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1. Ann N Y Acad Sci 1998 Nov 30;855:762-75
Cellular and molecular neuropathology of the olfactory epithelium and central olfactory pathways in Alzheimer's disease and schizophrenia.
Arnold SE, Smutzer GS, Trojanowski JQ, Moberg PJ
Department of Psychiatry, University of Pennsylvania, Philadelphia 19104, USA.
Specific deficits in odor detection threshold, identification, and memory have been recognized in a variety of disorders including the neurodegenerative disorder, Alzheimer's disease (AD), and the psychiatric illness, schizophrenia, which is likely due to abnormalities in neurodevelopment. Neuropathological abnormalities in peripheral and central olfactory systems have been described in both disorders. In the olfactory, epithelium, dystrophic neurites that are immunoreactive for tau, neurofilaments and other polypeptides, as well as deposits of beta-amyloid have been observed, and these findings have been thought to contribute to the olfactory dysfunction of these disorders. However, similar findings also occur in the olfactory epithelium of many normal individuals and those with various other neurodegenerative diseases. In contrast, neuropathological studies have reported selective vulnerability of central olfactory pathways for the accumulation of neurofibrillary pathology in AD, and for cytoarchitectural, neuronal morphometric, and cytoskeletal protein abnormalities suggestive of abnormal neurodevelopment in schizophrenia. Thus, it is likely that the olfactory impairments associated with these diseases are due to damage within central olfactory pathways, and that they are further amplified by the less specific impairments associated with age-related sensory neuroepithelial abnormalities. Finally, both the olfactory epithelium and central olfactory pathways represent model systems in which to study the neurobiology of these disorders, which ultimately may yield clues with diagnostic and therapeutic utility.
2. Ann N Y Acad Sci 1998 Nov 30;855:723-31
Very early changes in olfactory functioning due to Alzheimer's disease and the role of apolipoprotein E in olfaction.
Bacon AW, Bondi MW, Salmon DP, Murphy C
SDSU-UCSD Joint Doctoral Program in Clinical Psychology, San Diego, California 92103, USA.
Alzheimer's disease (AD) is a progressive neurodegenerative illness marked by memory loss and at least one other cognitive disturbance. Early diagnosis of the disease has proved difficult and has therefore been the focus of much research. Apolipoprotein E (ApoE), a protein manufactured and distributed throughout the body, has shown specificity of binding to the beta A4 peptide, the primary component in the senile plaques of AD. Furthermore, the ApoE, epsilon 4 (epsilon 4) allele, is overrepresented in AD. These two lines of evidence suggest that ApoE, specifically the epsilon 4 allele, plays an important role in the development of AD. Further support for this hypothesis appears in neuropsychological data showing cognitive decrements in ostensibly nondemented individuals with the epsilon 4 allele, compared to those without the allele. It is also well known that olfaction is compromised in AD. Thus, the purpose of this study was twofold: (1) to examine very early changes in olfactory functioning due to AD and (2) to examine the role of ApoE in olfactory functioning in people at risk for AD by virtue of early cognitive decline. Results demonstrated changes in olfactory threshold the year immediately preceding change in diagnosis from normal control to AD. Also, in individuals with mild cognitive impairment, those with the ApoE epsilon 4 allele show poorer thresholds than those without the epsilon 4 allele.
3. J Clin Exp Neuropsychol 1999 Jun;21(3):341-51
A test of odor fluency in patients with Alzheimer's and Huntington's disease.
Bacon Moore AS, Paulsen JS, Murphy C
Joint Doctoral Program in Clincial Psychology, San Diego State University/University of California San Diego
In the present study, an olfactory analog to the verbal fluency test was designed and administered to 40 patients with Alzheimer's disease (AD) and 11 patients with Huntington's disease (HD). Because onset of AD is typically in the sixties while onset of HD is typically in the mid-thirties, the patient groups had their own control group, an older (ONC) and younger (YNC) control group, respectively. Both control groups included 40 participants who were age- and education-matched to their respective patient group. Odor threshold, odor identification, and odor fluency measures were administered to each participant. Results of the study indicate that patients with dementia perform more poorly on all three measures of olfactory functioning. Our results suggest that tests of odor memory show differential performance in healthy and demented patients, leading to the suggestion that tests of olfactory functioning may be useful in detection and diagnosis of neurodegenerative disease.
4. J Neurosci 1999 Nov 1;19(21):9180-91
Multiple and opposing roles of cholinergic transmission in the main olfactory bulb.
Castillo PE, Carleton A, Vincent JD, Lledo PM
Centre National de la Recherche Scientifique, Institut Alfred Fessard, 91198 Gif-sur-Yvette Cedex, France.
The main olfactory bulb is a critical relay step between the olfactory epithelium and the olfactory cortex. A marked feature of the bulb is its massive innervation by cholinergic inputs from the basal forebrain. In this study, we addressed the functional interaction between cholinergic inputs and intrinsic bulbar circuitry. Determining the roles of acetylcholine (ACh) requires the characterization of cholinergic effects on both neural excitability and synaptic transmission. For this purpose, we used electrophysiological techniques to localize and characterize the diverse roles of ACh in mouse olfactory bulb slices. We found that cholinergic inputs have a surprising number of target receptor populations that are expressed on three different neuronal types in the bulb. Specifically, nicotinic acetylcholine receptors excite both the output neurons of the bulb, i.e., the mitral cells, as well as interneurons located in the periglomerular regions. These nicotine-induced responses in interneurons are short lasting, whereas responses in mitral cells are long lasting. In contrast, muscarinic receptors have an inhibitory effect on the firing rate of interneurons from a deeper layer, granule cells, while at the same time they increase the degree of activity-independent transmitter release from these cells onto mitral cells. Cholinergic signaling thus was found to have multiple and opposing roles in the olfactory bulb. These dual cholinergic effects on mitral cells and interneurons may be important in modulating olfactory bulb output to central structures required for driven behaviors and may be relevant to understanding mechanisms underlying the perturbations of cholinergic inputs to cortex that occur in Alzheimer's disease.
5. Ann N Y Acad Sci 1998 Nov 30;855:681-5
Abnormality of semantic network in patients with Alzheimer's disease. Evidence from verbal, perceptual, and olfactory domains.
Chan A, Salmon D, Nordin S, Murphy C, Razani J
Department of Psychology, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
A series of studies was initiated to model the organization of semantic memory in Alzheimer's disease (AD) patients using multidimensional scaling (MDS) and Pathfinder analyses. The resulting models (cognitive maps or semantic networks) embed studied stimuli in a coordinate space or network where distances between points are assumed to reflect psychological proximity between items. The organization of semantic networks in verbal and sensory domains were modeled based upon the frequency of the subject's choice of two concepts as most alike. Results suggested that while the organization of concepts in the semantic networks of AD patients was primarily based upon a concrete perceptual dimension in both verbal and olfactory domains, those of normal controls subjects were predominantly organized by an abstract conceptual attribute. Also, networks of AD patients were more complex and chaotic than normal, that is, they consisted of more unnecessary connections and of atypical strengths of association between concepts.
6. Ann Otol Rhinol Laryngol 1995 Aug;104(8):655-61
Beta-Amyloid peptide and amyloid precursor proteins in olfactory mucosa of patients with Alzheimer's disease, Parkinson's disease, and Down syndrome.
Crino PB, Martin JA, Hill WD, Greenberg B, Lee VM, Trojanowski JQ
Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, USA.
Dystrophic neurites are present in olfactory epithelium (OE) of patients with Alzheimer's disease (AD), Parkinson's disease (PD), and Down syndrome (DS) and occasionally in normal individuals. Cultured olfactory neuroblasts from AD patients generate carboxy terminal amyloid precursor protein (APP) fragments that contain beta-amyloid (A beta), but it is not known if deposits of A beta and/or APP fragments occur in the OE of individuals with or without AD, PD, or DS. To determine if A beta accumulates in the OE in situ, we probed postmortem samples of olfactory mucosa from patients with AD, PD, and AD (PD/AD), and DS and AD (DS/AD), as well as from controls, using polyclonal and monoclonal antibodies to A beta and flanking sequences in APPs. Samples of OE also were examined by thioflavin-S and electron microscopy. Labeling of A beta was observed in 10 of 12 AD cases, 2 of 3 PD/AD cases, 3 of 4 DS/AD cases, 3 of 10 adult controls, and 4 of 6 fetal cases. The A beta staining was seen in the basal third of the OE, in axons projecting through the lamina propria, and in metaplastic respiratory epithelium within the OE. Antibodies to other APP domains stained the OE of patients and controls. Thioflavin-S staining was present in the basal third of the OE of 8 of 9 AD patients and several PD/AD and DS/AD patients, but only in rare cells of 3 controls. Electron microscopy did not reveal amyloid fibrils in the OE.
7. Am J Psychiatry 2000 Sep;157(9):1399-405
Olfactory deficits in patients with mild cognitive impairment predict Alzheimer's disease at follow-up.
Devanand DP, Michaels-Marston KS, Liu X, Pelton GH, Padilla M, Marder K, Bell K, Stern Y, Mayeux R
New York State Psychiatric Institute, New York, NY 10032, USA.
OBJECTIVE: This study evaluated the predictive utility of olfactory identification deficits in patients with mild cognitive impairment for follow-up diagnosis of probable Alzheimer's disease. METHOD: Ninety outpatients with mild cognitive impairment were examined at 6-month intervals. Matched healthy comparison subjects (N=45) were examined annually. The University of Pennsylvania Smell Identification Test was given at baseline. RESULTS: Olfaction scores were lower in patients with mild cognitive impairment than in healthy comparison subjects. Seventy-seven patients were followed up; 19 were diagnosed with Alzheimer's disease by 2 years. Patients with low olfaction scores (< or =34 of 40), and patients with low olfaction scores who reported no subjective problems smelling, were more likely to develop Alzheimer's disease than other patients. In a Cox proportional hazards model adjusted for age, sex, modified Mini-Mental State score, and education, low olfaction scores did not predict time until development of Alzheimer's disease, but low olfaction scores accompanied by lack of awareness of olfactory deficits predicted time to development of Alzheimer's disease. This effect remained when attention or memory measures replaced modified Mini-Mental State score in the model. In patients with high Mini-Mental State scores (> or =27 of 30), low olfaction with lack of awareness remained a significant predictor of Alzheimer's disease. Olfaction scores of 30-35 showed moderate to strong sensitivity and specificity for diagnosis of Alzheimer's disease at follow-up. CONCLUSIONS: In patients with mild cognitive impairment, olfactory identification deficits, particularly with lack of awareness of olfactory deficits, may have clinical utility as an early diagnostic marker for Alzheimer's disease.
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