Alzheimer's special

Hard arteries, soft brain?

Lines blur between vascular dementia and Alzheimer's. Hippocampus damage, though, may not lead to AD

By Emily Andrews

There's a high correlation between atherosclerosis of the cerebral arteries and brain changes indicating Alzheimer's disease (AD), reported a study in the November issue of Arteriosclerosis and Vascular Biology. A link between cardiovascular disease and AD is already well established. What's new is the use of statistical analysis and rigorous measurements to examine the correlation between arterial stenosis and pathological indicators of AD.

The "observations bolster an increasing convergence between clinical evidence and basic science data linking vascular dementia and AD pathophysiology," observes the team headed by Dr Alex E Roher and colleagues at the Sun Health Research Institute and the Longtime Center for Molecular Biology and Genetics, in Sun City, Arizona.

To establish the link the researchers did post-mortem assessments and analyses on the brains of deceased nursing home residents. They used several established methods to estimate densities of amyloid plaque and neurofibrillary tangles, the pathologic hallmarks of AD. In addition, they documented white matter changes in each cerebral lobe. To evaluate cerebral atherosclerosis, they measured internal and external volumes of 3-mm segments of the Circle of Willis, the interconnected arterial system that supplies the brain. The chief finding? Substantially more stenosis in subjects determined to have AD compared to those without.

These results, says Dr Costantino Iadecola in an accompanying editorial, "call for a revision of the diagnostic criteria for vascular and neurodegenerative dementia." He proposes "a spectrum of diseases in which vascular factors and neurodegeneration coexist with various degrees of overlap." Traditional thinking posits separate mechanisms: as yet undetermined for AD or neurogenerative dementia and arterial blockage with or without strokes for vascular or multi-infarct dementia.

One in 13 Canadians over 65 has AD or a related dementia, and about 65% of these are believed to be AD. The number of "mixed" cases with both types is controversial, as diagnosis is extremely difficult.

Dr Iadecola suggests a vicious loop whereby the narrowing of large cerebral blood vessels caused by atherosclerosis reduces cerebral blood flow, facilitating amyloidogenesis. The resulting increased amyloid-beta peptide -- the main constituent of the amyloid plaques characterizing AD -- produces arterial constriction and endothelial dysfunction, further impairing cerebral blood flow. Independently, other avenues also contribute to increased amyloid-beta peptide -- not all AD patients show evidence of cerebral atherosclerosis.

Neither article discusses the relationship of these findings to the two other main varieties: Lewy body dementia and frontotemporal dementia, each with characteristic behavioural manifestations and physiological changes. Importantly, as noted by Dr Roher et al, their post-mortem study provides no information on the relative timing of atherosclerosis progression with signs and symptoms of dementia.

NUNS AND THE BRAIN
An entirely different pathway, cumulative hippocampal damage caused by chronic psychological distress, is another avenue of research into the causes and potential treatments for AD. A study of about 800 older Catholic nuns, priests and brothers published in the December 9 issue of Neurology found that the tendency to experience distress at baseline correlated with subsequent cognitive decline and occurrence of AD by clinical assessment. In autopsy examinations of subjects who died, however, the degree of initial distress-proneness bore no relation to pathological evidence of AD, nor to the correlation between pathological and clinical evidence of AD. These results imply that the memory loss associated with hippocampal damage doesn't directly contribute to Alzheimer's development.

A decade ago there was little or no treatment for dementia so there was little need to distinguish between different types or their etiologies, once treatable causes such as metabolic disturbances had been ruled out. That has changed: drugs available now can help slow progression and alleviate symptoms, and research on many fronts seeks ways to prevent and cure AD and/or vascular dementia.

Loss of cholinergic neuronal function in the brain areas involved with attention, learning and memory is an important feature of AD. Cholinesterase inhibitors, drugs that augment remaining cholinergic activity, slow early cognitive deterioration but don't delay the long-term course of AD. The cholinesterase inhibitors currently available in Canada are donepezil (Aricept), galantamine (Reminyl) and rivastigmine (Exelon). Memantine (Ebixa, Namenda), long available in Europe and approved in October 2003 by the FDA for treatment of moderate to severe AD, operates by a different mechanism important to learning and memory involving glutamate activation at the N-methyl-D-aspartate (NMDA) receptors.

Statins, drugs that correct dyslipidemia and reduce cardiovascular risk, are under intense scrutiny to see whether they might prevent or delay AD and vascular dementia. Other studies have recently looked at transdermal nicotine (i.e. a patch) for a potential to improve attention and subjective perceptions of memory in people with age-associated memory impairment (AAMI) and mild cognitive impairment (MCI), conditions which sometimes progress to AD (for more, see Patching memory on this page).

Drugs based on enhancing nerve regeneration (leteprinim) and neuroprotection (propentofylline) are also currently in development. Patients treated with clioquinol, a metal chelator, showed a decline in plasma beta-amyloid levels compared to those treated with placebo in a small, randomized trial reported in the December 15 issue of Archives of Neurology. Slowing of cognitive decline was seen as well, but only in more severely affected patients.