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Journal ofGerontology: BIOLOGICAL SCIENCES 1999, Vol. 54A, No.9, B363-B368 Copyright 1999 by The Gerontological Society ofAmerica Neuronal Loss in the Brainstem and CerebellumPart of the Normal Aging Process? A Morphometric Study of the Vermis Cerebelli and Inferior Olivary Nucleus Martin Sjobeck, Staffan Dahlen, and Elisabet Englund Divisionof Neuropathology, Departmentof Pathology and Cytology,UniversityHospital,Lund, Sweden. Basedon the known age-relatedlossofPurkinjecells (PC)in the cerebellum, this studyfocuses on whethera markedloss of PCoccursin individuals ofveryhigh age. The inferiorolive, whichis intimately connectedwiththe cerebellum anatomicallyas wellasfunctionally, wasalsostudied. The study group included 15 nondementedand basically healthycasesaged 32-104 years.linear neuronaldensitywasexpressedas number ofPCper millimetertissuemeasuredin the vermisand as neuronalnumbersper squaremillimetertissuein the inferiorolive. The linearPCdensityclearly decreased withincreasing age, R2 =0.82and p < .001. The inferioroliveshoweda smallbut insignificantage-related neuronalloss.Weconcludethat agingresultsin reducedPC density in the vermis cerebelli, further accentuated in the verylatestagesoflife. EUROPATHOLOGY is, as the name implies, aimed at describing the morphological changes induced in the CNS in disease. Pathological processes occurring late in life may be difficult to distinguish from those of normal aging. It has been shown that different parts of the human brain are affected differently by aging (1,2) and that phylogenetically younger parts of the brain such as the cerebral and cerebellar cortex are more likely to undergo morphological changes (3) than do the phylogenetically older subcortical structures. It has also been shown that aging confers neuronal loss in various parts of the central nervous system (2). Elderly persons often exhibit decreased motor functions (e.g., increased postural sway and gait impairment). These "symptoms of age" are quite often associated with higher incidence of falls among the elderly population (4). This may relate to detoriation or loss of neurons in areas involved in motor function (i.e., the primary motor cortex, subcortical nuclei, and cerebellar Purkinje cells [PC]). Atrophy and loss of PC in the cerebellum are reported to occur in normal aging. Ellis (5) showed a gradual decrease in PC density of 21% in the cerebellar hemispheres of individuals aged 20 to 90 years. The vermis cerebelli (6) showed an agerelated loss of PC in 65 individuals aged 49 to 89 years. Besides the mild and diffuse cerebral neuronal loss seen in the very aged (7), loss of PC in the cerebellum of elderly individuals, especially above the age of 100 years, is according to our own experience regularly observed. Whereas the neocortex (8-11), hippocampus (12) and subcortical structures (13) have been extensively studied morphometrically in man, no quantitative studies have been performed on the cerebellum in the very old (more than 100 years of age). In addition, other primates as well as rodents have been well characterized in terms of age-related cerebellar cell loss (14,15). The cerebellum, in which the PC are involved in motor function, is anatomically and functionally intimately connected with the inferior olive in the medulla oblongata (16-18). It therefore seems possible that a cerebellar, age-related cell loss may lead to a secondary cell loss in the inferior olive. However, it is not N fully known to what extent these regions lose neurons among the oldest old. ArM The aim of this study was to determine the magnitude of the age-related PC loss in the cerebellum in individuals of very high ages and, consequently, whether an age-associated loss of neurons could be observed also in the inferior olive of the brainstem. MATERIAL The specimens were selected from 15 nondemented, basically healthy (i.e., without major known disorders), subjects dead in accidents or from nonneurological disorders, aged 32 to 104 years. The cases were not primarily chosen for the present study, which thus is a retrospective analysis on material already available. Six of the cases were centenarians. Apart from regular autopsy procedures, the 15 cases were histopathologically analyzed with a whole-brain semiserial technique and found to be normal. In the initial selection procedure, cases with marked intracranial atherosclerosis including considerable atheromatosis in the Circle of Willis were excluded, as were those with signs of final anoxia. Among the specimens, no cerebral arteriolosclerosis was found. Cause of death, age, gender, and brain weights are shown in Table 1. The six centenarians had previously been included and thoroughly studied in the Swedish Centenarian Study (19). Mental, physical, and intellectual abilities of the individuals reaching 100 years of age are presented in Table 2 demonstrating their good general condition. In this table the Katz index of independence in activities of daily living (ADL) is also presented for the six centenarians evaluated in the Swedish Centenarian Study (19). The Katz index reflects motor function in general. It is based on an evaluation of the functional independence or dependence in bathing, dressing, going to the toilet, transferring into and out of bed/chair, continence and feeding according to the following: (a) independent in feeding, B363 B364 SJOBECK ETAL. continence, transferring, going to toilet, dressing, and bathing; (b) independent in all but one of these functions; (c) independent in all but bathing and one additionalfunction; (d) independent in all but bathing, dressing, and one additional function; (e) independent in all but bathing, dressing, going to toilet, and one additional function; (f) independent in all but bathing, dressing, going to toilet, transferring, and one additional function; (g) dependentin all six functions (20). All the autopsy reports were examined to rule out ethylassociated pathologicalchanges,such as pancreatititsor hepatic cirrhosisand steatosis.In all cases, overconsumption of alcohol could be excluded, which otherwise could have had influence on the PC numbers (21). Table 1. Cause of Death Case No. Age/Gender Year of Death Cause of Death Brain Weight (g) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 32, Female 41, Male 47, Male 51, Male 52, Female 73, Male 74, Male 89, Female 97, Female 100, Female 100, Female 102, Female 102, Female 103, Female 104, Female 1988 1990 1984 1988 1992 1988 1989 1987 1984 1990 1992 1990 1991 1994 1992 Massive lung hemorrhage Acute myocardial infarction Acute myocardial infarction Acute myocardial infarction Rupture of heart (infarction) Disseminated cancer of pancreas Rupture of aortic aneurysm Acute myocardial infarction Lung embolus Sepsis Pneumonia Pneumonia Acute myocardial infarction Lung embolus Heart failure 1340 1410 1290 1350 1420 1286 * 1180 1210 1315 1110 1133 980 1156 845 *No brain weight was indicated in the autopsy records other than a comment: "Normal weight." METHODS Method ofPreparation The brains were fixed in 4% formaldehyde within 48 hours after death for no shorter than 2 and no longer than 4 weeks. The brains were then cut in 1 em thick slices and were dehydrated in solutionswith rising alcohol concentration. The slices were embedded in paraffinand sectioned at 6 urn. In the initial diagnostic procedure, prior to this study, one cerebellar section was prepared and analyzed for the original neuropathological investigation. This section was used for the PC quantification. Due to the large size of the PC, the 6 urnthickness was judged to be adequatefor the countingprocedure (6).The myelin staining Luxol Fast Blue (LFB) with counter staining Cresyl Violet (CV) proved to be the best for counting.Accordingto the previous diagnostic procedure, the cut brain slices had an angle as to include the inferior olivary nucleus and inferior vermis (nodulus, uvula) in the same section. In order to obtain homogenous localization, this was the sectionchosen in the present study. Measuringand Counting Procedures In the anterior-inferior vermis (nodulus and uvula), the PCs lie in an orderly row and could be identifiedeasily (see Figures 1 and 2). In the brain stem, inferior olive neurons on the slide were counted. This portion represented well the central part of the nucleus. To reduce the risk for bias (22), only numbersidentified the slides; thus, the individual cases remained unidentified during the counting.The histological slides were projected on a big round table via a microscope and a mirror attached to the ceiling. The prism and mirror were calibrated with an electronic water level before each counting in order to minimize the variation of magnification to a maximum of 1% between the part of the table with the highest versus the lowest magnification. Two persons performed repeated counts on test sections until identicalresults were obtained.All the measurements were Table2. ClinicalRecordsand Neuronal Densities Case No. Psychological/Mental Clinical Records and Katz Index of ADL Linear PC Density Vermis (Neurons/mm) Density Inferior Olive (Neurons/mrrr') 1 8.36 0.47 2 8.95 3 6.89 0.53 0.29 4 5.65 0.33 5 6 5.90 0.48 5.32 0.51 7 4.59 0.50 8 9 6.13 0.39 3.04 0.34 10 Well functioning: Verbal ability, memory, and learning ability not impaired. Katz Index: D 3.52 0.28 11 Mentally very clear. Katz Index: B 2.57 0.34 12 Mildly impaired word understanding, memory, and orientation ability. Katz Index: E 3.51 0.34 13 Good cognitive ability and verbal understanding but dysartria. Katz Index: E 1.47 0.32 14 Very well preserved, well functioning at home, good verbal ability and memory function. Katz Index: A 3.04 0.47 15 Very vital. Katz Index: F 2.98 0.30 CEREBEllAR NEURONAL LOSS IN AGING ., " .. : _. . - .' . . .. ... . .. '. . ·0-. .. . .. .. ~ ' .' .. I' ~ ~ . .... ..: .... .. I"; '" ..... ...... ... . .. .. . . ,. ~ '. v • ..; .. .. . . OJ :. . " . o.. ~ .. .... , .. ---~", .... , ~ .: . . 8365 .. . O' : .. .S _ .. .. ! . .. ; .. .. ... . ... . .. ,/ . .... Figure 1. Purkinje cell stretch in the vermis cerebelli of a normal 32-year-old female. LFB/CV staining, bar = 40 urn. Arrow indicates a Purkinje cell, M: molecular cell layer, G: granular cell layer . Note the orderly layered and high density of Pes, a total number of 14 Pes are seen. .. . - .. Figure 2. Purkinje cell stretch in the vermis cerebelli of a normall 02-ycar· old female . LFB/CV staining, bar = 40 Jlm. Arrow indicates a Purkinje cell. Note the relatively low number (total 6) of Pes. made by the same person and controlled at least once. The counts were performed on randomized slides, which were identified only after the counting. Counting Procedure-s-vermis PC layers were labeled and defined. The layers were then measured with a measuring tape on the table, and the corresponding neurons were counted. The length of the PC layer counted was 103 m. On the slide, this distance corresponded to 363 rom. Parameters of the cells to be counted were defined. These parameters were: (a) nucleus: appearance of a clearly visible nucleus; (b) size: PCs had to be significantly larger than the surrounding astrocytes, oligodendrocytes, and intemeurons; (c) site : PCs that were dislocated from the expected positionlline (i.e., more than 1/3 of the width of the molecular layer) were excluded (22); (d) color: cells had to be distinctively stained with the LFB/CV staining. The linear cell density was then calculated for each case as number of neurons per millimeter on the slide. Counting Procedure-Inferior Olivary Nucleus The neurons of the inferior olivary nucleus lie scattered along a broad serpentine (see Figure 3). The nucleus that was most easily identified and exhibited least artifacts was projected on the table at the same magnification as used for the vermis. A standardized square of 30 em' was constructed and placed at 10 different, nonoverlapping (23) locations along the olive, starting at its medial ventral part. The procedure was chosen to avoid double counting . Two series of quantification were performed and the mean was used to calculate the cell density defined as number of cells per square millimeter on the section. The neurons in the inferior olive were defined by the same criteria as the PC in vermis except for the criteria of site. Statistical Analysis Statistical analysis of the results was conducted using Abacus Statview 4.0 (Abacus Concepts) software package running on a Macintosh computer and Excel 7.0 (Microsoft Corporation) on a personal computer. The quantitative data were expressed as Figure 3. Th e infe rio r oli vary nucleu s of a normal 32-y ear·old female. LFB/CV staining, bar 500 urn. Note the serpentine-lik e shape of the inferior olive. = the mean, the standard deviation (SD), and the standard error of the mean (SEM). The difference in PC density between the centenarian and noncentenarian groups was evaluated with the Mann- Whitney U-test for level of significance. For evaluation of a possibly age-dependent PC decrease, a simple linear regression analysis was performed. This analysis was also used to study the relationship between the counts in the vermis and the inferior olivary nucleus. The relation and accuracy is presented as the R value, the R 2 value, and the p value. Statistical significance was set at p < .05 for all analyses. REsULTS The mean brain weight for the 15 cases in this study was 1216 g, SD = 164 and SEM = 44. The brain weight clearly correlated negatively with increasing age, R 2 = .56 and p = .002 (see Figure 4). In the vermis, the mean linear PC density was 4.79/mm, SD = 2.19 and SEM = 0.57. The density decreased with increasing age with R 2 =.82 and p < .001 (see Table 2 and Figures 5, 6, SJOBECK IT AL. B366 , 10 1600 1400 • 8 1200 :3 1000 ! 800 ~ 600 .5 '" ! • • -t P = .002 R=-.75 R'=.56 400 • 6 4 p < .OOI R = -.90 R'= .82 Cl Ii! 13 ....l 2 • 200 o. 0 0 10 20 30 40 50 60 70 80 90 100 110 0 10 20 30 40 Age (Years) Figure 4. Brain weights, and 7). In a comparison between the the centenarian group and noncentenarians, the mean PC density in the vermis of the former group was 6.09/mm (95% confidence interval 4.9-7.28), and of the latter 2.85/mm (95% confidence interval 2.24-3.46). The difference between the two groups was statistically significant with p < .005. In the inferior olivary nucleus, the mean neuronal density was 0.39 neurons/nun", SD = 0.090 and SEM = 0.023. The neuronal density in the inferior olivary nucleus showed a tendency to decline with increasing age, but this was not statistically significant (see Table 2 and Figure 8). The centenarians had a mean neuronal density of 0.34/mm 2 (95% confidence interval 0.29-0.39) and the noncentenarian group had a mean neuronal density of 0.43/mm 2 (95% confidence interval 0.37-0.49). The difference between the two groups was not statistically significant. The neuronal counts in the vermis and inferior olive showed a weak but not statistically significant correlation, when comparing the two locations with linear regression analysis. SO 60 70 80 90 100 110 Age (Years ) Figure 5. Linear density vermis. = Figure 6. Same case as in Figures I and 3, LFB/CV, bar 10 urn, Arrow indicates a Purkinje cell. Note the high density of PC compared to Figure 7. DISCUSSION This study shows that aging in neurologically healthy individuals affects the PC numbers in the vermis cerebelli neg atively. With another techniqu e using vertical/sagittal plane sections, it would have been possible to choose the vermal regions reported to be the mo st vulnerable in aging [i.e., the superior/dorsal part (3,6)]. However, vertical/sagittal sections were not available in the present study of cases previously examined with routine diagnostic horizontal plane sections. A decrease of neuronal numbers was nevertheless observed in the region s studied, a finding in line also with that of Torvik and colleagues (6). Thus, if anything, any other regions could be expected to have shown an even more pronounced PC decrease , had they been studied. The limited number of sections used in this study precluded a stereological analysis, which would have the advantage of higher numerical values and probably higher accuracy in quantitative groupwise comparison. However, the aim of this study was not to reach total neuronal numbers within the studied structures, but rather to evaluate cell numbers, density, and vitality in a defined limited area. Furthermore, a computerassisted stereometric technique was initially considered but rejected because of uncertainties in the computer's ability to assess neuronal identity and viability. The loss of neurons is statistically significant in the very old Figure 7. Same case as in Figure 2, LFB/CV, bar Purkinje cell. =10 urn. Arrow indicates a (laO years and older). A significant age-related loss of neurons was not observed in the inferior olive, which is consistent with other studies (24,25). These findings, although restricted to the limited number of cases, are corroborated by our personal , previously nonobje ctivized experience from histopathological ex- CEREBELLAR NEURONAL LOSS IN AGING 0.6 N e 0.5 ~ 0.4 r-----------------------, • ~ ~ • '~ 0.3 • 2; <; 0.2 p = .09 R = -.46 2 R = .21 ~ Z 0.1 _ ___,_,._ 60 70 OL-,._--.-......-+----~-+..,__.._ o 10 20 30 40 50 _+-.,....,.....~-+-....___1 80 90 100 110 Age (Years) Figure 8. Neuronal density inferior olive. B367 leagues (19) found visual impairment of some degree among 73% of the centenarians (n = 100). Since the cerebellum together with the vestibular and visual systems are essential for regulation of equilibrium and control of muscles that are used to maintain balance (29), it is possible that the reduced PC number could be connected to the increased number of falls seen among elderly persons (30). Comparing PC numbers and Katz index for rough evaluation of general motor function, there is some concordance, although not complete. This evaluation must be considered with caution because the cases are few. Furthermore, the presence of impaired vision and/or status after hip fracture within this group may hamper motor abilities unevenly, something that prevents a more detailed evaluation in this respect. ACKNOWLEDGMENTS amination on cases dying at very old age. As a contrast case, not within this study, dying from committing suicide and concomitant hypoxia showed a brain weight of 1695 g, histopathological oedema, and venous stasis. Altogether, these changes resulted in the impression of very low vermal PC density. As shown in the 15 cases of this study, the reported cerebellar neuronal loss was seen in aging individuals without any underlying neurological disease that could explain the observation. The reduced neuronal number could thus be a part of the normal aging process with an accentuation in late stages of life. In favor of this explanation is the finding that the mean brain weight correlated negatively with increasing age (p = .002), which is in accordance with many other reports (1,26). The age-related shrinkage and atrophy of the cerebellum generally leads to tissue condensation and, hence, reduces the impression of neuronal loss, which consequently may be underestimated. We did not attempt to correlate these findings with neuronal cell counts in other brain regions, for which the different reports on age-related cell loss diverge (2,10,12,27). We may conclude, however, that cell loss in the vermis cerebelli proportionally was at least of the same magnitude as that reported for other regions-and probably larger. Hypothetically, decline of the neuronal population seen in the vermis cerebelli/ inferior olivary system may relate to the mild impairment of motor functioning that can be seen with increasing, especially very old age. The underlying mechanism of this cell loss may, at least in part, relate to reduced oxygen supply. With increasing age, the heart and lung function is often reduced, whereas the blood vessels become more sclerotic and, hence, have impaired motility and permeability. Through hardening, blood vessels lose compliance and capacity to meet physiological fluctuations in blood pressure levels. Impaired function of the heart, lungs, and cerebral vessels may lead to a reduced cerebral blood flow. The PCs, especially of the vermis, have a relatively high metabolic demand, are sensitive to variations of perfusion, and are therefore injured early (3). They may also be susceptible to mild changes in metabolic supply and reduced energy production [e.g., through mitochondrial DNA mutations (28)]. Furthermore, neuronal loss in other parts of the central nervous system, which projects to the vermis, could cause a PC loss by deafferentation. In this study, 5 of the 6 centenarians had visual impairment, which through reduced input from the inferior colliculus to the cerebellum could lead to a PC reduction. In The Swedish Centenarian Study, Samuelsson and col- This study was supported by the Lund University Medical Faculty and The Foundation of Konsul Thure Carlssons Minne. The authors wish to thank the Gerontology Research Centre, Lund, Sweden, for kindly providing material from the Centenarian Project. Address correspondence to Elisabet Englund, Department of Pathology and Cytology, University Hospital, S-221 85 Lund, Sweden. E-mail: [email protected] REFERENCES 1. Tomlinson BE, Blessed G, Roth M. Observations on the brains of non-demented old people. J Neurol Sci. 1968;7:331-356. 2. Coleman PD, Flood DG. Neuron numbers and dendritic extent in normal aging and Alzheimer's disease. Neurobiol Aging. 1987;8:521-545. 3. Raz N, Torres D, Spencer WD, White K, Acker JD. Age-related regional differences in cerebellar vermis observed in vivo. Arch Neurol. 1992; 49(4):412--416. 4. Pathy MSJ. Neurological signs in old age. In: Brocklehurst JC, Talls RC, Fillit HM, ed. Textbook of Geriatric Medicine and Gerontology. New York: Churchill Livingstone; 1992:302-306. 5. Ellis RS. A preliminary quantitative study of the purkinje cells in normal, subnormal and senescent human cerebella with some notes on functional organisation. J Comp Neurol. 1919;30:229-252. 6. Torvik AS, Torp S, Lindboe CF. Atrophy of the cerebellar vermis in ageing. A morphometric and histologic study. J Neurol Sci. 1986;76:283-294. 7. Brun A, Gustafson L, Samuelson SM, Ericsson C. Neuropathology of late life. 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A standardized measure of biological and psychosocial function. JAMA (Chicago a) 1963;185:914-919 21. Karhunen PJ, Erkinjuntti T, Laippala P. Moderate alcohol consumption and loss of cerebellar Purkinje cells. BMJ. 1994;308:1663-1667. 22. Ritvo ER, Freeman BJ, Scheibel AL, et al. Lower purkinje cell counts in the cerebella of four autistic subjects. Am J Psychiatry. 1986;143(7): 862-866. 23. Mlonyeni M. The number of purkinje cells and inferior olivary neurones in the cat. J CompNeural. 1973;147(1):1-10. 24. Monagle RD, Brody H. The effects of age upon the main nucleus of the inferior olive in the human. J CompNeural. 1974;155(l):61~. 25. Pesce C, Provera P, Dessanti P, Provaggi MA. Densitometric analysis of the nerve cell population of the inferior olive in aging. Acta Neuropathol Berl. 1990;80(1)95-97. ( \ • • 26. Dekaban AS, Sadowsky D. Changes in brain weights during the span of human life: relation of brain weights to body heights and body weights. Ann Neural. 1978;4:345-356. 27. Anderson 1MB, Hubbard BM, Coghill GR, Slidders VV.The effect of advanced old age on the neurone content of the cerebral cortex. Observations with an automatic image analyser point counting method. J NeuralSci. 1983;58(2):235-246. 28. Wallace DC. Mitochondrial DNA in aging and disease. Sci Am. 1997; 8:22-29. 29. Ghez C. The cerebellum. In: Kandel ER, Schwartz JH, Jessell TM, ed. Principles of Neural Science. 3rd ed. East Norwalk, CT: Appleton and Lange; 1991:626-647. 30. Overstal1 PW, Exton-Smith AN, Imms FJ, Johnson AL. Falls in the elderly related to postural imbalance. Br Med J. 1977;29(1):261-264. ReceivedSeptember15,1998 AcceptedFebruary 23, 1999 •• Advanta~e of GSA's Advertisin~ Opportunities Take Trying to find the best gerontologist to fill a position at your institution? Or to attract the best and brightest to your gerontology program? 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