'Just in case': the fertility information needs of teenagers and young adults with cancer.

Understanding the reproductive and fertility concerns of teenagers and young adults with cancer (TYA) is one aspect of comprehensive age appropriate care. However, limited options for fertility preservation, coupled with vague policy recommendations, give rise to variations in information-sharing between health care professionals and TYAs, particularly as it involves sensitive discussions regarding the short- and long-term effects of cancer and treatments on fertility and reproduction. This paper presents findings from a wider evaluation at a specialist unit for TYAs with cancer. Forty people participated in semi-structured interviews, including 20 young people, parents and partners. Young people were between 2 months and 4 years from finishing treatment. Most young people received mixed levels of information on fertility and counselling before treatment. Diagnosis in the early teens meant how, and from whom, young people received information varied. Young women tended to receive incomplete information. The majority of young people were unaware of their fertility status after treatment had finished. Findings point to the inherent challenges that exist in ensuring young people aged between 13 and 25 years receive comprehensive information on their fertility and potential risk, as well as advice on how to determine their fertility status after treatment has finished.

Arterial stiffness, endothelial function and microcirculatory reactivity in healthy young males.

Large (C1) and small (C2) arterial stiffness has been suggested to parallel endothelial reactivity and has led researchers to suggest parameters of arterial stiffness may be alternative measures to brachial sonographic assessments of flow-mediated dilatation (FMD). However, past studies comparing these measures can be criticized. In addition to %FMD responses, we recorded concurrent hyperaemic responses of the microcirculation and both were compared with C1 and C2. Twenty-nine subjects 18-30 years of age were investigated. Radial blood pressure was recorded with a tonometer. Pulse waveform analysis was performed to calculate C1 and C2. These were compared with %FMD responses and responses of finger flux measured by laser Doppler fluxmetry (LDF); pulsatile finger volume measured by photoplethysmography (PPG); and palm skin temperature measured by infrared thermography (Tpalm) (i.e. microcirculatory responses). Responses were determined as % changes from control. We only found weak relationships between C1 and %FMD (r=0.4, P=0.04); C2 and %PPG (r=0.38, P=0.07); and C2 and %LDFdorsal (r=-0.38; P=0.04). Responses of %FMD weakly parallel those of C1. Neither C2 nor C1 are viable indicators of endothelial or microcirculatory reactivity (i.e. hyperaemic or venous constriction) in healthy, resting young males. These findings refute the claims that C1 and C2 are substitute measures to sonographic assessments of brachial FMD.

The relation of arterial stiffness to endothelial function in healthy subjects.

Local wall stiffness affects endothelial responsiveness but how global measures affect responsiveness is unanswered. We assessed this by comparing reactive hyperaemic responses of brachial diameter (RHRBD) with central (heart-to-brachial artery pulse wave velocity (PWV); large (C1)) and peripheral (C2) arterial stiffness. Twelve healthy subjects were investigated. RHRBD was induced via an upper- or forearm occluding cuff. Arterial diameter changes were measured using echo ultrasound. Arterial stiffness and RHRBD were compared using a Pearson correlation coefficient (r) and Bland-Altman analysis of Z-scores (indicated as 95% confidence intervals (CI) and expressed in units of standard deviation (SD) from the mean). Weak relations were found between upper-arm RHRBD responses and C2 (r = 0.56, P = 0.06; 95% CI +/- 1.84 SDs) and C1 (r = 0.55, P = 0.06; 95% CI +/- 1.86 SDs). An inverse relation was found between upper-arm RHRBD responses and PWV (r = -0.55, P = 0.06), but Bland-Altman plots revealed no agreement between these parameters (P > 0.05; 95% CI +/- 3.46 SDs). Forearm RHRBD were not related to PWV, C1 or C2 (P > 0.05; 95% CI > 2 SDs). The weak relation between upper-arm endothelial responses and C2 and C1 seems to suggest that C2, and also C1, is not a good and reliable method for assessments of endothelial health. Furthermore, if anything, upper-arm mediated RHRBD responses are more affected by arterial stiffness than forearm responses.

Herbal medicines as diuretics: a review of the scientific evidence.

There is increasing interest in the health and wellness benefits of herbs and botanicals. This is with good reason as they might offer a natural safeguard against the development of certain conditions and be a putative treatment for some diseases. One such area may be the lowering of blood pressure in those where it is elevated (i.e., hypertension). One class of clinical medicines used to lower blood pressure are known as diuretics and work by increasing the excretion of urine from the body as well as the amount of sodium in urine. There are a growing number of studies purporting diuretic effects with traditional medicines. The aim of this article was to review these studies and identify which extracts promote diuresis (which we assessed on terms of urine excreted and urinary sodium excretion) and also to identify the research needs in this area. We identified a number of species and genuses reporting diuretic effects. Of these, the most promising, at the present time, are the species Foeniculum vulgare, Fraxinus excelsior, Hibiscus sabdariffa, Petroselinum sativum and Spergularia purpurea, and species from the genuses Cucumis (Cucumis melo and Cucumis trigonus), Equisetum (Equisetum bogotense, Equisetum fluviatile, Equisetum giganteum, Equisetum hiemale var. affine and Equisetum myriochaetum), Lepidium (Lepidium latifolium and Lepidium sativum), Phyllanthus (Phyllanthus amarus, Phyllanthus corcovadensis and Phyllanthus sellowianus) and Sambucus (Sambucus mexicana and Sambucus nigra). However, there the number of studies is limited and we recommend that further studies be conducted to confirm reported effects. Such evidence is needed to provide scientific credence to the folklore use of traditional medicines and even be helpful in the development of future medicines, treatments and treatment guidelines.

Non-invasive methods and stimuli for evaluating the skin's microcirculation.

Vessels in the skin are arranged into superficial and deep horizontal plexuses and they are involved in thermoregulation, oxygen and nutritional support. The skin has a large number of functions and broad appeal spanning basic mechanistic and clinical research. Indeed, the skin can be used as a marker of normal and impaired vascular control and, owing to its accessibility and frequent involvement, is easy to investigate non-invasively. A large number of non-invasive methods are available for investigating the skin, ranging from those that permit the visualisation of microvessels, to those that monitor blood flow or one of its derivatives (e.g., skin temperature and transcutaneous oxygen). Such methods can be combined with non-invasive, dynamic stimuli (e.g., the use of cold or warm stimuli, activation of the peripheral nervous system or local neuronal systems, and the topical application of vasoactive drugs) and this potentially enables the differentiation of underlying disorders (e.g., primary from secondary Raynaud's phenomenon) and also to quantify changes over time or following intervention. The present article outlines the non-invasive methods and dynamic tests that can be used to investigate the microcirculation of the skin.

Patterns of convergence and segregation in the medial nucleus accumbens of the rat: relationships of prefrontal cortical, midline thalamic, and basal amygdaloid afferents.

In the rat, fibers from the prelimbic cortex terminate in the medial nucleus accumbens. Anterior paraventricular thalamic and parvicellular basal amygdaloid fibers reached both the prelimbic cortex and the medial nucleus accumbens. All three afferent systems have an inhomogenous distribution within the nucleus accumbens, and whether or not these projections actually reach the same areas is unknown. Our aim was to evaluate the relationships of the three afferents with respect to the shell, the core, and the cell clusters of the nucleus accumbens. Double anterograde tracing and single anterograde tracing combined with immunohistochemistry for calbindin (D28k) or Nissl stain was used. Following tracer injections in the prelimbic cortex and the anterior paraventricular thalamus, a complementary (i.e., nonoverlapping) pattern of fibers was found in the shell. Thus, afferents from the prelimbic cortex are associated with cell clusters, whereas those from the anterior paraventricular thalamus avoid these cells but are affiliated with regions exhibiting weak homogeneous calbindin immunoreactivity. In the calbindin-poor patches of the core, the situation is reversed as both sets of fibers overlap. In cases with injections in the prelimbic cortex and the parvicellular basal amygdala, a pattern of overlap was seen in the shell and core. Thus, the fibers in the shell were found together in association with cell clusters, whereas regions of weak homogeneous calbindin immunoreactivity were avoided. In the core, overlap was seen in the patch compartment. Finally, with parvicellular basal amygdala/paraventricular thalamus injections, a complementary fiber organization was present in the shell, but overlap was prominent in the patches of the core. The results demonstrate that the relationships of prelimbic cortical, paraventricular thalamic, and parvicellular basal amygdaloid afferents in the nucleus accumbens vary according to their compartmental (immunohistochemical and cellular) affiliation. Compartmentalization is therefore a possible anatomical substrate for condensation or segregation of neuronal signals passing through the nucleus accumbens.

Patterns of overlap and segregation between insular cortical, intermediodorsal thalamic and basal amygdaloid afferents in the nucleus accumbens of the rat.

Regions of the prefrontal cortex that project to the nucleus accumbens in the rat receive input from midline thalamic and basal amygdaloid nuclei which also project to the same striatal region as their prefrontal cortical target. For example, the prelimbic cortex projects to the medial nucleus accumbens, and receives input from the paraventricular thalamic nucleus and the parvicellular basal amygdala. These latter two areas also project to the medial nucleus accumbens. It has been shown that afferents from the prelimbic cortex, the paraventricular thalamic nucleus and the parvicellular basal amygdala to the nucleus accumbens overlap or are separated in the nucleus accumbens, depending upon their position in the shell and core. The dorsal agranular insular cortex, the intermediodorsal thalamic nucleus and the magnocellular basal amygdaloid nucleus terminate in the lateral part of the nucleus accumbens and adjacent ventral part of the caudate-putamen. The intermediodorsal thalamic nucleus and the magnocellular basal amygdaloid nucleus reach both the dorsal agranular insular cortex and the lateral nucleus accumbens, and thus appear positioned to influence the prefrontal corticostriatal system at cortical and striatal levels. However, all three afferent systems have a heterogeneous distribution within this striatal region, and whether these projections actually reach the same areas is unknown. We investigated the patterns of separation and overlap in the nucleus accumbens between dorsal agranular insular cortical, magnocellular basal amygdaloid and intermediodorsal thalamic afferents with respect to the histochemical features of the nucleus. Techniques allowing the detection of two different anterograde tracers, or a single anterograde tracer and Calbindin-D28k immunoreactivity, in the same tissue sections were used. The results demonstrate that the afferents from the dorsal agranular insular area and the intermediodorsal thalamic nucleus avoid the shell of the lateral nucleus accumbens, which receives strong inputs from the magnocellular basal amygdala. In the matrix of the core and the ventral part of the caudate-putamen, fibers from the superficial layers of the dorsal agranular insular area overlap precisely with afferents from the intermediodorsal nucleus. In the patches, projections from the deep layers of the dorsal agranular insular cortex coincide with those from the magnocellular basal amygdala. The present findings have implications for the compartmental structure of the nucleus accumbens and provide novel insights into the organizational principles of prefrontal corticostriatal circuits.

Protease inhibitors and indolamines selectively inhibit cholinesterases in the histopathologic structures of Alzheimer's disease.

Neurofibrillary tangles and amyloid plaques express acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity in Alzheimer's disease. We had found that traditional AChE inhibitors such as BW284C51, tacrine and physostigmine were more potent inhibitors of the AChE in normal axons and cell bodies than of the AChE in plaques and tangles. We now report that the reverse pattern is seen with indolamines, carboxypeptidase inhibitor, and the nonspecific protease inhibitor bacitracin. These substances are more potent inhibitors of the cholinesterases in plaques and tangles than of those in normal axons and cell bodies. These results show that the enzymatic properties of plaque and tangle-associated cholinesterases diverge from those of normal axons and cell bodies. The selective susceptibility to bacitracin and carboxypeptidase inhibitor indicates that the catalytic sites of plaque and tangle-bound cholinesterases are more closely associated with peptidase or protease-like properties than the catalytic sites of cholinesterases in normal neurons and axons. This shift in enzymatic affinity may lead to the abnormal protein processing which is thought to play a major role in the pathogenesis of AD. The availability of pharmacological and dietary means for altering brain indolamines raises novel therapeutic possibilities for inhibiting the abnormal cholinesterase activity associated with Alzheimer's disease.

Convergence and segregation of ventral striatal inputs and outputs.

The ventral striatum, which prominently includes the nucleus accumbens (Acb), is a heterogeneous area. Within the Acb of rats, a peripherally located shell and a centrally situated core can be recognized that have different connectional, neurochemical, and functional identities. Although the Acb core resembles in many respects the dorsally adjacent caudate-putamen complex in its striatal character, the Acb shell has, in addition to striatal features, a more diverse array of neurochemical characteristics, and afferent and efferent connections. Inputs and outputs of the Acb, in particular of the shell, are inhomogeneously distributed, resulting in a mosaical arrangement of concentrations of afferent fibers and terminals and clusters of output neurons. To determine the precise relationships between the distributional patterns of various afferents (e.g., from the prefrontal cortex, the basal amygdaloid complex, the hippocampal formation, and the midline/intralaminar thalamic nuclei) and efferents to the ventral pallidum and mesencephalon, neuroanatomical anterograde and retrograde tracing experiments were carried out. The results of the double anterograde, double retrograde, and anterograde/retrograde tracing experiments indicate that various parts of the shell (dorsomedial, ventromedial, ventral, and lateral) and the core (medial and lateral) have different input-output characteristics. Furthermore, within these Acb regions, various populations of neurons can be identified, arranged in a cluster-like fashion, onto which specific sets of afferents converge and that project to particular output stations, distinct from the input-output relationships of neighboring, cluster-like neuronal populations. These results support the idea that the nucleus accumbens may consist of a collection of neuronal ensembles with different input-output relationships and, presumably, different functional characteristics.

Differential prefrontal cortex and amygdala habituation to repeatedly presented emotional stimuli.

Repeated presentations of emotional facial expressions were used to assess habituation in the human brain using fMRI. Significant fMRI signal decrement was present in the left dorsolateral prefrontal and premotor cortex, and right amygdala. Within the left prefrontal cortex greater habituation to happy vs fearful stimuli was evident, suggesting devotion of sustained neural resources for processing of threat vs safety signals. In the amygdala, significantly greater habituation was observed on the right compared to the left. In contrast, the left amygdala was significantly more activated than the right to the contrast of fear vs happy. We speculate that the right amygdala is part of a dynamic emotional stimulus detection system, while the left is specialized for sustained stimulus evaluations.

The anatomical relationships of the prefrontal cortex with limbic structures and the basal ganglia.

This paper briefly discusses the anatomical criteria that have been used to delineate the prefrontal cortex (PFC) from the (pre)motor cortical areas in the frontal lobe. Single anatomical criteria, such as cytoarchitecture, connectivity with the mediodorsal thalamic nucleus or a dopaminergic innervation, are insufficient to unequivocally define the PFC. It is argued that, with respect to a number of structural aspects, the prefrontal and the (pre)motor cortical areas must be viewed as a continuum, whereas a (functional) differentiation is based on the type of information that is being processed in different parts of the frontal lobe. The involvement of the PFC, like the premotor cortex, in a number of basal ganglia-thalamocortical circuits may be interpreted in the same way. The paper also summarizes the organization of the inputs from midline/intralaminar thalamic nuclei, the basal amygdaloid complex and the hippocampus into the PFC-ventral striatal system. The results of tracing studies in rats indicate that these thalamic and limbic inputs both at the level of the PFC and the ventral striatum show various patterns of convergence and segregation. This leads to the conclusion that the PFC-ventral striatal system consists of a number of smaller modules.

A functional MRI study of human amygdala responses to facial expressions of fear versus anger.

Functional magnetic resonance imaging (fMRI) of the human brain was used to compare changes in amygdala activity associated with viewing facial expressions of fear and anger. Pictures of human faces bearing expressions of fear or anger, as well as faces with neutral expressions, were presented to 8 healthy participants. The blood oxygen-level dependent (BOLD) fMRI signal within the dorsal amygdala was significantly greater to Fear versus Anger, in a direct contrast. Significant BOLD signal changes in the ventral amygdala were observed in contrasts of Fear versus Neutral expressions and, in a more spatially circumscribed region, to Anger versus Neutral expressions. Thus, activity in the amygdala is greater to fearful facial expressions when contrasted with either neutral or angry faces. Furthermore, directly contrasting fear with angry faces highlighted involvement of the dorsal amygdaloid region.

Acute autonomic effects of vitamins and fats in male smokers.

BACKGROUND/OBJECTIVES: Vitamins can help improve cardiovascular control. In contrast, smoking works in the opposite fashion, reducing the baroreflex control of heart rate (HR) possibly via oxidative stress. High-fat challenges also impair cardiovascular regulation. Whether vitamins have acute beneficial effects on the baroreflex control of HR in smokers is unclear. SUBJECTS/METHODS: A randomized, placebo-controlled crossover study in 30 male smokers (34.2+/-6.9 years). Interventions were: (1) moderate (vitamin C (300 mg) and E (75 IU) and folic acid (1 mg)); (2) high doses of vitamins (vitamin C (2 g) and E (800 IU), and folic acid (5 mg)); or, (3) placebo. Vitamins were ingested with cream (a high-fat challenge) or milk (low-fat control). Four hours later, blood was withdrawn and radial pulse wave forms recorded via tonometry. Spontaneous beat-to-beat variations in HR and systolic blood pressure (SBP) were analysed by spectral analysis techniques and sympathovagal control of HR and baroreflex sensitivity (BRS) were assessed. RESULTS: High doses of vitamins increased plasma vitamin C, E and folic acid levels (P<0.05) with no change in SBP, HR or BRS (P>0.05, analysis of variance). Plasma vitamin levels did not correlate with any cardiovascular parameters. Moderate vitamins increased the vagal control of HR (+23%; P<0.05) and cream led to small increases (P<0.05) in SBP (+2 mm Hg) and HR (+2 beats min(-1)) with no change in BRS. CONCLUSIONS: In male smokers, circulating antioxidants had no effect on BRS and minor effects on the cardiovascular system were seen following acute fat and vitamin ingestion.

Neurological cholinesterases in the normal brain and in Alzheimer's disease: relationship to plaques, tangles, and patterns of selective vulnerability.

Butyrylcholinesterase (BChE) and an altered form of acetylcholinesterase (AChE) accumulate in the plaques and tangles of Alzheimer's disease (AD). The sources for these plaque- and tangle-bound cholinesterases have not been identified. We now report that AChE and BChE activities with pH preferences and inhibitor selectivities identical to those of plaque- and tangle-bound cholinesterases are found in the astrocytes and oligodendrocytes of control and AD brains. These glial-type cholinesterases are selectively inhibited by indolamines and protease inhibitors. In control brains glial-type cholinesterases appear confined to the intracellular space, whereas in patients with AD they decorate plaques and tangles as well. In control and AD brains AChE-positive glia are distributed throughout the cortical layers and subcortical white matter, whereas BChE-positive glia reach high densities only in the deep cortical layers and white matter. In non-AD control brains, the ratio of BChE to AChE glia was higher in entorhinal and inferotemporal cortex, two regions with a high susceptibility to the pathology of AD, than in primary somatosensory and visual cortex, two areas with a relatively lower susceptibility to the disease process. There was no age-related differences in the density or distribution of cholinesterase-positive glia. In comparison with age-matched control specimens, AD brains had a significantly higher density of BChE glia and a lower density of AChE glia in entorhinal and inferotemporal regions but not in the primary somatosensory or visual areas. These results suggest that glia constitute a likely source for the cholinesterase activity of plaques and tangles and that a high ratio of BChE- to AChE-positive glia may play a permissive or causative role in the neuropathology of AD.

Reflex vascular responses to independent changes in left ventricular end-diastolic and peak systolic pressures and inotropic state in anaesthetised dogs.

1. Ventricular mechanoreceptors are known to exist and can when stimulated induce reflex vasodilatation, but the nature of the effective stimuli and the physiological role of the reflex remain to be established. 2. Dogs were anaesthetised with chloralose and a cardiopulmonary bypass established. Ventricular pressures were separated from those in the aortic root and coronary arteries by a balloon inflated in the ventricular outflow tract. Ventricular filling was controlled by adjusting the rate of inflow of blood through an apical cannula and peak pressure by regulating the outflow pressure from the same cannula. Carotid and aortic pressures were also controlled and vascular resistance was assessed from changes in perfusion pressure (constant flow conditions) to the descending abdominal aorta. 3. Increased coronary or carotid sinus pressure induced a significant vasodilatation. Changes in ventricular peak systolic pressure, without associated changes in end-diastolic pressure, had no significant effect on vascular resistance. In contrast, changes in end-diastolic pressure did induce vasodilatation that, although small, was proportional to the magnitude of the end-diastolic pressure change. 4. Changes in ventricular inotropic state induced by dobutamine infusion or by stimulation of efferent cardiac sympathetic nerves did not induce significant responses. Furthermore, the combined effects of reduced ventricular filling and increased inotropic state were also ineffective in inducing responses. 5. We conclude that, to induce reflex responses, the only effective stimulus to ventricular mechanoreceptors was an increase in filling. Compared with other mechanoreflexes, however, responses to ventricular distension were small and seem unlikely to be of importance except perhaps during abnormal ventricular distension.

Responses to stimulation of coronary and carotid baroreceptors and the coronary chemoreflex at different ventricular distending pressures in anaesthetised dogs.

Stimulation of left ventricular mechanoreceptors was believed not only to exert important effects on the circulation, but also to influence the responses to baroreceptor reflexes. However, most previous work is flawed due to inadequate localisation of stimuli to specific reflexogenic areas. In this study, we applied a discrete stimulus to left ventricular mechanoreceptors to examine other reflexes known to effect the circulation. Dogs were anaesthetised, artificially ventilated and a cardiopulmonary bypass established. The pressure distending the left ventricle was controlled through an apical cannula with the aortic valve obstructed by a balloon. Changes in ventricular systolic and end-diastolic pressure had only a small effect on vascular resistance, assessed as perfusion pressure in the systemic circulation (flow constant). Responses to changes in carotid or coronary pressure or to stimulation of chemosensitive afferents by injecting veratridine into the coronary circulation were always much larger. Responses to stimulation of these reflexes were little affected by the level of stimulus to the ventricular receptors. These experiments confirm that responses to stimulation of ventricular mechanoreceptors are very small and show that they remain small at different levels of input to other baroreceptive regions. There was no evidence of interaction between ventricular mechanoreceptor reflexes and carotid or coronary baroreceptors or ventricular chemosensitive reflexes.

Basal amygdaloid complex afferents to the rat nucleus accumbens are compartmentally organized.

The basal amygdaloid complex (BAC) topographically projects to the nucleus accumbens (Acb) in patchy, inhomogeneous patterns. These termination patterns may be related to the histological features of the Acb that define the shell, core, and adjacent ventral caudate-putamen (CPv), and the ventral striatal compartments providing output to different autonomic, motor, and endocrine targets. Knowledge of the relationships of BAC afferents with these compartments is essential for understanding the activities of amygdalostriatal circuits. Therefore, anterograde tracing experiments were performed, combined with calbindin-D28K (CaB) immunohistochemistry or Nissl staining. The results demonstrated that the caudal parvicellular basal amygdala (Bpc) projected primarily to cell clusters in the dorsal shell of the medial Acb, and to patches in the core/CPv. Fibers from the caudal accessory basal nucleus (AB) selectively reached CaB-immunoreactive cell clusters in the ventral shell, avoiding the core/CPv. The rostral AB projected to the same ventral shell compartments as the caudal AB; in addition, dense terminations were found in the matrix of the core/CPv, avoiding the patches. Caudal magnocellular basal amygdala (Bmg) fibers reached ventral parts of the shell, including the CaB-immunoreactive cell clusters. The caudal Bmg projected strongly to the patches of the core/CPv, evading the matrix. Finally, the rostral Bmg densely innervated the moderately CaB-immunoreactive lateral shell and the patches of the core/CPv, largely avoiding the matrix. These results indicate the specific compartmental relationships of the patchy BAC terminations and suggest that BAC subregions differentially influence particular ventral striatal outputs.

Protease inhibitors and indoleamines selectively inhibit cholinesterases in the histopathologic structures of Alzheimer disease.

Neurofibrillary tangles and amyloid plaques express acetylcholinesterase and butyrylcholinesterase activity in Alzheimer disease. We previously reported that traditional acetylcholinesterase inhibitors such as BW284C51, tacrine, and physostigmine were more potent inhibitors of the acetylcholinesterase in normal axons and cell bodies than of the acetylcholinesterase in plaques and tangles. We now report that the reverse pattern is seen with indoleamines (such as serotonin and its precursor 5-hydroxytryptophan), carboxypeptidase inhibitor, and the nonspecific protease inhibitor bacitracin. These substances are more potent inhibitors of the cholinesterases in plaques and tangles than of those in normal axons and cell bodies. These results show that the enzymatic properties of plaque and tangle-associated cholinesterases diverge from those of normal axons and cell bodies. The selective susceptibility to bacitracin and carboxypeptidase inhibitor indicates that the catalytic sites of plaque and tangle-bound cholinesterases are more closely associated with peptidase or protease-like properties than the catalytic sites of cholinesterases in normal axons and cell bodies. This shift in enzymatic affinity may lead to the abnormal protein processing that is thought to play a major role in the pathogenesis of Alzheimer disease. The availability of pharmacological and dietary means for altering brain indoleamines raises therapeutic possibilities for inhibiting the abnormal cholinesterase activity associated with Alzheimer disease.