Interaction of exogenous acetylcholinesterase and butyrylcholinesterase with amyloid-ß plaques in human brain tissue.

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are associated with amyloid-ß (Aß) plaques and exhibit altered biochemical properties in human Alzheimer's disease (AD), as well as in the transgenic 5XFAD mouse model of AD amyloidosis. In the brains of the 5XFAD mouse model devoid of BChE enzyme (5XFAD/BChE-KO), incubation of tissue sections with exogenous BChE purified from human plasma (pl-BChE) leads to its association with Aß plaques and its biochemical properties are comparable to those reported for endogenous BChE associated with plaques in both human AD and in 5XFAD mouse brain tissue. We sought to determine whether these observations in 5XFAD/BChE-KO mice also apply to human brain tissues. To do so, endogenous ChE activity in human AD brain tissue sections was quenched with 50 % aqueous acetonitrile (MeCNaq) leaving the tissue suitable for further studies. Quenched sections were then incubated with recombinant AChE (r-AChE) or pl-BChE and stained for each enzymes' activity. Exogenous r-AChE or pl-BChE became associated with Aß plaques, and when bound, had properties that were comparable to the endogenous ChE enzymes associated with plaques in AD brain tissues without acetonitrile treatment. These findings in human AD brain tissue extend previous observations in the 5XFAD/BChE-KO mouse model and demonstrate that exogenously applied r-AChE and pl-BChE have high affinity for Aß plaques in human brain tissues. This association alters the biochemical properties of these enzymes, most likely due a conformational change. If incorporation of AChE and BChE in Aß plaques facilitates AD pathogenesis, blocking this association could lead to disease-modifying approaches to AD. This work provides a method to study the mechanism of AChE and BChE interaction with Aß plaque pathology in post-mortem human brain tissue.

Interaction of Exogenous Butyrylcholinesterase with ß-Amyloid Plaques in 5XFAD/Butyrylcholinesterase-Knockout Mouse Brain.

BACKGROUND: In Alzheimer's disease (AD), and amyloid models such as the 5XFAD mouse, butyrylcholinesterase (BChE) is associated with ß-amyloid (Aß) plaques and has unique biochemical features which distinguish it from that found in neurons. It has been suggested that BChE associated with Aß plaques may be involved in the maturation of this structure and thus disease progression. OBJECTIVE: Currently, it is unknown whether BChE bound to Aß plaques has altered biochemical properties due to a different primary structure or because of the association of this enzyme with Aß plaques. Also, the source and binding mechanism of this BChE remains unknown. METHODS: Brain tissue sections from the 5XFAD/BChE-KO mouse were incubated with exogenous sources of BChE and stained for this enzyme's activity. Efforts were made to determine what region of BChE or Aß may be involved in this association. RESULTS: We found that incubation of 5XFAD/BChE-KO brain tissues with exogenous BChE led to this enzyme becoming associated with Aß plaques and neurons. In contrast to neuronal BChE, the BChE bound to Aß plaques had similar biochemical properties to those seen in AD. Mutations to BChE and efforts to block Aß epitomes failed to prevent this association. CONCLUSION: The association of BChE with Aß plaques, and the resultant biochemical changes, suggests that BChE may undergo a conformational change when bound to Aß plaques but not neurons. The 5XFAD/BChE-KO model is ideally suited to explore the binding mechanism of BChE to Aß plaques as well as the involvement of BChE in AD pathogenesis.

Imaging Butyrylcholinesterase in Multiple Sclerosis.

PURPOSE: Molecular imaging agents targeting butyrylcholinesterase (BChE) have shown promise in other neurodegenerative disorders and may have utility in detecting changes to normal appearing white matter in multiple sclerosis (MS). BChE activity is present in white matter and localizes to activated microglia associated with MS lesions. The purpose of this study was to further characterize changes in the cholinergic system in MS pathology, and to explore the utility of BChE radioligands as potential diagnostic and treatment monitoring agents in MS. PROCEDURE: Cortical and white matter lesions were identified using myelin staining, and lesions were classified based on microglial activation patterns. Adjacent brain sections were used for cholinesterase histochemistry and in vitro autoradiography using phenyl 4-[123I]-iodophenylcarbamate (123I-PIP), a previously described small-molecule cholinesterase-binding radioligand. RESULTS: BChE activity is positively correlated with microglial activation in white matter MS lesions. There is no alteration in cholinesterase activity in cortical MS lesions. 123I-PIP autoradiography revealed uptake of radioactivity in normal white matter, absence of radioactivity within demyelinated MS lesions, and variable uptake of radioactivity in adjacent normal-appearing white matter. CONCLUSIONS: BChE imaging agents have the potential to detect MS lesions and subtle pathology in normal-appearing white matter in postmortem MS brain tissue. The possibility of BChE imaging agents serving to supplement current diagnostic and treatment monitoring strategies should be evaluated.

Intact olfactory memory in the 5xFAD mouse model of Alzheimer's disease from 3 to 15 months of age.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder that causes profound cognitive dysfunction. Deficits in olfactory memory occur in early stages of AD and may be useful in AD diagnosis. The 5xFAD mouse is a commonly used model of AD, as it develops neuropathology, cognitive and sensori-motor dysfunctions similar to those seen in AD. However, olfactory memory dysfunction has not been studied adequately or in detail in 5xFAD mice. Furthermore, despite sex differences in AD prevalence and symptom presentation, few studies using 5xFAD mice have examined sex differences in learning and memory. Therefore, we tested olfactory memory in male and female 5xFAD mice from 3 to 15 months of age using a conditioned odour preference task. Olfactory memory was not impaired in male or female 5xFAD mice at any age tested, nor were there any sex differences. Because early-onset impairments in very long-term (remote) memory have been reported in 5xFAD mice, we trained a group of mice at 3 months of age and tested olfactory memory 90 days later. Very long-term olfactory memory in 5xFAD mice was not impaired, nor was their ability to perform the discrimination task with new odourants. Examination of brains from 5xFAD mice confirmed extensive Aß-plaque deposition spanning the olfactory memory system, including the olfactory bulb, hippocampus, amygdala and piriform cortex. Overall this study indicates that male and female 5xFAD mice do not develop olfactory memory deficits, despite extensive Aß deposition within the olfactory-memory regions of the brain.

Cholinesterases in normal and Alzheimer's disease primary olfactory gyrus.

AIMS: Alzheimer's disease (AD) is characterized by cholinergic dysfunction and deposition of ß-amyloid (Aß) plaques and tau neurofibrillary tangles (NFTs) in the brain. Olfactory abnormalities often precede cognitive symptoms in AD, indicating early involvement of pathology in olfactory structures. The cholinergic system is important not only in cognition but also in modulation of the olfactory system. The primary olfactory gyrus (POG) is comprised of the olfactory tract, anterior olfactory nucleus (AON) and olfactory area (OA). Because of the importance of the olfactory and cholinergic systems, we examined the anatomical and cholinergic organization of the POG in normal human brain and neuropathology in AD. METHODS: Cytoarchitecture of the POG was studied using Nissl staining in normal (n = 8) and AD (n = 6) brains. Distributions of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were determined using histochemical methods. Aß plaques and tau NFTs were detected using immunohistochemistry. Abundance of AD pathology was assessed using a semi-quantitative approach. RESULT: Nissl staining showed pyramidal cells in the AON and paleocortical organization of the OA. AChE stained neurons and neuropil in the AON and OA, while BChE activity was noted in the olfactory tract and in AON and OA neurons. Pathology was frequent in the AD POG and the abundance of BChE-associated AD pathology was greater than that associated with AChE. CONCLUSIONS: AChE and BChE activities in normal POG recapitulated their distributions in other cortical regions. Greater abundance of BChE-associated, in comparison to AChE-associated, AD pathology in the POG suggests preferential involvement of BChE in olfactory dysfunction in AD.

Reduced fibrillar ß-amyloid in subcortical structures in a butyrylcholinesterase-knockout Alzheimer disease mouse model.

The serine hydrolase, butyrylcholinesterase (BChE) is known to have a variety of enzymatic and non-enzymatic functions. In the brain, BChE is expressed mainly in glia, white matter and in distinct populations of neurons in areas important in cognition. In Alzheimer's disease (AD), many ß-amyloid (Aß) plaques become associated with BChE activity, the significance of which is unclear. A mouse model of AD containing five familial AD genes (5XFAD) also exhibits Aß plaques associated with BChE. We developed a comparable strain (5XFAD/BChE-KO) that is unable to synthesize BChE and reported diminished fibrillar Aß deposits in the cerebral cortex of 5XFAD/BChE-KO mice, compared to 5XFAD counterparts at the same age. This effect was most significant in male mice. The present study extends comparison of the two strains with a detailed examination of fibrillar Aß plaque burden in other regions of the brain that typically accumulate pathology and exhibit neurodegeneration. This work demonstrates that, as in the cerebral cortex, the absence of BChE leads to diminished fibrillar Aß deposition in amygdala, hippocampal formation, thalamus and basal ganglia. This reduction is statistically significant in males, with a trend towards such reduction in female mice.

Early detection of cerebral glucose uptake changes in the 5XFAD mouse.

Brain glucose hypometabolism has been observed in Alzheimer's disease (AD) patients, and is detected with (18)F radiolabelled glucose, using positron emission tomography. A pathological hallmark of AD is deposition of brain ß- amyloid plaques that may influence cerebral glucose metabolism. The five times familial AD (5XFAD) mouse is a model of brain amyloidosis exhibiting AD-like phenotypes. This study examines brain ß-amyloid plaque deposition and (18)FDG uptake, to search for an early biomarker distinguishing 5XFAD from wild-type mice. Thus, brain (18)FDG uptake and plaque deposition was studied in these mice at age 2, 5 and 13 months. The 5XFAD mice demonstrated significantly reduced brain (18)FDG uptake at 13 months relative to wild-type controls but not in younger mice, despite substantial ß- amyloid plaque deposition. However, by comparing the ratio of uptake values for glucose in different regions in the same brain, 5XFAD mice could be distinguished from controls at age 2 months. This method of measuring altered glucose metabolism may represent an early biomarker for the progression of amyloid deposition in the brain. We conclude that brain (18)FDG uptake can be a sensitive biomarker for early detection of abnormal metabolism in the 5XFAD mouse when alternative relative uptake values are utilized.

Butyrylcholinesterase and the cholinergic system.

The cholinergic system plays important roles in neurotransmission in both the peripheral and central nervous systems. The cholinergic neurotransmitter acetylcholine is synthesized by choline acetyltransferase (ChAT) and its action terminated by acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The predominance of AChE has focused much attention on understanding the relationship of this enzyme to ChAT-positive cholinergic neurons. However, there is ample evidence that BuChE also plays an important role in cholinergic regulation. To elucidate the relationship of BuChE to neural elements that are producing acetylcholine, the distribution of this enzyme was compared to that of ChAT in the mouse CNS. Brain tissues from 129S1/SvImJ mice were stained for BuChE and ChAT using histochemical, immunohistochemical and immunofluorescent techniques. Both BuChE and ChAT were found in neural elements throughout the CNS. BuChE staining with histochemistry and immunohistochemistry produced the same distribution of labeling throughout the brain and spinal cord. Immunofluorescent double labeling demonstrated that many nuclei in the medulla oblongata, as well as regions of the spinal cord, had neurons that contained both BuChE and ChAT. BuChE-positive neurons without ChAT were found in close proximity with ChAT-positive neuropil in areas such as the thalamus and amygdala. BuChE-positive neuropil was also found closely associated with ChAT-positive neurons, particularly in tegmental nuclei of the pons. These observations provide further neuroanatomical evidence of a role for BuChE in the regulation of acetylcholine levels in the CNS.

Biochemical and histochemical comparison of cholinesterases in normal and Alzheimer brain tissues.

Cholinesterase activity associated with neuritic plaques (NPs) and neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brains exhibit altered histochemical properties, such as requiring lower pH (6.8) for optimal cholinesterase staining compared to the pH (8.0) for best visualization of cholinesterases in neurons. Furthermore, visualization of NPs and NFTs can be prevented by agents like the peptidase inhibitor/metalloantibiotic bacitracin. The anomalous behavior of cholinesterases associated with pathological lesions needs to be elucidated because of the putative links between these enzymes and the disease process in AD. In this study, cholinesterases were extracted from AD and normal brain tissue to determine whether the differences observed in histochemical analyses in the two sources were reflected in kinetic properties measured in solubilized enzymes. Isolated brain enzymes from both these sources exhibited comparable kinetic parameters with respect to pH dependence, substrate affinity and inhibitor sensitivity and were not significantly affected by other agents that blocked cholinesterase histochemical visualization, such as the structurally diverse metal-chelating antibiotics bacitracin, doxycycline, minocycline and rifampicin. Although the cholinesterases from AD brain tissue examined here represented a total pool of these enzymes from AD brain, rather than enzymes specifically from NPs and NFTs, their kinetic behavior being comparable to cholinesterases isolated from normal brain tissues implies that these enzymes do not undergo disease-related modification in their primary structures. This suggests that the atypical histochemical behavior of cholinesterases in NPs and NFTs may result from interaction of cholinesterases with other molecules within these lesions, mediated by transition metal ions known to be present in AD pathology lesions.

Comparison of cognitive functions between people with silent and wild-type butyrylcholinesterase.

In the human brain, butyrylcholinesterase (BuChE) is expressed in neurons and glia. For example, many nuclei in the human thalamus, with projections to the cerebral cortex, contain a large number of neurons with intense BuChE activity. Thalamocortical projections subserve a variety of cognitive functions. Due to genetic mutations, there are individuals who do not have detectable BuChE activity (silent BuChE). While the prevalence of silent BuChE is only 1:100,000 in European and American populations, it is 1:24 in the Vysya community in Coimbatore, India. To examine whether there are differences in cognitive functions between individuals with silent BuChE and those expressing normal BuChE (wild-type), twelve healthy individuals with silent BuChE and thirteen healthy individuals with wild-type BuChE, all from the Vysya community in Coimbatore, were tested for cognitive function using the Automated Neuropsychological Assessment Metrics test battery. The silent BuChE group was slightly faster on simple reaction tasks, but slower on a visual perceptual matching task. Furthermore, discriminant function analyses correctly classified 11/12 silent and 8/13 wild-type BuChE subjects (76% correct classification overall) based on BuChE status. Different profiles of cognitive test performance between individuals with silent and wild-type BuChE were observed. These observations suggest a function for BuChE in cognition.

The behavioural neurology assessment.

BACKGROUND: We present information regarding the standardization, reliability and clinical validity of two versions of the Behavioural Neurology Assessment (BNA). The BNA-Long Form consists of 24 subtests within separate domains: Attention, Memory, Language, Visuospatial Function, Executive Function, and Praxis. The BNA-Short Form consists of 13 subtests within the domains of Attention, Memory, Naming, Visuospatial Function and Executive Function. In addition to individual domain indices, a Grand Total score was calculated for both BNA versions. OBJECTIVE: To standardize the administration and scoring and validate the BNA for detection of dementia. METHODS: Standardized normative data were obtained on 115 healthy subjects ranging in age from 50 to 95. Test-retest stability was obtained on 19 subjects and clinical validity was investigated by administering the BNA and Mini-Mental Status Examination (MMSE) to 29 patients with dementia and 29 age-matched healthy subjects (controls). RESULTS: Age had a significant effect on all but the Visuospatial and Praxis indices of the BNA-Long Form and an effect on Naming and Grand Total score of the Short-Form. Internal consistency (Cronbach's coefficient alpha) was .87 and .67 for the Long and Short Forms (.95 and .96 for dementia and control groups combined). Test-retest stability was acceptable. Grand Total indices of both BNA versions showed significant, positive correlations with the MMSE. Both BNA versions had superior sensitivity to dementia relative to the MMSE (.93 versus .79). Specificity was equivalent to the MMSE (.93 versus .97). CONCLUSIONS: Positive predictive values of the BNA and MMSE are equivalent but the BNA provides superior negative predictive value.

Butyrylcholinesterase-Mediated enhancement of the enzymatic activity of trypsin.

1. Acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholinesterase (BuChE, EC 3.1.1.8) are enzymes that catalyze the hydrolysis of esters of choline. 2. Both AChE and BuChE have been shown to copurify with peptidases. 3. BuChE has also been shown to copurify with other proteins such as transferrin, with which it forms a stable complex. In addition, BuChE is found in association with beta-amyloid protein in Alzheimer brain tissues. 4. Since BuChE copurifies with peptidases, we hypothesized that BuChE interacts with these enzymes and that this association had an influence on their catalytic activities. One of the peptidases that copurifies with cholinesterases has specificity similar to trypsin, hence, this enzyme was used as a model to test this hypothesis. 5. Purified BuChE causes a concentration-dependent enhancement of the catalytic activity of trypsin while trypsin does not influence the catalytic activity of BuChE. 6. We suggest that, in addition to its esterase activity, BuChE may assume a regulatory role by interacting with other proteins.

Butyrylcholinesterase and cognitive function.

Butyrylcholinesterase (BuChE) is expressed in brain structures involved in cognition, but the effect of selective BuChE inhibitors on human cognitive function is unknown. We report a patient whose cognitive function deteriorated following a reduction and improved following reinstitution of ethopropazine, a selective BuChE inhibitor. We suggest that, because neurons expressing BuChE may be involved in cognition, there is merit to further evaluation of selective BuChE inhibitors in treating cognitive dysfunction.

Estimating the prevalence of dementia in elderly people: a comparison of the Canadian Study of Health and Aging and National Population Health Survey approaches.

The Canadian Study of Health and Aging (CSHA) and the National Population Health Survey (NPHS) collected data on the prevalence of dementia in differing fashions. The CSHA used a two-stage method with objective testing and expert judgment, and the NPHS used self-report and proxy data. The present report compares estimates of prevalence and the methodology for ascertainment in the two surveys. The more detailed approach of the CSHA offers the more valid means of estimating prevalence and providing data on subtypes, and can be used in naturalhistory studies. TheNPHSmeasures, including a self/proxy report of diagnosed dementia and a derived cognitive measure, are not sufficiently valid for useful inferences to be made. However, the NPHS method can be improved through supplementation with data on functional disability, providing age group-specific point estimates closer to the CSHA's estimates of cognitive impairment and dementia from the community sample. Future waves of the NPHS may wish to include objective cognitive function measures as a cost-efficient and more accurate method of estimating the prevalence of the dementia syndrome without attempting to estimate the prevalence of particular causes of that syndrome.

Inter-rater reliability of the diagnosis of vascular cognitive impairment at a memory clinic.

Consensus criteria for the diagnosis of vascular dementia (VaD) are gradually being replaced with data-based criteria. We report the inter-rater reliability of a new set of empirically-derived criteria for vascular cognitive impairment (VCI). Stratified sampling, with optimal allocation, was employed to randomly select 36 patients from the Queen Elizabeth II Health Science Centre's Memory Disability Clinic. Chart reviews were conducted independently by 4 physicians. Each physician classified the patients as having either: no cognitive impairment, VCI or Alzheimer's disease (AD). VCI was further classified both clinically (VCI without dementia, VaD or AD with a vascular component) and radiographically (infarcts, white matter changes, single strategic stroke). The intraclass correlation coefficient (ICC) for the diagnosis by physicians of VCI or otherwise was based on a repeated-measures analysis of variance with raters as the independent variable. A significant coefficient of reliability (average ICC = 0.88, 95% CI = 0.80-0.93) was obtained (H(o): rho

Enhancement of survival of stored dopaminergic cells and promotion of graft survival by exposure of human fetal nigral tissue to glial cell line--derived neurotrophic factor in patients with Parkinson's disease. Report of two cases and technical considerations.

The authors have studied the ability of glial cell line-derived neurotrophic factor (GDNF) to promote survival of human fetal dopaminergic tissue after a storage period of 6 days and subsequent implantation into the human putamen. The results indicate that GDNF promotes survival of stored dopaminergic cells. Cells stored without GDNF had a 30.1% decrease in survival time compared with those exposed to GDNF. Two patients with Parkinson's disease received bilateral putaminal implants of fetal dopaminergic cells exposed to GDNF for 6 days and showed enhancement of graft survival as assessed by positron emission tomography scanning. A mean increase of 107% in putaminal fluorodopa uptake from baseline values was observed 12 months postgrafting.

Spectrum of disease in vascular cognitive impairment.

The recognition that cognitive impairment of vascular origin is not limited to multi-infarct dementia has led to the development of several sets of new criteria for vascular dementia (VaD). We set out to define the spectrum of disease in patients presenting with vascular cognitive impairment (VCI). Of 412 patients consecutively seen at a memory clinic, 80 had VCI. These patients had vascular cognitive impairment not dementia (n = 19), VaD (n = 48), and mixed Alzheimer's disease-VaD (n = 13). Radiographic patterns were: white matter changes only (40%); multiple infarcts (30%); single strategic stroke (14%), and no identified lesion (16%). Of note, 19 (24%) of these patients meet none of the currently published criteria for VaD. To better understand and treat ischaemic causes of cognitive impairment, the concept of VaD should be expanded to include patients who do not meet traditional dementia criteria.

Cholinesterases in cardiac ganglia and modulation of canine intrinsic cardiac neuronal activity.

Cholinergic neurotransmission plays a significant role in intrinsic cardiac ganglia with the action of acetylcholine being terminated by acetylcholinesterase (AChE, EC 3.1.1.7). Anatomical studies were performed to characterize neurons associated with AChE and a closely related enzyme, butyrylcholinesterase (BuChE, EC 3.1.1.8), in canine intrinsic cardiac ganglia. Histochemical staining for AChE and BuChE in canine right atrial neurons showed that there were four neuronal populations, namely, those that contained AChE only, BuChE only, both AChE and BuChE, and those that did not contain either enzymes. The neuronal activity of intrinsic cardiac neurons in response to substrates and inhibitors of cholinesterases were studied in anesthetized dogs. The activity of intrinsic cardiac neurons, as measured by changes in the number of action potentials, increased by local application of acetylcholine. However, local application of butyrylcholine led to a considerably greater increase in the activity of intrinsic cardiac neurons. In keeping with the neurochemical heterogeneity in intrinsic cardiac ganglia with respect to cholinesterases, the activity generated by most butyrylcholine-sensitive neurons was not influenced by acetylcholine and the activity generated by the most acetylcholine-sensitive neurons was not influenced by butyrylcholine. This suggests that these two agents preferentially influence different populations of intrinsic cardiac neurons. Enzyme kinetic studies demonstrated that canine AChE preferentially catalyzed the hydrolysis of acetylcholine while canine BuChE preferentially catalyzed the hydrolysis of butyrylcholine. Cholinesterase inhibitors Ro 2-1250 and Ro 2-0638 inhibited both canine cholinesterases, while huperzine A preferentially inhibited canine AChE and ethopropazine inhibited canine BuChE. The activity of neurons in the intrinsic cardiac ganglia significantly increased when Ro 2-1250 or Ro 2-0638 was administered locally. The activity of neurons was not affected when huperzine A or ethopropazine was administered, indicating that both cholinesterases must be inhibited to increase neuronal activity. In summary, these data show that in addition to AChE, intrinsic cardiac ganglia also contain distinct populations of neurons that are associated with BuChE, and the activity generated by these neurons is differentially influenced by their substrates. Because simultaneous inhibition of AChE and BuChE leads to increased neuronal activity, it is concluded that AChE- and BuChE-positive intrinsic cardiac neurons may act synergistically to influence the overall tonic activity of intrinsic cardiac ganglia.

Retrospective diagnosis of dementia using an informant interview based on the Brief Cognitive Rating Scale.

The accuracy of a dementia diagnosis by specialist physicians, as verified at an autopsy, is greater than 90% in many series. Donations of brains to the Maritime Brain Tissue Bank (MBTB) by individuals who did not have expert dementia diagnoses before death led us to investigate whether clinical features could also be detected retrospectively. Informants for 36 individuals whose brains were in the MBTB (18 women, mean age = 79 years; pathologic diagnoses: 75% Alzheimer's disease [AD]; 8.4% vascular or mixed dementia) were interviewed by specialist physicians using a semistructured retrospective interview based on the Brief Cognitive Rating Scale (BCRS) (range = 1 [no impairment] to 7 [terminal dementia]). The mean duration of dementia was 8.5 +/- 12.8 years based on proxy reports, and most cases suggested severe dementia--(stage 6 [severe] or 7 [terminal])--on the retrospective BCRS (RetroBCRS) before death. A score of 4 or more on the RetroBCRS had 100% sensitivity and specificity in detecting dementia. The RetroBCRS score correlated moderately with duration (.51). In linear and logistic regression models adjusted for age and sex, RetroBCRS staging helped explain 93% of the variation in duration. The accuracy of the retrospective diagnosis of the cause of dementia, compared with autopsy, was 92%. The RetroBCRS used by an expert physician with a reliable informant is a valid method of detecting dementia and determining whether AD was present.

Distribution of butyrylcholinesterase in the human amygdala and hippocampal formation.

The distribution of the major cholinergic regulatory enzyme acetylcholinesterase (AChE, EC 3.1.1.7) has been extensively studied in the human brain, but the distribution of the closely related enzyme butyrylcholinesterase (BuChE, EC 3.1.1.8) is largely unknown. Because of the importance of BuChE and AChE in Alzheimer's disease, we have studied the distribution of BuChE in the normal human amygdala and hippocampal formation and compared it with that of AChE by using histochemical techniques. In the amygdala, the distribution of BuChE differed significantly from that of AChE in that BuChE was found primarily in neurons and their dendritic processes, whereas AChE was found predominantly in the neuropil. BuChE-positive neurons were present in up to 10% of the neuronal profiles in lateral, basolateral (basal), basomedial (accessory basal), central, cortical, and medial amygdaloid nuclei. AChE was found primarily in the neuropil in these nuclei with only a few AChE-positive neurons. In the hippocampal formation, BuChE was also found in neurons and not in the neuropil, whereas AChE was found in both neurons and in the neuropil. BuChE and AChE neurons were present in the polymorphic layer of the dentate gyrus, as well as the stratum oriens and stratum pyramidale of the hippocampus proper. There was considerable overlap in shapes, sizes, and numbers of BuChE- and AChE-positive neurons, suggesting that the enzymes were colocalized in neurons of the hippocampal formation. The distinct distribution of BuChE suggests that it may have specific functions including coregulation of cholinergic and noncholinergic neurotransmission in human amygdala and hippocampal formation.