AD brain. Disease-modifying treatments could potentially influence metabolism of the APP, by increasing use of the =-secretase pathway or by decreasing use of the >- and C-secretase pathways. Other approaches to treatment in AD include the development of agents to modulate the phosphorylation of tau protein in neurofibrillary tangles or stimulate nerve growth factor receptors.10 Possible but not yet proven protective factors include the use of estrogen replacement therapy and nonsteroidal anti-inflammatory agents (NSAIDs), such as cyclo-oxygenase-2 (cox-2)
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selective inhibitors.1 In the field of botanical medicines, the naturally occurring compound ginkgo biloba is under study. Modeled on a study of antioxidative therapy and Parkinsons disease, until the time for need of symptomatic therapy with levodopa was used as a primary endpoint, the irreversible monoamine oxidase B selegiline and the antioxidant =-tocopherol (vitamin E) were studied in moderate stage AD.11 The positive results were so convincing that vitamin E, being both inexpensive and low-risk, is now widely used in clinical practice in patients at all disease stages. Atypical anti-psychotic drugs are also employed to treat late symptoms of psychotic behavior and aggressiveness. In response to AD afflicting a growing segment of our population, the need of a vaccine has recently received wide attention in both the scientific and lay media. Immunizations of young transgenic mice have been successful in preventing accumulation of cerebral A>, neuritic dystrophy, and astrogliosis, while treatment of older mice also markedly reduced neuropathology.12 Clinical studies for safety and efficacy are underway. The development of a successful A> vaccine with minimal complications, the possibility for prevention of AD and the potential positive implication on public health is at least encouraging. Secretase inhibitors to reduce production of the A> fragment from the APP are also in development.

Disorders of the =-synuclein

Dementia with Lewy bodies is a diagnostic term referring to the group of dementia patients in whom Lewy bodies are present within cortical neurons.13,14 Although there may exist some overlap of DLB with AD and the dementia of PD, autopsy studies have indicated that 15 percent to 25 percent of dementias are DLB, making it the largest pathologic subgroup of dementias after pure AD.13 There is no evidence of a major genetic mutation or susceptibility factor for the development of pure DLB and patients usually lack a strong family history of this dementia subtype.13,14 Genetic analyses thus far have only helped to elucidate the overlap between AD and DLB associated with Alzheimers by describing an elevated APOE A-4 allele frequency in AD and the Lewy body variant of AD.15 However, an increase in the APOE A-4 allele is not consistent in pure DLB. Progressively disabling mental impairment progressing to dementia is the central feature of a clinical diagnosis of DLB along with at least one of three core symptoms: visual hallucinations, spontaneous Parkinsonism, and alterations of alertness and attention.13 Additional elements include falls, syncope, transient loss of consciousness, neuroleptic sensitivity, delusions, and hallucinations in other modalities.13
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This patient group is considerably challenging to manage. Their visual hallucinations are vivid, oftentimes even frightening, while their delusional symptoms are severe. Moreover, this patient group is subject to adverse responses to medications, particularly neuroleptic medications. They frequently become activated by sedatives, more psychotic in response to a neuroleptic agent, and awoken by sleep medications. Additionally, patients with DLB are frail and may decompensate clinically with a minor infection, metabolic stress, or change in environment. In many cases, the physician will help the patient by reducing doses of current medications or eliminating medications, carefully searching for infection, normalizing the patients environment, or treating a metabolic abnormality. All medications should be introduced with extreme care in this patient group because of their distinguished potential for paradoxical responses. Interestingly, these patients have greater cholinergic losses than patients with AD16,17 due to the formation of Lewy bodies in the neurons of the cholinergic nucleus basalis of Meynert. They often respond well to cholinergic enhancers if introduced and built up gradually. The only features considered essential for a pathologic diagnosis of DLB are brainstem or cortical =-synucleincontaining Lewy bodies. Classic Lewy bodies are spherical intracytoplasmic eosinophilic neuronal inclusion bodies, but may be extracellular, mulitilocular, or fusiform in shape. The reason why =-synuclein aggregates abnormally and precipitates into Lewy bodies remains unknown. However, epitope mapping studies of the =-synuclein protein indicate that the mechanism of aggregation may be similar in all conditions where neuronal Lewy bodies occur, including DLB and PD.18,19 Distinguishing factors for DLB and dementia in patients with PD include resting tremor (more common in PD), consistent response to Sinemet (most PD respond well, some DLB do), and the presenting symptom (patients with PD do not present with cognitive symptoms). At this time, whether DLB and PD are pathogenically similar with varying symptoms due to different regional distribution of Lewy bodies between diseases is unknown.

Disorders of tau
Tau-related disorders include frontotemporal dementia. Some tauopathies are sporadic, while others are related to alterations of the tau protein on chromosome 17. Individuals with frontotemporal dementia are important to distinguish from patients with AD because their brains do not have notable cholinergic losses. Although some cognitive neurologists utilize cholinesterase inhibitors in this patient group, care must be taken in such instances, since these patients may also demonstrate
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Figure 1. Microphotographs of the three pathological proteins, >-amyloid, =-synuclein, and tau. Figure 1A is a low-magnification image of a large, extracellular >-amyloid plaque after staining with a silver stain. The entire core is composed of amyloid. Some dystrophic neurites are seen in the peripheral portions of the plaque. Figure 1B is stained with antibodies to =-synuclein. The photo shows a ring-link intraneuronal Lewy body in the cytoplasm of a pigmented neuron. Figure 1C shows a Pick body. Like the Lewy body, the inclusion is contained within the cytoplasm of the neuron. However, the Pick body stains with antibodies to tau instead of =-synuclein.

adverse reactions to cholinergic enhancers. Frontotemporal dementias, such as Picks disease (PcD), are often difficult to differentiate clinically from AD and other progressive dementias. A recent study found that personality change and language impairment were significantly more common in PcD than in AD, while deficits in memory were common in both groups, but more prevalent in patients with AD.20 In addition, patients with PcD declined significantly faster than those with AD on language tests and global measures of dementia severity, whereas measures of explicit memory and visuospatial and reasoning abilities worsened comparably in both patient groups.20 PcD is often characterized pathologically by widespread occurrence of Pick inclusion bodies, containing the protein tau as well as others, along with swollen achromatic Pick cells, neuronal loss, and astrocytosis in the setting of marked atrophy in the frontal and temporal lobe.21 Clinical features usually include progressive cognitive impairment (with or without behavioral change) sufficient to interfere with social or occupational function, onset before 70 years of age, and indication of asymmetry on neuropsychological testing.21 Other unique aspects of PcD may include apraxia, impulsivity, impaired judgment and social behavior, apathy, carbohydrate craving, manic states, or grandiose delusions. Progressive supranuclear palsy (PSP) and cortical basal degeneration (CBD) are two additional types of dementia, characterized pathologically by the deposition of intraneuronal tau protein. Although their prevalence in the general population is unknown, some have suggested that cases have been underestimated and possibly misdiagnosed as Parkinsons disease or Parkinsonism.22
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Highly specific but much less sensitive inclusion criteria have been developed to help differentiate between these and other presenting dementias. PSP, one of the most common atypical Parkinsonian syndromes, is a gradually progressive disorder with onset at age 40 or later. The diagnosis is suggested when a vertical supranuclear palsy is present in addition to prominent postural instability with falls in the first year of disease onset.23 The disease is thought to be sporadic, but there is evidence that patients with PSP have a more frequent occurrence of one allele of an intronic polymorphism of the tau gene. One large study confirmed the overrepresentation of the A0 allele and the A0/A0 genotype in patients with PSP, while finding no significant difference in polymorphisms of the tau gene in patients with Parkinsons disease, frontotemporal dementia, or corticobasal degeneration as compared to controls.24 Predictors for the diagnosis of CBD include an asymmetric akinetic-rigid syndrome with late-onset gait or balance disturbance, jerky limb dystonia, and early cognitive symptoms, including ideomotor apraxia.25 One longitudinal study has recently shown that patients with PSP undergo greater cognitive impairment than patients with striatonigral degeneration (SND) or PD, which may correlate with greater anatomical compromise in PSP, involving both subcortical (pallidum, mesencephalic tegmentum, striatum) and cortical structures (prefrontal and premotor cortex).26 Progression to dementia was prominent in PSP, but not consistent across patients, and the variety may be related to differential development of neurofibrillary tangles in the cortex. The cognitive performance of patients with SND was similar to that of patients with PD both at first and second evaluations;
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however, the SND group was characterized by slightly greater deterioration with time.26 SND of the frontal lobe is similar to that found in PD, but milder than in PSP. The apparent difference in severity of SND as a dysexecutive syndrome may contribute to the clinical distinction between SND and PSP.27 Unfortunately, treatments are currently lacking for the tauopathies. No specific neurotransmitter system has been demonstrated to be clinically significant; cholinergic losses are not prominent so that there is little scientific rationale for the use of cholinergic enhancers in this group. Agents that influence the phosphorylation of tau or modify tau isoform ratios may plausibly be included in future treatment protocols for the tauopathies.

Additionally, cholinesterase inhibitors are differentially effective, and side effects and paradoxical responses to medications differ between patient groups. Differentiating dementia from normal aging can also be a challenge that is oftentimes complicated by intangible pathology and a lack of sensitive diagnostic testing. Fortunately, pharmacologic and psychosocial therapy have been shown to improve symptoms for dementia subjects, and there is new hope for the development of agents that prevent these diseases or significantly modify their outcome.

References
1. Small GW, Rabins PV, Barry PP, et al.: Diagnosis and treatment of Alzheimer disease and related disorders: Consensus statement of the American Association for Geriatric Psychiatry, the Alzheimers Association, and the American Geriatrics Society. JAMA. 1997; 278: 1363-1371. 2. Folstein MF, Folstein SE, McHugh PR: Mini-mental state: A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975; 12: 189-198. 3. National Institute on Aging, and Reagan Institute working group on diagnostic criteria for the pathological assessment of Alzheimers disease: Consensus recommendations for the postmortem diagnosis of Alzheimers disease. Neurobiol Aging. 1997; 18: 51-52. 4. Selkoe DJ: Alzheimers disease: genotypes, phenotypes, and treatments. Science. 1997; 275: 630-631. 5. McKhann G, Drachman DA, Folstein MF, et al.: Clinical diagnosis of Alzheimer disease: Report of the NINCDS-ADRDA work group under the auspices of Health and Human Services task force on Alzheimers disease. Neurol. 1984; 34: 939-944. 6. Lippa CF: Familial Alzheimers disease: Genetic influences on the disease process (review). Int J Mol.Med. 1999; 4: 529-536. 7. Seshadri S, Drachman DA, Lippa CF: Apolipoprotein E epsilon-4 allele and the lifetime risk of Alzheimers disease: What physicians know, and what they should know. Arch Neurol. 1995; 52: 1074-1079. 8. Meyers K, Griggin M: The play project: Use of stimulus objects with demented patients. J Gerontol Nurs. 1990; 16: 32-37. 9. Danner DD, Snowdon DA, Friesen WV: Positive emotions in early life and longevity: Findings from the nun study. J Pers.& Soc. Psychol. 2001; 80: 804-813. 10. Larson EB: New drug treatments for Alzheimer disease. Arch Intern Med. 1998; 158: 941-942. 11. Sano M, Ernesto C, Thomas RG, et al.: A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimers disease: The Alzheimers Disease Cooperative Study [see comments]. NEJM. 1997; 336: 1216-1222. 12. Schenk D, Barbour R, Dunn W, et al.: Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999; 400: 173-177. 13. McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): Report of the consortium on DLB international workshop. Neurol. 1996; 47: 1113-1124. 14. Lippa CF, Koffler S: Dementia with Lewy bodies: Review of a common subtype of dementia. In: Research and Practice in Alzheimers Disease. 1998: 203-212. 15. Galasko D, Saitoh T, Xia Y, et al.: The apolipoprotein E allele epsilon-4 is over represented in patients with the Lewy body variant of Alzheimers disease. Neurol. 1994; 44: 1950-1951. 16. Lippa CF, Smith TW, Perry E: Dementia with Lewy bodies:

Other disorders
Vascular dementia is caused by one or more small or large brain infarctions and constitutes about 5 percent to 10 percent of all dementias.28 The diagnosis is supported by an acute onset of dysfunction in one or more cognitive domains, a stepwise deteriorating course, focal neurologic signs including extremity weakness, hyperreflexia and gait abnormalities, history or neuroimaging confirmation of previous strokes and risk factors, or systemic vascular disease. Treatment is geared toward identifying and modifying risk factors for stroke and subsequently improving functional outcome with physical therapy and other such modalities. In summary, degenerative diseases are currently being reclassified according to their underlying protein abnormalities. Alzheimers disease, being the most common condition, is thought to be related to APP misprocessing. Therapy is now aimed at neurotransmitter supplementation while treatments that hold potential to alter the longterm disease course are in development. Patients with DLB show the triad of Parkinsonism, visual hallucinations, and fluctuating cognition. Early diagnosis of this dementia subtype is critical because the patients are notably medication-sensitive so that physicians must use caution when prescribing new pharmacological agents. These patients show even greater cholinergic losses than those with AD and may respond positively to cholinesterase inhibitors. Tau-related disorders include the frontotemporal dementias, some of which are sporadic, whereas others are due to mutations on chromosome 17. These individuals are important to recognize and diagnose, since they are less likely to improve with cholinergic enhancers and may, in fact, worsen. To treat a patient with dementia is a complicated endeavor for both the physician and caregiver. To diagnose the disease in its early clinical stages is important because the management issues differ for each disease.
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Choline acetyltransferase parallels nucleus basalis pathology. J Neural Transm. 1999; 106: 525-535. 17. Perry EK, Haroutunian V, Davis KL, et al.: Neocortical cholinergic activities differentiate Lewy body dementia from classical Alzheimers disease. Neuroreport. 1994; 5: 747-749. 18. Duda JE, Giasson BI, Gur TL, et al. Immunohistochemical and biochemical studies demonstrate a distinct profile of alpha-synuclein permutations in multiple system atrophy. J Neuropathol Exp Neurol. 2000; 59: 830-841. 19. Lippa CF, Schmidt ML, Lee VM, Trojanowski JQ. Alpha-synuclein in familial Alzheimers disease: Epitope mapping parallels DLB and Parkinsons disease. Arch Neurol. 2001; [in press]. 20. Binetti G, Locascio JJ, Corkin S, et al.: Differences between Pick disease and Alzheimer disease in clinical appearance and rate of cognitive decline. Arch Neurol. 2000; 57: 225-232. 21. The Lund and Manchester Groups: Clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neurosurg Psychiatry. 1994; 57: 416-418. 22. Schrag A, Ben-Shlomo Y, Quinn NP: Prevalence of progressive supranuclear palsy and multiple system atrophy: A cross-sectional

study. Lancet. 1999; 354: 1771-1775. 23. Litvan I, Hutton M: Clinical and genetic aspects of progressive supranuclear palsy. J Geriatr Psychiatry Neurol. 1998; 11: 107-114. 24. Morris HR, Perez-Tur J, Janssen JC, et al.: Mutation in the tau exon 10 splice site region in familial frontotemporal dementia [letter]. Ann Neurol. 1999; 45: 270-271. 25. Litvan I, Agid Y, Goetz C, et al.: Accuracy of the clinical diagnosis of corticobasal degeneration: A clinicopathologic study. Neurol. 1997; 48: 119-125. 26. Soliveri P, Monza D, Paridi D, et al.: Neuropsychological follow up in patients with Parkinsons disease, striatonigral degenerationtype multisystem atrophy, and progressive supranuclear palsy. J Neurol Neurosurg. Psychiatry. 2000; 69: 313-318. 27. Pillon B, Gouider-Khouja N, Deweer B, et al.: Neuropsychological pattern of striatonigral degeneration: Comparison with Parkinsons disease and progressive supranuclear palsy. J Neurol Neurosurg. Psychiatry. 1995; 58: 174-179. 28. American Psychiatric Association: Practice guideline for the treatment of patients with Alzheimers disease and other dementias of late life. Am. J Psychiatry. 1997; 154: 1-39.

Bookmarks
The new and noteworthy titles listed below have recently crossed the Managing Editors desk. We hope to publish reviews for many of these works in upcoming issues. In the meantime, if any of these titles pique your interest, consult your bookseller or librarian for more information. The Best Friends Staff: Building a Culture of Care in Alzheimers Program by Virginia Bell, MSW, and David Troxel, MPH (Baltimore: Health Professions Press, 2001). Can Do Activities for Adults with Alzheimers Disease: Strength-Based Communication and Programming by Eileen Eisner, CCC, SLP (Austin, TX: Pro-Ed, Inc., 2001). Depression in Late Life, Third Edition, by Dan G. Blazer, MD, PhD (New York: Springer, 2002). The Lost Art of Caring edited by Leighton E. Cluff, MD, and Robert H. Binstock, PhD, with Foreword by Rosalyn Carter (Baltimore: Johns Hopkins University Press, 2001). Moving a Relative with Memory Loss: A Family Caregivers Guide by Laurie White and Beth Spencer (Santa Rosa, CA: Whisp Publications, 2001). Parkinsons Disease: A Complete Guide for Patients and Families by William J. Weiner, MD, Lisa M. Shulman, MD, and Anthony E. Lang, MD, FRCP (Baltimore: Johns Hopkins University Press, 2001). Symphony of Spirits: Encounters with the Spiritual Dimensions of Alzheimers Disease by Deborah A. Forrest, PhD, with Clint Richmond (New York: St. Martins Press, 2000).

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