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37. Percept Mot Skills 1994 Apr;78(2):627-31
Olfactory deficits in Down subjects: a link with Alzheimer disease.
Zucco GM, Negrin NS
Dipartimento di Psicologia Generale, Universita di Padova, Italia.
Two groups of subjects, 14 young (ages 20 to 31 years) and 14 adults (ages 32 to 54 years), both groups with Down Syndrome, were examined on a matching and naming olfactory task. On the former, subjects were required to recognize among four a previously sniffed odour, while on the latter they had to label an odour by choosing among four alternatives provided by the examiner. Analysis indicated that the adults with Down Syndrome scored worse than the young group on both tasks and that the impairment of the two groups was more pronounced on the matching task. On considering the similarity between the neurodegenerative brain pathology exhibited by Alzheimer patients and Down subjects and a recent observation that the former show pathological changes also in the olfactory epithelium (neuritic plaques and neurofibrillary tangles), these two olfactory tasks could represent a useful noninvasive diagnostic method.
38. Alzheimer Dis Assoc Disord 1994 Spring;8(1):38-48
The olfactory bulb in Alzheimer disease: a morphologic study of neuron loss, tangles, and senile plaques in relation to olfaction.
ter Laak HJ, Renkawek K, van Workum FP
Institute of Neurology, University of Nijmegen, The Netherlands.
Complete pairs of olfactory bulbs of six Alzheimer disease (AD) patients and of six age- and sex-matched controls were morphologically investigated using a random systematic sampling procedure. The total number of cells and the number of mitral cells were the same for controls and patients, but the volume of the bulb and the number of neurons in the anterior olfactory nucleus (AON) were decreased in AD patients. The loss of AON neurons was limited to the younger AD patients and was very severe (75%). Neurofibrillary tangles (NFT) and senile plaques (SP) were found in controls, but they were more frequent in AD, especially in the younger cases. A new finding was the occurrence of very large numbers of so-called diffuse or "very primitive plaques" with the methenamine-silver stain (MS-SP). NFT and SP were limited to the AON but MS-SP also occurred in other parts of the bulb. The data are discussed in relation to olfaction, and it was concluded that odor identification is processed in central rather than in peripheral olfactory structures.
39. Nippon Jibiinkoka Gakkai Kaiho 1994 Jan;97(1):51-60
[Definitive diagnosis of Alzheimer's disease using olfactory mucosal biopsy].
[Article in Japanese]
Yamagishi M, Ishizuka Y, Seki K
Department of Otolaryngology, Mizonoguchi Hospital, Teikyo University School of Medicine, Kawasaki.
Characteristic changes appearing in the biopsied olfactory mucosa of Alzheimer's disease (AD) patients were investigated using immunohistochemical staining. Specimens were obtained from 6 patients who were clinically diagnosed with AD, 2 patients with cerebrovascular dementia and 5 age-matched patients with olfactory disturbance without dementia. In most AD cases, polyclonal tau protein immunoreactivity was seen in the dendrites, perikarya of the olfactory receptor cells in the olfactory epithelium and the olfactory nerve bundles in the lamina propria. In a few cases, tau protein immunoreactivity was found in the extracellular mass in the epithelium. Ubiquitin immunoreactivity was seen is the dendrites of olfactory receptor cells. On the other hand, in control cases, only dendrites and olfactory nerve bundles reacted to anti-polyclonal tau protein antiserum in a few cases. These results indicate that the neurofibrillary tangle-like tau protein immunoreactivity in the perikarya senile plaque-like extracellular mass and ubiquitin immunoreactivity in the olfactory epithelium were characteristic changes in AD, and olfactory mucosal biopsy is a useful method for the definitive diagnosis of AD.
40. Biol Psychiatry 1993 Dec 15;34(12):824-38
A.E. Bennett Research Award 1993. Olfactory neuroblasts from Alzheimer donors: studies on APP processing and cell regulation.
Wolozin B, Lesch P, Lebovics R, Sunderland T
Section of Geriatric Psychiatry, National Institutes of Mental Health, Bethesda, MD 20892.
Cell lines of continuously dividing human olfactory neuroblasts can be propagated using olfactory epithelium obtained from human donors at biopsy or autopsy. The expression of neuronal proteins in these cells, such as neurofilament protein and tau protein, can be increased using a combination of factors including nerve growth factor, fibroblast growth factor, interleukin 1 and interleukin 6. These cells also express aspects of human disease. Olfactory neuroblasts generated from donors with the common, sporadic forms of Alzheimer's disease, show elevated levels of the direct precursor to beta-amyloid, the amyloid precursor protein C-terminal derivative (CTD). When treated with the lysosomal inhibitor chloroquine, immunoblots of Alzheimer olfactory neuroblasts show seven-fold higher levels of CTDs than immunoblots from age-matched control neuroblasts. The disease related increases in CTDs can be reversed by treatment with agents that increase intracellular cyclic adenosine monophosphate (cAMP), such as dibutyryl-cyclic-AMP, theophylline, and isoproterenol.
41. Neurobiol Aging 1993 Jul-Aug;14(4):353-7
Axonal loss from the olfactory tracts in Alzheimer's disease.
Davies DC, Brooks JW, Lewis DA
Department of Anatomy, St. George's Hospital Medical School, Tooting, London, UK.
Senile dementia of the Alzheimer type has been shown to be associated with impaired olfactory function early in the course of the disease. Neuropathology in the olfactory system is also a feature of Alzheimer's disease (AD) and it has been suggested that the disease may be caused by a pathogen entering the brain via olfactory pathways. To investigate this hypothesis, the effect of AD on the olfactory tract was investigated. There was a 40% decrease in the cross-sectional area of the olfactory tract and a 52% loss of myelinated axons from the tract in AD. These results, together with those of previous studies suggest that peripheral regions of the olfactory system, i.e., the olfactory bulb and primary sensory olfactory neurons are less affected by the pathologyof AD than more central parts, i.e., cortical regions, the anterior olfactory nuclei, and olfactory tract. This less severe pathology at the periphery argues against a pathogen entering the brain via the peripheral olfactory apparatus and suggests a central pathogenesis which spreads centrifugally along olfactory pathways.
42. Brain Res Bull 1993;32(1):1-5
Olfactory-related changes in Alzheimer's disease: a quantitative neuropathologic study.
Reyes PF, Deems DA, Suarez MG
Department of Neurology and Pathology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA 19107.
Neuropathological studies of 10 confirmed cases of Alzheimer's disease (AD) revealed increased numbers of neurofibrillary tangles and neuritic plaques in olfactory cortex compared to other brain regions. This was most evident when AD tissues were compared to tissues from seven gender- and age-matched controls. In the AD cases, examination of other brain regions which receive olfactory projections also revealed high concentrations of neuritic plaques and neurofibrillary tangles. These data also confirm previous observations that neurofibrillary tangle formation is more prevalent than neuritic plaque formation in AD. This is the first quantitative neuropathological study that demonstrates significant damage to various components of the central olfactory apparatus in AD. Our data suggest that damage to these areas may be related to the behavioral, emotional, and cognitive abnormalities commonly observed in affected patients. The use of antemortem evaluation of the olfactory system as a diagnostic tool for AD is discussed.
43. Neurobiol Aging 1992 Jul-Aug;13(4):469-73
Olfactory bulb lesions in Alzheimer's disease.
Struble RG, Clark HB
Department of Psychiatry, Memorial Medical Center Southern Illinois School of Medicine, Springfield 62794.
The olfactory bulb (OB), with its comparatively simple and well-delineated connectivity, presents an interesting system for examining cell-specific pathology in neurologic degenerative disorders such as Alzheimer's disease (AD). We have found that in AD the large, efferently projecting neurons (mitral cells) of the OB degenerate, typically without classical Alzheimer neurofibrillary changes. In some cases, with less severe neocortical pathology, the terminal arborizations of olfactory nerve appear hyperplastic and are associated with focal accumulations of A-4 (beta-amyloid) immunoreactivity that are not detectable by standard amyloid stains. These abnormalities may represent a pathologic manifestation of normally occurring plasticity in the olfactory system.
44. Laryngoscope 1991 Nov;101(11):1198-202
The rhinologic evaluation of Alzheimer's disease.
Feldman JI, Murphy C, Davidson TM, Jalowayski AA, de Jaime GG
Department of Surgery, San Diego School of Medicine, CA.
Olfactory dysfunction is currently not listed among the NINCDS-ADRDA clinical criteria for the diagnosis of Alzheimer's disease. There is a large amount of psychophysical and neuropathologic evidence to suggest that patients with Alzheimer's type dementia have olfactory system abnormalities. The rhinologic status of this group has not been characterized. The authors examined 21 Alzheimer's patients and 21 age-matched controls to determine whether 1. the Alzheimer's group, in fact, had a diminished sense of smell, and whether 2. rhinologic factors were responsible for this nasal dysfunction. The findings support a neurologically mediated phenomenon as the cause for significant impairment in olfactory function in patients with probable Alzheimer's disease.
45. J Comp Neurol 1991 Aug 15;310(3):365-76
Human olfactory epithelium in normal aging, Alzheimer's disease, and other neurodegenerative disorders.
Trojanowski JQ, Newman PD, Hill WD, Lee VM
Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia 19104-4283.
By use of immunohistochemistry, we characterized the molecular phenotype of human olfactory epithelial (OE) cells and assessed the nature of the dystrophic olfactory neurites described initially in Alzheimer's disease (AD). Keratin 8 was present in all classes of OE cells. Sustentacular cells lacked other cell type specific polypeptides and were distinguished from neurons and basal cells because the latter two classes of OE cells expressed neural cell adhesion molecules (N-CAMs) and microtubule associated proteins (MAPs), i.e., MAP5. Basal cells expressed nerve growth factor receptors (NGFRs), which distinguished them from olfactory neurons. Unlike their perikarya, olfactory axons expressed vimentin and GAP-43, but not peripherin or neurofilament (NF) proteins. Olfactory nerves were distinguished from other axons because the latter were positive for all three NF subunits and peripherin, in addition to vimentin and GAP-43. Dystrophic neurites in the OE were GAP-43 positive, but they also expressed proteins that were not detected in normal olfactory nerves (i.e., synaptophysin, MAP2, tau, peripherin, NF proteins). Further, rare NF positive olfactory neurons gave rise to NF positive dystrophic neurites. These neurites were present in all 11 AD cases, 11 of 14 subjects with other neurodegenerative diseases, and 6 of 8 neurologically normal adult controls, but no dystrophic neurites were seen in 9 fetal and neonatal cases. We conclude that the molecular phenotype of different human OE cells is distinct and that dystrophic olfactory neurites occur very frequently in neurologically normal adults. The relevance of these neurites to aging or specific disease processes remains speculative.
46. Yakubutsu Seishin Kodo 1991 Aug;11(4):223-35
[Involvement of the olfactory system in learning and memory: a close correlation between the olfactory deficit and the course of Alzheimer's disease]?
[Article in Japanese]
Yamamoto T
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Alzheimer's disease is characterized pathologically by the development of numerous neuritic plaques (NP) and neurofibrillary tangles (NFT) within the brain. Recent studies of Alzheimer's disease patients have uniformly shown marked impairment on odor recognition. In Alzheimer's disease, brain structures closely related to the olfactory bulb (OB) or the olfactory system demonstrate significantly histopathological changes. Anatomically, the olfactory bulbs project through the lateral olfactory tracts to the olfactory tubercules, the pyriform cortex, the cortical amygdala nucleus, and the ventrolateral entorhinal area. In addition,the olfactory system is particularly rich in acetylcholine and other neurotransmitters, many of which are deficient in Alzheimer's disease. Furthermore, increased numbers of NP and NFT in the OB and anterior olfactory nucleus have been demonstrated in patients with Alzheimer's disease. These findings suggest that there is a close correlation between the impairment of olfactory processes and the course of Alzheimer's disease. In animal study, many investigators have become interested in the role that olfactory cues play in learning/memory. Bilateral olfactory bulbectomy in rats impairs passive avoidance and radial-maze task in acquisition. In both working and reference memory tasks using a 3-panel runway apparatus, OB-lesioned rats showed a marked increase of errors (pushes made on the two incorrect panels of the 3-panel gates located at 4 choice points). Furthermore, in 3-lever operant task using a delayed matching-to-lever location procedure, OB lesions decreased significantly the correct response in test trials without affecting that in training trials. These findings indicate that olfactory bulbectomy leads to severe impairment of memory in rats. Interestingly, the appearance of memory impairment is delayed following OB lesions. Earlier studies also had shown that the rats do not require olfactory cues for efficient performance in some learning tasks. Judging from these findings, the impairment of memory do not attribute solely to olfactory deficit. Therefore, it seems likely that the impairment of memory following the bulbectomy might be due to secondary degeneration in several areas projected from the OB rather than to the olfactory deficit. Unfortunately, investigation of the mechanism underlying the development of Alzheimer's disease has been hampered by the lack of an animal model. In this context, as reviewed here, since OB-lesioned rats show severe impairment of memory with some emotional changes, the olfactory bulbectomy syndrome may be a useful model of Alzheimer's disease. Such a review inevitably raises more questions than it answers, but it is hoped that it may stimulate further investigation in this new field.
47. Neurology 1991 May;41(5 Suppl 2):77-80; discussion 80-1
Odor identification deficit of the parkinsonism-dementia complex of Guam: equivalence to that of Alzheimer's and idiopathic Parkinson's disease.
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