Download Neuronal Loss in the Brainstem and Cerebellum

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
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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.
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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
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20
30
40
50
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90
100
110
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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]
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ReceivedSeptember15,1998
AcceptedFebruary 23, 1999
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