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ScienceWeek
MEDICAL BIOLOGY: ON PARKINSON'S DISEASE DEMENTIA
Notes by ScienceWeek:
The term "Lewy bodies" refers to intracytoplasmic neuronal inclusions ("Lewy inclusion bodies"), especially noted in brainstem neurons and seen in Parkinson's disease. They are named after the neurologist Frederic H. Lewy (1885-1950).
The following points are made by Daniel Z. Press (New Engl. J. Med. 2004 351:2547):
1) The hallmark of Parkinson's disease is involvement of the motor system, causing tremor, rigidity, and slowness of movement. But cognitive symptoms are frequently present at the time of diagnosis,[1] contribute heavily to disability,[2] and progress to dementia at an alarming rate. Dementia will develop in 40 to 70 percent of patients with Parkinson's disease during the course of their illness.[3]
2) The term "Parkinson's disease dementia" refers to dementia that develops at least two years after the diagnosis of Parkinson's disease. If dementia develops before or within two years after the onset of motor symptoms, then the criteria are met for the related condition, diffuse Lewy-body disease. Risk factors for Parkinson's disease dementia include advanced age, treatment-induced visual hallucinations, and more severe motor symptoms.[4] The cognitive profile is similar to that of Alzheimer's disease, but patients with Parkinson's disease dementia generally have more severe visuospatial deficits, large fluctuations in attention, frequent visual hallucinations, and less severe memory problems.[5]
3) Parkinson's disease dementia and diffuse Lewy-body disease share a common neuropathological pattern, cognitive profile, and clinical course. The two conditions lie on the same disease spectrum, with the system that is initially involved -- motor in Parkinson's disease dementia and cognitive in diffuse Lewy-body disease -- artificially splitting them. Both can be considered subtypes of the more inclusive diagnosis of dementia with Lewy bodies. This larger category probably accounts for 10 to 15 percent of cases of dementia, making it the second most common cause of dementia after Alzheimer's disease. The pathological hallmark of both Parkinson's disease dementia and diffuse Lewy-body disease is the presence of Lewy bodies -- intracytoplasmic neuronal inclusions containing alpha-synuclein -- in neocortical and paralimbic regions. By contrast, Lewy bodies are generally restricted to subcortical structures such as the substantia nigra in patients who have Parkinson's disease without dementia. The majority of patients who have dementia with Lewy bodies also have pathological findings characteristic of Alzheimer's disease, which adds to the nosologic challenge.
4) The care of patients who have dementia with Lewy bodies is extremely challenging. Dopaminergic agents frequently worsen hallucinations and cognitive symptoms, whereas the older antipsychotic agents, or typical neuroleptics, can precipitate a profound, even fatal worsening in the motor symptoms of patients with parkinsonism. In general, the goal of therapy is to achieve acceptable motor function with the use of the lowest dose of levodopa and to control troubling hallucinations by adding low doses of atypical neuroleptics such as olanzapine, quetiapine, or clozapine. Evidence from a number of lines of study suggests that increasing cholinergic function can be particularly beneficial for both cognitive and behavioral symptoms in patients with Parkinson's disease dementia, since it has already been found to be effective for these symptoms in a smaller study of patients with diffuse Lewy-body disease. Patients with Parkinson's disease dementia have a greater cholinergic deficit than those with Alzheimer's disease, and the extent of the deficit correlates with the severity of cognitive symptoms; patients with Parkinson's disease dementia also have less devastation in the number of neocortical neurons, which can benefit from cholinergic repletion.
References (abridged):
1. Foltynie T, Brayne CE, Robbins TW, Barker RA. The cognitive ability of an incident cohort of Parkinson's patients in the UK: the CamPaIGN study. Brain 2004;127:550-560
2. Weintraub D, Moberg PJ, Duda JE, Katz IR, Stern MB. Effect of psychiatric and other nonmotor symptoms on disability in Parkinson's disease. J Am Geriatr Soc 2004;52:784-788
3. Aarsland D, Andersen K, Larsen JP, Lolk A, Kragh-Sorensen P. Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study. Arch Neurol 2003;60:387-392
4. Hobson P, Meara J. Risk and incidence of dementia in a cohort of older subjects with Parkinson's disease in the United Kingdom. Mov Disord 2004;19:1043-1049
5. Calderon J, Perry RJ, Erzinclioglu SW, Berrios GE, Dening TR, Hodges JR. Perception, attention, and working memory are disproportionately impaired in dementia with Lewy bodies compared with Alzheimer's disease. J Neurol Neurosurg Psychiatry 2001;70:157-164
New Engl. J. Med. http://www.nejm.org
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Related Material:
DEMENTIA: EVALUATION BY POSITRON EMISSION TOMOGRAPHY
The following points are made by D.H. Silverman et al (J. Am. Med. Assoc. 2001 286:2120):
1) Dementia due to progressive neurodegenerative disease is tremendously costly to patients, their families, and society in general, and is increasing in prevalence. Alzheimer's disease, the most common form of dementia, is estimated to affect 4 million people in the US alone, at a cost of approximately $70 billion; when indirect costs such as the lost productivity of caregivers are considered, total annual expenditures are estimated to approach $100 billion.
2) Optimal management of patients with dementia depends on early recognition and accurate assessment of their cognitive and behavioral symptoms. The assessment is conducted with a combination of diagnostic tools, including history and physical examination, mental status testing, a detailed neurologic examination, common laboratory tests, structural neuroimaging (computed tomography, magnetic resonance imaging) in many instances, and specialized tests (e.g., electroencephalography, cerebrospinal fluid examination) in selected patients.
3) Numerous studies have found that Alzheimer's disease and other neurodegenerative diseases can produce significant alterations in brain metabolism detectable with positron emission tomography (PET), even at very early stages of disease. The actual sensitivity and specificity of PET for the evaluation dementia, however, has been difficult to asses, since data from only a few cases of patients who underwent both PET and brain autopsy (the criterion standard for the diagnosis of Alzheimer's disease) have been available.
4) The authors present a report of an international collaborative effort by multiple medical centers. The authors report that in patients presenting with cognitive symptoms of dementia, regional brain metabolism was a sensitive indicator of Alzheimer's disease and of neurodegenerative disease in general, and that a negative PET scan indicated that pathological progression of cognitive impairment during the mean 3-year follow-up was unlikely to occur.
J. Am. Med. Assoc. http://www.jama.com
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MEDICAL BIOLOGY: APHASIA AND DEMENTIA
The following points are made by M.-Marsel Mesulam (New Engl. J. Med. 2003 349:1535):
1) Dementia is a generic term used to designate chronically progressive brain disease that impairs intellect and behavior to the point where customary activities of daily living become compromised.(1,2) In some patients, specific abnormalities, such as a vitamin B12 deficiency, normal pressure hydrocephalus, multiple strokes, paraneoplastic encephalitis, or human immunodeficiency virus infection, are identified as the underlying cause. In others, characteristic sensory or motor abnormalities indicate that the dementia is a component of a more extensive neurologic disease such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, or multiple sclerosis. In the majority of patients with dementia, however, none of these diseases are diagnosed. These patients can be said to have a "primary" dementia that is characterized by four features: normal findings on elementary neurologic examination, signs and symptoms confined to abnormalities of behavior or cognition, brain scans that may reveal the anatomical distribution of disease but that do not show its specific nature, and identification of the exact cause of the dementia only on postmortem examination.
2) Alzheimer's disease is the single most common cause of primary dementia. Its cardinal feature is a progressive loss of memory of recent events and experiences. The high prevalence of Alzheimer's disease may lead to the belief that dementia is always due to Alzheimer's disease and that, as stated in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders,(3) memory loss is a feature of all dementias. A rapidly growing body of evidence, however, indicates that nearly a quarter of all primary dementias, especially those of presenile onset, may be caused by diseases other than Alzheimer's disease and that some of these so-called atypical dementias involve cognitive abnormalities in areas other than memory.(1,4,5).
3) Patients with Alzheimer's disease come to medical attention because of forgetfulness, usually accompanied by apathy. Misplacing personal objects, repeating questions, and forgetting recent events are among the presenting symptoms. Although the patient may forget people's names, word-finding during conversation is usually not a major problem. In contrast, patients with primary progressive aphasia come to medical attention because of the onset of word-finding difficulties, abnormal speech patterns, and prominent spelling errors. Primary progressive aphasia is diagnosed when other mental faculties, such as memory of daily events, visual and spatial skills (assessed by tests of drawing and face recognition), and behavior (assessed by a history obtained from a third party), remain relatively intact; when language is the only area of prominent dysfunction for at least the first two years of the disease; and when structural brain imaging studies do not reveal a specific lesion, other than atrophy, that can account for the language deficit.
4) Standardized neuropsychological tests are helpful in reaching an early diagnosis, but because most such tests depend on verbal instructions, verbal responses, or covert verbal reasoning, the strict reliance on these tests occasionally leads to the erroneous conclusion that areas other than language are also impaired. Although the language disorder in primary progressive aphasia may interfere with the patient's ability to memorize word lists or solve reasoning tasks, the patient typically has no difficulty in recalling daily events or behaving with sound judgment, indicating that explicit memory, reasoning, and social skills remain relatively intact.
5) In some patients, the principal signs and symptoms are confined to the area of language for as many as 10 to 14 years. In others, impairments in other cognitive functions emerge after only a few years, but the deficit in language remains the salient feature throughout the illness and progresses more rapidly than deficits in other areas. Primary progressive aphasia is considered a form of dementia because it causes a gradual cognitive decline to the point where activities of daily living become compromised, but it is an unusual dementia because core memory functions remain largely preserved. In contrast to many patients with Alzheimer's disease, who tend to lose interest in recreational and social activities, some patients with primary progressive aphasia maintain and even intensify their involvement in complex hobbies such as gardening, carpentry, sculpting, and painting. One patient continued to fly his airplane until aphasia prevented him from communicating with ground control.
References (abridged):
1. Mesulam M-M. Aging, Alzheimer's disease, and dementia: clinical and neurobiological perspectives. In: Mesulam M-M, ed. Principles of behavioral and cognitive neurology. 2nd ed. New York: Oxford University Press, 2000:439-522
2. Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998;51:1546-1554
3. Diagnostic and statistical manual of mental disorders, 4th ed.: DSM-IV. Washington, D.C.: American Psychiatric Association, 1994
4. Grossman M. A multidisciplinary approach to Pick's disease and frontotemporal dementia. Neurology 2001;56:Suppl 4:S1-S2
5. 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. Neurology 1996;47:1113-1124
New Engl. J. Med. http://www.nejm.org
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Related Material:
NEUROPSYCHIATRIC SYMPTOMS IN DEMENTIA AND COGNITIVE IMPAIRMENT
The following points are made by C.G. Lyketsos et al (J. Am. Med. Assoc. 2002 288:1475):
1) Dementia is a serious public health problem with an increasing prevalence because of the aging of the population.(1) Dementia is characterized by global cognitive decline sufficient to affect functioning.(2) It is a chronic illness with seriously disabling effects for patients, their families, and society.(2) Mild cognitive impairment (MCI) describes cognitive impairment in elderly persons not of sufficient severity to qualify for a diagnosis of dementia.(3) Individuals with MCI have complaints of impairment in memory or other areas of cognitive functioning usually noticeable to those around them. In addition, their performance on memory and cognitive tests is below that expected for their age and education. However, their day-to-day functioning is generally preserved. Several operational definitions for MCI have been proposed.(3,4) Mild cognitive impairment is a chronic condition and may be a precursor to Alzheimer-type dementia.(4) Mild cognitive impairment is often worrisome to patients and families, and is increasingly a presenting complaint for care.
2) Neuropsychiatric symptoms are a common accompaniment of dementia.(5) These include agitation, depression, apathy, delusions, hallucinations, and sleep impairment. In some cases, they cluster into syndromes, leading to the proposal of operational criteria for specific dementia-associated psychotic or mood disturbances. These symptoms have serious adverse consequences for patients and caregivers, such as greater impairment in activities of daily living, more rapid cognitive decline, worse quality of life, earlier institutionalization, and greater care-giver depression. Thus, the neuropsychiatric accompaniments of dementia are serious conditions that are increasingly becoming a focus of attention.
3) The authors report a population-based study to estimate the prevalence of neuropsychiatric symptoms in dementia and MCI. A total of 3608 participants were cognitively evaluated using data collected longitudinally over 10 years and additional data collected in 1999-2000 in 4 US counties. Dementia and MCI were classified using clinical criteria and adjudicated by committee review by expert neurologists and psychiatrists. A total of 824 individuals completed the Neuropsychiatric Inventory (NPI); 362 were classified as having dementia, 320 as having MCI; and 142 did not meet criteria for MCI or dementia. From their results, the authors conclude: Neuropsychiatric symptoms occur in the majority of persons with dementia over the course of the disease. These are the first population-based estimates for neuropsychiatric symptoms in MCI, indicating a high prevalence associated with this condition as well. The authors suggest these symptoms have serious adverse consequences and should be inquired about and treated as necessary.
References (abridged):
1. Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Am J Public Health. 1998;88:1337-1342.
2. Rabins PV, Lyketsos CG, Steele C. Practical Dementia Care. New York, NY: Oxford University Press; 1999.
3. Petersen RC, Stevens JC, Ganguli M, et al. Practice parameter: Early detection of dementia: mild cognitive impairment (an evidence-based review). Neurology. 2001;56:1133-1142.
4. Morris JC, Storandt M, Miller JP, et al. Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol. 2001;58:397-405.
5. Finkel SI, Costa e Silva J, Cohen G, et al. Behavioral and psychological signs and symptoms of dementia. Int Psychogeriatr. 1996;8(suppl 3):497-500.
J. Am. Med. Assoc. http://www.jama.com
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