Article Type : Research Article
Authors : De Reuck J, Auger F, Durieux N, Maurage CA, Deramecourt V, Cordonnier C, Pasquier F, Leys D and Bordet R
Keywords : Post-mortem 7.0-tesla magnetic resonance imaging; Hippocampal atrophy; Hippocampal micro-bleeds; Hippocampal micro-infarcts; Normal brain aging; Alzheimer’s disease; Frontotemporal lobar degeneration; Lewy body disease; Progressive supranuclear palsy; Corticobasal degeneration
Except for atrophy of the
hippocampus no other lesions have been investigated in neurodegenerative
dementia diseases. The present post-mortem study with additional 7.0-tesla
magnetic resonance imaging investigates the incidence and the degree of the
severity of the hippocampal atrophy and the incidence of hippocampal
micro-bleeds and micro-infarcts.
Hippocampal atrophy is
significantly more severe not only in Alzheimer’s disease but also in
frontotemporal lobar degeneration, compared normal age-related brains and other
neurodegenerative diseases, such Lewy body disease, progressive supranuclear
palsy and corticobasal degeneration. Cerebrovascular lesions are rare except
for small bleeds in FTLD. The hippocampi in most of the neurodegenerative
diseases seem to be protected from cerebrovascular involvement, in contrast to
the overall high frequency of these lesions in the largest part of the
hemispheric cerebral cortex.
In vivo measurement of
human hippocampal volume (HV) and shape with magnetic resonance imaging (MRI)
has become an important element of neuroimaging research [1]. HVs are inversely
correlated with age in older healthy persons [2]. Hippocampal atrophy (HA), as
evidenced using MRI, is one of the most validated biomarkers of Alzheimer’s
disease (AD). However, its imperfect sensitivity and specificity have
highlighted the need to improve the analysis of the MRI data [3]. HV as an
index of AD in post--mortem MRI scans of brains in the Nun study is a better
indicator than delayed memory measure [4]. Also faster HV loss is observed in
the presence of the ApoE genotype epsilon4 and in decreased cerebrospinal fluid
Abeta [5].
On MRI HA is as severe in
fronto-temporal lobar degeneration (FTLD) as in AD [6,7]. On MRI HA in Lewy
body disease (LBD) is found to be absent [8] or less important than in AD [9]
and in Parkinson’s disease [10]. However, when LBD is associated with AD-type
pathology, the HA is more important [11]. MRI findings in progressive
supranuclear palsy are mainly focused on midbrain atrophy and diffuse white
matter changes. No specific references are found concerning hippocampal lesions
[12,13]. In corticobasal degeneration (CBD) the MRI is mainly focused on the
asymmetrical cortical atrophy and the white matter lesions. Hippocampal lesions
are not specifically mentioned [14,15]. The present post-mortem 7.0-tesla MRI
examines selectively the structural changes in the hippocampus during normal
aging and in different neurodegenerative dementia diseases.
The examined post-mortem brains consisted of 34 normal ones and 107 with different neurodegenerative diseases. The normal brains were subdivided in those of 20 middle-aged with on average age of 43 (31-55) years and 14 elderly persons with average age of 75 (67-83) years. The demographic features of the different examined groups are labeled in (Table 1).
Table 1: Demographic data of the different patient groups.
Items |
Amount |
Age (SD) |
Male (%) |
Normal middle-aged |
20 |
43 (31-55) yrs |
50% |
Normal elderly |
14 |
75 (67-87) yrs |
64% |
Alzheimer’s disease |
45 |
78 (65-83) yrs |
41% |
Frontotemporal lobar degeneration |
21 |
69 (63-75) yrs |
59% |
Lewy body disease |
15 |
80 (74-87) yrs |
73% |
Progressive supranuclear palsy |
20 |
67 (56-73) yrs |
50% |
Corticobasal degeneration |
6 |
71 (67-75) yrs |
33% |
A previously obtained informed consent of the patients or
from the nearest family allowed an autopsy for diagnostic and scientific
purposes.
The brain tissue samples were acquired from the Lille
Neuro-Bank of the Lille University that is part of the “Centres des Resources
Biologiques” and acts as an institutional review board. The neuropathological
diagnosis of “pure” neurogenerative diseases, without associated pathology, was
made according a standard procedure. Several small samples of the cerebral
cortex and of the hippocampus of one fresh cerebral hemisphere were taken for
histochemical examination. The remaining brain was fixed in formalin and, after
3 weeks, samples were taken from the primary motor cortex, the associated
frontal, temporal and parietal cortex, the primary and secondary visual cortex,
the cingulate gyrus, the basal nucleus of Meynert, the amygdaloid body, the
hippocampus, basal ganglia, mesencephalon, pons, medulla and cerebellum. Slides
from paraffin-embedded sections were immunostained for protein tau, ?-amyloid,
alpha-synuclein, prion protein and TDP43.
A 7.0-tesla MRI Bruker BioSpin SA was used with an
issuer-receiver cylinder coil of 72 mm inner diameter (Ettlingen, Germany),
according to a previously described method [16]. Previous to the brain
sampling, three up to six coronal sections of a cerebral hemisphere were
submitted to SPIN ECHO T2 and T2* MRI sequences: frontal, central and
parieto-occipital ones. The hippocampus was evaluated on the most
representative section. The degree of HA was determined according to the
classification of Scheltens in 4 grades [17,18]. Also the incidence of
hippocampal micro-bleeds (HMBs) and micro-infarcts (HMIs) was evaluated as
previously described for cortical hemispheric cortical micro-bleeds (CoMBs) and
cortical micro-infarcts (CoMIs) [19]. Also the findings in middle-aged and
normal elderly persons were mutually compared.
Univariate comparisons of unpaired groups were performed
with the Fisher's exact test for categorical data. The non-parametric
Mann-Whitney U test was used to compare continuous variables. The significance
level, two-tailed, was set at ? 0.01 for significant and ? 0.001 for highly
significant. Values set at ? 0.05 and more than > 0.01 were considered as
marginal significant.
When comparing the middle-aged with the
elderly normal persons a non-significant increase of the HA and of the number
of HMBs and HMIs was observed (Table 2). When comparing the age-related normal
elderly brains to those with a neurodegenerative dementia disease only in AD
and FTLD a very significant degree of HA was observed. No significant HA was
found in the LBD, PSP and CBD, compared to the normal age-related brains. Only
in FTLD a significant increase of HMBs was seen. HMIs were not significantly
more frequent in the different neurodegenerative dementia brains compared to
normal brains of the same age group (Table 3).
Table 2: Comparison of the non-significant average incidence (standard deviation) of hippocampal lesions between middle-aged and elderly persons with a history of normal cognition.
Items |
Hippocampal
atrophy |
Cortical
micro-bleeds |
Cortical
micro-infarcts |
Aged 43 (31-55) years |
0.0
(0.0) |
0.0
(0.0) |
0.0
(0.0) |
Aged 75
(67-83) years |
0.4 (0.8) |
0.4 (0.8) |
0.1 (0.3)
|
Table 3: Comparison of the average incidence (standard
deviation) of the hippocampal changes of age-controlled normal brains to those
with different neurodegenerative dementia diseases.
Items |
Hippocampal atrophy |
Cortical micro-bleeds |
Cortical
micro-infarcts |
Alzheimer’s disease |
2.5 (1.1)*** |
0.4 (0.8) |
0.1 (0.3) |
Frontotemporal lobar
degeneration |
2.0 (1.0)*** |
1.3 (1.0)** |
0.3 (0.1) |
Lewy body disease |
0.5 (0.7) |
0.3 (0.6) |
0.2 (0.4) |
Progressive
supranuclear palsy |
0.4 (0.6) |
0.5 (1.0) |
0.0 (0.0) |
Corticobasal
degeneration |
0.2 (0.4) |
0.0 (0.0) |
0.5 (0.8) |
*** p value ? 0.001; ** p value ? 0.01. |
Visual assessment of medial temporal lobe
atrophy correlates well with hippocampal volume [20]. There is a mild reduction
in cerebral volumes with age, more marked in males [21]. In addition to some
degree of brain shrinkage and increase of white changes, only a more or less
similar increase of CoMBs is observed in middle-aged and elderly persons compared
to young adults. The increase of CoMBs is probably due to mixed age-related
cerebrovascular and neurodegenerative pathology [19,22] (Figures 1-2).
Figure 1: T2 and T2* sequences of a coronal section of a cerebral hemisphere in Alzheimer’s disease. The temporal horn is enlarged (*) with severe atrophy of the hippocampus (black arrow).
In the present study HA is significantly severe in AD and FTLD compared to normal aging, LBD, PSP and CBD. The degree of HA alone does not allow differentiating AD from FTLD, as previously shown [6,7]. Post-mortem studies have not identified an association between ß-amyloid or tau and rates of HA in patients with AD. TDP-43 on the other hand appears as a potential factor related to increased rates of HA [23]. The average HV and ratio in AD is estimated to be reduced by 25% compared to 21% in mixed dementia and 11 % in vascular dementia [24]. There are also some differences in atrophy location in AD compared to other brain diseases [25]. CoMBs are significantly increased in AD brains, in particular when associated to cerebral amyloid angioaphy, in contrast to the hippocampus [26].
Figure 2: T2 and T2* sequences of a coronal section of a cerebral hemisphere in frontotemporal lobe degenertion. The temporal horn is enlarged (*) with severe atrophy of the hippocampus and a small bleed (black arrow).
The increase of HMBs in FTLD is more
probably related to the severe neurodegenerative changes in the fronto-temporal
regions rather than due to additional cerebro-vascular pathology [27]. The
medial temporal lobe atrophy allows to differenciate AD from LBD [28]. CoMBs
are frequent in LBD, in particular when associated to AD features [29,30]. This
is in contrast to their low incidence in the hippocampus in pure LBD as well as
pure AD.
MBs and MIs are restricted to the
neurodegenerative changes of the brainstem and cerebellum in PSP. The
hippocampus is not significantly affected [31]. Hemispheric CoMBs are increased
in brains with CBD, in contrast to the hippocampus [32]. CoMIs are frequently
observed in different neurodegenerative diseases, mainly in the mixed forms [33,34].
However, the hippocampus seems to be spared in the present study.
The involvement of hippocampus in
neurodegenerative dementia diseases shows significant differences. Atrophy is
only observed in AD and FTLD. Cerebrovascular lesions are rare except for small
bleeds in FTLD. Most of the neurodegenerative diseases seem to be protected for
cerebro-vascular participation, in contrast to their overall frequent involvement.
Jacques De Reuck has designed the study.
Together with Florent Auger and Nicolas Durieux he performed the MRI
examinations. Claude-Alain Maurage and Vincent Deramecourt performed the
macroscopic and histological examinations of the brains. Charlotte Cordonnier,
Florence Pasquier, Didier Leys and Regis Bordet were responsible for clinical
evaluation during life.
Funding
No funding was received for the
publication of this article.
Competing Interests
The authors have declared that no
competing interests exist.