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Small provides a thoughtful analysis of memory loss with aging by asking and answering the important questions. Is cognitive decline diffuse or selective? Is memory localized anatomically? Does decline represent an abnormal state? What are the causes of memory decline? Where do we go from here? He tells us where we are and what is needed in designing future research.
Maragakis and Rothstein deliver an incisive review of glutamate transporters in neurologic disease, including Alzheimer disease (AD), pointing out that altered glutamate uptake contributes significantly to neurodegeneration. As they point out, understanding the biology of the glutamate reuptake system will be essential to develop strategies for developing therapy in the near future.
Andreasen and colleagues define the precise and specific value of cerebrospinal fluid tau and β-amyloid 42 levels in diagnosing and following up patients with AD. These markers, as they point out, have great clinical utility in defining what is and what is not AD in relation to normal aging, psychiatric disorders, depressive pseudodementia, and the frontal temporal dementias. Editorial perspective is provided by David Knopman, MD.
How Common Are Tau Gene Mutations?
Poorkaj and colleagues provide a superb clinical and molecular analysis of the frequency of tau mutations in patients with non-AD, nonvascular dementia. This is an important study showing that up to one third of familial cases with tau pathologic findings had mutations in the tau gene. The etiologic heterogeneity of the frontal temporal dementias is proving to be similar to that previously discovered in AD. Editorial perspective is provided by Bruce L. Miller, MD.
Hydroxyguanine Marks AD
Lovell and Markesbery describe a highly significant 108-fold increase in the ratio of 8-hydroxyguanine bound to DNA to free 8-hydroxyguanine in the cerebrospinal fluid in AD patients compared with age-matched control subjects. This is a highly significant finding and may be useful as a marker of disease progression or response to antioxidant therapy in the future. Editorial perspective is provided by Ramon Diaz-Arrastia, MD, PhD, and Fred Baskin, PhD.
Mild Cognitive Impairment Is AD
Morris and colleagues provide a new, interesting, and convincing study showing that individuals currently characterized as having mild cognitive impairment (MCI) progress steadily into dementia and develop the neuropathologic features of AD. Their important thesis that MCI represents early-stage AD supports the objective to intervene therapeutically as soon as possible.
Memory Loss Predicts Dementia
Bozoki and colleagues have studied patients with MCI to see what their risk is for developing AD in the future. They find that the risk of dementia is significantly increased among patients with clear cognitive impairments beyond simple memory loss. Again, memory loss may not be innocent, and therapeutic intervention in this spectrum of patients needs to begin early.
Rivastigmine vs AD
Farlow and colleagues find that the rate of disease progression for patients with mild to moderate AD appears to predict patients' response to rivastigmine. Patients with more rapidly progressive disease may be particularly likely to benefit from this anticholinesterase inhibitor.
Donepezil vs AD
Doody and colleagues find that donepezil has long-term benefits. Donepezil, they conclude, is an effective, safe, and long-term anticholinesterase therapy for AD.
Estrogen Replacement and AD
Seshadri and colleagues find that the use of estrogen replacement therapy in women after the onset of menopause was not associated with a reduced risk of developing AD. Estrogen therapy in women has many benefits, but unfortunately, preventing AD is not one of them.
Amyloid Levels and AD
Borroni and colleagues have studied whether acetylcholinesterase inhibitor treatment affects the ratio of platelet amyloid precursor protein (APP) isoforms in patients with AD. Donepezil was studied for 30 days in patients with AD, and an increase in the APP ratio was found in treated AD patients compared with control AD subjects. There was also improvement in Mini-Mental Status Examination scores in the treated AD patients. The platelet APP ratio may be a peripheral, surrogate marker in evaluating AD patients receiving anticholinesterase therapy.
Rates of Progression in AD
Smith Doody and colleagues use neuropsychological test scores to measure the rate of progression in individual patients with AD. An easily calculable rate of early disease progression can be used to classify patients as rapid, intermediate, or slow progressors with a good predictive value, even at initial presentation. Their rating scale may be a useful prognosis index.
Clinical Correlates of Lewy Bodies
Stern and colleagues have rigorously studied the clinical features of patients shown to have Lewy bodies at postmortem examination. In short, they were not able to observe a correlation of Lewy bodies at autopsy with the presence of any clinical feature or with rapidity of disease progression. Lewy bodies are indeed elusive for the clinician.
The Lewy Body and the Dopamine Receptor—Not Good Company
Sweet and colleagues, in a rigorous study, show that the Lewy body variant of AD is associated with selective alterations in dopamine receptor density that may contribute to the distinct clinical profile in this group. The extrapyramidal features seen in patients with Lewy body involvement may be explained, in part, on this basis.
Stern and colleagues, in a series of patients with human immunodeficiency virus (HIV) infection, demonstrate that those variables significantly associated with time to develop dementia included depression, altered executive abilities, and the presence of motor abnormalities on neurological examination. These clinical features are of clear practical value in evaluating this emerging group of HIV patients.
Visual Variant of AD
Bokde et al studied AD patients who had prominent visual and visuospatial symptoms. The resting cerebral metabolic rate for glucose was measured using positron emission tomographic (PET) brain scans both in patients with routine AD and in those with visual symptoms. Altered functional activity was shown to be directly caused by cerebral hypometabolism and not simply by brain atrophy. These findings are of considerable interest in differentiating metabolic from structural changes.
COX-2 and AD
Ho and colleagues have studied cyclooxygenase-2 (COX-2) expression in the brain as a function of clinical progression of early AD. An enzyme involved in inflammatory mechanisms, COX-2 is up-regulated in brains with AD and is now a therapeutic target for anti-inflammatory therapy. In this study, neuronal COX-2 content in specific regions of the hippocampus increased in AD brains as the disease progressed. Thus, COX-2 is likely to be a key indicator of clinical progression in AD and supports the approach of anti–COX-2 therapy.
Frontal Lobe Hypometabolism With Lacunar Infarcts
Reed and colleagues have shown that cognitive decline in patients with lacunae may occur in part from progressive vascular compromise in subcortical frontal circuits. Lacunae contribute to cognitive decline, as elegantly shown in this study with PET scanning; bilateral and right hemisphere dorsolateral frontal metabolism significantly predicted cognitive decline of a significant degree.
How to Avoid Dementia: Exercise
Laurin and colleagues show in this rigorous, comprehensive study that regular physical activity, especially in women, is an important protective factor against cognitive decline and dementia. The more exercise, the better the effect!
Dementia With Lewy Bodies
Cordery and colleagues, in an interesting case report of a patient with dementia and Lewy bodies, found a pattern of hypometabolism characteristic of AD using oxygen 15–labeled PET. At postmortem examination, there was no pathological evidence of AD, but diffuse cortical Lewy bodies were seen in the pigmented brainstem nuclei and cerebral cortex. The occipital metabolism was normal. It has been reported that PET studies show low occipital metabolism in diffuse dementia with Lewy bodies; as shown in this study, while occipital hypometabolism may favor that diagnosis, it is not necessary for diagnosis.
Missing Article Title. Arch Neurol. 2001;58(3):343–345. doi:10.1001/archneur.58.3.343
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