Morphological substrates of cognitive decline in nonagenarians and centenarians: a new paradigm?
ABSTRACT Brain aging is characterized by the formation of neurofibrillary tangles (NFT) and senile plaques (SP) in both cognitively intact individuals and patients with Alzheimer's disease (AD). The ubiquitous presence of these lesions and the steady increase of the prevalence of dementia up to 85 years have strongly supported a continuum between normal brain aging and AD. In this context, the study of nonagenarians and centenarians could provide key informations about the characteristics of extreme aging. We provide here a detailed review of currently available neuropathological data in very old individuals and critically discuss the patterns of NFT, SP and neuronal loss distribution as a function of age. In younger cohorts, NFTs are usually restricted to hippocampal formation, whereas clinical signs of dementia appear when temporal neocortex is involved. SPs would not be a specific marker of cognitive impairment as no correlation was found between their quantitative distribution and AD severity. The low rate of AD lesions even in severe AD as well as the weakness of clinicopathological correlations reported in the oldest-old indicate that AD pathology is not a mandatory phenomenon of increasing chronological age. Our recent stereological observations of hippocampal microvasculature in oldest-old cases challenge the traditional lesional model by revealing that mean capillary diameters is an important structural determinant of cognition in this age group.
- Folia Neuropathologica 01/2013; 3:169-188. · 1.67 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Periodontitis is a polymicrobial chronic inflammatory disease of tooth-supporting tissues with bacterial etiology affecting all age groups, becoming chronic in a subgroup of older individuals. Periodontal pathogens Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola are implicated in the development of a number of inflammatory pathologies at remote organ sites, including Alzheimer's disease (AD). The initial inflammatory hypothesis proposed that AD hallmark proteins were the main contributors of central nervous system (CNS) inflammation. This hypothesis is expanding to include the role of infections, lifestyle, and genetic and environmental factors in the pathogenesis of AD. Periodontal disease (PD) typifies a condition that encompasses all of the above factors including pathogenic bacteria. These bacteria not only are the source of low-grade, chronic infection and inflammation that follow daily episodes of bacteremia arising from everyday tasks such as brushing, flossing teeth, chewing food, and during dental procedures, but they also disseminate into the brain from closely related anatomical pathways. The long-term effect of inflammatory mediators, pathogens, and/or their virulence factors, reaching the brain systemically or otherwise would, over time, prime the brain's own microglia in individuals who have inherent susceptibility traits. Such susceptibilities contribute to inadequate neutralization of invading agents, upon reaching the brain. This has the capacity to create a vicious cycle of sustained local inflammatory milieu resulting in the loss of cytoarchitectural integrity and vital neurons with subsequent loss of function (deterioration in memory). The possible pathways between PD and AD development are considered here, as well as environmental factors that may modulate/exacerbate AD symptoms.Journal of Alzheimer's disease: JAD 06/2014; · 3.61 Impact Factor
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ABSTRACT: As of 2010, the worldwide economic impact of dementia was estimated at $604 billion USD; and without discovery of a cure or effective interventions to delay disease progression, dementia’s annual global economic impact is expected to surpass $1 trillion USD as early as 2030. Alzheimer’s disease (AD) is the leading cause of dementia accounting for over 75% of all cases. Toxic accumulation of amyloid beta (Aβ), either by overproduction or some clearance failure, is thought to be an underlying mechanism of the neuronal cell death characteristic of AD—though this amyloid hypothesis has been increasingly challenged in recent years. A compelling alternative hypothesis points to chronic neuroinflammation as a common root in late-life degenerative diseases including AD. Apolipoprotein-E (APOE) genotype is the strongest genetic risk factor for AD: APOE-ε4 is proinflammatory and individuals with this genotype accumulate more Aβ, are at high risk of developing AD, and almost half of all AD patients have at least one ε4 allele. Recent studies suggest a bidirectional relationship exists between sleep and AD pathology. Sleep may play an important role in Aβ clearance, and getting good quality sleep vs. poor quality sleep might reduce the AD risk associated with neuroinflammation and the ε4 allele. Taken together, these findings are particularly important given the sleep disruptions commonly associated with AD and the increased burden disrupted sleep poses for AD caregivers. The current review aims to: (1) identify individuals at high risk for dementia who may benefit most from sleep interventions; (2) explore the role poor sleep quality plays in exacerbating AD type dementia; (3) examine the science of sleep interventions to date; and (4) provide a road map in pursuit of comprehensive sleep interventions, specifically targeted to promote cognitive function and delay progression of dementia.Frontiers in Aging Neuroscience 12/2014; 6:325. · 2.84 Impact Factor
Morphological substrates of cognitive decline in nonagenarians
and centenarians: A new paradigm?☆
Anouk Imhofa, Enikö Kövaria, Armin von Guntenb, Gabriel Goldc,
Claire-Bénédicte Rivarad, François R. Herrmannc, Patrick R. Hofd,e,
Constantin Bourasa,d, Panteleimon Giannakopoulosa,b,⁎
aDepartment of Psychiatry, HUG, Belle-Idée, University of Geneva School of Medicine, Geneva, Switzerland
bDivision of Old Age Psychiatry, University of Lausanne School of Medicine, Lausanne, Switzerland
cDepartment of Geriatrics, HUG, Belle-Idée, University of Geneva School of Medicine, Geneva, Switzerland
dDepartment of Neurosciences, Mount Sinai School of Medicine, New York, NY, USA
eDepartments of Geriatrics and Adult Development, and Ophthalmology, Mount Sinai School of Medicine, New York, NY, USA
Available online 15 February 2007
Brain aging is characterized by the formation of neurofibrillary tangles (NFT) and senile plaques (SP) in both cognitively intact
individuals and patients with Alzheimer's disease (AD). The ubiquitous presence of these lesions and the steady increase of the prevalence of
dementia up to 85 years have strongly supported a continuum between normal brain aging and AD. In this context, the study of
nonagenarians and centenarians could provide key informations about the characteristics of extreme aging. We provide here a detailed review
of currently available neuropathological data in very old individuals and critically discuss the patterns of NFT, SP and neuronal loss
distribution as a function of age. In younger cohorts, NFTs are usually restricted to hippocampal formation, whereas clinical signs of
dementia appear when temporal neocortex is involved. SPs would not be a specific marker of cognitive impairment as no correlation was
found between their quantitative distribution and AD severity. The low rate of AD lesions even in severe AD as well as the weakness of
clinicopathological correlations reported in the oldest-old indicate that AD pathology is not a mandatory phenomenon of increasing
chronological age. Our recent stereological observations of hippocampal microvasculature in oldest-old cases challenge the traditional
lesional model by revealing that mean capillary diameters is an important structural determinant of cognition in this age group.
© 2007 Elsevier B.V. All rights reserved.
Keywords: Brain aging; Dementia; Lesions; Neuropathology; Oldest-old; Vascular
The continued expansion of the elderly population and a
growing awareness of age-related diseases such as dementia
have prompted considerable interest in the study of the aging
human brain. The aging population is rapidly growing as a
result of increased accessibility of advanced medical
technology and declining birth rates. By 2020 it is estimated
that at least 1 billion people will be older than 60 years
representing more than 20% of the total population. The few
individuals who reach very old ages are called “longevity
outliers”. This particular group represents the fastest growing
age group worldwide. For instance, people over age 85
accounts for 2.1% of the general population in France and
this proportion is expected to increase to 3.3% in 2020 and
6.8% in 2050. Similarly, the number of centenarians in-
creases steadily in the US population and their numbers are
expected to grow to more than 400000 in the next 30 years
(for review see ). This phenomenon has been also
Journal of the Neurological Sciences 257 (2007) 72–79
☆This work was supported by grants AG02219 and AG05138 from the
National Institutes of Health, Bethesda, Md (PRH), the Doris Duke
Foundation, New York, Ny (TLB) and the Jérôme Tissières Foundation,
Geneva, Switzerland (PG).
⁎Corresponding author. Service of Geriatric Psychiatry, Department of
Psychiatry, University of Geneva School of Medicine, CH-1225 Chêne-
Bourg, Geneva, Switzerland. Tel.: +41 22 305 5001; fax: +41 22 305 5044.
E-mail address: Panteleimon.Giannakopoulos@medecine.unige.ch
0022-510X/$ - see front matter © 2007 Elsevier B.V. All rights reserved.
confirmed in New Zealand and Japan [2,3]. A well-known
paradox is the high proportion of centenarians in the African
American community (19.6 per 100000) in spite of a lower
life expectancy at birth .
The growing evidence for a steady increase of the num-
ber of centenarians worldwide was paralleled by several
community-based longitudinal and cross-sectional studies
aiming to determine possible psychobiological particularities
of these individuals [5–10]. These studies showed that the
known predictors of mortality such as socio-demographic
factors, smoking and obesity are less important in this age
group. In contrast, levels of disability as well as depression
are key determinants of both morbidity and mortality after
90 years. Centenarians are less prone to oxidative stress and
are thought to have better antioxidant defences, nutritional
status, immunologic profile, endocrinologic and metabolic
characteristics than younger elderly cohorts [11,12]. Psy-
chologically, they report greater satisfaction with life and
social and family relations and display lower scores for
anxiety and depression and better coping abilities compared
to less elderly individuals . In this age group, good health
and not moving home are associated with greater intellectual
activity, while extraversion and negative life events with
greater social activity . These data support the possibility
that centenarians form a select cohort with relatively slow
rates of aging and increased resistance to biological and
psychological stress and age-related diseases such as cancer,
stroke and heart disease.
2. Dementia in the oldest-old
Although prevalence and incidence data are still scarce in
this age group, it has long been thought that very old age is
associated with the highest prevalence of dementia .
Several earlier studies reported an increased prevalence of
dementia with aging, to 100% in the 100-year age group
[16,17]. Methodological biases were present in most of these
studies and limit the validity of their conclusions. First, the
samples included only a limited number of nonagenarians
and centenarians. Second, the clinical diagnosis of dementia
made by the physician was based on the global decline of
cognitive performances rather than on a detailed analysis of
each cognitive function leading to an overestimation of the
prevalence of dementia in the oldest-old. In fact, recent
epidemiological studies in larger cohorts of very old individ-
uals showed prevalence rates which varied from 27 to 62%
pointing to the fact that dementia is not inevitable in very old
individuals (for review see [1,18]). In an epidemiological
survey of 1694 patients who met criteria for probable or
definite Alzheimer’s disease (AD), Lautenschlager and col-
leagues  also reported that the risk of AD decreases
significantly after age 90. Similar results were drawn by
a community-based study of 402 individuals older than
85 years who have been assessed using structured interviews
in Munich . A relative resistance of centenarians to the
degenerative process was also suggested by the observations
of Howieson and collaborators  who performed a
longitudinal study of 31 non-demented individuals older
than 80 years and reported a preservation of cognitive
abilities during a follow-up period of 5 years. Furthermore, a
lack of association between AD and apolipoprotein E allele
epsilon 4, a major risk factor for late-onset AD in younger
cohorts, has been demonstrated in centenarians [22–25].
However, one may argue that these epidemiological findings
reflect only the fact that younger cohorts are at higher risk to
develop AD and do not necessarily support differential
neuronal aging in this age group. During the period 1990–
2000, case-control neuropathological studies provided the
first lines of evidence supporting the presence of distinct
patterns of neuronal vulnerability to the degenerative process
3. Patterns of AD-related lesion distribution in the
oldest-old: early contributions
From a neurobiological point of view, the study of oldest-
old individuals may permit to define the spectrum and extent
of changes in brain morphology that occur with normal brain
aging and assess correlations between the neuropathological
definition of normal brain aging and clinical development of
dementing process [26–28]. Brain aging is characterized by
the formation of neurofibrillary tangles (NFT) and senile
plaques (SP), as well as neuronal and synaptic loss in both
cognitively intact individuals and patients with AD. In non-
demented cases, NFT are usually restricted to the hippo-
campal formation, whereas the progressive involvement of
the association areas in the temporal neocortex parallels the
development of overt clinical signs of dementia. In contrast,
severe SP formation may take place in several neocortical
areas in the presence of very mild cognitive impairment and
there is no correlation between the quantitative distribution
of SP and severity of AD (for review see [29,30]). With
regard to neuronal loss, stereological analyses have revealed
age-related decreases in total neuron number of 30% and
50% in the dentate hilus of the hippocampus and subiculum,
respectively, between ages 13 and 85. Conversely, no neu-
ronal loss was found in CA1-3 fields and entorhinal cortex
where AD lesions are also observed [31–33]. These studies
also showed that in AD, there is an additional depletion of
neuronal cell bodies in the dentate hilus and subiculum, as
well as a massive reduction in the numbers of pyramidal
neurons in the CA1 field and layers II and Vof the entorhinal
cortex [31–35]. Moreover, earlier and recent studies have
shown a neuronal reduction in temporal, inferior and
superior parietal and frontal cortices of AD cases [35,36].
Does the pattern of lesion distribution and neuronal loss
change in extreme aging? A first observation concerns the
presence of several cases with minimal AD pathology and
preserved cognitive functions [26,28,37]. These individuals,
also called “supernormal centenarians”, represent a rare
phenotype relatively protected from AD pathology and may
be thus an example of successful aging near the upper age
73A. Imhof et al. / Journal of the Neurological Sciences 257 (2007) 72–79
limit of life. Several neuropathologic analyses postulated that
in contrast to younger cases where dementia is mainly related
to severe NFT formation within adjacent components of the
medial and inferior aspects of the temporal cortex, oldest-old
individuals display a preferential involvement of the anterior
part of the CA1 field of the hippocampus whereas the
inferior temporal and frontal association areas are relatively
spared [34,37]. The first contributions in this field have
considered that the extent of NFT development in the hippo-
campus is the key determinant of dementia in the very old.
For instance, Hauw et al.  examined the NFT distribution
in the cerebral cortex of 12 centenarians (1 case with AD),
and found higher NFT densities in the CA1 field in the
demented patient than in cognitively intact centenarians. In
their study of 27 non-demented centenarians and younger
AD cases, Mizutani and Shimada reported that demented
patients had dramatically higher NFT densities in the dentate
hilus of the hippocampus, whereas no difference was
observed in the entorhinal cortex and the subiculum .
More recent studies attempted to define the exact cognitive
impact of NFT, SP, and neuronal loss in this age group (see
Table 1). We found a significant difference in NFT densities
in the anterior CA1 field, but not in the posterior CA1 field
and entorhinal cortex, between demented and non-demented
very old patients and suggested that nonagenarians and
centenarians may show a specific subregional distribution of
NFT within the CA field [26,34,39]. Two recent reports led
to discrepant conclusions. In their study of 19 centenarians
(including 4 AD cases), Garcia-Sierra et al.  found a
substantial NFTinvolvement of hippocampus and entorhinal
cortex supporting the notion of a limbic dementia in the
oldest-old. Using a semiquantitative assessment of AD
lesions, the longitudinal Oregon Brain Aging study reported
that NFT and SP densities in neocortical areas were signifi-
cantly related to cognitive scores . Moreover, it has been
reported that overt clinical signs of AD in oldest-old
individuals requires a progressive damage of areas 7, 22,
23 and 24 suggesting a displacement of NFT, such that
parietal and cingulate cortex are more affected than is usually
the case in AD, whereas superior frontal and inferior tem-
poral association areas are relatively preserved [34,41].
Unlike younger cohorts where SP formation does not cor-
relate with neuronal depletion and cognitive status [42–44],
earlier and more recent studies suggested that SP densities in
the neocortex are related to the degree of neuronal loss and
severe AD in the oldest-old [27,34]. Moreover, the extensive
neuronal loss in the hippocampal formation reported in
younger AD series  appears to be confined to the layer II
of the entorhinal cortex in nonagenarians and centenarians
Three main methodological issues explain the discor-
dance between these contributions. First, most of them
compared controls to severe AD cases without taking into
account cases with questionable and mild dementia. Second,
estimates of AD-related pathology were performed with non-
stereologic methods which are subject to sampling bias.
Most importantly, AD pathologic hallmarks are usually
studied separately without taking into account the well es-
tablished interaction between amyloid deposition, NFT for-
mation and neuronal loss [for review see [29,30]]. Using
rigorous stereological design, we recently analyzed the pat-
terns of AD lesion distribution and clinicopathological
correlations in a prospectively documented series of non-
agenarians and centenarians. In the following chapters, we
summarize these data and critically discuss their pertinence in
the context of the debate regarding the relationship between
AD pathological process and normal brain aging.
4. Hippocampal AD-related pathology after 90 years:
sparing of the entorhinal cortex and CA1 field
Our first stereologic study included 12 patients older than
90 years who died and were autopsied in the Departments of
Geriatrics and Psychiatry of the University of Geneva School
of Medicine . All cases underwent neuropsychological
assessment within the last 6 months prior to their death and a
Clinical Dementia Rating (CDR) scale score was available
for all of them. This analysis revealed several differences in
lesion distribution within the hippocampus and entorhinal
cortex between oldest-old individuals and previously
analyzed younger cohorts of elderly persons [47,48]. In
particular, the progression of NFT formation across the
different CDR groups was significantly slower in nonagen-
arians and centenarians (from 1 to 17% in the entorhinal
cortex and 1.7 to 37% in the CA1) compared to younger
cases [from 4 to 79% in the entorhinal cortex and 3 to 80% in
the CA1 field ]. Interestingly, the only community-based
neuropathologic study of oldest-old individuals also con-
firmed this pattern of NFT distribution in the CA1 field .
The relative resistance of the hippocampal formation to NFT
development in this age group was even more striking in
respect to the entorhinal cortex. In agreement with our
previous observations in centenarian brains , even cases
with moderate dementia display only mild NFT formation in
this area with more than 80% of preserved neurons. This
contrasts with the results of several previous studies in
younger samples which demonstrated that the entorhinal
cortex is more severely affected and involved earlier in the
degenerative process than other hippocampal regions
[30,41,49,50]. Our cases also displayed significantly lower
total amyloid volume in the areas studied compared to that
reported in younger series . Similarly, the magnitude of
neuronal loss in the entorhinal cortex and CA1 field in these
cases was also significantly lower than that reported in
younger AD cases [35,48,51–53]. In this latter group, the
number of layer II entorhinal cortex neurons is thought to
decrease even by 60% in patients with CDR 0.5 and by 90%
in severe AD cases . In the CA1 field, a depletion of 38%
to 69% was also reported [35,48,51–53]. These data also
imply that, like AD pathologic changes, neuronal loss is
less prominent in the oldest-old even in the presence of AD
. In conjunction with the observations of Itoh and
74 A. Imhof et al. / Journal of the Neurological Sciences 257 (2007) 72–79
collaborators  who first reported only mild synaptic loss
and cerebral amyloid angiopathy in centenarians, these
findings give additional experimental support to the notion
that the occurrence and progression of AD-relatedpathologic
changes are not a sine qua non concomitant of increasing
Another intriguing result of this study was the clear
dissociation between total neuron numbers and AD-related
lesions in the hippocampal formation. Although this is
expected for amyloid deposits based on previous work in
elderly individuals younger than 85 [for review see ],
it may be more surprising for NFT numbers, given that
Neuropathological studies in the oldest-old from 1995 to 2006
Cognitive status AD pathologyVessels
Giannakopoulos et al. x 2910 non demented,
Dementia severity was related
to SP formation; differential
distribution of NFT compared
to younger cohorts
Correlation between cognitive
decline and amyloid deposits
in neocortex; absence of SP in
non demented cases
Dementia in very old age requires
both high NFT densities in the anterior
CA1 field and progressive damage
of the neocortex; dissociation between
NFT and neuronal loss
No relationship between hippocampal
NFT and cognitive status
Troncoso et al. x63 possible AD,
1 probable AD,
2 definite AD
Giannakopoulos et al. x50 13 non demented,
Itoh et al. x 135 non demented,
angiopathy in 53.8%
Green et al. x15 6 non demented,
15 non demented,
Strong positive correlation between
rate of cognitive decline and AD lesions
Garcia-Sierra et al. x 19 The density of intracellular NFTs in
the entorhinal cortex correlates
with mental status
Very old age does not influence
NFT formation in the primary
Extensive overlap of intermediate
Alzheimer-type pathology among
demented and non demented very
No difference in AD-related
hippocampal pathology between
oldest-old and younger cases
Absence of relationship between
AD lesions and cognition in 4 cases
AD-related pathology is related to small
vessel changes due to cerebral
Leuba et al. x 21 10 non demented,
9 MCI, 2 AD
Neuropathol. Group of
medical research council
cognitive function and
ageing study 
Iseki et al. 
x 65 29 non demented,
No correlation between
vascular disease and
n.s.6 6 dementedNo information
Silver et al. x146 non demented,
4 AD demented
1 non demented,
Thal et al. n.s.3
between the extension
of small vessel lesions
and cognitive status
No informationSnowdon x3 2 non demented,
4 non demented,
No clinicopathological correlations
von Gunten et al. x 12 Decreased NFT numbers and amyloid volume
in hippocampus compared to younger series;
only mild neuronal loss in CA1 field and
entorhinal cortex in demented centenarians
Dementia severity is unrelated to
neuropathological markers; decreased
SP densities in very old AD cases
Total amyloid volume was not related to
cognitive status; significant relationship
between NFT number and CDR scores in
the CA1 field, but not in the entorhinal cortex
Prohovnik et al.  x8118 non demented,
4 non demented,
Bouras et al. x 19Mean capillary diameters
in entorhinal cortex
predict more than 30%
of CDR variability
n.s. not specified, MCI: mild cognitive impairment.
75 A. Imhof et al. / Journal of the Neurological Sciences 257 (2007) 72–79
several stereologic and non-stereologic quantitative studies
have reported strong relationships between NFT counts and
neuron loss in the hippocampal formation and neocortex
suggesting that NFT-dependent neuronal loss may be the
rule in the cerebral cortex . In contrast, non-NFT-
related mechanisms of neurodegeneration may determine
neuronal depletion in this age group . Although these
mechanisms remain largely speculative, recent contribu-
tions postulate that apoptosis, oxidative stress and excito-
toxic mechanisms play a key role in inducing neuronal
death that would predate NFT formation in some regions
[for review see ].
The most striking finding of this study was the relative
paucity of correlations between AD pathological hallmarks
in the hippocampal formation and clinical status after
90 years. Only a modest percentage of the CDR variability
was explained by NFT counts in CA2-3 (18%) and dentate
gyrus (17%). In contrast, neither Nissl-stained neuron
numbers nor total amyloid volume was significantly related
to CDR score in both univariate and multivariate models. In
this respect, it is worth noting that in spite of the clear
neuronal loss observed in cases with moderate to severe
dementia, total neuron numbers in the entire sample did not
significantly predict cognitive status. Moreover, NFT
numbers in the CA2-3 fields and dentate gyrus predict at
the best less than 25% of CDR variability indicating that
independent morphometric variables may decisively con-
tribute to the cognitive decline in this age group .
Besides AD-related pathology, structural parameters of
the cerebral vasculature have been thought to determine
cognitive performances in the elderly. In the 90's, several
age-related alterations of the microvascular ultrastructure
(such as perivascular collagen deposits, atrophy of
endothelium, basement membrane thickening and pericyte
degeneration) as well as qualitative changes in microvas-
cular structure (such as glomerular loops and twisted
capillaries) have been described both in the aging brain and
in AD [for review see [57–60]. In contrast, quantitative
analyses of structural parameters in brain capillaries led to
controversial data. Increased age-related capillary density
attributed to tissue shrinkage in the human neocortex and
hippocampus has been reported earlier , but more
recent animal and human studies challenged these findings
[62–66]. Similarly, an age-related increase of capillary
diameters and decrease of capillary length has been found
in the aging human hippocampus  but not in neo-
cortical areas [65,68]. As for AD-related lesions, the
discordance of the previous observations mainly reflects
methodological biases related to the use of density-based
estimates of microvascular parameters. Recently, the devel-
opment of modern design-based stereological techniques
allowed for an accurate assessment of age-related changes
in the capillary network [69,70]. Using this design, we
explored the morphometric characteristics of the capillary
network in nonagenarians and centenarians as well as their
impact on cognition.
5. Microvascular morphology in the oldest-old: a new
correlate of cognitive status?
This second stereologic study included 19 very old
individuals with various degrees of cognitive impairment.
Besides estimates of total NFT and neuron numbers as well
as total amyloid volume, we also assessed total capillary
length, number, and length-weighted mean diameters in the
CA1 and entorhinal cortex . Both mean diameters and
total capillary numbers were strongly related to total neuron
numbers in the CA1 field and entorhinal cortex. In a multi-
variate model including total NFTand capillary numbers (or
diameters) in the CA1, both variables significantly explained
neuron number variability. In contrast, there was no signifi-
cant association between total capillary length and neuron
number in the areas studied. No relationship was found
between AD-related lesions and capillary morphological
parameters in the CA1 and entorhinal cortex. These results
revealed that total capillary numbers may explain more than
40% of the neuron number variability in the CA1 and
entorhinal cortex, supporting a strong relationship between
microvascular changes and AD-related neuronal depletion.
Importantly, previous studies postulated that decreases in
capillary number and diameter could disrupt the balance
between energy requirements and cerebral blood supply,
rendering the brain more vulnerable to oxidative stress
damage and ultimately neuronal death [58,72,73]. In partic-
ular, an early animal study showed that chronic brain hypo-
perfusion in rats induces ultrastructural capillary changes in
CA1 field which were accompanied by a substantial
compromise of spatial memory . Supporting a primary
role of cerebral hypoperfusion in triggering AD-related
pathology, a single photon emission computerized tomogra-
phy study revealed the presence of regional cerebral
perfusion abnormalities which preceded clinical symptoms
in presenilin-1 mutation carriers .
In terms of clinicopathological correlations, mean capil-
lary diameters in the CA1 field and entorhinal cortex were
significantly related to CDR scores. In a univariate model,
they explained respectively 19% and 31.1% of the cognitive
variability. Importantly, these associations persisted in
multivariate models where total neuron numbers, NFT
numbers or amyloid volume were considered . The
biological significance of these findings remains unclear. A
critical assumption that has to be made in this context is that
the capillaries observed in postmortem material correspond
to the structure in its in vivo state. Such a correlation has
been reported [76,77] and it seems likely that instead of the
recruitment of additional capillaries, increased cognitive load
induces differential distribution of flow , heterogeneity
in blood flow velocity  and changes in diameters .
Changes in the flow distribution are usually regulated in the
capillary network itself through the local diffusion of nitric
oxide , serotonin and other neurotransmitters [82,83].
Decreased capillary diameters may lead to impaired micro-
circulation within the hippocampal formation and thus
76A. Imhof et al. / Journal of the Neurological Sciences 257 (2007) 72–79
prevent adaptive responses to local changes in metabolic
The debate whether there is continuity or discontinuity
between normal brain aging and dementia has a long history
is an aging-related condition is supported by the nearly
ubiquitous presenceofADpathologic changes inthe course of
brain aging and the exponential increase of AD prevalence
aging strongly suggests that very old individuals with AD
display a striking resistance to the neurodegenerative process
hospital-based findings supporting a dissociation between the
consistent with the recent neuropathological observations of
of the “lesional” model for explaining the expression of
dementia symptoms in this particular age group. Furthermore,
they offer a new perspective in the field of clinicopathological
The biological background of the increased resistance to
AD lesion development after 90 years is still poorly
understood. Thirty years ago, it was suggested for the first
time that oldest-old people show genetic variations which
influence basic mechanisms of brain aging resulting in a
decreased susceptibility to age-associated diseases . In
particular, it has been proposed that nonagenarians and
centenarians may lack the “disease genes” that predispose to
fatal age-related diseases . Alternatively, they may have
genetic variations that confer protection against age-related
illnesses (the“longevity-enabling” genes ).Inthisrespect,
the sparing of CA1 field and entorhinal cortex may be related
to a genetically determined resistance of these neuronal sub-
populations in very old people. Importantly, evidence from
genetic studies of aging and AD implies that a number of
susceptibility genes may modify or delay the onset of late-life
brain failure. These gene families form a natural target for
devising strategies to delay the onset of late-onset dementia
further stressed by studies of centenarian pedigrees showing
increasedrelativesurvivalprobabilities incentenarian siblings
compared to the general population . The fist community-
based linkage and association studies identified two candidate
genes predisposing to longevity. Both of them were related to
lipoprotein synthesis suggesting that protection against
cardiovascular diseases may be primordial to achieve extreme
old age [89–91]. Although the relationship between these
vascular “longevity-enabling” genes and AD-related patholo-
gy is not clear, the link between preserved cognition and brain
capillary diameter points to the need for exploring the genetic
determinants of the microvascular system in very old
individuals. Moving away from the classical link between
lesion and function, the research on extreme brain aging
should focus on the mechanisms surrounding the activation of
functional brain reserve. With the population of centenarians
growing at such a rapid rate, complex longitudinal studies
microvascular parameters in neocortical areas and differential
both genetic and neurobiological dimensions of longevity.
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