Effects of Aging on
Cerebral Circulation and
Metabolism in Man

by Darab K. Dastur, Mark H. Lane,
Douglas B. Hansen, Seymour S. Kety,
Robert N. Butler, Seymour Perlin, and
Louis Sokoloff
Effects of Aging on

CHAPTER 6

Cerebral Circulation and

Metabolism in Man

The commonly expressed idea that “man
is as old as his arteries” reflects the widely
accepted view that the state of the circula-
tory system plays a major role in the patho-
genesis of human aging. Since many of
the more prominent clinical features of old
age are attributable to changes in the central
nervous system, considerable attention has
been directed in the last few years to the
circulation and gross metabolism of the aged
human brain. Most studies have indicated
a decline in cerebral blood flow and meta-
bolic rate, and a rise in cerebrovascular
resistance with advancing age (Fazekas,
Alman, and Bessman, 1952; Fazekas, Kleh,
and Finnerty, 1955; Fazekas, Kleh, and
Witkin, 1953; Scheinberg, Blackburn, Rich,
and Saslaw, 1953; Schieve and Wilson,
1953); several have failed to confirm such
age-dependent changes (Gordan, 1956;
Shenkin, Novak, Goluboff, Soffe, and Bor-
tin, 1953); and Shenkin and his coworkers
have concluded that there are no significant
alterations in cerebral circulation and me-
tabolism in old age except in the presence of
both hypertension and arteriosclerosis. In
a recent critical and comprehensive review
of the subject, Kety (1956) has interpreted
the available evidence as indicating rapid
decreases in overall cerebral blood flow and
oxygen consumption during childhood and

669795—63——-6

adolescence, and more gradual but nonethe-
less progressive declines in these functions
in the remaining lifespan.

Several pertinent questions appeared,
however, to remain unanswered. In his
review Kety (1956) attempted, as far as
possible, to exclude from consideration all
studies performed on patients with a diag-
nosis of hypertension, arterioclerosis, or
senile psychosis. ‘The remaining series were
composed almost entirely of hospitalized
patients; they included, therefore, a variety
of diseases even if they were of a type
deemed unlikely to alter cerebral circulation
and metabolism. As he himself pointed
out, studies on such patients represented
“only an approximation of the normal aging
process.” Furthermore, vascular disease
such as arteriosclerosis, which is known to
impair the cerebral circulation (Fazekas,
Kleh, and Finnerty, 1955; Shenkin, Novak,
Goluboff, Soffe, and Bortin, 1953; Schieve
and Wilson, 1953), is so frequently and
often so subtly intertwined with the aging
process that it is doubtful if it can be suc-
cessfully excluded without the exercise of the
most stringent criteria for its detection and
rejection. There is little evidence to indi-
cate that adequately rigorous measures to
exclude less than clinically obvious arterio-
sclerosis were employed in any of the

59
previously cited studies. The possibility
remained, therefore, that their results re-
flected more the effects of vascular or other
types of diseases commonly associated with
aging rather than the effects of chronologi-
cal or physiological age per se.

The objectives of the present study were
several. First, it was hoped to ascertain
clearly and conclusively whether reductions
in cerebral blood flow and metabolic rate
were inevitable accompaniments of the ag-
ing process and occurred in the absence of
any detectable cardiovascular or other dis-
eases so often present in the aged. In the
event that such changes did indeed occur,
evidence was sought which might indicate
whether the primary defect was cerebral
circulatory insufficiency with secondary
neuronal damage and reduced cerebral
metabolic rate or, contrariwise, primary
neuronal or metabolic impairment followed
by secondary diminution in blood flow in
response to the reduced metabolic demand.
Finally, in view of the rare opportunity af-
forded by the broad multidisciplinary na-
ture of this project, possible correlates of
cerebral circulatory and metabolic functions
in the aged were sought in their clinical
state, electroencephalographic patterns, cog-
nitive, perceptual, and behavioral functions,
psychiatric signs and symptoms, and socio-
logical status and performance. The re-
sults of the latter investigations are reported
elsewhere in this volume.

METHODS

Subject Material

In order to isolate the effects of aging per
se from those of other common age-asso-
ciated variables on the cerebral circulatory
and metabolic functions studied, a highly
selected group of normal male subjects over
65 years of age were chosen for these in-
vestigations. A detailed description of the

60

group and the exact criteria for acceptance
or rejection are presented in chapters 2 and
3. Two stages of selection were carried out,
a careful preliminary screening in the field
and then a thorough, rigorous series of ex-
aminations and evaluations after admission
to the National Institutes of Health. Fifty-
four subjects met the criteria of the prelimi-
nary selection and were admitted for study.
Of these, only 27 fulfilled the exacting re-
quirements of the second-stage evaluations
for consideration as noninstitutionalized,
normal elderly men as free of any apparent
disease as possible, and functioning normal-
ly in their communities (group I). Twenty
subjects were found to be suffering from
minimal subclinical or asymptomatic dis-
eases of various types, mainly vascular, and,
therefore, did not meet the standards of
group I. However, since their medical
status was at least equal to and probably
better than that of average men of similar
age, they were included in the study as a
separate group (group II). Seven of the
admitted subjects were found to be suffer-
ing from serious or advanced diseases which,
it was felt, might themselves influence the
results of the experimental studies; they
were, therefore, excluded from either of the
preceding groups (group III).

Cerebral circulatory and metabolic
studies were successfully accomplished in 26
of the 27 subjects in group I, 17 of the 20
subjects in group IT, and 4 of the 7 sub-
jects in group III. Except for mean
arterial blood pressure, none of the data
obtained in these studies played any part
in the evaluation and classification of the
subjects into their respective groups. The
normal range of mean arterial blood pres-
sure was defined as the mean value + three
standard deviations (8423) obtained dur-
ing similar cerebral circulatory and meta-
bolic studies performed simultaneously on
a group of 15 normal young subjects for
the purpose of obtaining comparative data.
On the basis of this definition, 5 elderly
subjects (Subjects Nos. 8, 18, 28, 33, and
35), who fulfilled all the clinical require-
ments for inclusion in group I, were found
to be hypertensive at the time of the cerebral
blood flow determinations and were, there-
fore, relegated to group IJ. In addition
to the previously described groups of elderly
men and normal young subjects, a series
of 10 patients suffering from chronic brain
syndrome with psychosis were admitted
from St. Elizabeths Hospital (Washington,
D.C.) and Spring Grove Hospital (Catons-
ville, Md.), and studied in a similar fashion
in order to investigate further the relation-
ship between this clinical condition
and cerebral circulatory and  meta-
bolic functions.

Procedures

Cerebral blood flow (CBF) was deter-
mined by the nitrous oxide method as de-
scribed by Kety and Schmidt (1948), ex-
cept that the measurement period was
extended to 15 minutes to allow more time
for equilibration between brain tissue and
cerebral venous blood. Mean arterial blood
pressure (MABP) was measured directly
in the femoral artery by means of an air-
damped mercury manometer adjusted to
the level of the carotid artery; mean in-
ternal jugular venous blood pressure
(MJVP) was measured directly in the in-
ternal jugular vein by means of a Statham
strain gauge (Model No. P23B) and Brush
Universal Analyser (Model No. BL-320)
and oscillograph (Model No. BL~202).

Blood oxygen and carbon dioxide con-
tents were determined by the manometric
method of Van Slyke and Neill (1924), but
blood oxygen saturation was measured di-
rectly by the Triton X—100 spectrophoto-
metric technique (Deibler, Holmes,
Campbell, and Gans, 1959). Blood pH

was measured anaerobically at ambient
temperature with a MacInnes-Belcher glass
electrode and Cambridge potentiometer
(Model R), and was then corrected to its
value at 37° C by means of the factors of
Rosenthal (1948). The Nelson-Somogyi
method (Nelson, 1944) was employed for
the determination of blood glucose concen-
tration, and arterial hemoglobin concentra-
tion was determined by conversion to
cyanmethemoglobin and photometric meas-
urement (Evelyn and Malloy, 1938).

The following functions were computed
from the directly measured variables de-
scribed above. Cerebral oxygen consump-
tion (CMRoz) and glucose utilization
(CMRe) were calculated as the products
of the CBF and the arteriovenous oxygen
({A-V]oz) and glucose ([A-V]c) differ-
ences, respectively. The O2/glucose ratio
(Oza) was determined from the molar
values of (A-V)O2z and (A-V)c, and the
cerebral respiratory quotient (R.Q.) was
obtained by division of (A—V)oz into the
cerebral arteriovenous carbon dioxide dif-
ference. Cerebral vascular resistance, the
ratio of cerebral blood pressure gradient to
blood flow, was calculated as the ratio
of the MABP-MJVP difference to the CBF.
Blood carbon dioxide tension (pCOz) was
determined by means of the nomogram of
Van Slyke and Sendroy (1928), and the
nomogram. based on the data of Dill (Na-
tional Research Council, 1944) was em-
ployed for the determination of the
internal jugular venous oxygen tension

Results

In tables 1a and 1b are presented the
individual data obtained in the normal el-
derly men (group I) ; these include not only
the values of the cerebral circulatory and
metabolic functions but also of a variety of
blood constituents known to influence these

61
69

TasLe 1a—Cerebral circulation, metabolism, and related functions in normal elderly men

 

 

 

 

 

 

— ~ on
&o bo nl se * ~~ : :
o oO a g
g f ge |F. |e | ge] » | ee] g |S 18a | és;
. E g = gS | < Ez; 8 Eg as | re
Subject No. ~ ~ r: ES oO ee. o we " go bbs opt
BS | SB | rE LSE Sa | g8 | s | GF] 5 | SS | BSal Bos
ge om Pon 8 eg LBS Ss i 3S e os sad! sag
< = = o 5 x GS x 5 5 ° 4 4
26 NORMAL ELDERLY MEN
Lecce cece eee 69 97 6 43 2.1 6.61] 2.9 7.4 3.2] 1.03 7.21 53 33
Qeevvee cece eee. 79 89 7 75 1.2 5.29} 4.0 6.8 5.1 £95 6.2] 43 34
Bee eeee scenes. 66 94 3 72 1.3 5.41) 3.9 7.3 5.3 96 5.9] 51 33
Bole ee eee ee, 69 89 5 56 1.5 7.00 | 3.9 8.5 4.8 .78 6.6] 50 33
Ooo eve cece ees 72 89 9 56 1.4 5.56, 3.1 6.8 3.8 97 6.6] 52 33
Toc cvcecceevees 67 101 8 58 1.6 5.56 | 3.2 9.8 5.7 95 4.6 | 47 35
Dieeceeee cena 67 104 4 50 2.0 6.25 | 3.1 6.5 3.2 99 7.7| 52 38
rr 70 81 3 51 1.5 6.26 | 3.2 6.3 3.2] 1.00 8.0} 52 37
Tere, 69 88 6 70 1.2 4.81 | 3.4 8.1 5.7 85 4.8] 48 39
eevee, 75 98 5 63 1.5 4.91 | 3.1 5.7 3.6} 1.04 6.9 |e clee cca
i re 71 95 9 75 1.1 5.25} 3.9 6.2 4.7} 1.02 6.8] 56 40
Doe, 70 101 4 48 2.0 6.50} 3.1 9.2 4.4] 1.01 5.71 53 37
QW. ceee cee 73 94 17 46 1.7 7.25 | 3.3 8.4 3.9 94 6.9] 53 34
WGoveecce ees, 76 104 4 51 2.0 6.30 | 3.2 8.4 4.3 .79 6.0} 50 34
80... c cele, 73 86 4 66 1.3 5.09} 3.4 8.0 5.3 .81 5.21 49 43
BO... cee eee. 69 103 |... cee 61 |........ 5.52 | 3.3 6.8 4.1 . 86 6.5] 49 37
AT eee, 65 79 6 73 1.0 5.78 | 4.2 |... lessees L944, 57 37
49 ee. 72 96 7 73 1.2 4.261 3.1 5.8 4,3 85 5.9) 45 35
50.00. ee 72 99 6 52 1.8 5.87 | 3.1 8.7 4.6 . 87 5.5] 53 36
Ble eee 71 96 12 66 1.3 6.14] 4.0 11.0 7.2 90 4.51 57 38
BB eee 81 91 4 42 21 7.19] 3.0 15.5 6.5 89 3.71 58 34
BAL ee, 72 93 5 50 1.8 6.76 | 3.4 10.0 5.0 97 5.0] 49 32
55. 65 86 5 56 1.5 4.98 | 2.8 6.1 3.4 . 83 6.5] 41 40
56... eee 69 93 10 52 1.6 6.36) 3.3 |rccceeecheeee aes 682 foo... ee. 52 36
5B eee. 71 90 5 57 1.5 4.58| 2.6 |........ 00.0... 684]... 0, 55 37
59. eee 74 96 6 42 2.2 7.49 | 3.1 10.3 4.3 .81 5.9 | 54 33
Mean.......... *71.0 | *93.2 6.4] 57.9] *1.58] 5.88] 3.33 3.2] *4.6 91 6.0] 51.2 35.9
On +.8| -+1.3 +.6] +£2.1] 4.07} 4.17] +.08] 4.5 +.2{ +.02] 4.2; +.8 +.6
15 NORMAL YOUNG SUBJECTS
Mean.......... 20.8 | 84.2 7.1 62. 1 1.29] 5.70] 3.51 9.3 6.0} 0.92 5.5] 51.9 37.5
S.E..cc. cece. +.4] £19] 4.5] 42.9] +.06] +£.30] +.21 &.8{ +.7{ £.02; +#.5] 41.5] +£1.5

 

 

 

 

 

 

 

 

 

 

 

 

 

 

* Significantly different from normal young subjects at the 0.05 level.
69

Taste 1b.—Blood constituents in normal elderly men

 

 

 

 

 

 

 

 

 

 

 

 

Art. Blood O; Content {Blood CO, Content} Blood Glucose Blood CO, Ten- Blood OQ, Satu-
Hemoglobin (Vol. %) (Vol. %) Concentration Blood pH sion (mm. Hg.) ration (in
Subject No. | Concen- (mg. %) percentage)
tration
(grams 7%) :
Arterial | Int. Jug. | Arterial | Int. Jug. | Arterial | Int. Jug. | Arterial Int. Jug. | Arterial | Int. Jug. | Arterial | Int. Jug.
26 NORMAL ELDERLY MEN
; rn 16.04 | 19.92) 13.31 | 48.40] 55.20 91.8 84.4 7. 42 7.35 41 53 97.0 60. 1
Deveecceneeee 13.78 | 17.38 | 12.09 | 47.91 | 52.94 94.9 88.7 7.43 7.41 38 43 95.8 64.5
Bivcececeeeee 13.49 | 16.78 | 11.37 | 49.64 | 54.86 86.8 79.5 7. 41 7. 33 41 51 90. 8 59.3
Boece eee eee 15.09 |} 18.93} 11.93 | 47.52] 53.01 | 106.0 97.5 7. 39 7.35 42, 50 92.5 58. 6
Govrec eee eeee 13.28 | 16.76] 11.20] 50.13 | 55.47 87.8 81.0 7.38 7, 34 44 52 93. 8 59.6
Tivscncce eens 14.56 | 18.65] 13.09 | 49.22 | 54.49 89.9 80.1 7. 41 7.39 41 47 98.3 66. 6
Doce eens 14.35 | 18.56 | 12.31 | 44.87 | 51.04 96.5 90.0 7. 38 7. 31 40 52 97.2 65.7
| 14.68 | 19.10} 12.84] 45.32) 51.58 96.9 90. 6 7. 41 7.31 38 52 97.9 64. 1
14.......005 14.27] 18.17} 13.36] 51.79} 55.89 99.7 91.6 7. 43 7.40 42 48 97.5 72. 2
Tb. c cece eeeee 14.68 | 17.94} 13.03] 50.11 4 55.23 83.5 TTB lice eee elec seen fee eee ele erences 96.1 68. 4
16......0006. 13.12 | 17.36 | 12.11 | 53.08 | 58. 44 83. 3 77.1 7. 36 7. 34 49 56 98.1 69.7
19,... eee ee 14.27 | 18.66} 12.16 | 45.38} 51.93 87.4 78. 2 7. 36 7. 30 42 53 98. 6 63.8
20.......000. 13.98 | 18.64} 11.39 | 46.33 | 53.15 84.8 76.4 7.39 7. 32 41 53 97.1 59.4
2G... cece eeee 13.20 | 17.28} 10.98 | 50.03 | 55.01 92.9 84.5 7. 40 7. 36 42 50 96.7 61.8
BOL. cece eee 12.46 | 16.35 | 11.26 | 52.20 | 56.34 74.0 66.0 7. 41 7.37 42 49 99.0 74. 6
a 14.89 | 18.67] 13.15 | 48.91 | 53.68 85.3 78.5 7.37 7. 36 45 49 98.9 66. 3
AT ccc cee 11.94 | 15.85 | 10.07} 52.58 | 58.00 ]........J.....--- 7. 36 7.31 47 57 98. 6 63.6
AD. cee 14.35 | 17.53 | 13.27] 50.99 | 54, 63 77.3 71.5 7. 46 7.41 39 45 91.8 66.0
BO... eee eee 14.07 | 17.93 | 12.06 | 51.78 | 56.89 85.9 77.2)... e eee 7.33 |i cee eee 53 97.6 64, 2
5live cece eee 13,28 | 17.36 { 11.12] 51.10 | 56. 62 75. 6 64. 6 7.35 7. 30 49 57 99.0 66. 1
BB. ee eee 14.27 | 18.21] 11.02 | 50.21 | 56.60 97.4 81.9 7. 32 7. 31 52 58 97.5 58.9
D4. eee 13.98 | 18.23 | 11.47] 48.88 | 55,41 82.9 72.9 7. 43 7.37 39 49 98. 8 60. 0
BB. e eee 16.04 | 20.70} 15.72 | 45.38 | 49.53 82.7 76.6 7. 44 7. 42 37 41 98.5 74.0
5G. . cece 14.68 | 18.63 | 12.27 | 48.26 | 53.46 |........]...eeee- 7. 38 7. 33 43 52 96. 6 63. 2
BB. eee eee 11.94 | 15.12 } 10.54 | 53.26 | 57.12 |.......-[eeee eee 7.35 7.31 48 55 95.8 63.8
): 13.49 | 17.72 | 10.23} 49.43 | 55.48 81.0 70.7 7. 38 7. 32 43 54 99.4 57.8
Mean........ 14.01 | 17.94] 12.05 | 49.34] 54.69 88.0 ; * 79.9 7. 39 7.35 42.7 51.1 96.9 64.3
S.E.......66. +.20| 4.24] +.24] 4.48] 4.43] 41.7) 21.7] 4.01] +.01] 4.8 .9 +.5 +.9
15 NORMAL YOUNG SUBJECTS

Mean........ 13.87 | 18.241 12.52) 48.12] 53.38 83.2 73.8 7. 39 7. 33 42. 4 51.9 98.9 63.1
S.E.......e. 4.36) +.42/ +£.46] 4.56] 4.57] 43.3] 41.1] 4.02] 4.01 +1.6] 41.5 +.3 2.3

 

 

 

 

 

 

 

 

 

 

 

 

 

 

* Significantly different from normal young subjects at the 0.05 level.
functions. The mean values and standard
errors obtained in similar measurements in
the group of normal young subjects are in-
cluded for comparison. It is immediately
apparent that, despite an age difference of
five decades, there is a striking paucity of
statistically significant differences between
the two groups. Significant increases in
both mean arterial blood pressure
(MABP) and cerebral vascular resistance
{CVR) were observed in the aged group,
suggesting that vascular changes are so
closely associated with aging that they can-
not be avoided even by the stringent selec-
tion process employed in these studies.
Similarly, the slight but significant decrease
in arterial Oz saturation probably indicates
some pulmonary changes with age. Cere-
bral blood flow (CBF) and oxygen con-
sumption (CMRoz) in both groups were
well within the ranges generally observed in
normal young people (Sokoloff, 1960), and
although they were slightly lower in the
elderly than in the young, the differences
were far from being statistically significant.
On the other hand, cerebral glucose utiliza-
tion (CMRe) in the aged was significantly
reduced (p, approximately 0.05), and in
association with the discrepancy between
the changes in CMRoz and CMRe, the
oxygen:glucose ratio (Ozc) was corre-
spondingly though not significantly in-
creased; the possible implications of these
findings will be discussed below. No other
distinguishing features were observed.

The results of the same studies in the
elderly men with asymptomatic or subclini-
cal disease (group II) are summarized in
tables 2a and 2b. Since the criteria for
selection and classification relegated to this
group all those subjects who were rejected
from group I only because of an elevated
blood pressure at the time of the cerebral
flow studies, it is, of course, not surprising
that the MABP of group II was markedly

64

higher than observed in either the young
or normal elderly groups. In line with the
generally observed relationship between ar-
terial blood pressure and cerebral vascular
resistance (Lassen, 1959), CVR was also
elevated, but the rise in CVR in this group
was disproportionately greater than that of
the MABP, resulting in a statistically signifi-
cant 16-percent fall in CBF below the level
of the normal young subjects and a 10-per-
cent decline, just short of statistical signifi-
ance, below that of group I. CMRo:, how-
ever, was negligibly lower than that of group
I and not significantly different from that of
the normal young group. As might be ex-
pected from a fall in blood flow without a
proportionate decrease in oxygen consump-
tion, there were tendencies though not quite
statistically significant, for the (A-V)os to
widen and the internal jugular venous pOz,
which probably reflects the O; tension of the
brain tissues, to fall. Cerebral glucose utili-
zation (CMRc) was similar to that of group
I and significantly lower than that of the
normal young subjects. In all other re-
spects, group I was similar to the normal
elderly and normal young subjects.
Evidence of vascular disease was by far
the most common cause of assignment of
subjects to the group II category. In order
to assess better the influence of such disease
on the cerebral circulation and metabolism
of the aged, subjects in group II so diag-
nosed were classified into several smaller
but homogeneous subgroups based on the
nature of their vascular disease. These sub-
groups included: (1) normal hypertensives,
who manifested elevated mean arterial
blood pressure (above 107 mm Hg) (see
“Methods”), but no noteworthy evidence
of arteriosclerosis; (2) normotensive arterio-
sclerotics, who showed clear evidence of
arteriosclerosis but no hypertension; and
(3) hypertensive arteriosclerotics who, of
69

TasLe 2a.—Cerebral circulation, metabolism, and related functions in elderly men with miscellaneous asymptomatic disease

 

 

= |8 4 s y |e |g é
e |e |e | | | eel e || 2 |S, |88 jes
Subject No. = s eg. | 8. 3 a a we 3 ES tS" oe
oe we ~'s Sa] oa 2 > we A aot Age | age
, | Sf | 22 | ab |SPE) 78 | SS | 7 | SS | 8 | Se | gem | vos
< = = 5 5 s 5 s S 5 o 4 5
Boece eeeeee ees 71 112 11 40 2.5 9.58 | 3.8 1.4] 4.6 .931 68] 48 24
10.0 -ssceee eee 92 114 4 46 24 | 5.69] 2.6 8.0 3. 6 83 5.7] 51 39
Wve 73 106 14 44 2.4 5.98 | 2.6 11.7 5.1 199{ 411 56 33
1Bl oe 66 111 10 50 20 | 6.98} 3.5 10.4 5.2| 1.06| 4.0] 52 33
25.0. eevee eee 74 112 7 65 1.6 5.46 | 3.6 6.3 4.1} 1.05 7.0{ 50 36
2B... ieee 73 170 11 69 2.3 | 4.87] 3.4 7.8 5.4] .93] 5.0] 56 42
9. vv veveeee eee 77 116 5 49 23 | 6.33| 3.4 f.ccceeeedeeeeeee 1.02 }........ 52 37
Bloc svc 72 117 5 62 18 | 4.92] 3.1 7.1 44] .98/ 5.6] 52 36
cy ree 76 127 9 43 2.8 5.62} 2.4 7.0 3.0 (941 6.4] 51 37
33.0 ces 72 132 7 51 2.4 | 6.57] 3.4 9.5 4.8 85 5.6} 50 37
B50 ieee 7 | 116 |... 67 |... eee 6.09 | 4.4 12.2 8. 2 81 40] 49 34
3B. eee 7 | 104 |........ 440 fn, 5.66 | 2.5 9.6 4.2{ 1.00] 4.7] 44 35
cre 68 90 7 62 1.3 | 6.42| 4.0 6.6 4.4 91 7.8| 46 33
Moo. 65 80 8 61 12 | 5.62] 3.4 4.5 2.7 88} 10.0] 51 37
42. ees 68 96 7 49 1.8 | 5.65) 2.8 10.6 52] .95) 43| 52 37
52. eee 69 91 5 34 2.5 | 10.68] 3.6 19.7 6.7 (96) 44] 40 24
BT oo cscs eee 74 90 8 49 1.7 5.89 | 2.9 |...eeee feeeee ee 186 |... cee 57 35
Mean.......... «72.8 41110.8| 7.9 | #521 [#1205] 6.35] 3.22] 9.5] *4.8 94} 5.7] 50.4] 34.7
SE... sce e. 415| 45.0] 4.7] £25] £.12] £.37] £.13] 4.9] 4.4] +.02] 4.4] 41.0] 41.1

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1 Significantly different from normal elderly men (group I) at the 0.05 level.
* Significantly different from normal young subjects at the 0.05 level.
99

TABLE 2b.—Blood constituents in elderly men with miscellaneous asymptomatic disease

 

Blood CO, Ten-

Blood O, Satu-

 

 

 

 

 

Art. Blood O, Content |Blood CO, Content} Blood Glucose
Hemoglobin (Vol. %) (Vol. %) Concentration Blood pH sion (mm. Hg.) _ Tation
Subject No. | Concen- (mg. %) (in percentage)
tration
(grams %)

Arterial | Int. Jug. | Arterial | Int. Jug. | Arterial | Int. Jug. | Arterial | Int. Jug. | Arterial | Int. Jug. | Arterial | Int. Jug.
Boo ee. 13.86 | 18.14 8.56 | 45.49 | 54.38 90. 4 79.0 7.47 7. 38 34 48 98.8 44.4
10........... 13, 49 17.78 | 12.09 | 47.11 51. 81 84. 2 76.2 7. 34 7.31 45 51 96.9 67.2
ee 13. 98 18.19 12, 21 51.71 57. 62 94.8 83.1 7.41 7.33 42 56 96.2 58.9
1B... 14. 56 19. 10 12.12 | 46.72 | 54.09 90. 7 80. 3 7.35 7. 33 44 52 98. 6 60. 5
25... eee, 13. 37 17.74 | 12.28 | 49.28 55. 02 81.0 74.7 7.39 7.36 43 50 97.9 65.9
28... cea 14. 27 18.64 | 13.77 | 53.91 58. 44 76. 6 68.8 7.37 7. 34 49 56 98.5 73.2
Vn 15. 71 19.91 13.58 | 47.13 | 53.58 |........f........ 7. 38 7.34 43 52 97.6 66. 6
5 ee 13.12 16. 59 11.67 |] 51.80] 56. 63 83.2 76.1 7. 40 7. 36 44 52 98, 2 66.0
B32. eee 13. 57 17, 87 12.25 | 49.79 | 55.05 77.6 70. 6 7.39 7.35 44 51 99.7 66. 1
i 15. 71 20. 75 14, 18 44.59 50.16 82.9 73.4 7. 38 7. 32 41 50 99.5 64. 8
B53. eee 13.12 17.10 11.01 50. 88 55.81 90. 4 78.2 7.41 7. 38 41 49 96. 8 62.9
38.......004. 15. 30 18. 90 13. 24 48. 31 53.97 82. 6 73.0 7.42 7. 36 40 44 95.0 64.0
39... ee 14. 89 18. 64 12, 22 46. 44 52. 39 151.0 144.4 7. 44 7.39 37 46 94.7 63.1
41e... ee. 14.15 18. 05 12. 43 49.97 54. 87 100. 0 95.5 7. 44 7.35 40 51 96.7 65.7
42.0. ee 13. 98 18.22 | 12.57 | 50.06] 55.44 85.5 74.9 7.41 7.35 41 52 98.2 65.9
BQ. eee 15.63 | 20.76 10.08 | 41.29) 51.53 84.4 64.7 7.52 7. 45 28 40 100. 0 45.5
BT ceca ee 13. 86 17. 08 11.19 | 50.24] 55.32 ).......0,..00.... 7.35 7. 30 47 57 95.2 59.8
Mean........ 14. 27 18.44 | 12.09 | 48.51 54. 48 90. 4 80. 9 7. 40 7.35 41.4 50.4 | * 97.6 62.4
S.E.......... +. 22 +. 29 +. 33 2.75 +. 52 +4.6 +4.9 +.01 +.01 +1.2 +1.0 +.4 +1.8

 

 

 

 

 

 

 

 

 

 

 

* Significantly different from normal young subjects at the 0.05 level.
course, manifested both conditions. These
subgroups included 14 of the 17 subjects
studied in group II; in addition, one subject
(No. 17), who had been rejected altogether
because of moderately severe arteriosclerosis,
was added for the purposes of this analysis
to the normotensive arteriosclerotic sub-
group. The results obtained in these indi-
viduals are presented in tables 3a and 3b,
as well as the means and standard errors
of the normal young subjects, normal elderly
subjects, and the patients suffering from
chronic brain syndrome, which are included
for comparison. Despite the limited size
of the subgroups, it is clear that it was the
arteriosclerotic subjects who were chiefly
responsible for the finding of a significant re-
duction in the CBF of group IT. Except for
the expected higher values for MABP and
CVR and a significant increase in the arteri-
ovenous glucose difference, the results in the
normal hypertensive subjects were essen-
tially the same as in the normal young and
normal elderly groups. On the other hand,
the arteriosclerotic subjects, both hyperten-
sive and normotensive, revealed significant,
indeed considerable, reductions in CBF
which could account for almost all of the
decrease observed in group II as a whole
(table 2a). One of the normotensive ar-
teriosclerotic subjects (No. 32) obviously
hyperventilated at the time of the study,
and it was probably his contribution which
was mainly responsible for the significant
reductions in the mean values for arterial
pCO: and cerebral venous pOz observed in
this subgroup; although in this one subject
the hyperventilation undoubtedly contrib-
uted to cerebral vascoconstriction and re-
duced cerebral blood flow, it does not ac-
count for the low mean cerebral blood flow
of the subgroup as a whole, which remains
significantly reduced even when he is ex-
cluded from the data. Although there were

no statistically significant changes in cere-
bral oxygen consumption and glucose utili-
zation in the subgroups with vascular dis-
ease, CMRoz tended to be substantially
lower in the arteriosclerotic subjects and
might, perhaps, have been found to be sig-
nificantly so had the series been larger. In
general, all the vascular disease subgroups
tended to have increased arteriovenous oxy-
gen and glucose differences, and the internal
jugular venous pOz tended to fall progres-
sively in going from the normal young group
through the normal elderly and hyperten-
sive groups, and finally, to the arterioscler-
otic subjects.

In the patients with chronic brain syn-
drome and psychosis, there was unequivocal
evidence of disturbances in both cerebral
circulation and metabolism. Cerebral cir-
culatory functions were essentially the same
as in the arteriosclerotic subgroups of group
II, but there were in addition marked re-
ductions in cerebral oxygen consumption
and glucose utilization. Internal jugular
venous pO: was statistically significantly be-
low that of the normal young and normal
elderly subjects, but the arteriovenous oxy-
gen and glucose differences were similar to
those of the normal subjects and consider-
ably less than those of the subjects with
vascular disease. ‘The combination of a
low CBF, low CMRo, and normal
(A-V) oz fails to distinguish between the
possibilities of a reduced cerebral oxygen
supply or a reduced cerebral oxygen
demand in the pathogenesis of these
changes; however, the additional finding
of a low cerebral venous pOz suggests an
anoxia of the cerebral tissues and a defi-
ciency in supply relative to demand which
in these patients was undoubtedly aggra-
vated by a significant reduction in their
arterial Oz saturation, presumably second-
ary to pulmonary dysfunction.

67
89

TaBie 3a.—Comparison of cerebral circulatory and metabolic functions in various categories of elderly men and normal young subjects

 

 

 

 

 

 

 

 

 

 

 

 

— ~ can
86 & a x - ~ ; .
° ~~ Y g a
E fe jay (© | ie! = | ve | & |e iff |e:
g = gs <3 & | 84 fe Se [7S _#
Subject No. a = ey fs Oo Os o os s Eg tes be
ae S| <8 | ese] Ss s | F j}#s | 8 |  |F5B | age
, | 22 | oP | se |SEE) TS | SS] F | SS |] zB of | sar | LS
< a a 0 6 <= S = |S 0 6 5 5
NORMAL YOUNG (15 SUBJECTS)
Mean.......... 84, 7A 1.29] 5.70} 3.51] 9.3 0.92] 5, 51.9
S.E..... 0.0... “ef. £.5 £.06} +.30] 4.21] +.8 #02) 4.5] 41.
NORMAL ELDERLY MEN (26 SUBJECTS)
Mean.......... # 93, 7.1 *1.58| 5.88] 3.33] 8.2 6f .1] 6. 51.
SE... £1. £15 £4.07} £17} £.08] £55 12} 4:02] +. e
NORMAL HYPERTENSIVES (5 SUBJECTS)
Boece cee, 112 25 | 9.58] 3.8 | a4] 46] .93f 68] 48
18.00, 111 20 | 698] 3.5 | 104] 5.2] 106} 40] 52
2B... 170 23 | 4.87| 3.4 7.8} 5.4] 193] 5.0] 56
BB. eee 132 2.4 6. 57 3.4 9.5 4.8 .85 5.6 50
35.0.0. 16 fo...) 67 J, 6.09] 41 | 122] 82] ‘81| 40] 49
Mean.......... #1128, *12.30] 6.82} 3.64] 1103] 5.6] .92] 5.1] 51.
SE... +11. 4.41] 4.77] 4.14] 4:8} 4:7] 4104] 4:5] 41.
NORMOTENSIVE ARTERIOSCLEROTICS (6 SUBJECTS)
Wee 106 1 21 | 5.98] 26 | 114.7 .99 56
Woo 83 13 | 6.66] 3.9 9.9 197 43
38.0 oll. 104 f.. | 48 fo, 5.66} 2.5 9.6 ‘00 44
39.0 ee, 90 13 | 6.421 40 6.6 ‘91 46
52... es, 91 25 | 10.68] 3.6 | 19.7 96 40
7 rrr 90 17 | 5.89} 29 fo... ‘86 57
Mean.......... *94.0 *1.78| 6.88] 3.25} 111.5 £95 47.7
SE... £3.7 +.23} 4:77} £.27] 42:2 02 +2.9

 

 

 

 

 

 

 

 

 

 

 

 

 

 
HYPERTENSIVE ARTERIOSCLEROTICS (4 SUBJECTS)

 

eee eee es 74 112 it 40 2.5 9. 58 3.8 11.4 4.6 » 93 6.8 48 24
eee ee 77 116 5 49 2.3 6. 33 Bead [eee cece dee ee eees 1.02 ]........ 52 37
eee eee 72 117 5 62 1.8 4, 92 3.1 7.1 4.4 98 5.6 52 36
eee eens 76 127 9 43 2.8 5. 62 2. 4 7.0 3.0 94 6.4 51 37
Mean.......... * 74,8 |*1118.0 7.5 | * 48.5 | * 2.35 6. 61 3.10 8.5 4.0 .97 6.3 50. 8 33.
1 Oa 1.1 43.2 #1.5 44.9 a&.21 | £1.03 +. 29 41.5 +.5 . 02 +.4 +.9 +3.

 

CHRONIC BRAIN SYNDROME WITH PSYCHOSIS (i0 PATIENTS)

 

Mean.........- *71.8 |*1101.7

tres

*148.5 |*12. 41 5.69 |*12.72 7.06 | *

6.2 6 94 7 50.5 | *133.
ho Oa 41.8 +6, 2 +.3 +3.8 +. 25 +. 23 +. 18 +. 87 6

. 5
+. 02 +.8 41.0 +1.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

69

1 Significantly different from normal elderly men (group 1) at the 0.05 level.
* Significantly different from normal young subjects at the 0.05 level.
OL

TaBLe 3b.—Comparison of blood constituents in various categories of elderly men

 

 

 

 

 

 

 

 

 

 

 

Art. Blood O; Content |Blood CO, Content] Blood Glucose Blood CO, Ten- Blood O, Satu-
Hemoglobin (Vol. %) (Vol. %) Concentration Blood pH sion (mm. Hg.) ration (%)
Subject No. | Concen- (mg. %)
tration
(grams %) .
Arterial | Int. Jug. | Arterial | Int. Jug. | Arterial | Int. Jug. | Arterial | Int. Jug. | Arterial | Int. Jug. | Arterial | Int. Jug.
NORMAL YOUNG (15 SUBJECTS)

Mean........ 13. 87 18. 24 12. 52 48.12 53. 38 83.2 73.8 7.39 7. 33 42.4 51.9 98.9 63.1
S.E...... 6... ok. 36 +. 42 +. 46 +.56 +.57 +£3.3 #1.1 +. 02 +. 01 +1.6 #1.5 +.3 #£2.3
NORMAL ELDERLY MEN (26 SUBJECTS)

Mean........ 14. 01 17. 94 12. 05 49. 34 54. 69 88.0 | * 79,9 7.39 7.35 42.7 51.1 | * 96.9 64. 3
S.E.......... +. 20 +. 24 2. 24 +. 48 +. 43 +1.7 +1.7 +. 01 +.01 +.8 +.9 +.5 +.9
NORMAL HYPERTENSIVES (5 SUBJECTS)

a 13. 86 18. 14 8.56 45. 49 54, 38 90. 4 79.0 7.47 7. 38 34 48 98. 8 44.4
18........0.. 14. 56 19.10 12.12 46.72 54. 09 90.7 80. 3 7.35 7. 33 44 52 98. 6 60. 5
28.0... 060. 14. 27 18. 64 13.77 53.91 58. 44 76. 6 68. 8 7,37 7. 34 49 56 98.5 73.2
1 15.71 20. 75 14. 18 44.59 50. 16 82.9 73.4 7, 38 7.32 41 50 99.5 64.8
B35... eee 13.12 17.10 11. 01 50. 88 55. 81 90. 4 78,2 7.41 7. 38 41 49 96.8 62.9
Mean........ 14. 30 18. 75 11. 93 48. 32 54. 58 86. 2 75.9 7,40 7.35 41.8 51.0 98. 4 61.2
S.E........0. a. 43 2%.60 | £1.02 | 41.76 | 41.35 #2. 8 42.1 +. 02 +.01 +#2.4 +£1.4 +. 4 4.7
NORMOTENSIVE ARTERIOSCLEROTICS (6 SUBJECTS)

11... ee... 13. 98 18. 19 12. 21 51.71 57. 62 94. 8 83.1 7.41 7. 33 42 56 96. 2 58.9
17..... 6. ee. 15. 71 20. 14 13. 48 42. 37 48. 80 85. 2 75.3 7. 40 7. 33 37 43 94.4 63.0
38... eee eee 15. 30 18.90 13.24 | 48.31 53. 97 82. 6 73.0 7.42 7.36 40 44 95.0 64.0
39... eee ee 14. 89 18. 64 12. 22 46. 44 52. 39 151.0 144. 4 7.44 7.39 37 46 94.7 63.1
by 15. 63 20. 76 10. 08 41.29 51. 53 84. 4 64.7 7.52 7. 45 28 40 100. 0 45.5
BT ices ee ceeee 13. 86 17. 08 11.19 50. 24 oo a 7 a 7.35 7.30 47 57 95. 2 59. 8
Mean........ 114,90 18. 95 12.07 | 1 46. 73 53. 27 99. 6 88. 1 7.42 7.36 | 138.5 49.3 | * 95.9 159.1
rr +. 33 a. 54 #.52 | #1.72 | £1.26 | 413.0) 414.4 a+. 02 +.02 +2.6 +2. 5 +.9 +2. 8

 

 

 

 

 

 

 

 

 

 

 

 

 

 
IZ

HYPERTENSIVE ARTERIOSCLEROTICS (4 SUBJECTS)

 

 

 

V1 13. 37 17.74 | 12.28 | 49.28 55. 02 81.0 74,7 7.39 7. 36 43 50 97.9 65.9
29... cae 15.71 19. 91 13.58 | 47.13 | 53.58 [........]..-..06- 7. 38 7. 34 43 52 97.6 66.6
31... 6. eee. 13.12 16.59 | 11.67 51.80 | 56.63 83.2 76.1 7. 40 7. 36 44 52 98. 2 66.0
BZ... eee ees 13. 57 17. 87 12.25 | 49.79 | 55.05 77.6 70. 6 7.39 7.35 44 51 99.7 66.1
Mean........ 13. 94 18. 03 12.45 | 49.50 | 55. 07 80. 6 73.8 7.39 7.35 43. 51. 98. 4 66. 2
S.E...... 6... +. 60 +. 69 +. 40 +. 96 +. 62 +1.6 1.7 +. 00 +.01 +. ck. +.5 +.2
CHRONIC BRAIN SYNDROME (10 PATIENTS)
Mean........ 13. 81 17.54 | 11.86 | 48.02 | 53.38 | *92.1 | * 85.1 7. 38 7. 34 42. 50. *#194,7 159.4
S.B.. cee +. 41 +. 32 +. 35 +. 87 +. 89 +#2.1 1.9 +.01 +.01 a. #1. +.9 #1.9

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1 Significantly different from normal elderly men (group I) at the 0.05 level.
* Significantly different from normal young subjects at the 0.05 level.
DISCUSSION

To a great extent, the results almost speak
for themselves. Despite a 50-year difference
in age, cerebral blood flow and oxygen con-
sumption in normal elderly men (group 1)
were essentially the same as in normal young
subjects. The slight declines that were ob-
served in the aged, 7 percent in CBF and
3 percent in CMRoz, may lead some to
speculate concerning their possible meaning-
fulness. It must be emphasized, however,
that these were statistically insignificant
changes in series of rather appreciable size.
Furthermore, even if these changes could be
construed to reflect something more than
random variation, it would, in view of our
findings in the arteriosclerotic subjects, most
likely be the impossibility of completely rul-
ing out the variable of arteriosclerosis from
a presumably healthy aged population.

On the other hand, these results do not
refute the previous evidence (Kety, 1956)
that these functions usually decrease in the
aged. The subjects comprising our group
of normal elderly men were highly selected
according to rigorous criteria and could
hardly be considered representative of the
aged population at large; they were, as re-
gards relative freedom from vascular and
other diseases, far superior. Group II, the
subjects with asymptomatic or subclinical
disease, were probably more representative
of their age group, and, indeed, in this group
CBF was significantly reduced, and CMRo>
tended to be lower though still not statisti-
cally significantly. The possibility may be
entertained that our normal old men in
group I may, because they were so select,
have suffered declines in CBF and CMRoz
from initially higher than average values
which could have been detected only by
longitudinal studies. However, the basis of
their selection was general freedom from
disease, and since there is no evidence to in-

72

dicate that high values for CBF and CMRoz
tend to promote general good health, it
would indeed be fortuitous if such were the
case. It is, therefore, difficult on the basis
of our results to avoid the conclusions that
blood flow and oxygen consumption of the
cerebral tissues during adulthood is not a
function of chronological age, and that the
decreases in these functions so often observed
in the elderly are not directly attributable
to the process of aging per se but rather to
some frequent accompaniment of old age.
The possible nature of this deteriorative
concomitant of old age is suggested by the
results obtained in the group of elderly men
with asymptomatic or subclinical disease
(group II). This group differed from the
normal elderly only in that they exhibited
evidence of mild subclinical disease, gen-
erally vascular, when subjected to an exact-
ing clinical examination; yet in contrast to
the normal elderly men, their CBF was sig-
nificantly reduced below that of the young
subjects. On further examination of the
subgroups with vascular disease (table 3a),
it is clear that this reduction was not asso-
ciated with hypertension, but could be ac-
counted for entirely by the findings in the
subjects with arteriosclerosis. In the sub-
jects with hypertension alone, CBF and
CMRo: were like those of the normal young
and elderly subjects. On the other hand,
in the arteriosclerotic patients, both normo-
tensive and hypertensive, CBF was signif-
icantly reduced by about 16-20 percent,
and CMRo: also tended to be lower though
not statistically significantly so in this small
series. Furthermore, in all of the subjects
with vascular disease there was a tendency
for the arteriovenous oxygen difference to
increase and the internal jugular venous
pO: to fall. The latter change was par-
ticularly pronounced and statistically sig-
nificant in the normotensive arteriosclerotic
subjects; inasmuch as this function reflects
the oxygen tension of the cerebral tissues,
the observed changes suggest cerebral ische-
mia and anoxia in the arteriosclerotic group.
It would appear then from these results that
it is arteriosclerosis which is responsible for
the decline in cerebral blood flow in the
aged; secondarily there is an anoxia of the
cerebral tissues and ultimately a fall in oxy-
gen consumption which, although not sta-
tistically significant in these studies, has
frequently been observed by others (Faze-
kas, Alman, and Bessman, 1952; Fazekas,
Kleh, and Finnerty, 1955; Fazekas, Kleh,
and Witkin, 1953; Heyman, Patterson,
Duke, and Battey, 1953; Kety, 1956; Las-
sen, Feinberg, and Lane, 1960), Schieve
and Wilson, 1953. We are, therefore, es-
sentially in agreement with Shenkin and his
coworkers (Shenkin, Novak, Goluboff,
Soffe, and Bortin, 1953) who concluded
that cerebral blood flow and metabolism are
impaired in the aged only in the presence of
both hypertension and arteriosclerosis; our
results also implicate vascular disease but
suggest that it is arteriosclerosis alone which
is responsible. They are, however, at vari-
ance with the recent findings in a small
group of normal aged men by Lassen and
his coworkers (Lassen, Feinberg, and Lane,
1960) of a slight but significant reduc-
tion in GMRoz without any comparable
impairment of CBF.

Cerebral blood flow in the patients with
chronic brain syndrome and psychosis was
reduced, but no more so than in the arterio-
sclerotic subjects. However, in the former
group cerebral Oz consumption was mark-
edly depressed below the levels found in any
of the other groups, resulting in the restora-
tion of a more or less normal proportion of
oxygen utilization to supply. Similar re-
sults have been reported by Freyhan and his
associates (Freyhan, Woodford, and Kety,
1951). Such a situation could have re-
sulted from a primary decrease in metabolic

rate, except that in this series the cerebral
venous pO: was also significantly reduced,
suggesting a primary circulatory deficit, tis-
sue anoxia, and secondary reduction in
metabolic rate. It is conceivable that the
changes observed in our chronic brain syn-
drome patients merely reflect the ultimate
consequences of those occurring in arterio-
sclerosis, that after a prolonged period of
cerebral ischemia and hypoxia the cerebral
tissues lose their ability to utilize or extract
from the blood the quantities of oxygen nec-
essary to maintain normal metabolic proc-
esses and mental function. There may,
perhaps, even be an acceleration in the loss
of neuronal elements reported to occur in
the cortex in association with aging (Brody,
1955).

The significance of the differences in
cerebral glucose utilization observed in sev-
eral of the groups of elderly men is difficult
to evaluate. Usually glucose and oxygen
are consumed by the brain in almost
stoichiometric amounts (Kety, 1957; Soko-
loff, 1960). In these studies, however,
CMRe was significantly reduced in both
the normal elderly men and in the subjects
with asymptomatic or subclinical disease,
while the CMRo: in both groups was only
negligibly altered. In the subgroups with
vascular disease, there did appear to be a
correlation between the two metabolic
rates; the hypertensive arteriosclerotics
showed the greatest reductions in both, al-
though only the change in CMRa was
Statistically significant. In the chronic
brain syndrome series also, both CMRoz
and CMRe were significantly and almost
proportionately reduced. It may be that
CMRe is a more sensitive indicator of cere-
bral metabolic rate than CMRoz, but this
would indeed be surprising, for blood glu-
cose determinations in our laboratory, and
probably in most others, are far less ac-
curate or reliable than blood oxygen

73
measurements. On the other hand, it is not
inconceivable that there are with aging
subtle changes in cerebral metabolism which
result in a lowering of glucose utilization
before a reduction in CMRoz becomes ap-
parent. Normally there is slightly more
glucose utilized by the brain than can be
accounted for by the oxygen consumption,
assuming complete oxidation of glucose
(Kety, 1957; Sokoloff, 1960). The fate
of this excess glucose is at present uncer-
tain. Himwich and Himwich (1946) have
accounted for it by the cerebral pyruvate
and lactate production, but others have
failed to confirm this (Kety, 1957). It is
likely that some of this glucose and its de-
rivatives are incorporated into the complex
chemical constituents constantly being re-
synthesized by the brain (Geiger, 1958).
In any case, there may be, in the aged,
alterations in these aspects of cerebral car-
bohydrate metabolism which would not be
reflected in cerebral oxygen consumption,
but until there is confirmation of our find-
ings and additional experimental evidence,
further speculation would be unjustified.

As in most studies of this type, our data
were obtained by means of the nitrous oxide
method, and, therefore, apply only to a
representative fraction of the brain as a
whole rather than to the total brain. They
are completely independent of changes in
brain weight, but are more relevant to the
events occurring within the tissues of the
brain. The question of the total quantity
of brain tissue or the amount of functioning
tissue in the aged brain is an entirely
different problem.

The absence of any significant changes in
cerebral blood flow and oxygen consump-
tion in the normal elderly men (group I)
should not be construed as evidence that
there are no age changes in the central
nervous system in the absence of disease.
The fact that such changes do occur is

74

demonstrated by the findings of alterations
in their cognitive and perceptual functions
(chs. 8 and 9) and electroencephalographic
activity (ch. 7). It suggests rather that
these functions may be more sensitive indi-
cators of the aging phenomenon in the brain
or that they involve processes too subtle to
be reflected in the gross blood flow and
metabolic rate of the brain as a whole. On
the other hand, when vascular disease is
present and leads to reductions in cerebral
blood flow and oxygen tension, as it did in
the arteriosclerotic patients, then it becomes
the pacemaker of the aging process in the
brain and results in more rapid deterioration
of these other functions (chs. 7, 8, and 9).

SUMMARY

1. Studies of cerebral circulation and me-
tabolism revealed no significant differences
in cerebral blood flow and oxygen consump-
tion between a group of normal young sub-
jects (mean age, 20.8 years) and a group
of highly selected normal elderly men (mean
age, 70.0 years) who were functioning effec-
tively in their communities and were as free
of evidence of disease, including vascular
disease, as was possible to obtain in their
age group.

2. In a similar group of elderly men dif-
fering from the previous one only in that
they exhibited clear evidence of mild asymp-
tomatic or subclinical disease, chiefly vascu-
lar, there was a statistically significant de-
cline in cerebral bloow flow of 10-16 per-
cent. Cerebral oxygen consumption also
tended to be lower but not statistically sig-
nificantly.

3. All of the reductions in cerebral blood
flow and oxygen consumption in the group
of elderly men with asymptomatic disease
could be accounted for by the results ob-
tained in the arteriosclerotic subjects. Hy-
pertensives without arteriorsclerosis were
normal with regard to these functions.
4, The cerebral arteriovenous oxygen dif-
ference tended to be increased and the
cerebral venous oxygen tension tended to fall
in all the categories of vascular disease, par-
ticularly the arteriorsclerotic groups. These
changes, though not quite statistically sig-
nificant probably because of the small size
of the individual categories, were pro-
nounced and were, therefore, interpreted as
evidence of relative cerebral circulatory in-
sufficiency and hypoxia.

5. Although cerebral oxygen consump-
tion was not decreased, there was a consider-
able and statistically significant fall in cere-
bral glucose utilization in the normal elderly
subjects. The possible implications of this
discrepancy between the two metabolic rates
are discussed.

6. In patients with chronic brain syn-
drome and psychosis, cerebral blood flow
was markedly reduced, but no more so than
in the arteriosclerotic subjects. However, in
contrast to the arteriosclerotics, cerebral oxy-
gen and glucose utilization was proportion-
ately depressed so that the arteriovenous
differences were within normal limits. Cer-
ebral venous pO: remained low, however,
indicating relative cerebral anoxia.

7. It is suggested that decreases in cere-
bral blood flow and oxygen consumption are
not the consequences of chronological aging
per se, but rather of arteriosclerosis which
causes first a relative cerebral circulatory in-
sufficiency and anoxia and then ultimately
a secondary reduction in cerebral metabolic
rate.

ACKNOWLEDGMENTS

The authors wish to express their appre-
ciation to Mrs. Mary S. Holmes, Mrs.
Gladys E. Deibler, and Miss Phyllis L.
Campbell for their outstanding technical
assistance in the experimental procedures;
to Dr. Samuel Greenhouse and Mr. Don-
ald F. Morrison, for the statistical analyses;

and to Miss Carol L. Talley for the prepara-
tion of the tables.

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Evetyn, K. A., and Matioy, H. T. 1938. Micro-
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Fazexas, J. F., ALMAN, R. W., and Bessman, A.N.
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; , and Wrrxin, L. 1953. Cerebral
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