ENZYME MAY HELP CONTROL AMYLOID-β PRODUCTION

In addition to preventing the formation of the tangle-like lesions in patients with Alzheimer’s disease, the prolyl isomerase Pin1 also plays a key role in guarding against the development of amyloid peptide plaques, according to a study in the March 23 Nature.

Lucia Pastorino, PhD, and colleagues hypothesized that Pin1 might be regulating amyloid precursor protein cleavage and amyloid-β production. First, the investigators examined the relationship between amyloid precursor protein and Pin1 using nuclear magnetic resonance spectroscopy. They found that when amyloid precursor protein became phosphorylated, the resulting misshapen structure could be restored quickly by the introduction of Pin1. Next, the researchers used cell models to examine the effects of Pin1 on amyloid-β production and found that while up-regulation of Pin1 reduced generation of amyloid-β, the removal of Pin1 increased amyloid-b production.

In addition, Dr. Pastorino and colleagues studied changes in amyloid precursor protein processing and production of different amyloid-β peptides in Pin1-knockout mice and mice in which Pin1 had been knocked out and mutant amyloid precursor protein was overexpressed. Results from the mouse models revealed that in Pin1-knockout mice, amyloid-β₄₀ or amyloid-β₄₂ levels were not significantly altered at two to six months, and soluble amyloid-β₄₀ or amyloid-β₄₂ levels or insoluble amyloid-β₄₀ levels were also not significantly changed at 15 months. However, at 15 months, levels of insoluble amyloid-β₄₂ were increased by 32% in the brains of Pin1-knockout mice compared with controls. In a separate mouse model, knockout of Pin1 did not obviously affect amyloid-b levels at two months, but at six months it significantly increased insoluble amyloid-β—especially amyloid-β42—by 46%, compared with levels in controls—without affecting soluble amyloid-β40 and amyloid-β42 or causing neurodegeneration.

"These results indicate that Pin1 knockout in mice causes an age-dependent and selective increase in insoluble amyloid-β₄₂, which is accelerated by amyloid precursor protein overexpression," Dr. Pastorino’s team stated. "Of note, similar increases in amyloid-β₄₂ levels have been documented in transgenic mice overexpressing familial Alzheimer’s disease presenilin mutants, or in familial Alzheimer’s disease brains, indicating that small shifts in amyloid-β₄₂ production may have an important impact on the development of Alzheimer’s disease."

The investigators concluded that "further studies on Pin1-catalyzed conformational regulation and its biological and pathological significance should help elucidate the molecular events leading to Alzheimer’s disease and cancer, and might also lead to the development of new therapies."

Suggested Reading
Pastorino L, Sun A, Lu P-J, et al. The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-b production. Nature. 2006;440:528-534.

STROKE DAMAGE IN BRAIN MAY LEAD TO HEART IMPAIRMENT

Infarctions in the right insula and other specific brain regions in stroke patients also show evidence of myocardial injury, according to Hakan Ay, MD, and colleagues. Their findings were published in the May 9 Neurology.

From a group of 738 consecutive patients with acute ischemic stroke, the researchers observed 50 patients in whom serum cardiac troponin T elevation occurred in the absence of any apparent cause within three days of symptom onset. The control group consisted of 50 randomly selected age- and sex-matched patients with ischemic stroke without cardiac troponin T elevation. Results showed the right posterior, superior, and medial insula, as well as the right inferior parietal lobule, as brain regions that were a priori associated with cardiac troponin T elevation. For patients with right middle cerebral artery infarction, the insular cluster was involved in 88% and 33% of patients with and without cardiac troponin T elevation, respectively.

Dr. Ay and colleagues stated that traditionally, estimation of the prevalence of cardiac abnormalities in patients grouped according to the involvement of a specific brain region has been used to link cardiac disturbances to cerebral locations. However, the researchers noted that this method does not allow for coincidental associations, may preclude point localizations, and could produce certain false-negative associations. Instead, they suggested a nonparametric permutation approach, which deals with both nonnormal distribution and multiple comparisons, as "a feasible way to make lesion–deficit correlation in patients with ischemic stroke ... and thus holds promise for broader application in localizing deficits in clinical neurology."

In an accompanying editorial, William P. Cheshire, Jr, MD, and Clifford B. Saper, MD, PhD, pointed out the possibility of using β-blocker therapy to protect the heart in patients with right insular infarctions. "If the use of β-blockers in acute stroke were without risk, then the accumulating evidence of elevated cardiac troponin levels would argue for their use in right insular stroke," the authors stated. "The absence of an increased incidence of detectable adverse cardiac outcomes following insular infarction in some studies may have been due to the cardioprotective effect of β-blockers used for concurrent coronary artery disease."

However, Drs. Cheshire and Saper noted that use of β-blockers could lead to arterial hypotension and the risk of ischemia to the stroke penumbra. "A prospective clinical trial with cautious attention to blood pressure changes would be necessary to answer this question," they stated.

Suggested Reading
Ay H, Koroshetz WJ, Benner T, et al. Neuroanatomic correlates of stroke-related myocardial injury. Neurology. 2006;66:1325-1329.
Cheshire WP Jr, Saper CB. The insular cortex and cardiac response to stroke. Neurology. 2006;66:1296-1297.

RESEARCH SHEDS LIGHT ON NEUROPATHOLOGIC FEATURES OF AMNESTIC MCI

In patients with amnestic mild cognitive impairment, the neuropathologic features match the clinical features and seem to be intermediate between the neurofibrillary changes of aging and the pathologic features of very early Alzheimer’s disease, according to a report published in the May Archives of Neurology.

Ronald C. Petersen, MD, PhD, and colleagues studied 66 participants, 15 of whom had memory impairment beyond that associated with normal aging but who did not have dementia. The researchers also examined 28 clinically healthy persons and 23 patients with probable Alzheimer’s disease. Results showed that although most patients with amnestic mild cognitive impairment did not meet the neuropathologic criteria for Alzheimer’s disease, "their pathologic findings suggest a transitional state of evolving Alzheimer’s disease." Pathologic findings involving medial temporal lobe structures were found in all patients with amnestic mild cognitive impairment. In addition, concomitant pathologic abnormalities were observed, including argyrophilic grain disease, hippocampal sclerosis, and vascular lesions.

Dr. Petersen and colleagues noted that in comparing Alzheimer’s disease patients with healthy participants, they found "an interesting contrast for the interpretation of the neuropathologic features of amnestic mild cognitive impairment." When comparing plaques, the researchers found that patients with mild cognitive impairment appeared to be more similar to the healthy participants than to those with Alzheimer’s disease. Patients with mild cognitive impairment also appeared to have a greater degree of neurofibrillary tangle distribution as measured by Braak staging, stated the researchers.

Dr. Petersen and colleagues concluded that "although the concept of amnestic mild cognitive impairment remains under study, data are converging on the clinical characterization, rates of progression, clinical predictors, and now the neuropathologic substrate. This study provides data on individuals who died while their clinical classification was amnestic mild cognitive impairment and contributes to our understanding of the neuropathologic substrate of these patients."

In an accompanying editorial, Harry V. Vinters, MD, FCAP, FRCPC, noted, "It is not yet clear from a clinical perspective whether patients who have amnestic mild cognitive impairment might be amenable to pharmacologic interventions ... that prevent their developing Alzheimer’s disease, or whether the presence of early ‘Alzheimerization’ in their brains means that irreversible cellular/molecular events that will culminate in Alzheimer’s disease have been set in motion." However, Dr. Vinters concluded it has been "firmly established" by Dr. Petersen and colleagues’ study that patients with amnestic mild cognitive impairment show early Alzheimer’s disease pathologic change within the central nervous system.

Suggested Reading
Petersen RC, Parisi JE, Dickson DW, et al. Neuropathologic features of amnestic mild cognitive impairment. Arch Neurol. 2006;63:665-672.
Vinters HV. Neuropathology of amnestic mild cognitive impairment. Arch Neurol. 2006;63:645-646.

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