Abstract
Cholinergic therapies have proven efficacious in the treatment of Alzheimer's disease,
and recently in vascular and mixed dementia. We set out to evaluate the impact of
putative cerebrovascular lesions involving cholinergic pathways in patients with cognitive
impairment. White matter signal hyperintensities on magnetic resonance imaging involving
cholinergic projections were classified according to a three-point rating scale for
171 individuals with cognitive impairment and 34 normal elderly controls. Medial temporal
lobe width was measured, and a neuropsychological test battery was administered. Moderate
or severe involvement of cholinergic pathways by white matter signal hyperintensities
were identified in 60% of subjects with probable vascular dementia, 30% of subjects
with possible/probable Alzheimer's disease, and 40% of subjects with cognitive impairment
but no dementia. All control subjects were found to have minimal cholinergic pathway
involvement. Medial temporal lobe width and signal hyperintensities on magnetic resonance
imaging affecting cholinergic pathways were inversely related. Individuals with moderate
and severe involvement of cholinergic pathways by white matter signal hyperintensities
had greater impairment of executive function and visuospatial attention, despite equivalent
degrees of global impairment and memory dysfunction when compared to those with minimal
cholinergic pathway involvement. This is the first study to suggest that cerebrovascular
disease may directly affect cholinergic projections and may exacerbate pre-existing
cholinergic deficits of a degenerative nature, especially in probable Alzheimer's
disease. Cerebrovascular compromise of cholinergic white matter projections may therefore
be relevant in understanding the effects of cholinergic therapies. Copyright © 2003
by National Stroke Association
Keywords
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References
- Clinical-neuropathologic findings in multi-infarct dementia: a report of six autopsied cases.Neurology. 1997; 48: 668-672
- Brain infarction and the clinical expression of Alzheimer disease. The Nun Study.JAMA. 1997; 277: 813-817
- Prevalence and risk factors of silent brain infarcts in the population-based Rotterdam Scan Study.Stroke. 2002; 33: 21-25
- The cholinergic system in old age and Alzheimer's disease.Age Ageing. 1980; 9: 1-8
- Practice parameter: Management of dementia (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology.Neurology. 2001; 56: 1154-1166
- Efficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomized trial.Lancet. 2002; 359: 1283-1290
- A comparison of the effects of donepezil in patients with probable and possible vascular dementia: A combined analysis of two 24-week, randomized, double-blind, placebo-controlled trials (abstract).Neurology. 2002; 58: A382
- Nucleus basalis (Ch4) and cortical cholinergic innervation in the human brain: observations based on the distribution of acetylcholinesterase and choline acetyltransferase.J Comp Neurol. 1988; 275: 216-240
- Trajectories of cholinergic pathways within the cerebral hemispheres of the human brain.Brain. 1998; 121: 2249-2257
- Alzheimer disease, attention, and the cholinergic system.Alzheimer Dis Assoc Disord. 1995; 9: 43-49
- Selective lesion of cholinergic neurons in the medial septum by 192 IgG-saporin impairs learning in a delayed matching to position T-maze paradigm.Brain Res. 2002; 943: 132-141
- Excitotoxic lesions of basal forebrain cholinergic neurons: effects on learning, memory and attention.Behav Brain Res. 1993; 57: 123-131
- Basal forebrain lesions in monkeys disrupt attention but not learning and memory.J Neurosci. 1994; 14: 167-186
- Nucleus basalis magnocellularis and attention: effects of muscimol infusions.Behav Neurosci. 1993; 107: 1031-1038
- Diagnostic and statistical manual of mental disorders.in: American Psychiatric Association, Washington DC1994: 4
- Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA Workgroup under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease.Neurology. 1984; 34: 939-944
- Vascular dementia: Diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop.Neurology. 1993; 43: 250-260
- Prevalence and severity of cognitive impairment with and without dementia in an elderly population.Lancet. 1997; 349: 1793-1796
- Mental Status Examination for Organic Mental Syndrome in the Elderly Patient.in: Geriatric Psychiatry. Grune and Stratton, New York1976
- California Verbal Learning Test: Adult Version.The Psychological Corporation, San Antonio, Texas1987
- Wechsler Memory Scale—Revised.The Psychological Corporation, New York1987
- Neuropsychological assessment.Oxford University Press, New York1983
- Wisconsin Card Sorting Test manual.Psychological Assessment Resources, Odessa, Florida1981
- Contributions to Neuropsychological Assessment.Oxford University Press, New York1983
- The Boston Naming Test.Lea and Febiger, Boston1978
- A reliable MR measurement of medial temporal lobe width from the Sunnybrook Dementia Study.Neurobiol Aging. 2003; 24: 49-56
- Reliability of measurement. The Design and Analysis of Clinical Experiments.in: John Wiley and Sons, New York1986: 1-32
- The nucleus basalis magnocellularis cholinergic system: one hundred years of progress.Neurobiol Learn Mem. 1997; 67: 85-95
- Impact of white matter changes on clinical manifestation of Alzheimer's disease: A quantitative study.Stroke. 2000; 31: 2182-2188
- Small concomitant vascular lesions do not influence rates of cognitive decline in patients with Alzheimer disease.Arch Neurol. 2000; 57: 1474-1479
- Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer's disease.Lancet. 1999; 354: 919-920
- Cognitive correlates of leukoaraiosis in the early stages of Alzheimer's disease.Funct Neurol. 1998; 13: 17-25
- The effect of white matter hyperintensity volume on brain structure, cognitive performance, and cerebral metabolism of glucose in 51 healthy adults.Neurology. 1995; 45: 2077-2084
- The effect of white matter low attenuation on cognitive performance in dementia of the Alzheimer type.Age Ageing. 1996; 25: 443-448
- Sensitivity and specificity of newly proposed clinical criteria for possible vascular dementia.Neurology. 1997; 49: 690-694
- Clinical overdiagnosis of vascular dementia versus necropsy confirmed series.J Neurol Neurosurg Psychiatry. 1997; 62: 677-678
- Leukoaraiosis and vascular dementia.Neurology. 1998; 51: S3-S8
- Role of white matter lesions in cognitive impairment of vascular origin.Alzheimer Dis Assoc Disord. 1999; 13: S49-S54
- Research criteria for subcortical vascular dementia in clinical trials.J Neural Transm Suppl. 2000; 59: 23-30
- Prevalence and risk factors of silent cerebral infarction in apparently normal adults.Hypertension. 2000; 36: 73-77
Article info
Publication history
Accepted:
November 11,
2002
Received:
September 26,
2002
Footnotes
*Supported by a pilot grant from the Ontario Mental Health Foundation and the Canadian Institutes of Health Research (CIHR) grant # MT13129 to S.E.B. Financial support was provided to R.H.S. through an MD/PhD student fellowship from the CIHR, and to D.J.S. through a partnership grant from the Heart and Stroke Foundation of Canada (HSFC) and CIHR.
**Address reprint requests to: Richard H. Swartz, MD, Room A-421, Sunnybrook & Women's College Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada, M4N 3M5.
Identification
Copyright
© 2003 National Stroke Association. Published by Elsevier Inc. All rights reserved.
