Acta Neuropathol (Berl) (1986) 71:332-337
Heuropatholog,ca
The nucleus basalis of Meynert
in multi-infarct (vascular) dementia*
D. M.A. Mann, P.O. Yates, and B. Marcyniuk
Department of Pathology, The University, Manchester M13 9PT, Great Britain
Summary. The number and nucleolar volume o f nerve
cells within the nucleus basalis of Meynert were
estimated in 10 patients with Alzheimer's disease, 12
with multi-infarct dementia, 9 with a mixed Alzhei-
mer/multi-infarct dementia and in 10 age-matched
controls. As reported previously in Alzheimer's dis-
ease, both the number and nucleolar volume of
surviving cells was reduced, whereas in multi-infarct
dementia no significant change in either measure was
noted. In patients with Alzheimer's disease/multi-in-
farct dementia the loss of nerve cells and reduction in
nucleolar volume varied greatly in severity from
patient to patient according to the relative balance
of Alzheimer and vascular type pathological changes
present within each patient.
Key words: Nucleus basalis - Multi-infarct dementia
Degeneration of the nucleus basalis of Meynert (nbM)
has been recently reported to occur in various neuro-
logical illnesses in which dementia is present, including
Alzheimer's disease (Whitehouse et al. 1982; Rossor
et al. 1982; Perry et al. 1985; Candy et al. 1983; Nagai
et al. 1983; Tagliavini and Pilleri 1983; Wilcock et al.
1983; Arendt et al. 1983; Mann et al. 1984a, b;
McGeer et al. 1984; Rogers et al. 1985), Parkinson's
disease (Candy et al. 1983; Mann and Yates 1983;
Whitehouse et al. 1983; Arendt et al. 1983; Gaspar and
Gray 1984; N a k a n o and Hirano 1984; Perry et al.
1985; Rogers et al. 1985), Down's syndrome (Price et
al. 1982; M a n n et al. 1984b, 1985c; Casanova et al.
1985), Parkinson dementia of G u a m (Nakano and
Hirano 1983), progressive supranuclear palsy
Offprint requests to: D. M. A. Mann (address see above)
* Supported in part by a grant from the North Western Regional
Health Authority to one of us (BM)
Acta
9 Springer-Verlag1986
(Tagliavini et al. 1984; Rogers et al. 1985), Pick's dis-
ease (Uhl et al. 1983; Rogers et al. 1985), boxer's
encephalopathy (Uhl et al. 1982), Korsakoft's
psychosis (Arendt et al. 1983), olivopontocerebellar
atrophy (Tagliavini and Pilleri 1985) and Creutzfeldt-
Jakob disease (Rogers et al. 1985). N o such degener-
ation apparently occurs in Huntington's chorea
(Arendt et al. 1983; Clark et al. 1983; Tagliavini and
Pilleri 1983). To our knowledge, the nbM has not been
examined in multi-infarct (vascular) dementia. In this
study, therefore, we have counted the number of nerve
cells in the nbM and measured their nucleolar volume,
in patients with multi-infarct dementia alone. We have
compared these data with findings from patients with
Alzheimer's disease alone and patients with a
combined multi-infarct Alzheimer type dementia.
Materials and methods
Brains were obtained at postmortem from 31 moderately to
severelydemented patients and these were subdivided, according
to standard pathological criteria, into three groups:
1. Twelve patients (mean age 78.3 _+2.0 years) dying with
dementia associated with cerebrovascular disease (Table 1). In
all these cases substantial areas of cerebral cortex (usually within
frontal, temporal or occipital lobes and sometimes including
hippocampus) or basal ganglia, or both, had been destroyed
by gross infarction or by micro-infarctions, or by both, either
recently or more distantly, or occasionally both. In all these
patients Alzheimer-type changes (senile plaques and
neurofibrillary tangles) within surviving areas of cortex and
hippocampus were either absent or minimal. In none of this
group was the nbM itself damaged by infarction. These 12
patients were classed as having multi-infarct (vascular)
dementia.
2. Ten patients (mean age 79.1 +_2.0 years) dying with
Alzheimer's disease. In these cases numerous senile plaques and
neurofibrillary tangles were present within cerebral cortex and
hippocampus; there was no evidence of cerebral infarction or
serious cerebrovascular disease in these patients.
3. Nine patients (mean age 83.8 +_1.2 years) dying with a
pathological picture typical of Alzheimer's disease (see above)
combined with substantial amounts of cerebral infarction
D. M. A. Mann et al. : Nucleus basalis in multi-infarct dementia 333

Table 1. Selected pathological details of 31 demented and 10 non-demented patients

Patient Age Brain Infarctions Rating of Rating of Rating of

(years)/ weight (gross and microscopic") vascular cortical tangles in
sex (g) disease b plaques nucleus
and tangles b basalis b

Diagnostic group: Multi-infarct dementia

1 65 M 1,548 L parietal, L superior temporal, +++ + 0
L precentral, L mid frontal
2 65 M 1,280 R frontal, R calcarine, R hippocampus, +++ + 0
L and R parietal, basal ganglia ~ and
cortex a
3 76M 1,375 L temporal, basal ganglia a and cortex" ++ 0 0
4 78 F 1,230 R frontoparietal, L parietal, cerebellum +++ + 0
(white)
5 78 F 1,270 L parietal ++ 0 0
6 79 M 1,450 R occipital, basal ganglia" and cortex a ++ + 0
7 79M 1,145 L and R temporal, R occipital, R frontal +++ + +
8 80M 1,120 L calcarine, R occipital, R thalamic +++ 0 0
9 83 F 1,244 L parietal, basal ganglia" and cortex" ++ + +
10 84F 1,230 L occipital, L post-central, L parietal, +++ + 0
L internal capsule
11 84F 1,030 R occipital, R hippocampus, ++ + 0
R thalamus, L caudate,
L internal capsule, basal ganglia"
12 88F 1,110 L hippocampus, basal ganglia" and ++ ++ +
cortex"
Mixed dementia
13 78 F 1,275 R parietal, L parietal, R globus +++ ++ +
pallidum, R internal capsule,
R caudate, basal ganglia" and cortex"
14 80F 1,050 Basal ganglia" and cortex a + +++ ++
15 83 F 1,050 L insular, L claustrum, posterior corpus +++ ++§ +++
callosum
16 84F 1,170 Basal ganglia" and cortex a + +++ +
17 84F 1,140 R calcarine, R hippocampus, +++ +++ +++
R temporal, R amygdala, L putamen,
L internal capsule, basal ganglia a
18 85F 1,240 R frontal, R temporal, basal ganglia" +++ ++ 0
and cortex a
19 85F 1,100 R cingulate ++ +++ +++
20 87F 1,130 R temporal, R hippocampus, +++ ++ 0
R occipital, R calcarine, R thalamus,
basal ganglia a
21 89F 1,020 L and R temporal, basal ganglia a and +++ ++ ++
cortex a
Alzheimer's disease
2 2 - 31 68 - 88 950- Minimal or no change in cortex" and 0 to + ++ to q-+ to
8F, 2 M 1,365 basal ganglia" +++ +++
Control
32-41 6 5 - 90 1,260- Minimal or no change in cortex" and 0to + 0to+ 0to +
7F, 3M 1,485 basal ganglia"

" Microscopic infarctions

b Key to rating: Vascular disease: 0 = absence of gross or microscopic damage, + = microscopic damage in cerebral cortex or basal
ganglia or both, + + = single gross infarction with or without microscopic damage, + + + = multiple gross infarctions with or
without microscopic damage. Corticalplaques and tangles: 0 = absent, + = few ( < 1/mmZ), + + = moderate (1 - 10/mm2), + + + =
numerous ( > 10/ram2). Tangles in nucleus basalis: 0 = absent, + = < 5 per section, + + = 5 - 1 0 per section, + + + = > 10 per
section
334 D . M . A . Mann et al.: Nucleus basalis in multi-infarct dementia

(Table 1). Such patients were considered to show a "mixed" Table 2. Individual mean values of number and nucleolar volume
Alzheimer/multi-infarct type of dementia. of nerve ceils in nucleus basalis of Meynert for 12 patients
Brains were also obtained from a further ten patients (mean with multi-infarct dementia and 9 with mixed (multi-infarct/
age 80.0 +_2.5 years) dying without obvious neurological or Alzheimer's disease) dementia. Also given are overall mean
psychiatric illness (Table 1). In these patients either no or (___SEM) values for these 2 groups and for age-matched
minimal Alzheimer-type changes were present in cerebral cortex Alzheimer's disease and mentally able control groups
and hippocampus or minimal amounts of infarction were present
in cortex or basal ganglia. These patients were aged controls. Patients Nerve cell number Nucleolar volume
For each patient, blocks from topographically defined areas (per section) (gm 3)
of middle temporal gyrus and nbM and where appropriate on
the side relevant to the maximal tissue damage (see Mann et al. Multi-infarct dementia
1984a, b, 1985a) were cut from the formalin-fixed brain tissue. 1 396 39.1
From these paraffin sections were prepared at 5 p.m and 16 Bin 2 372 28.0
thickness and stained with conventional neuropathological tech- 3 275 28.6
niques including a modified Palmgren stain for neurofibrillary 4 265 24.2
tangles (Cross t982) or with Azure B (16 I~m sections of nbM 5 288 30.4
only) for RNA (Shea 1970). The number of nucleolated nerve 6 304 31.7
cells in nbM was counted and volume of nucleolus measured as 7 306 31.4
we have described previously (Mann et al. 1984 a,b). The density 8 344 31.4
of senile plaques and neurofibrillary tangles within temporal 9 304 33.9
cortex were estimated, also as described previously (Mann et al. 10 243 22.8
1985 a). The number of neurofibrillary tangle containing cells 11 262 20.3
per section within nbM was counted directly under the 12 296 33.9
microscope. For each case, these changes were rated semi-
quantitatively according to the observed value (see Table 1) as Mean 304.6 +_ 13.2 29.4 +_ 1.5
was the extent of tissue damage resulting from vascular lesions
(see Table 1). Mixed dementia
13 198 22.2
14 93 18.8
Results 15 226 18.5
16 283 37.8
Cytological observations 17 88 16.4
18 277 19.8
The cytological changes seen in neurones of the nbM 19 127 30.7
in aged persons and in patients with Alzheimer's dis- 20 284 38.6
ease have been fully described by us elsewhere (Mann 21 121 19.2
et al. 1984a, b) and need not, therefore, be further Mean 188.6 + 27.6*** 24.7 ___2.9*
documented in this report. The nbM in all 12 patients
with multi-infarct dementia resembled that of the Alzheimer's Disease
controls (see Mann et al. 1984a, b) with most cells 22--31 157.2 + 14.0"** 22.2 _+ 1.3"**
appearing histologically normal; only occasional
atrophied cells and others containing neurofibrillary Controls
32-41 313.7 + 10.6 30.4 _+0.8
tangles were present. In the nine patients with mixed
Alzheimer/vascular dementia, a variable pathological *'*** Significantly different from mean control value
picture was seen. Some patients showed a pathology P < 0.05 < 0.001, respectively
akin to Alzheimer's disease alone with marked cell
loss, atrophy and neurofibrillary degeneration,
whereas in others a picture closely resembling multi- nucleolar volume (Table 2), although some individual
infact dementia alone was seen, with preservation of patients showed lower values than expected for age
nbM and few, if any, neurofibrillary tangles. alone for either cell number (patient 10) or nucleolar
volume (patients 10 and 11).
A much more variable picture was seen in patients
Quantitative findings with mixed Alzheimer/vascular dementia. On average
As we and other workers have found previously (see both cell number (P < 0.001) and nucleolar volume
introduction) the number and nucleolar volume of (P < 0.05) were reduced (Table 2) although the range
nerve cells in the ten patients with Alzheimer's disease of values obtained was wide. In general, patients
alone were greatly reduced (P<0.001), when scoring high on tangle counts, but usually low on
compared with age-matched control patients vascular damage (i.e., patients 14, 15, 17, 19 and 21)
(Table 2). By contrast those patients with multi-infarct had cell counts and nucleolar volume measures closer
dementia alone (patients 1 - 1 2 ) showed, on average, to the purely Alzheimer's disease group mean values
no significant changes in either cell number or (Fig. 1, Tables 2 and 3), whereas patients scoring low
D. M. A. Mann et al. : Nucleus basalis in multi-infarct dementia 335

Discussion
r 300- [] r]
I,LI
,,n
0
0 8 o The results of this study show that neurones of the
nbM are generally undamaged in patients with a
z purely multi-infarct (vascular) type of dementia. Such
,,-I
200- 0 o findings are consistent with those in our previous re-
,,-I
I/,,I ports (Mann et al. 1982, 1985 b) showing that neurones
r of another ascending subcortical projection system,
m
> 100- the locus caeruleus, are also undamaged in multi-in-
farct dementia. We have also reported here, that in
Z patients with a mixed Alzheimer/multi-infarct
dementia, the extent of damage to nbM reflects largely
O,
the relative balance of the separate pathologies within
I&l
this condition. Hence, patients tending towards a pre-
..I
dominantly vascular defect show little (if any) damage
0 40- o o O to nbM (consistent with that seen in purely vascular
>
9 []
dementia) whereas those tending towards a pre-
n,-
< E] 9 dominantly Alzheimer's disease defect show changes
0
20-
more consistent with that condition. This pattern was
0
W
i o o 1,, e also seen in a study of the locus caeruleus in mixed
-J
0 Alzheimer/vascular dementia (Mann et al. 1985b)
Z where, although cell number and nucleolar volume in
0 I I I I I I l I the mixed dementia group did not differ overall from
0 + ++ 4"1-+ 0 + 4+ +++ mean values in the Alzheimer's disease group, patients
13, 16, 18 and 20 of this study, with predominantly
"'PATHOLOGICAL SCORE'" vascular damage, showed higher mean values for cell
number (41.3 cells per section) and nucleolar volume
VASCULAR SP/NFT (62.8 ~tm3) than were seen in patients 14, 15, 17 and
21, with predominantly Alzheimer type pathology (cell
Fig. 1. Graphs of nerve cell number and nucleolar volume
plotted against rating of vascular disease or senile plaque (SP)/ number 22.8 cells per section; nucleolar volume
neurofibrillary tangle (NFT) formation for nine patients with 51.0 gm 3) (Mann, previously unpublished data).
mixed multi-infarct/Alzheimer type dementia. Those patients Similarly in Huntington's chorea both nbM
scoring high on SP/NFT formation are indicated (O), those (Arendt et al. 1983; Clark et al. 1983; Tagliavini and
low on SP/NFT formation (O). Alzheirner group mean values
indicated (11) and multi-infarct group mean values indicated Pilleri 1983; Mann, unpublished data) and locus
([]) caeruleus (Mann, unpublished data) are preserved.
Together, these findings in multi-infarct dementia and
Huntington's chorea indicate that the presence of a
dementia need not always be associated with damage
Table 3. Mean values (+__SEM) of number and nucleolar volume
of nerve cells in nucleus basalis of Meynert in nine patients with to ascending cholinergic or noradrenergic pathways,
mixed dementia, subdivided according to relative predominance though in conditions where damage to these pathways
of Alzheimer and vascular changes (see text for details) does occur (e.g. Alzheimer's disease, Down's
syndrome, Parkinson's disease) (see introduction for
Patients Nerve cell number Nucleolar volume
(per section) (gin 3) references) dementia is a likely feature of the disease.
In other words, while damage to ascending subcortical
13, 16,18, 260.5+20.9 29.6__.5.0 projections, like the nbM, in Alzheimer's disease
20 undoubtedly contributes to those cumulative patho-
14, 15, 17, 131.0 +__24.9 20.7 + 2.5 physiological changes within the brain that present
19, 21 clinically as dementia, it is unlikely that they are, per
se, the sole cause of such changes. Dementia probably
represents in clinical terms the net failure of the cortex
on tangle counts in nbM, but usually high on vascular to correctly fulfill its physiological functions, irrespec-
damage (i.e., patients 13, 16, 18, 20) tended to show tive of what the pathological cause or causes of that
cell counts and nucleolar volume measures closer to failure might be.
the purely vascular dementia group (Fig. 1, In view of the findings of Pearson et al. (1983)
Tables 2, 3). showing that retrograde cellular degeneration of the
3 36
ipsilateral n b M , involving nerve cell shrinkage a n d
loss o f Nissl, ( t h o u g h n o t necessarily an actual cell
loss) occurs in m o n k e y s after large lesions o f the
neocortex (particularly striatal cortex a n d internal
capsule) and in h u m a n s following hemidecortication
and leucotomy, it m i g h t have been predicted that some
o f our patients with large a m o u n t s o f tissue infarction
w o u l d also show such retrograde changes in n b M .
In general terms we f o u n d little definite evidence to
s u p p o r t this a l t h o u g h two patients (patients 10 and
11) did show a lower t h a n expected for age, cell
n u m b e r a n d / o r nucleolar volume. This m a y have re-
lated to their vascular lesions, particularly those in
their internal capsule (see P e a r s o n et al. 1983). I n other
patients who, despite m u c h tissue infarction, failed to
show any overall change in cell n u m b e r or nucleolar
volume, in n b M , it is possible that the cells we sampled
did n o t necessarily relate, in terms o f their projection
fields, to those areas destroyed by infarction, or that
the overall extent o f the d a m a g e or its particular
anatomical location (i.e. outside frontal cortex or in-
ternal capsule) were n o t sufficient to induce gross re-
trograde changes in n b M .
I n summary, therefore, it appears f r o m this study
t h a t in general cerebrovascular lesions causing tissue
infarction within the cerebral cortex a n d other areas,
result in little, if any, overall d a m a g e to the n b M .
However, it is possible that discrete lesions placed in
the relevant projection field target area, or the relevant
nerve pathway, m a y lead to a specific cellular degener-
ation within the a p p r o p r i a t e locus o f cells within the
n b M p o p u l a t i o n as a whole.
Acknowledgement. We thank Mrs. P. Bellinger for the prepara-
tion of the manuscript.
References
Arendt T, Bigl V, Arendt A, Tennstedt A (1983) Loss of
neurones in nucleus basalis of Meynert in Alzheimer's dis-
ease, paralysis agitans and Korsakoff's disease. Acta
Neuropathol (Berl) 61 : 101 - 108
Candy JM, Perry RH, Perry EK, Irving D, Blessed G, Fairburn
AF, Tomlinson BE (1983) Pathological changes in the nu-
cleus of Meynert in Alzheimer's and Parkinson's diseases. J
Neurol Sci 59: 277 - 289
Casanova MF, Walker LC, Whitehouse PJ, Price DL (1985)
Abnormalities of the nucleus basalis in Down's syndrome.
Ann Neurol 18:310-313
Clark AW, Parhad IM, Folstein SE, Whitehouse PJ, Hedreen
JC, Price DL, Chase GA (1983) The nucleus basalis in
Huntington's disease. Neurology 33:1262-1267
Cross RB (1982) Demonstration of neurofibrillary tangles in
paraffin sections - a quick and simple method using
Palmgren's technique. Med Lab Sci 39 : 6 7 - 69
Gaspar P, Gray F (1984) Dementia in idiopathic Parkinson's
disease. A neuropathological study of 32 cases. Acta
Neuropathol (Bed) 64:43 - 52
D . M . A . Mann et al. : Nucleus basalis in multi-infarct dementia
Mann DMA, Yates PO (1983) Pathological basis for neuro-
transmitter changes in Parkinson's disease. Neuropathol
Appl Neurobiol 9: 3 - 1 9
Mann DMA, Yates PO, Hawkes J (1982) The noradrenergic
system in Alzheimer and multi-infarct dementias. J Neurol
Neurosurg Psychiatry 45:113 - 119
Mann DMA, Yates PO, Marcyniuk B (1984a) Changes in nerve
cells of the nucleus basalis of Meynert in Alzheimer's disease
and their relationship to ageing and the accumulation of
lipofuscin pigment. Mech Ageing Dec 25:189-204
Mann DMA, Yates PO, Marcyniuk B (1984b) Alzheimer's pre-
senile dementia, senile dementia of Alzheimer type and
Down's syndrome at middle age all form an age-related
continuum of pathological changes. Neuropathol Appl
Neurobiol 10 : 185 - 207
Mann DMA, Yates PO, Marcyniuk B (1985a) Some morpho-
metric observations on the cerebral cortex and hippocampus
in presenile Alzheimer's disease, senile dementia of
Alzheimer type and Down's syndrome in middle age. J
Neurol Sci 69:139 - 159
Mann DMA, Yates PO, Marcyniuk B (1985b) Changes in
Alzheimer's disease in the magnocellular neurones of the
supraoptic and paraventricular nuclei and their re-
lationships to the noradrenergic deficit. Clin Neuropathol
4:127-134
Mann DMA, Yates PO, Marcyniuk B, Ravindra CR (1985c)
Pathological evidence for neurotransmitter deficits in
Down's syndrome of middle age. J Ment Defic Res 29:125 -
135
McGeer PL, McGeer EG, Suzuki J, Dolman CE, Nagai T (1984)
Aging, Alzheimer's disease and the cholinergic system of the
basal forebrain. Neurology 34:741- 745
Nagai T, McGeer PL, Peng JH, MeGeer EG, Dolman CE (1983)
Choline acetyltransferase immunohistochemistry in brains
of Alzheimer's disease patients and controls. Neurosci Lett
36:195-199
Nakano I, Hirano A (1983) Neurone loss in the nucleus basalis
of Meynert in Parkinsonism-dementia complex of Guam.
Ann Neurol 13 : 87 - 91
Nakano I, Hirano A (1984) Parkinson's disease: neurone loss in
nucleus basalis without concomitant Alzheimer's disease.
Ann Neurol 15 : 415 - 418
Pearson RCA, Gatter KC, Powell TPS (1983) Retrograde cell
degeneration in the basal nucleus in monkey and man. Brain
Res 261 : 321 - 326.
Perry EK, Curtis M, Dick D J, Candy JM, Atack JR, Bloxham
CA, Blessed G, Fairburn A, Tomlinson BE, Perry RH (1985)
Cholinergic correlates of cognitive impairement in
Parkinson's disease: comparisons with Alzheimer's disease.
J Neurol Neurosurg Psychiatry 48: 413 - 421
Price DL, Whitehouse P J, Struble RG, Coyle JT, Clark AW,
DeLong MR, Cork LC, Hedreen JC (1982) Alzheimer's dis-
ease and Down's syndrome. Ann NY Acad Sci 396:145-164
Rogers JD, Brogan D, Mirra SS (1985) The nucleus basalis of
Meynert in neurological disease. A quantitative morpho-
logical study. Ann Neurol 17:163 - 1 7 0
Rossor MN, Svendsen C, Hunt SP, Mountjoy CQ, Roth M,
Iverson LL (1982) The substantia innominata in Alzheimer's
disease: an histochemical and biochemical study of
cholinergic marker enzymes. Neurosci Lett 28:217-222
Shea JR (1970) A method for the in situ estimation of absolute
amount of ribonucleic acid using Azure B. J Histochem
Cytochem 18:143 - 152
Tagliavini F, Pilleri G (1983) Basal nucleus of Meynert. A
neuropathological study in Alzheimer's disease; simple
senile dementia, Pick's disease and Huntington's chorea. J
Neurot Sci 62: 243 - 260
D. M. A. Mann et al.: Nucleus basalis in multi-infarct dementia
Tagliavini F, Pilleri G (1985) Neuronal loss in the basal nucleus
of Meynert in a patient with olivopontocerebellar atrophy.
Acta Neuropathol (Berl) 66:127-133
Tagliavini F, Pilleri G, Bouras C, Constantinidis J (1984) The
basal nucleus of Meynert in patients with progressive
supranuclear palsy. Neurosci Lett 44: 3 7 - 42
Uhl GR, McKinney M, Hedreen JC (1982) Dementia pugi-
listica: loss of basal forebrain cholinergic neurones and
cortical cholinergic markers. Ann Neurol 12:99
Uhl GR, Hilt DC, Hedreen JC, Whitehouse PJ, Price DL (1983)
Pick's disease (lobar sclerosis). Depletion of neurones in the
nucleus basalis of Meynert. Neurology 33:1470-1473
337
Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT,
DeLong MR (1982) Alzheimer's disease and senile
dementia. Loss of neurones in the basal forebrain. Science
215:1237-1239
Whitehouse PJ, Hedreen JC, White CC, Price DL (1983) Basal
forebrain neurones in the dementia of Parkinson's disease.
Ann Neurol 13:243 -248
Wilcock GK, Esiri MM, Bowen DM, Smith CCT (1983) The
nucleus basalis in Alzheimer's disease: cell counts and corti-
cal biochemistry. Neuropathol Appl Neurobiol 9:175-179
Received May 22, 1986/Accepted June 30, 1986