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J Neural Transm (2015) 122:505521

DOI 10.1007/s00702-014-1288-x

NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - REVIEW ARTICLE

Challenges of multimorbidity of the aging brain: a critical update


Kurt A. Jellinger Johannes Attems

Received: 4 June 2014 / Accepted: 24 July 2014 / Published online: 5 August 2014
Springer-Verlag Wien 2014

Abstract A major problem in elderly patients is the high 81 %, and mixed pathologies in 1093 %. These data
incidence of multiple pathologies, referred to as multi- clearly suggest that pathologically deposited proteins in
morbidity, in the aging brain. It has been increasingly neurodegenerating diseases mutually interact and are
recognized that co-occurrence of neurodegenerative pro- influenced by other factors, in particular cardiovascular and
teinopathies and other pathologies including cerebrovas- cerebrovascular ones, to promote cognitive decline and
cular disorders is a frequent event in the brains of both other clinical symptoms. It is obvious that cognitive and
cognitively intact and impaired aged subjects. Although other neuropsychiatric impairment in the aged result from a
clinical and neuropathological diagnostic criteria of the multimorbid condition in the CNS rather than from a single
major neurodegenerative diseases have been improved, disease and that the number of complex pathologies pro-
major challenges arise from cerebral multimorbidity, and gresses with increasing age. These facts have implications
the thresholds to cause clinical overt dementia are ill for improvement of the clinical diagnosis and prognosis,
defined. More than 80 % of aged human brains show the development of specific biomarkers, preventive strate-
neurodegenerative non-Alzheimer type proteinopathies and gies and better treatment of cerebral multimorbidity.
other pathologies which, however, frequently have been
missed clinically and are even difficult to identify at Keywords Alzheimer disease  Cerebral multimorbidity 
neuropathological examination. Autopsy studies differ in Neurodegenerative disease  Proteinopathy 
selection criteria and the applied evaluation methods. Cerebrovascular lesions  Mixed pathology
Therefore, irrespective of the clinical symptoms, the fre-
quency of cerebral pathologies vary considerably: Alzhei- Abbreviations
mer-related pathology is seen in 19100 %, with pure AD Alzheimers disease
Alzheimers disease (AD) in 1772 %, Lewy pathology in AGD Argyrophilic grain disease
639 % (AD ? Lewy disease 928 %), vascular patholo- Ab b-Amyloid
gies in 2893 % (10.778 % pure vascular dementia), aSyn a-Synuclein
TDP-43 proteinopathy in 639 %, hippocampal sclerosis in CAA Cerebral amyloid angiopathy
CBD Corticobasal degeneration
CERAD Consortium to Establish a Registry for
To the memory of our old friend, Prof. Siegfried Hoyer, who passed Alzheimers Disease
away after a long way as an excellent neuroscientist, in January 2014. CN Cognitively normal
CVD Cerebrovascular disease
K. A. Jellinger (&)
Institute of Clinical Neurobiology, Kenyongasse 18, CVL Cerebrovascular lesion
1070 Vienna, Austria DLB Dementia with Lewy bodies
e-mail: kurt.jellinger@univie.ac.at FTLD Frontotemporal lobe degeneration
GCI Glial cytoplasmic inclusions
J. Attems
Institute for Ageing and Health, Newcastle University, HS Hippocampal sclerosis
Newcastle upon Tyne, UK LB Lewy body

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506 K. A. Jellinger, J. Attems

LBD Lewy body disease both cerebral and general multimorbidities increases con-
MCI Mild cognitive impairment siderably (Attems and Jellinger 2013a; Marengoni et al.
MSA Multiple system atrophy 2011; Rahimi and Kovacs 2014). Recent community-based
NACC National Alzheimers Coordinating Center studies have clearly shown that co-occurrence of Alzhei-
NFTs Neurofibrillary tangles mers disease (AD) and non-AD type proteinopathies as
NIA National Institute on Aging well as other superimposed pathologies, in particular
PSP Progressive supranuclear palsy cerebrovascular lesions (CVLs), are frequently occurring in
SVD Small vessel disease the brains of both cognitively unimpaired and demented
TDP-43 TAR DNA binding protein 43 aged individuals, whereas the presence of single disease is
VaD Vascular dementia rather the exception than the rule (Attems and Jellinger
VCI/ Vascular cognitive impairment/vascular 2013a). Multiple pathologies are suggested to interact in
VaD dementia promoting cognitive and other nervous symptoms in the
VCI Vascular cognitive impairment aged (Attems and Jellinger 2013a; Jellinger and Attems
VITA Vienna trans-danube aging study 2007, 2010; Kovacs et al. 2008). Of particular importance
WML White matter lesion is the frequent presence of confounding processes that
coexist with AD, such as cerebrovascular disease (CVD),
Lewy pathology, argyrophilic grain disease (AGD), TDP-
43 proteinopathies, and hippocampal sclerosis (HS)
Introduction (Davidson et al. 2011; Nagy et al. 1997; Nelson et al. 2007;
Rahimi and Kovacs 2014; Schneider et al. 2007a, b), which
Due to increased life expectancy, understanding of age- have, however, frequently been missed clinically and could
associated disorders including cognitive decline is more not be identified without neuropathological examination
and more important, since the prevalence and incidence of using modern bio/histochemical and molecular-biological
dementia increase exponentially with age. In 2010, 35.6 analyses.
million people worldwide lived with dementia, with around
8 million new cases every year. Numbers are expected to
double or triple every 510 years, to 135 millions in 2050, Diagnostic criteria and challenges
16 millions in Europe (Prince et al. 2013). With the dis-
proportional growth of the elderly population, dementia has Current guidelines for the clinical diagnosis of major
become a major public health and socio-economic problem dementia disorders include: revised National Institute of
that threatens to become the scourge of our century (Thies Neurological and Communicative Disorders and Stroke
and Bleiler 2013; Wimo et al. 2013). There are many and the Alzheimers Disease and Related Disorders Asso-
causes of dementia, however, neurodegenerative disorders ciation (NINCDSADRDA) and European Federation of
that are caused by the intra- and extra-cellular deposition of Neurological Societies (EFNS) criteria for AD (Dubois
aggregated misfolded proteins (proteinopathies) are et al. 2010; Sorbi et al. 2012), the National Institute on
thought to be the most prevalent in aged people. Modern Aging-Alzheimers Association (NIA-AA) criteria for AD
neuropathological examinations, have demonstrated that (McKhann et al. 2011; Sarazin et al. 2012; Sperling et al.
the brains of many elderly individuals had Alzheimer- 2011), consensus from the Canadian Consensus Confer-
related pathologies, featured by neurofibrillary tangles ence on the Diagnosis and Treatment of Dementia
(NFTs) and plaques together with a large number of (CCCDTD) (Chertkow et al. 2013) and the International
coincident non-Alzheimer type pathologies (Attems and Working Group 2 criteria for AD (Dubois et al. 2014),
Jellinger 2013a; Jellinger 2013, 2014; Rahimi and Kovacs criteria for Parkinsons disease (PD)-dementia (Dubois
2014). Cognitively normal elderlies may have substantial et al. 2007; Emre et al. 2007), dementia with Lewy bodies
AD-related pathology (Price et al. 2009); but, in general, (DLB) (McKeith et al. 2005), frontotemporal lobe degen-
the density of isocortical tangles correlates best with the eration (FTLD) (Josephs et al. 2011; Seltman and Mat-
severity of cognitive impairment (Nelson et al. 2007, thews 2012), vascular cognitive impairment/dementia
2012), which, however, may or may not apply for the (VCI/VaD) (National Institute of Neurological Disorders
oldest-old age group (Dolan et al. 2010; Purohit et al. 2008; and Stroke and Association Internationale pour la
Sinka et al. 2010). Others emphasized that much of late life Recherche et lEnseignement en Neurosciences/NINDS-
cognitive decline is not due to common neurodegenerative AIREN) (Gorelick et al. 2011; Roman et al. 1993), Inter-
pathologies (Boyle et al. 2013; Strozyk et al. 2010). national Society for Vascular Behavioral and Cognitive
The coexistence of multiple pathologies is referred to as Disorders (VASCOG) (Sachdev et al. 2014), Diagnostic
multimorbidity. With increasing age, the prevalence of and Statistical Manual of Mental Disorders 5th Ed. (DSM

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Challenges of multimorbidity of the aging brain 507

V) (American Psychiatric Association 2013), and other plaques in at least five neocortical regions (C), based on
neurodegenerative syndromes (Lopez et al. 2011). CERAD criteria, as well as more detailed approaches for
Current guidelines for the neuropathological diagnosis assessing co-morbid conditions, such as Lewy body disease
of major dementing disorders rely on qualitative, semi- (LBD), vascular brain injury, HS, and TDP-43 immuno-
quantitative and topographic assessment of morphological reactive lesions (Montine et al. 2012). However, these new
and bio-/histochemical markers, in particular specific pro- algorithms did not consider the various clinico-pathologi-
tein inclusions in neurons, glia and other cells (Arnold et al. cal subtypes of AD, e.g. tangle-predominant dementia
2013a; Jellinger 2010a; Kovacs et al. 2010). The classifi- (TPD) (Jellinger and Attems 2007; Nelson et al. 2009;
cation of neurodegenerative disorders, previously based on Santa-Maria et al. 2012), recently redefined as primary
the anatomical systems involved, has been replaced by age-related tauopathy (Crary et al. 2014), the hippocam-
molecular-pathological ones, which may provide a basis pal-sparing (HpSP-AD) and the limbic-predominant forms
for the neuropathological diagnosis in the future (Fig. 1). (LP-AD) both differing from the most frequent typical AD
A definite diagnosis of AD can only be made by (Janocko et al. 2012; Murray et al. 2011, 2014).
neuropathological examination. Neuropathological criteria Updated neuropathological criteria for the diagnosis of
for AD are (1) cut-off quantitative values of senile plaques other dementias include: three staging systems for a-syn-
and tangles (Duyckaerts and Dickson 2011), (2) their ucleinopathies, in particular LBDs, one for PD (Braak et al.
semiquantitative assessment and age-adjustment in the 2006a, b), another for dementia with Lewy bodies (DLB)
Consortium to Establish a Registry for Alzheimers Disease (McKeith et al. 2005), and revised guidelines for Lewy
(CERAD) protocol (Mirra et al. 1991), (3) topographic body disease (Zaccai et al. 2008). Parkinsons disease
staging of neuritic AD pathology (Braak and Braak 1991), dementia (PDD) and DLB share many clinical and mor-
re-evaluated recently (Alafuzoff et al. 2008; Braak et al. phological features that are suggested to form a continuum
2006a), (4) and the progress and distribution of b-amyloid within the spectrum of LB diseases, and show a variable
(Ab) deposition being different from tau pathology (Thal combination of Lewy and AD pathologies, which may act
et al. 2002b). The combination of CERAD and Braak synergistically (Clinton et al. 2010; Compta et al. 2011;
scores in the National Institute on Aging-Reagan Institute Irwin et al. 2012). In multiple system atrophy (MSA),
(NIA-RI) criteria related dementia to AD-typical lesions morphologically featured by a-synuclein (aSyn)-positive
with high, intermediate and low likelihood (Hyman and glial cytoplasmic inclusions (GCIs), the morphological
Trojanowski 1997), and the recently revised guidelines for correlates of cognitive impairment are under discussion
the neuropathological evaluation of AD and other diseases (Asi et al. 2014; Jellinger 2007b; Stankovic et al. 2014).
consider levels of AD pathology in the brain regardless of Frontotemporal lobe degeneration, the third most fre-
the clinical status of a given individual (Hyman et al. 2012; quent cause of dementias, includes three major clinical
Montine et al. 2012). They include an ABC score of subgroups, showing distinct patterns of brain atrophy (Lu
AD-related changes that incorporates histological assess- et al. 2013). The most common are: microtubule-associated
ment of Ab deposits (A), based on the Ab phases (Thal tau protein (FTLD-tau), TDP-43 (FTLD-TDP-43), and
et al. 2002b), staging of NFTs (B), based on the Braak fusion sarcoma protein (FTLD-FUS), but there is frequent
staging system, and semiquantitative scoring of neuritic overlapping pathology (Goedert et al. 2012; Halliday et al.
2012; Josephs et al. 2011), while various pathological
phenotypes are related to genetic causes (mutations in
MAPT, progranulin, C9ORF72) (Liu et al. 2013). TDP-43
inclusions are frequently observed in cases with AD and
LB pathologies (Arai et al. 2009), as an important factor of
clinico-imaging features of AD (Josephs et al. 2014), but
also in cognitively normal seniors (Arnold et al. 2013a, b).
However, it is not clear whether these changes are a pri-
mary, secondary or coincident event (Wilson et al. 2013).
Neuronal and glial 3-repeat (R) tau deposits in FTLD with
Pick bodies differ from 4R tau in progressive supranuclear
palsy (PSP), and corticobasal degeneration (CBD), both
frequently associated with dementia (Bruns and Jo-
sephs 2013; Burrell et al. 2014), and AGD (Ferrer et al.
2008; Grinberg and Heinsen 2009). For VCI/VaD, recently
Fig. 1 Molecular-pathologic classification of degenerative demen- determined vascular cognitive disease (VCD), despite
tias. From Jellinger (2013) several proposals (Kalaria et al. 2004; Montine et al. 2012),

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508 K. A. Jellinger, J. Attems

due to the high variability of morphological findings and (Dawe et al. 2011; Schneider et al. 2009), the Medical
multifactorial pathogenesis, no generally accepted mor- Research Council Cognitive Function and Ageing Study/
phological scheme for quantitating CVLs and no validated MRC CFAS/(Matthews et al. 2009); the Oregon Brain
neuropathological criteria have been established to date Aging study/OBAS/(Erten-Lyons et al. 2013a); the Reli-
(Jellinger 2014; Roman 2008). A recent staging scheme gious Orders study/ROS/(Schneider et al. 2009; Wilson
proposing semiquantitative assessment of CVLs in four et al. 2013); the Vantaa 85? study (Oinas et al. 2009;
brain regions with scores from IIV/VI (Deramecourt et al. Polvikoski et al. 2001, 2010); the Hisayama study (Fujimi
2012) needs further validation, and a harmonization of the et al. 2008; Wakisaka et al. 2003); the 90? study (Rob-
criteria and techniques for the assessment of cerebral inson et al. 2011); and the Vienna Trans-Danube Aging
lesions of presumable vascular origin in cognitively (VITA) study (Kovacs et al. 2013)]; based on Braak,
impaired is necessary (Alafuzoff et al. 2012; Pantoni et al. CERAD and NIA criteria, irrespective of clinical symp-
2006). toms, ranged from 19 to 67 %, while in some other studies
Hippocampal sclerosis of aging (HSA), a causative AD-pathology occurred between 42 and 100 %. However,
factor in a large proportion of elderly dementia cases the frequency of pure AD, i.e. AD (Braak stages V and
(Dickson et al. 1994), strongly associated with TDP-43 VI) without essential concomitant pathologies, ranged from
pathology (Nelson et al. 2013; Rauramaa et al. 2011), 12 to 72 %, the combination of AD pathology and LB
differs morphologically from HS related to anoxia (epi- disorders from 9 to 28 % and of AD with CVLs from 19 to
lepsy) or AD (Cendes et al. 2014; Nelson et al. 2013; 93 % (Table 1).
Rauramaa et al. 2013), and shows neuropathological and The second most common neurodegenerative disorder is
genetic deviations from typical AD (Murray et al. 2014). featured by Lewy pathology with a range between 6 and
39 %, but its evaluation (detection of cortical LBs) varied
considerably, depending on the methodology (use of a-Syn
Frequency of neurodegenerative lesions in the aged immunostaining), the regions assessed, and the use of
brain classification criteria for LB disorders (Aho et al. 2008;
Parkkinen et al. 2008). The implication of neocortical LBs
The frequency of neurodegenerative diseases in different for cognitive decline is under discussion (Boyle et al. 2013;
studies has been summarized recently (Rahimi and Kovacs Horvath et al. 2013; Kotzbauer et al. 2012), since signifi-
2014). AD-related pathology, previously suggested to be cant cortical Lewy pathology occurs in older people in the
the most frequent type of cerebral lesions in the elderly, absence of clinical symptoms (Byford et al. 2009; Frigerio
according to the statistical evaluation of 12 community- et al. 2011; Markesbery et al. 2009; Parkkinen et al. 2005).
based studies [Adult Changes in Thought study/ACT/ However, it has been suggested that incidental Lewy body
(Cholerton et al. 2013), the Baltimore Longitudinal study disease (iLBD) that shows LBs and decreased tyrosine
of Aging/BALS/(Dolan et al. 2010; Troncoso et al. 2008), hydroxylase reactivity in striatum similar to but much less
the Cambridge City of 75s cohort/CC75C/(Brayne et al. than PD, is a precursor to or a preclinical form of PD that
2009), the Honolulu-Asian Aging study/HAAS/(White lacks parkinsonian symptoms due to a sub-threshold
et al. 2005), the Rush Memory and Aging project/ROS/ pathology (DelleDonne et al. 2008; Frigerio et al. 2011).

Table 1 Mixed pathologies frequent in demented elderly


References n Pathologies (%)
AD lesions AD alone AD ? CVL AD ? LBD VaD

Nolan et al. (1998) 87 87 50 34


Lim et al. (1999) NA AD cases 36 45 22
Riley et al. (2002) AD cases 57 73/93
Petrovitch et al. (2005) (HAAS study) 333 \60 36 24 24
Fernando and Ince (2004) (MRC-CFAS (UK)) 209 (48 % dem.) 70 21 78
Andin et al. (2005) 175 (clin. VaD) 72 28
Schneider et al. (2007a, b) 141 82.7 30 38 12 12
Jellinger (2008) (retrospective) 1,700 (dem.) 83.2 41.1 24.2 9.1 10.7
Jellinger (prospective, unpubl.) 180 82.7 48.8 23.9 10.0 7.8
Kovacs et al. (2013) (other pathologies 23.2 %) 233 100 12 48.9 24 NA
NA not available

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Challenges of multimorbidity of the aging brain 509

Although the prevalence of HS is rather low in the features of cognitive impairment, while large cystic
general population, it is twice as frequent in a demented infarcts are less common (Gold et al. 2005; Jellinger
cohort (Robinson et al. 2011), but the frequency of TDP-43 2007a; Kalaria et al. 2004; Kovari et al. 2004; Troncoso
pathology varies considerably among aged subjects (range et al. 2008). Microinfarcts are an important correlate of
1346 %), partly due to methological and classification age-related VCI, but are not associated with an increased
differences (Wilson et al. 2013). Other neurodegenerative burden of AD pathology (Richardson et al. 2012; Zheng
diseases, such as MSA, PSP, CBD, TDP-43, Pick disease et al. 2013). The presence of both SVD and AD pathologies
and other FTLDs, have been less frequently reported in can summate, particularly at mild levels of AD pathology
aged subjects (less than 510 %) (Byford et al. 2009; (Esiri et al. 1999; Petrovitch et al. 2005), but there is no
Keage et al. 2012; Kovacs et al. 2013; Polvikoski et al. good evidence that one promotes the other (Esiri and
2010; Schneider et al. 2009; Wakisaka et al. 2003), but Englund 2014). Evaluation of the type and topographic
their clinical presentation varies in relation to concomitant pattern of CVLs in a large autopsy series of demented
pathologies (Dugger et al. 2014). subjects, in cases with pure VaD, i.e. without essential
other pathologies, showed a significantly higher frequency
of small subcortical lesions (70 %) than of large infarcts
Vascular pathologies in the aging brain (volume \10 ml) involving one or both hemispheres
(32.5 %). This pattern differed considerably from that in
Cerebrovascular pathologies have been reported in cases with mixed dementia (AD ? vascular encephalopa-
5085 % of elderly subjects, but due to the lack of clearly thy), where 56.6 % revealed large, often lobar infarcts of
defined assessment criteria, their reported frequency varies multiple cortical and subcortical lesions larger than
considerably. Of note, this association was recently found 510 mm in diameter involving one or both hemispheres,
to be stronger in cases with lower NFT pathology (Toledo whereas lacunes and small subcortical microinfarcts were
et al. 2013), similar to earlier studies on respective asso- seen in only 36 %. These data suggest different pathogenic
ciations with subcortical vascular pathology (Chui et al. mechanisms between both types of disorders (Jellinger and
2006) and general CVD (Petrovitch et al. 2005). The Attems 2010).
spectrum of vascular pathologies assessed at autopsy ran- Recent emphasis on comorbidity of AD and CVD,
ges from small vessel disease (SVD), microinfarcts, lac- detected in 3060 % of AD brains and showing a large
unes, white matter lesions, cerebral amyloid angiopathy variety of lesions (Jellinger and Attems 2005, 2014;
(CAA) to large infarcts due to large vessel disease of Schneider et al. 2007a, b), and many other data indicate an
various extent in multi-infarct encephalopathy, cerebral association between AD and CVD. However, their role in
microbleeds and hemorrhages (Grinberg and Thal 2010; dementia is still under discussion and data obtained from
Jellinger 2007a, 2008; Richardson et al. 2012; Thal et al. epidemiological and clinico-pathological studies regarding
2012). Multiple lacunar microinfarcts were most frequent their relation are controversial (Esiri et al. 1999; Jellinger
in Japanese dementia cases with a prevalence of 42 %, 2008; Jellinger and Attems 2014; Rincon and Wright 2014;
suggesting that VaD was more frequent in the Japanese Zekry et al. 2002). Small vascular and AD-related patho-
than in Western populations (Fujishima and Kiyohara logical determinants of dementia have been demonstrated
2002). Vascular brain injury is commonly encountered in in the oldest old (Sinka et al. 2010). In elderly patients with
elderly subjects with and without AD pathology (Ferrer subclinical AD, either critically located CVLs or cortical
2010; Grinberg and Thal 2010; Jellinger 2007a). However, microinfarcts may worsen cognitive impairment due to a
subcortical SVD is increasingly recognized as a predictor synergistic interaction between both pathologies (Esiri
of cognitive impairment (Smallwood et al. 2012). The et al. 2014; Iadecola 2010; Miklossy 2003), while in
NUN study suggested that individuals with NFT pathology advanced of full-blown stages of AD, concomitant small
and one or two lacunar infarcts experienced a steeper drop vascular lesions do not significantly influence the overall
in cognitive function than those without cerebral infarcts state and progression of cognitive decline that is mainly
(Snowdon et al. 1997). On the other hand, in the Vienna related to the severity and extent of AD pathology over-
VITA study, single microinfarcts and territorial infarcts whelming the modest effects of CVD (Chui et al. 2006;
were found in up to 33 % in both demented and non- Esiri et al. 2014; Jellinger and Attems 2005; Jellinger
demented aged individuals (Kovacs et al. 2013). Several 2007a). The thresholds for vascular and degenerative
studies discussed that the presence of multiple infarction is lesions for distinguishing pure VaD or AD from mixed
more relevant for cognitive decline than the size of single cases have been critically discussed (Gold et al. 2007).
infarcts (Schneider et al. 2003; Troncoso et al. 2008; White The burden of vascular and AD-type pathologies are
et al. 2002), and that subcortical lacunes and multiple considered to be independent of each other, and are con-
disseminated microinfarcts appear to be the most common sistent with an additive or synergistic effect of both types

123
510 K. A. Jellinger, J. Attems

of lesions on cognitive impairment (Andin et al. 2005; increased from aged controls (total 30 %, 20 % severe) to
Jellinger 2007a; Kalaria et al. 2004; Launer et al. 2008; AD (total 97.7 %, among which 75 % severe). In 75 % of
Lim et al. 1999; Schneider et al. 2004; Strozyk et al. 2010). AD patients, hemorrhages were associated with severe and
An interesting finding is the inverse correlation of the only in 10 % with mild to moderate CAA, while only 20 %
volume of white matter lesion (WML) with NFT pathol- of cerebral infarcts were associated with severe CAA.
ogy, supporting the concept of synergistic effects and These studies confirmed previous ones documenting
suggesting that AD pathology might be driving the white significantly higher frequency of vascular pathology in AD
matter pathology (Shim et al. 2014). The variability of data than in age-matched non-demented controls. Like in the
on the neuropathologies of WMLs has been emphasized Einstein Aging Study in 67 patients with autopsy-proven
(Erten-Lyons et al. 2013b; Schmidt et al. 2011), and their AD showing additional vascular pathology in 82.1 %
significance may be different to the state of the disease, (Crystal and Dickson 2002), no significant differences in
subjects with early AD probably being more vulnerable the severity of cognitive decline between AD with and
than cognitively normal older adults with similar WML without concomitant CVLs were observed, which suggests
burden (Burns et al. 2005). AD-related pathology alone a floor effect of high-grade AD pathology in these patients.
more frequently accounts for dementia than both macro- These studies corroborated with another study comparing a
scopic and microscopic infarcts (Troncoso et al. 2008). In a large number of seniors showing similar age and Braak
recent study, global AD pathology significantly correlated scores but less severe dementia and more frequent histories
to global cognition, whereas infarct and Lewy pathologies of stroke in AD cases with additional CVD (Jellinger
did not (Bennett et al. 2012). 2002), but are at variance with others reporting more
In a population-based study in the UK, among 209 severe dementia and less severe AD pathology in patients
autopsies of elderly subjects, 48 % being demented, 78 % with concomitant CVD (Esiri et al. 1999; Petrovitch et al.
had evidence of CVD and 70 % of AD pathology. The 2005; Snowdon et al. 1997; Zekry et al. 2002).
proportion of multiple vascular lesions was higher in the The contribution of CVD in neurodegenerative diseases
demented group, while only 21 % showed pure AD, was recently studied in 5,715 autopsy cases of the National
indicating that most patients had mixed disease (Fernando Alzheimers Coordinating Center (NACC) database. For
and Ince 2004). In a health maintenance organization comparison, 210 unremarkable cases without cognitive
dementia register, only 36 % of patients had AD without impairment and 280 cases with pure CVD were included.
any other pathologies, while 4 % had definite AD plus The latter were older than those without CVD in all groups
coexistent CVD (Lim et al. 1999). Among 333 autopsied except for those with HS. a-Synucleinopathies, FTLD and
men in the Honolulu Asian Aging Study (120 demented, prion diseases showed a lower coincident CVD than AD
114 marginal, 96 normal cognition), 24 % of dementias patients, and those with both AD and synucleinopathies
were linked with CVD and dementia frequency more than revealed a lower burden of their relative lesions than those
doubled in AD with coexistent CVD (45 vs. 20 %). These without CVD in the context of comparable dementia. In
findings suggest that CVD is associated with a marked conclusion, CVD as a common finding in aged subjects
excess of dementia in cases with low neuritic plaque fre- with dementia, is more common in AD than in other
quency (Petrovitch et al. 2005). In a retrospective series of neurodegenerative disorders and lowers the threshold for
730 autopsy cases of AD and 535 age-matched controls, dementia due to AD or synuclein pathologies (Toledo et al.
using a 4-grade scale for the severity of CVLs, the total 2013), confirming previous findings (Jellinger 2008;
prevalence of CVD in AD was significantly higher than in Schneider et al. 2004; Strozyk et al. 2010; Zekry et al.
controls (31.6 vs. 23.4 %) (Jellinger and Mitter-Ferstl 2003a).
2003). Cerebral amyloid angiopathy is a very frequent but not
Retrospective examination of the prevalence of CVD in consistent feature of AD (Attems 2005; Attems et al. 2005,
a consecutive autopsy series of 621 autopsy-proven AD 2011), and is also a relevant cause for hemorrhages and
cases and 486 age-matched NC controls, using a 4-degree brain infarction (Tanskanen et al. 2012). Capillary CAA
scale for cerebrovascular pathology, showed 67.8 % CVLs can occur without the presence of general CAA in the
in AD versus controls (29.4 %); severe CVLs [old/recent meningeal and cortical arteries and it allows the distinction
infarcts and hemorrhages were more frequent in AD between two types: CAA type 1 characterized by the pre-
(23.6 %) than in controls (5.4 %)]. Cortico-subcortical sence of capillary CAA with or without concomitant gen-
infarcts and subcortical vascular lesions were more fre- eral CAA, while in CAA type 2, no capillary CAA is
quent in AD than in controls (41.2 vs. 11.6 %). Both the present (Thal et al. 2002a). The presence of capillary CAA
incidence and severity of CVLs, similar to the previous has been suggested to identify a subtype of AD that is
study, increased with higher neuritic Braak stages (Jellin- characterized by a stronger association to the APOE e4
ger 2010b). Likewise, the prevalence and severity of CAA genotype, higher Ab load and higher Braak neuritic stages

123
Challenges of multimorbidity of the aging brain 511

Table 2 Frequency of different neuropathological variables in community-based studies


Study (n) N AD-related pathologies a-Syn TDP-43 HS Vascular Mixed
(%) (%) pathologies pathology
Braak III CERAD NIA (%) (%)
VI (%) (%)
(%)

MAP study 425 59 15 % 13 46a 23


ROS study 539 61 21 % 46 13 49a 28
MRC CFAS 525 52 46 39 % (29 % amygdala) 70b
Cambridge 75C 224 39l 28 15 % 56c
h
Vantaa 85? 304 70 66 41 36 % 5 55a 40
Hisayama 205 62 29 % 31 10d
studyk
HAAS 439 19e 10 %k 9k 28c 39.5
ACT study 438 62 47 14 % 35c
BALS 209 56f 6 %k 44a
OBAS 125 62 44 20 % 7 46c
90? study 108 67 6 %g 31 29k 19i
j
VITA study 223 38 35 25 % (17.2 % 13 3 49 74
amygdala)
Total 3,775
Modified from Rahimi and Kovacs (2014)
a
Macroscopic and microscopic infarcts/brain infarcts
b
Any vascular disease
c
Microinfarcts/cortical microvascular lesions
d
AD ? VD
e
Pure AD cases defined as frequent NP according to CERAD or Braak stages V and VI
f
Composite AD pathology score by summing CERAD and Braak in equal measures (score [4 included)
g
DLB high likelihood
h
Braak stages IVVI with moderate or frequent NP
i
AD ? DLB/FTD
j
Vascular pathology including bleeding and ischemic lesions
k
Data only reported for demented subjects
l
Severe hippocampal NFTs

as compared to other subtypes of AD (Thal et al. 2010). A processes in the aged brain that coexist with AD-related
consensus protocol for the assessment of CAA in post- lesions, as for example CVD, Lewy pathology, AGD, TDP-
mortem brain tissue has been published recently (Love 43 pathology, and HS. Of note, mixed dementia should not
et al. 2014). be used to describe the presence of additional minimal or
limited pathologies, e.g. AD with minor CVLs (Jellinger
2008). Depending on the definition of mixed dementia/
Mixed dementia: mixed pathologies mixed pathologies, the prevalence lies between 2 and 93 %
(Table 2) (Davidson et al. 2011; Jellinger and Attems
Although no standardized criteria for mixed dementia are 2010; Jellinger 2013; Nagy et al. 1997; Nelson et al. 2007;
currently available (Gold et al. 2007; Jellinger and Attems Rahimi and Kovacs 2014; Schneider et al. 2007a, b).
2007; Jellinger 2008), this neuropathological diagnosis Although several clinico-pathological studies used differ-
should be made if more than one disease or type of lesions ent recruitment and neuropathological methods, they all
is detected at postmortem brain examination. The most concluded that mixed pathologies are frequent and increase
frequent form is the simultaneous presence of both AD and with age (Gelber et al. 2012; Jellinger 2007a; Jellinger and
cerebrovascular pathology, but the co-occurrence of sev- Attems 2010; Nelson et al. 2013). In a consecutive autopsy
eral pathologies has been observed frequently. Of partic- series of 1,110 patients (mean age 83.3 5.6 years; 90 %
ular importance is the frequent presence of confounding over age 70), the prevalence of pure AD increased from

123
512 K. A. Jellinger, J. Attems

32.3 % in the 7th decade to 45.1 % in the 9th decade but demented subjects (mean age 74.14 12.07 years)
decreased in the 10th decade to 39.2 %. By contrast, AD showed mixed pathology in 53 % of the cases, that was
with minor CVLs as well as AD ? severe CVD both most frequently seen in synucleinopathies (PD 92 %, DLB
increased from 7.8 % in the 7th decade to 32.9 % in the 61 %), followed by cases with vascular pathology (61 %),
10th decade (Jellinger and Attems 2010). Mixed patholo- AGD (61 %), and AD (43 %), less frequent in PSP (22 %),
gies increase the odds of dementia to almost ten times and CBD (21 %), frontotemporal lobe degeneration with
up to three times compared to patients with only one brain ubiquitin-positive inclusions (FTLD-U) (9 %), and Cre-
pathology (Schneider et al. 2007a, b). utzfeldtJakob disease (2 %). The most frequent diagnoses
The rate of neuropathologically confirmed intermediate in mixed cases was AD in 89.6 % (p \ 0.01), followed by
and high likelihood AD plus any other pathology was vascular pathology (52.6 %), synucleinopathy (50 %), and
reported to be as almost 54 % in the Rush Memory and AGD (11.4 %) (Kovacs et al. 2008).
Aging Project cohort (Schneider et al. 2007a, b), while in In several autopsy series of oldest-old individuals, the
the VITA study, the presence of mixed pathologies was frequency of AD ranged from 12 to 66 %, that of vascular
over 70 % (Kovacs et al. 2013). In a large retrospective dementia from 9 to 46.8 %, of DLB between 9 and 24 %,
autopsy study of demented patient (N = 1,700, mean age and that of mixed pathologies between 2 and 86 % (Jel-
83.3 6.0 years; 52 % with the clinical diagnosis of linger and Attems 2010).
probable AD) 83.2 % revealed AD-related pathology, but Many studies emphasize multiple confounding pathol-
only 41.1 % were diagnosed as pure AD without con- ogies in non-demented elderly subjects, in particular CVLs,
comitant pathologies; 24.2 % showed additional cerebro- e.g. small or large infarctions, lacunes, and white matter
vascular lesions (infarcts, hippocampal sclerosis, lacunar lesions, in up to 10 % (Davis et al. 1999; Jentoft et al.
state, etc.), 9.1 % additional Lewy pathology, and 2.6 % 2011; Knopman et al. 2003; Schneider et al. 2009). Eval-
various other concomitant brain lesions, while 10.7 % were uation of 336 cognitively normal (CN) seniors from four
diagnosed as pure vascular dementia without AD- studies revealed moderately to frequent neuritic plaque
pathology superior to age-related intensity. 5.5 % of the density in 47 %; of these 6 % had Braak neuritic stages I
demented patients showed other non-AD related disorders VI, medullary, nigral, and cortical LBs in 15, 8, and 4 %,
(other neurodegenerative diseases, like MSA, multiple respectively; cerebral microinfarcts in 33 %, and high-level
sclerosis or tumors), while in 0.9 % of the total, no microinfarcts in 10 %. The burden of brain lesions and
pathology other than mild age-related lesions were detected comorbidities varied widely within each study, but was
(Jellinger 2008). similar across studies (Sonnen et al. 2011).
Using the NACC database, a retrospective review of 533 Among 418 non-demented participants of the Religious
patients clinically diagnosed as AD, showed that the Order Study (age 88.5 5.3 years), 35 % showed mac-
pathological results of 199 subjects (36 %) did not meet the roscopic brain infarcts, 8 % microinfarcts, 14.8 % arterio-
criteria of definite AD. The neuropathological diagnoses of sclerosis, 5.7 % both, only 37.5 % being free of CVLs
these cases consisted of DLB (29 %), insufficient AD (Buchman et al. 2011). Up to 75 % of CN elders had
(18 %), vascular disease (13 %), FTLD (12 %), and HS various degrees of CAA, argyrophilic grains in up to 23 %
(8 %) (Shim et al. 2013). These data emphasize that (Jentoft et al. 2011), LBs in up to 18 % (Jellinger and
continuing systematic comparisons of clinical data are Attems 2012; Knopman et al. 2003; Schneider et al. 2009;
essential to clinical practice and research, and may also White 2009), occasional HS (Jentoft et al. 2011; Schmitt
lead to further improvement of the diagnostic procedure. et al. 2000), and mixed pathologies in 715 % (Schneider
A recent study of 2,083 autopsy cases from the NACC et al. 2009; White 2009). Among 100 non-demented
database correlating the clinical dementia rate within elderly, mild, moderate and severe intracranial athero-
2 years before death in 835 subjects showed that the cause sclerosis was present in 31, 17 and 6 %, respectively,
of mild to moderate dementia remained uncertain in 14 %. lacunar state in basal ganglia and/or white matter in 73 %,
Plaques and tangles independently correlated with cogni- HS in 3 %, LBs in 5 % but tau pathology in brainstem in
tive dysfunction, and severe SVD. CAA and HS were also 60 %, and other mixed cerebral pathologies in 6 %,
independently associated with the degree of cognitive whereas only 9 % were free of CVLs (Jellinger and Attems
impairment, while concomitant CVD strongly correlated 2012). A recent British non-demented sample (n = 53,
with cognitive impairment in the sample selected to rep- mean age 81.5 7.4 years) showed maximum score neu-
resent AD pathological continuum, confirming the uncer- ritic plaques in 3294 %, NFTs in hippocampus and neo-
tainty of AD clinico-pathological correlations based only cortex in 81 and 30.8 %, respectively, white matter lesions
on tangles and plaques (Serrano-Pozo et al. 2013). in 5583 %, SVD in 45 %, brain infarcts in 13.7 %, lac-
A study across nine centers of the BrainNet Europe unes in 6 %, and cerebral hemorrhages in 10 % (Stephan
Consortium evaluating neuropathological data of 3,303 et al. 2012). A community-based autopsy series from the

123
Challenges of multimorbidity of the aging brain 513

Viennese VITA study (Fischer et al. 2002) of 233 subjects a single distinct neurodegenerative disease and age-related
over age 75 (range 7787 years), in addition to some changes that are not directly associated. For example, the
degrees of NFTs in 100 %, showed Ab deposits (68.7 %), high prevalence of CVLs in AD brains of aged subjects
CVLs (48.9 %), non-AD tauopathies (23.2 %), TDP-43 mirrors the prevalence of vascular disease in the aged per
proteinopathy (13.3 %), and others (inflammation, tumors, se, rather than suggesting causal relationships between AD
etc., 15.1 %). Most of these lesions did not increase the and CVLs. However, this does not preclude the possibility
probability of the co-occurrence of others, while the that CVLs exert influence on AD pathology itself, and it
number of coincidental pathologies correlated significantly has been suggested that CVLs lower the threshold for overt
with AD-related changes (Kovacs et al. 2013). clinical dementia, i.e. that less AD pathology is needed to
A recent cross-sectional study in a community-based cause clinical symptoms in the simultaneous presence of
sample of 72 CN older individuals (mean age CVD (Jellinger and Attems 2007; Zekry et al. 2003a, b).
74.9 5.7 years) confirmed that a substantial number Another example for the simultaneous presence of a dis-
harbored neurodegeneration without Ab burden, but asso- tinct neurodegenerative disease with age-associated chan-
ciation of neurodegenerative lesions with CVD can emerge ges is the co-occurrence of AD pathology in DLB
through non-Ab pathways within regions most affected by biochemical overlapping between DLB and AD, including
AD pathology (Wirth et al. 2013). co-localization on aSyn and tau epitopes in LBs, suggests
that the process of LB formation is triggered, at least in
part, by AD pathology (Iseki et al. 2003). Similarly to the
Impact of comorbidity presumed impact of CVLs in AD, aSyn pathology in DLB
is aggravated by AD pathology (Merdes et al. 2003; Per-
Data from many different autopsy studies indicate the neczky et al. 2005).
presence of additional lesions in otherwise well-charac- The synergistic interaction between Ab, tau, aSyn and
terized cases that may fulfill the criteria for a single distinct other pathological proteins, demonstrated in in vitro and in
disorder: animal models (Giasson et al. 2003; Oddo et al. 2003)
accelerating neuropathology and cognitive decline, and
1. In AD that is characterized by Ab and tau pathology,
explaining overlap between synucleinopathies, tauopathies,
LBs were seen in up to 43 %; AD with amygdala LBs
and other neurodegenerative disorders (Compta et al. 2011;
is considered a distinct form of aSynucleinopathy
Wills et al. 2010) has been summarized recently (Clinton
(Uchikado et al. 2006). TDP-43 pathology is seen in up
et al. 2010; Colom-Cadena et al. 2013; Jellinger 2010a,
to 43 % (Amador-Ortiz et al. 2007; Arai et al. 2009;
2012). The high prevalence of mixed pathologies con-
Bigio et al. 2010; Davidson et al. 2011; Duyckaerts
firmed by many autopsy studies supports the notion that a
et al. 2009; Josephs et al. 2008, 2014; Rauramaa et al.
combination of neuropathological alterations often has a
2011; Robinson et al. 2011), and severe CVLs in up to
cumulative effect and, if reaching the individual threshold
50 % of the AD cases (Jellinger and Attems 2010).
for cognitive impairment, manifests as clinical dementia
2. In LBD that is characterized by aSyn pathology,
(Kovacs et al. 2013; Savva et al. 2009). When discussing
coincident Ab pathology is found in 95 %, considerable
the prevalence of mixed pathologies, not only their fre-
tau pathology (Braak stages V/VI) in 55 %, and various
quency is important, but also that the number of combi-
degrees of CVD in 75 % (Jellinger and Attems 2008).
nations of major alterations can be very high (Kovacs et al.
Another autopsy study in investigating a cohort for the
2013). It should be emphasized that in the concept for the
presence of aSyn pathology reported that over 50 % of
understanding of aging brain, both AD-related and non-AD
the cases with widespread aSyn lesions did not show any
pathologies should be evaluated in details (Dugger et al.
clinical symptoms (Parkkinen et al. 2008).
2014; Nelson et al. 2013).
3. Pure VaD without additional lesions is rare (Jellinger
2007a; Jellinger and Attems 2010), and frequently
confounding, but often limited AD pathology is present.
Conclusions and future perspectives
However, since 5085 % of post mortem brains from
individuals dying over age 80, show appreciable CVLs
Currently, neuropathological assessment is based on
(Petrovitch et al. 2005), a specific problem is the impact
semiquantitative scoring of cerebral lesions, the criteria of
of CVD in relation to AD pathology (Bennett et al. 2005;
which have recently been standardized (Alafuzoff et al.
Chui 2006; Chui et al. 2006; Jellinger and Attems 2005;
2008; Braak et al. 2006a, 2006b; Montine et al. 2012).
Schneider et al. 2007a, b).
While these methods are used in routine neuropathological
The high prevalence of multiple pathologies in brains of diagnosis, they provide only a rough estimation of the
aged individuals could reflect the simultaneous presence of amount of pathology present in the brain. Algorithms for

123
514 K. A. Jellinger, J. Attems

the molecular-pathological classification of sporadic (non- et al. 2014; Jack 2012; Toledo et al. 2013; Vanderstichele
genetic) forms of neurodegenerative dementias have been et al. 2012; Weiner et al. 2010). In the majority of cases
proposed (Dickson et al. 1994; Jellinger 2010a; Kovacs except those with known genetic or metabolic back-
et al. 2010). However, due to variable overlap, these grounds, however, pathological examination may not be
changes may fail to distinguish between cognitively intact able to clarify the causes or etiology of most dementing
aged subjects from those with preclinical or mild to mod- disorders (Jellinger 2010a), while some conservative
erate AD (Jicha et al. 2012; Markesbery et al. 2009; Pet- authors emphasized that autopsy examination of well-
ersen et al. 2006). These latter groups show a wide variety studied cases of AD and other dementias still has a critical
in intensity and pattern of AD-related and other pathologies role to play (Esiri 2010). Therefore, the reliability and
(Schneider et al. 2009; Stephan et al. 2012). Although they clinical relevance of the current criteria for the neuro-
differ from normal aging, only a small proportion of pathological diagnosis of neurodegenerative disorders and
cognitively intact aged subjects are free of AD and other other brain pathologies need better qualification, quantita-
pathologies, while the majority shows multiple pathologies tion and validation in order to find a way out of the chaos
(Arriagada et al. 1992; Bennett et al. 2005; Davis et al. regarding the histopathological diagnosis of disorders of
1999; Jellinger and Attems 2012; Knopman et al. 2003). the aging brain. Molecular genetics, biochemistry, and
Additional challenges arise from the frequent coexistence animal models, at least in part reproducing the morphology
of various pathologies in the aging brain that may have an of human brain diseases, have produced a large body of
additive or synergistic effect (Fig. 2), although their mutual data on the pathogenesis and pathophysiology of these
impact often remains unclear. Community-based neuro- disorders, showing a complex cascade of events leading
pathological studies have shown that complex constella- from preclinical to fully developed neurodegeneration (de
tions of underlying pathologies may lead to cognitive Calignon et al. 2012; Gotz and Gotz 2009; Petiet et al.
decline and that the number and intensity of possible 2011). However, both their molecular backgrounds, basic
constellations increased in the aging brain. However, cau- etiological factors, pathogenic interrelations of the various
tion is needed for the interpretation of frequency values in concomitant pathologies, and their impact on the clinical
view of the differences in recruitment, assessment, meth- symptoms need further validation. Methodological issues
ods, criteria used, and brain regions examined. More in evaluating multimorbidity are to be considered as well as
accurate quantitative assessment of various neuropatho- future research needs, especially concerning etiological
logical lesions is necessary to further elucidate possible factors, combinations and clustering of chronic brain dis-
mutual relationships between coincident pathologies as eases, and new animal models for conditions affected by
well as their combined influence on the clinical picture. multiple disorders in order to provide further insights in the
Interdisciplinary projects/initiatives for the standardized problems of multimorbid patients (Marengoni et al. 2011).
assessment of clinical, biomarker, and neuropathological Neuropathological studies should use a wide range of
data are currently under way (Cairns et al. 2010; Dubois molecular-pathological methods and should evaluate as
many brain regions as possible. Harmonized and modern
techniques are required to increase the accuracy and
reproducibility of neuropathological diagnosis in view of
the frequent co-occurrence of multiple different patholo-
gies as a basis for further personalized treatment and
neuroprotection, an enormous challenge for modern
neurosciences.

References

Aho L, Parkkinen L, Pirttila T, Alafuzoff I (2008) Systematic


appraisal using immunohistochemistry of brain pathology in
Fig. 2 Multiple pathologies in brains of demented seniors. Full aged and demented subjects. Dement Geriatr Cogn Disord
arrows point towards the characteristic neuropathology of the 25:423432
respective disease, while dotted arrows point towards neuropatho- Alafuzoff I, Arzberger T, Al-Sarraj S, Bodi I, Bogdanovic N, Braak
logical lesions that are frequently seen in addition to the main H, Bugiani O, Del-Tredici K, Ferrer I, Gelpi E, Giaccone G,
pathological hallmark lesions. Approximate percentages are encir- Graeber MB, Ince P, Kamphorst W, King A, Korkolopoulou P,
cled. AD Alzheimers disease, LBD Lewy body diseases, FTLDTDP Kovacs GG, Larionov S, Meyronet D, Monoranu C, Parchi P,
frontotemporal lobar degeneration with TDP-43 pathology, VaD Patsouris E, Roggendorf W, Seilhean D, Tagliavini F, Stadel-
vascular dementia. From Attems and Jellinger (2013b) mann C, Streichenberger N, Thal DR, Wharton SB, Kretzschmar

123
Challenges of multimorbidity of the aging brain 515

H (2008) Staging of neurofibrillary pathology in Alzheimers aphasia and frontotemporal dementia with pathologic Alzheimer
disease: a study of the BrainNet Europe Consortium. Brain disease. Acta Neuropathol 120:4354
Pathol 18:484496 Boyle PA, Wilson RS, Yu L, Barr AM, Honer WG, Schneider JA,
Alafuzoff I, Gelpi E, Al-Sarraj S, Arzberger T, Attems J, Bodi I, Bennett DA (2013) Much of late life cognitive decline is not due
Bogdanovic N, Budka H, Bugiani O, Englund E, Ferrer I, to common neurodegenerative pathologies. Ann Neurol
Gentleman S, Giaccone G, Graeber M, Hortobagyi T, Hoftberger 74:478489
R, Ironside JW, Jellinger KA, Kavantzas N, King A, Korkolop- Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-
oulou P, Kovacs GG, Meyronet D, Monoranu C, Parchi P, related changes. Acta Neuropathol 82:239259
Patsouris E, Roggendorf W, Rozemuller A, Seilhean D, Strei- Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K
chenberger N, Thal DR, Wharton SB, Kretzschmar H (2012) The (2006a) Staging of Alzheimer disease-associated neurofibrillary
need to unify neuropathological assessments of vascular alter- pathology using paraffin sections and immunocytochemistry.
ations in the ageing brain. Multicentre survey by the BrainNet Acta Neuropathol 112:389404
Europe consortium. Exp Gerontol 47:825833 Braak H, Bohl JR, Muller CM, Rub U, de Vos RA, Del Tredici K
Amador-Ortiz C, Lin WL, Ahmed Z, Personett D, Davies P, Duara R, (2006b) Stanley Fahn Lecture 2005: the staging procedure for
Graff-Radford NR, Hutton ML, Dickson DW (2007) TDP-43 the inclusion body pathology associated with sporadic Parkin-
immunoreactivity in hippocampal sclerosis and Alzheimers sons disease reconsidered. Mov Disord 21:20422051
disease. Ann Neurol 61:435445 Brayne C, Richardson K, Matthews FE, Fleming J, Hunter S, Xuereb
American Psychiatric Association (2013) Diagnostic and statistical JH, Paykel E, Mukaetova-Ladinska EB, Huppert FA, OSullivan
manual of mental disorders, 5th edn (DSM-5). American A, Dening T (2009) Neuropathological correlates of dementia in
Psychiatric Association Arlington, VA over-80-year-old brain donors from the population-based Cam-
Andin U, Gustafson L, Passant U, Brun A (2005) A clinico- bridge city over-75s cohort (CC75C) study. J Alzheimers Dis
pathological study of heart and brain lesions in vascular 18:645658
dementia. Dement Geriatr Cogn Disord 19:222228 Bruns MB, Josephs KA (2013) Neuropsychiatry of corticobasal
Arai T, Mackenzie IR, Hasegawa M, Nonoka T, Niizato K, Tsuchiya degeneration and progressive supranuclear palsy. Int Rev
K, Iritani S, Onaya M, Akiyama H (2009) Phosphorylated TDP- Psychiatry 25:197209
43 in Alzheimers disease and dementia with Lewy bodies. Acta Buchman AS, Leurgans SE, Nag S, Bennett DA, Schneider JA (2011)
Neuropathol 117:125136 Cerebrovascular disease pathology and parkinsonian signs in old
Arnold SE, Toledo JB, Appleby DH, Xie SX, Wang LS, Baek Y, age. Stroke 42:31833189
Wolk DA, Lee EB, Miller BL, Lee VM, Trojanowski JQ (2013a) Burns JM, Church JA, Johnson DK, Xiong C, Marcus D, Fotenos AF,
Comparative survey of the topographical distribution of signa- Snyder AZ, Morris JC, Buckner RL (2005) White matter lesions
ture molecular lesions in major neurodegenerative diseases. are prevalent but differentially related with cognition in aging
J Comp Neurol 521:43394355 and early Alzheimer disease. Arch Neurol 62:18701876
Arnold SJ, Dugger BN, Beach TG (2013b) TDP-43 deposition in Burrell JR, Hodges JR, Rowe JB (2014) Cognition in corticobasal
prospectively followed, cognitively normal elderly individuals: syndrome and progressive supranuclear palsy: a review. Mov
correlation with argyrophilic grains but not other concomitant Disord 29:684693
pathologies. Acta Neuropathol 126:5157 Byford M, Brayne C, McKeith I, Chatfield M, Ince P, Matthews F
Arriagada PV, Marzloff K, Hyman BT (1992) Distribution of (2009) Lewy bodies and neuronal loss in subcortical areas and
Alzheimer-type pathologic changes in nondemented elderly disability in non-demented older people: a population based
individuals matches the pattern in Alzheimers disease. Neurol- neuropathological cohort study. BMC Geriatr 9:22
ogy 42:16811688 Cairns NJ, Taylor-Reinwald L, Morris JC (2010) Autopsy consent,
Asi YT, Ling H, Ahmed Z, Lees AJ, Revesz T, Holton JL (2014) brain collection, and standardized neuropathologic assessment of
Neuropathological features of multiple system atrophy with ADNI participants: the essential role of the neuropathology core.
cognitive impairment. Mov Disord 29:884888 Alzheimers Dement 6:274279
Attems J (2005) Sporadic cerebral amyloid angiopathy: pathology, Cendes F, Sakamoto AC, Spreafico R, Bingaman W, Becker AJ
clinical implications, and possible pathomechanisms. Acta (2014) Epilepsies associated with hippocampal sclerosis. Acta
Neuropathol 110:345359 Neuropathol 128:2137
Attems J, Jellinger K (2013a) Neuropathological correlates of Chertkow H, Feldman HH, Jacova C, Massoud F (2013) Definitions
cerebral multimorbidity. Curr Alzheimer Res 10:569577 of dementia and predementia states in Alzheimers disease and
Attems J, Jellinger KA (2013b) Neuropathology. In: Dening T, vascular cognitive impairment: consensus from the Canadian
Thomas A (eds) Oxford textbook of old age psychiatry, 2 edn. conference on diagnosis of dementia. Alzheimers Res Ther 5:S2
Oxford University Press, Oxford, pp 87105 Cholerton B, Larson EB, Baker LD, Craft S, Crane PK, Millard SP,
Attems J, Jellinger KA, Lintner F (2005) Alzheimers disease Sonnen JA, Montine TJ (2013) Neuropathologic correlates of
pathology influences severity and topographical distribution of cognition in a population-based sample. J Alzheimers Dis
cerebral amyloid angiopathy. Acta Neuropathol 110:222231 36:699709
Attems J, Jellinger K, Thal DR, Van Nostrand W (2011) Review: Chui HC (2006) Vascular cognitive impairment: today and tomorrow.
sporadic cerebral amyloid angiopathy. Neuropathol Appl Neu- Alzheimers Dement 2:185194
robiol 37:7593 Chui HC, Zarow C, Mack WJ, Ellis WG, Zheng L, Jagust WJ,
Bennett DA, Schneider JA, Bienias JL, Evans DA, Wilson RS (2005) Mungas D, Reed BR, Kramer JH, Decarli CC, Weiner MW,
Mild cognitive impairment is related to Alzheimer disease Vinters HV (2006) Cognitive impact of subcortical vascular and
pathology and cerebral infarctions. Neurology 64:834841 Alzheimers disease pathology. Ann Neurol 60:677687
Bennett DA, Schneider JA, Arvanitakis Z, Wilson RS (2012) Clinton LK, Blurton-Jones M, Myczek K, Trojanowski JQ, LaFerla
Overview and findings from the religious orders study. Curr FM (2010) Synergistic Interactions between Abeta, tau, and
Alzheimer Res 9:628645 alpha-synuclein: acceleration of neuropathology and cognitive
Bigio EH, Mishra M, Hatanpaa KJ, White CL 3rd, Johnson N, decline. J Neurosci 30:72817289
Rademaker A, Weitner BB, Deng HX, Dubner SD, Weintraub S, Colom-Cadena M, Gelpi E, Charif S, Belbin O, Blesa R, Marti MJ,
Mesulam M (2010) TDP-43 pathology in primary progressive Clarimon J, Lleo A (2013) Confluence of alpha-synuclein, tau,

123
516 K. A. Jellinger, J. Attems

and beta-amyloid pathologies in dementia with Lewy bodies. definition of Alzheimers disease: a new lexicon. Lancet Neurol
J Neuropathol Exp Neurol 72:12031212 9:11181127
Compta Y, Parkkinen L, OSullivan SS, Vandrovcova J, Holton JL, Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL,
Collins C, Lashley T, Kallis C, Williams DR, de Silva R, Lees Blennow K, DeKosky ST, Gauthier S, Selkoe D, Bateman R,
AJ, Revesz T (2011) Lewy- and Alzheimer-type pathologies in Cappa S, Crutch S, Engelborghs S, Frisoni GB, Fox NC, Galasko
Parkinsons disease dementia: which is more important? Brain D, Habert MO, Jicha GA, Nordberg A, Pasquier F, Rabinovici G,
134:14931505 Robert P, Rowe C, Salloway S, Sarazin M, Epelbaum S, de
Crary JF, Trojanowski JQ, Schneider JA, Abisambra JF, Alafuzoff I, Souza LC, Vellas B, Visser PJ, Schneider L, Stern Y, Scheltens
Arnold SE, Attems J, Beach TG, Cairns NJ, Dickson DW, P, Cummings JL (2014) Advancing research diagnostic criteria
Gearing M, Grinberg L, Hof PR, Hyman BT, Jellinger K, Kovacs for Alzheimers disease: the IWG-2 criteria. Lancet Neurol
GG, Knopman DS, Kofler J, Masliah E, McKee A, Murray ME, 13:614629
Neltner JH, Santa-Maria I, Seeley WW, Serrano-Pozo A, Dugger BN, Hentz JG, Adler CH, Sabbagh MN, Shill HA, Jacobson
Shelanski ML, Stein T, Takao M, Thal DR, Toledo JB, Troncoso S, Caviness JN, Belden C, Driver-Dunckley E, Davis KJ, Sue LI,
JC, Vonsattel JP, White Iii CL, Wisniewski T, Woltjer RL, Beach TG (2014) Clinicopathological outcomes of prospectively
Yamada M, Nelson PT (2014) Primary age-related tauopathy followed normal elderly brain bank volunteers. J Neuropathol
(PART): a common pathology associated with human aging. Exp Neurol 73:244252
Acta Neuropathol (submitted) Duyckaerts C, Dickson DW (2011) Neuropathology of Alzheimers
Crystal H, Dickson D (2002) Cerebral infarcts in patients with disease and its variants. In: Dickson DW, Weller RO (eds)
autopsy proven Alzheimers disease (abstr.). Neurobiol Aging Neurodegeneration. The molecular pathology of dementia and
23:207 movement disorders, 2nd edn. Wiley-Blackwell, Oxford,
Davidson YS, Raby S, Foulds PG, Robinson A, Thompson JC, pp 6291
Sikkink S, Yusuf I, Amin H, DuPlessis D, Troakes C, Al-Sarraj Duyckaerts C, Delatour B, Potier MC (2009) Classification and basic
S, Sloan C, Esiri MM, Prasher VP, Allsop D, Neary D, pathology of Alzheimer disease. Acta Neuropathol 118:536
Pickering-Brown SM, Snowden JS, Mann DM (2011) TDP-43 Emre M, Aarsland D, Brown R, Burn DJ, Duyckaerts C, Mizuno Y,
pathological changes in early onset familial and sporadic Broe GA, Cummings J, Dickson DW, Gauthier S, Goldman J,
Alzheimers disease, late onset Alzheimers disease and Downs Goetz C, Korczyn A, Lees A, Levy R, Litvan I, McKeith I,
syndrome: association with age, hippocampal sclerosis and Olanow W, Poewe W, Quinn N, Sampaio C, Tolosa E, Dubois B
clinical phenotype. Acta Neuropathol 122:703713 (2007) Clinical diagnostic criteria for dementia associated with
Davis DG, Schmitt FA, Wekstein DR, Markesbery WR (1999) Parkinsons disease. Mov Disord 22:16891707
Alzheimer neuropathologic alterations in aged cognitively Erten-Lyons D, Dodge HH, Woltjer R, Silbert LC, Howieson DB,
normal subjects. J Neuropathol Exp Neurol 58:376388 Kramer P, Kaye JA (2013a) Neuropathologic basis of age-
Dawe RJ, Bennett DA, Schneider JA, Arfanakis K (2011) Neuropa- associated brain atrophy. JAMA Neurol 70:616622
thologic correlates of hippocampal atrophy in the elderly: a Erten-Lyons D, Woltjer R, Kaye J, Mattek N, Dodge HH, Green S,
clinical, pathologic, postmortem MRI study. PLoS One 6:e26286 Tran H, Howieson DB, Wild K, Silbert LC (2013b) Neuropa-
de Calignon A, Polydoro M, Suarez-Calvet M, William C, Adam- thologic basis of white matter hyperintensity accumulation with
owicz DH, Kopeikina KJ, Pitstick R, Sahara N, Ashe KH, advanced age. Neurology 81:977983
Carlson GA, Spires-Jones TL, Hyman BT (2012) Propagation of Esiri MM (2010) Pro: can neuropathology really confirm the exact
tau pathology in a model of early Alzheimers disease. Neuron diagnosis? Alzheimers Res Ther 2:10
73:685697 Esiri MM, Englund E (2014) Pathological aspects of the ischemic
DelleDonne A, Klos KJ, Fujishiro H, Ahmed Z, Parisi JE, Josephs consequences of small vessel disease on brain parenchyma. In:
KA, Frigerio R, Burnett M, Wszolek ZK, Uitti RJ, Ahlskog JE, Pantoni L, Gorelick PB (eds) Cerebral small vessel disease.
Dickson DW (2008) Incidental Lewy body disease and preclin- Cambridge University Press, Cambridge, pp 1628
ical Parkinson disease. Arch Neurol 65:10741080 Esiri MM, Nagy Z, Smith MZ, Barnetson L, Smith AD (1999)
Deramecourt V, Slade JY, Oakley AE, Perry RH, Ince PG, Maurage Cerebrovascular disease and threshold for dementia in the early
CA, Kalaria RN (2012) Staging and natural history of cerebro- stages of Alzheimers disease. Lancet 354:919920
vascular pathology in dementia. Neurology 78:10431050 Esiri MM, Joachim C, Sloan C, Christie S, Agacinski G, Bridges LR,
Dickson DW, Davies P, Bevona C, Van Hoeven KH, Factor SM, Wilcock GK, Smith AD (2014) Cerebral subcortical small vessel
Grober E, Aronson MK, Crystal HA (1994) Hippocampal disease in subjects with pathologically confirmed Alzheimer
sclerosis: a common pathological feature of dementia in very disease: a clinicopathologic study in the Oxford project to
old ([ or =80 years of age) humans. Acta Neuropathol investigate memory and ageing (OPTIMA). Alzheimer Dis
88:212221 Assoc Disord 28:3035
Dolan D, Troncoso J, Resnick SM, Crain BJ, Zonderman AB, Fernando MS, Ince PG (2004) Vascular pathologies and cognition in
OBrien RJ (2010) Age, Alzheimers disease and dementia in the a population-based cohort of elderly people. J Neurol Sci
Baltimore longitudinal study of ageing. Brain 133:22252231 226:1317
Dubois B, Burn D, Goetz C, Aarsland D, Brown RG, Broe GA, Ferrer I (2010) Cognitive impairment of vascular origin: neuropa-
Dickson D, Duyckaerts C, Cummings J, Gauthier S, Korczyn A, thology of cognitive impairment of vascular origin. J Neurol Sci
Lees A, Levy R, Litvan I, Mizuno Y, McKeith IG, Olanow CW, 299:139149
Poewe W, Sampaio C, Tolosa E, Emre M (2007) Diagnostic Ferrer I, Santpere G, van Leeuwen FW (2008) Argyrophilic grain
procedures for Parkinsons disease dementia: recommendations disease. Brain 131:14161432
from the Movement Disorder Society task force. Mov Disord Fischer P, Jungwirth S, Krampla W, Weissgram S, Kirchmeyr W,
22:23142324 Schreiber W, Huber K, Rainer M, Bauer P, Tragl KH (2002)
Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Vienna transdanube aging VITA: study design, recruitment
Barberger-Gateau P, Delacourte A, Frisoni G, Fox NC, Galasko strategies and level of participation. J Neural Transm Suppl
D, Gauthier S, Hampel H, Jicha GA, Meguro K, OBrien J, 62:105116
Pasquier F, Robert P, Rossor M, Salloway S, Sarazin M, de Frigerio R, Fujishiro H, Ahn TB, Josephs KA, Maraganore DM,
Souza LC, Stern Y, Visser PJ, Scheltens P (2010) Revising the Delledonne A, Parisi JE, Klos KJ, Boeve BF, Dickson DW,

123
Challenges of multimorbidity of the aging brain 517

Ahlskog JE (2011) Incidental Lewy body disease: do some cases Irwin DJ, White MT, Toledo JB, Xie SX, Robinson JL, Van Deerlin
represent a preclinical stage of dementia with Lewy bodies? V, Lee VM, Leverenz JB, Montine TJ, Duda JE, Hurtig HI,
Neurobiol Aging 32:857863 Trojanowski JQ (2012) Neuropathologic substrates of Parkinson
Fujimi K, Sasaki K, Noda K, Wakisaka Y, Tanizaki Y, Matsui Y, disease dementia. Ann Neurol 72:587598
Sekita A, Iida M, Kiyohara Y, Kanba S, Iwaki T (2008) Iseki E, Togo T, Suzuki K, Katsuse O, Marui W, de Silva R, Lees A,
Clinicopathological outline of dementia with Lewy bodies Yamamoto T, Kosaka K (2003) Dementia with Lewy bodies
applying the revised criteria: the Hisayama study. Brain Pathol from the perspective of tauopathy. Acta Neuropathol (Berl)
18:317325 105:265270
Fujishima M, Kiyohara Y (2002) Incidence and risk factors of Jack CR Jr (2012) Alzheimer disease: new concepts on its neurobi-
dementia in a defined elderly Japanese population: the Hisayama ology and the clinical role imaging will play. Radiology
study. Ann NY Acad Sci 977:18 263:344361
Gelber RP, Launer LJ, White LR (2012) The Honolulu-Asia aging Janocko NJ, Brodersen KA, Soto-Ortolaza AI, Ross OA, Liesinger
study: epidemiologic and neuropathologic research on cognitive AM, Duara R, Graff-Radford NR, Dickson DW, Murray ME
impairment. Curr Alzheimer Res 9:664672 (2012) Neuropathologically defined subtypes of Alzheimers
Giasson BI, Forman MS, Higuchi M, Golbe LI, Graves CL, disease differ significantly from neurofibrillary tangle-predom-
Kotzbauer PT, Trojanowski JQ, Lee VM (2003) Initiation and inant dementia. Acta Neuropathol 124:681692
synergistic fibrillization of tau and alpha-synuclein. Science Jellinger KA (2002) Alzheimer disease and cerebrovascular pathol-
300:636640 ogy: an update. J Neural Transm 109:813836
Goedert M, Ghetti B, Spillantini MG (2012) Frontotemporal demen- Jellinger KA (2007a) The enigma of mixed dementia. Alzheimers
tia: implications for understanding Alzheimer disease. Cold Dement 3:4053
Spring Harb Perspect Med 2:a006254 Jellinger KA (2007b) More frequent Lewy bodies but less frequent
Gold G, Kovari E, Herrmann FR, Canuto A, Hof PR, Michel JP, Alzheimer-type lesions in multiple system atrophy as compared
Bouras C, Giannakopoulos P (2005) Cognitive consequences of to age-matched control brains. Acta Neuropathol 114:299303
thalamic, basal ganglia, and deep white matter lacunes in brain Jellinger KA (2008) The pathology of vascular dementia: a critical
aging and dementia. Stroke 36:11841188 update. J Alzheimers Dis 14:107123
Gold G, Giannakopoulos P, Herrmann FR, Bouras C, Kovari E (2007) Jellinger KA (2010a) Con: can neuropathology really confirm the
Identification of Alzheimer and vascular lesion thresholds for exact diagnosis? Alzheimers Res Ther 2:11
mixed dementia. Brain 130:28302836 Jellinger KA (2010b) Prevalence and impact of cerebrovascular
Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola lesions in Alzheimer and Lewy body diseases. Neurodegener Dis
C, Launer LJ, Laurent S, Lopez OL, Nyenhuis D, Petersen RC, 7:112115
Schneider JA, Tzourio C, Arnett DK, Bennett DA, Chui HC, Jellinger KA (2012) Interaction between pathogenic proteins in
Higashida RT, Lindquist R, Nilsson PM, Roman GC, Sellke FW, neurodegenerative disorders. J Cell Mol Med 16:11661183
Seshadri S (2011) Vascular contributions to cognitive impair- Jellinger KA (2013) Challenges in the neuropathological diagnosis of
ment and dementia: a statement for healthcare professionals dementias. Int J Neuropathol 1:825
from the American heart association/american stroke associa- Jellinger KA (2014) Neuropathology of dementia disorders. J Alzhei-
tion. Stroke 42:26722713 mers Dis Parkinsonism 4:117
Gotz J, Gotz NN (2009) Animal models for Alzheimers disease and Jellinger KA, Attems J (2005) Prevalence and pathogenic role of
frontotemporal dementia: a perspective. ASN Neuro cerebrovascular lesions in Alzheimers disease. J Neurol Sci
1:AN20090042 229230:3741
Grinberg LT, Heinsen H (2009) Argyrophilic grain disease: an update Jellinger KA, Attems J (2007) Neurofibrillary tangle-predominant
about a frequent cause of dementia. Dement Neuropsychol 3:27 dementia: comparison with classical Alzheimer disease. Acta
Grinberg LT, Thal DR (2010) Vascular pathology in the aged human Neuropathol 113:107117
brain. Acta Neuropathol 119:277290 Jellinger KA, Attems J (2008) Prevalence and impact of vascular and
Halliday GM, Bigio EH, Cairns NJ, Neumann M, Mackenzie IR, Alzheimer pathologies in Lewy body disease. Acta Neuropathol
Mann DM (2012) Mechanisms of disease in frontotemporal 115:427436
lobar degeneration: gain of function versus loss of function Jellinger KA, Attems J (2010) Prevalence and pathology of vascular
effects. Acta Neuropathol 124:373382 dementia in the oldest-old. J Alzheimers Dis 21:12831298
Horvath J, Herrmann FR, Burkhard PR, Bouras C, Kovari E (2013) Jellinger KA, Attems J (2012) Neuropathology and general autopsy
Neuropathology of dementia in a large cohort of patients with findings in nondemented aged subjects. Clin Neuropathol 31:8798
Parkinsons disease. Parkinsonism Relat Disord 19:864868 Jellinger KA, Attems J (2014) The overlap between vascular disease
Hyman BT, Trojanowski JQ (1997) Consensus recommendations for and Alzheimerslessons from pathology. BMC Med (in press)
the postmortem diagnosis of Alzheimer disease from the Jellinger KA, Mitter-Ferstl E (2003) The impact of cerebrovascular
National Institute on Aging and the Reagan Institute Working lesions in Alzheimer diseasea comparative autopsy study.
Group on diagnostic criteria for the neuropathological assess- J Neurol 250:10501055
ment of Alzheimer disease. J Neuropathol Exp Neurol Jentoft M, Parisi J, Dickson D, Johnson K, Boeve B, Knopman D,
56:10951097 Petersen R (2011) Neuropathologic findings in 32 nondemented
Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo elderly subjects (abs.). J Neuropathol Exp Neurol 70:531
MC, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra Jicha GA, Abner EL, Schmitt FA, Kryscio RJ, Riley KP, Cooper GE,
SS, Nelson PT, Schneider JA, Thal DR, Thies B, Trojanowski Stiles N, Mendiondo MS, Smith CD, Van Eldik LJ, Nelson PT
JQ, Vinters HV, Montine TJ (2012) National Institute on Aging- (2012) Preclinical AD workgroup staging: pathological corre-
Alzheimers Association guidelines for the neuropathologic lates and potential challenges. Neurobiol Aging
assessment of Alzheimers disease. Alzheimers Dement 8:113 33:622.e621622.e616
Iadecola C (2010) The overlap between neurodegenerative and Josephs KA, Whitwell JL, Knopman DS, Hu WT, Stroh DA, Baker
vascular factors in the pathogenesis of dementia. Acta Neuro- M, Rademakers R, Boeve BF, Parisi JE, Smith GE, Ivnik RJ,
pathol 120:287296 Petersen RC, Jack CR Jr, Dickson DW (2008) Abnormal TDP-

123
518 K. A. Jellinger, J. Attems

43 immunoreactivity in AD modifies clinicopathologic and JH, Miller BL, Bartzokis G, Thompson PM, Knopman DS
radiologic phenotype. Neurology 70:18501857 (2013) Patterns of brain atrophy in clinical variants of fronto-
Josephs KA, Hodges JR, Snowden JS, Mackenzie IR, Neumann M, temporal lobar degeneration. Dement Geriatr Cogn Disord
Mann DM, Dickson DW (2011) Neuropathological background 35:3450
of phenotypical variability in frontotemporal dementia. Acta Marengoni A, Angleman S, Melis R, Mangialasche F, Karp A,
Neuropathol 122:137153 Garmen A, Meinow B, Fratiglioni L (2011) Aging with
Josephs KA, Murray ME, Whitwell JL, Parisi JE, Petrucelli L, Jack multimorbidity: a systematic review of the literature. Ageing
CR, Petersen RC, Dickson DW (2014) Staging TDP-43 pathol- Res Rev 10:430439
ogy in Alzheimers disease. Acta Neuropathol 127:441450 Markesbery WR, Jicha GA, Liu H, Schmitt FA (2009) Lewy body
Kalaria RN, Kenny RA, Ballard CG, Perry R, Ince P, Polvikoski T pathology in normal elderly subjects. J Neuropathol Exp Neurol
(2004) Towards defining the neuropathological substrates of 68:816822
vascular dementia. J Neurol Sci 226:7580 Matthews FE, Brayne C, Lowe J, McKeith I, Wharton SB, Ince P
Keage HA, Ince PG, Matthews FE, Wharton SB, McKeith IG, Brayne (2009) Epidemiological pathology of dementia: attributable-risks
C (2012) Impact of less common and disregarded neurode- at death in the Medical Research Council Cognitive Function
generative pathologies on dementia burden in a population-based and Ageing Study. PLoS Med 6:e1000180
cohort. J Alzheimers Dis 28:485493 McKeith IG, Dickson DW, Lowe J, Emre M, OBrien JT, Feldman H,
Knopman DS, Parisi JE, Salviati A, Floriach-Robert M, Boeve BF, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H,
Ivnik RJ, Smith GE, Dickson DW, Johnson KA, Petersen LE, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B,
McDonald WC, Braak H, Petersen RC (2003) Neuropathology Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday
of cognitively normal elderly. J Neuropathol Exp Neurol G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D,
62:10871095 Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I,
Kotzbauer PT, Cairns NJ, Campbell MC, Willis AW, Racette BA, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA,
Tabbal SD, Perlmutter JS (2012) Pathologic accumulation of Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB,
alpha-synuclein and A-beta in Parkinson disease patients with Trojanowski JQ, Yamada M (2005) Diagnosis and management
dementia. Arch Neurol 69:13261331 of dementia with Lewy bodies: third report of the DLB
Kovacs GG, Alafuzoff I, Al-Sarraj S, Arzberger T, Bogdanovic N, Consortium. Neurology 65:18631872
Capellari S, Ferrer I, Gelpi E, Kovari V, Kretzschmar H, Nagy Z, McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr,
Parchi P, Seilhean D, Soininen H, Troakes C, Budka H (2008) Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R,
Mixed brain pathologies in dementia: the Brainnet Europe Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC,
Consortium experience. Dement Geriatr Cogn Disord Thies B, Weintraub S, Phelps CH (2011) The diagnosis of
26:343350 dementia due to Alzheimers disease: recommendations from the
Kovacs GG, Botond G, Budka H (2010) Protein coding of neurode- National Institute on Aging-Alzheimers Association work-
generative dementias: the neuropathological basis of biomarker groups on diagnostic guidelines for Alzheimers disease.
diagnostics. Acta Neuropathol 119:389408 Alzheimers Dement 7:263269
Kovacs GG, Milenkovic I, Wohrer A, Hoftberger R, Gelpi E, Merdes AR, Hansen LA, Jeste DV, Galasko D, Hofstetter CR, Ho GJ,
Haberler C, Honigschnabl S, Reiner-Concin A, Heinzl H, Thal LJ, Corey-Bloom J (2003) Influence of Alzheimer pathol-
Jungwirth S, Krampla W, Fischer P, Budka H (2013) Non- ogy on clinical diagnostic accuracy in dementia with Lewy
Alzheimer neurodegenerative pathologies and their combina- bodies. Neurology 60:15861590
tions are more frequent than commonly believed in the elderly Miklossy J (2003) Cerebral hypoperfusion induces cortical watershed
brain: a community-based autopsy series. Acta Neuropathol microinfarcts which may further aggravate cognitive decline in
126:365384 Alzheimers disease. Neurol Res 25:605610
Kovari E, Gold G, Herrmann FR, Canuto A, Hof PR, Michel JP, Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM,
Bouras C, Giannakopoulos P (2004) Cortical microinfarcts and Vogel FS, Hughes JP, van Belle G, Berg L (1991) The
demyelination significantly affect cognition in brain aging. Consortium to Establish a Registry for Alzheimers Disease
Stroke 35:410414 (CERAD). Part II. Standardization of the neuropathologic
Launer LJ, Petrovitch H, Ross GW, Markesbery W, White LR (2008) assessment of Alzheimers disease. Neurology 41:479486
AD brain pathology: vascular origins? Results from the HAAS Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Dickson
autopsy study. Neurobiol Aging 29:15871590 DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS, Nelson
Lim A, Tsuang D, Kukull W, Nochlin D, Leverenz J, McCormick W, PT, Schneider JA, Thal DR, Trojanowski JQ, Vinters HV,
Bowen J, Teri L, Thompson J, Peskind ER, Raskind M, Larson EB Hyman BT (2012) National Institute on Aging-Alzheimers
(1999) Clinico-neuropathological correlation of Alzheimers disease Association guidelines for the neuropathologic assessment of
in a community-based case series. J Am Geriatr Soc 47:564569 Alzheimers disease: a practical approach. Acta Neuropathol
Liu Y, Yu JT, Sun FR, Ou JR, Qu SB, Tan L (2013) The clinical and 123:111
pathological phenotypes of frontotemporal dementia with Murray ME, Graff-Radford NR, Ross OA, Petersen RC, Duara R,
C9ORF72 mutations. J Neurol Sci 335:2635 Dickson DW (2011) Neuropathologically defined subtypes of
Lopez OL, McDade E, Riverol M, Becker JT (2011) Evolution of the Alzheimers disease with distinct clinical characteristics: a
diagnostic criteria for degenerative and cognitive disorders. Curr retrospective study. Lancet Neurol 10:785796
Opin Neurol 24:532541 Murray ME, Cannon A, Graff-Radford NR, Leisinger AM, Ruther-
Love S, Chalmers K, Ince P, Esiri M, Attems J, Jellinger K, Yamada ford NJ, Ross OA, Duara R, Carrasquillo MM, Rademakers R,
M, McCarron M, Minett T, Matthews F, Greenberg S, Mann D, Dickson DW (2014) Differential clinicopathologic and genetic
Kehoe PG (2014) Development, appraisal, validation and features of late-onset amnestic dementias. Acta Neuropathol.
implementation of a consensus protocol for the assessment of doi:10.1007/s00401-014-1302-2
cerebral amyloid angiopathy in post-mortem brain tissue. Am J Nagy Z, Esiri MM, Jobst KA, Morris JH, King E-F, McDonald B,
Neurodegener Dis 3:1932 Joachim C, Litchfield S, Barnetson L, Smith AD (1997) The
Lu PH, Mendez MF, Lee GJ, Leow AD, Lee HW, Shapira J, Jimenez effects of additional pathology on the cognitive deficit in
E, Boeve BB, Caselli RJ, Graff-Radford NR, Jack CR, Kramer Alzheimer disease. J Neuropathol Exp Neurol 56:165170

123
Challenges of multimorbidity of the aging brain 519

Nelson PT, Jicha GA, Schmitt FA, Liu H, Davis DG, Mendiondo MS, elderly people: a prospective neuropathological study. Neurol-
Abner EL, Markesbery WR (2007) Clinicopathologic correla- ogy 56:16901696
tions in a large Alzheimer disease center autopsy cohort: neuritic Polvikoski TM, van Straaten EC, Barkhof F, Sulkava R, Aronen HJ,
plaques and neurofibrillary tangles do count when staging Niinisto L, Oinas M, Scheltens P, Erkinjuntti T, Kalaria RN
disease severity. J Neuropathol Exp Neurol 66:11361146 (2010) Frontal lobe white matter hyperintensities and neurofi-
Nelson PT, Abner EL, Schmitt FA, Kryscio RJ, Jicha GA, Santacruz brillary pathology in the oldest old. Neurology 75:20712078
K, Smith CD, Patel E, Markesbery WR (2009) Brains with Price JL, McKeel DW Jr, Buckles VD, Roe CM, Xiong C, Grundman M,
medial temporal lobe neurofibrillary tangles but no neuritic Hansen LA, Petersen RC, Parisi JE, Dickson DW, Smith CD, Davis
amyloid plaques are a diagnostic dilemma but may have DG, Schmitt FA, Markesbery WR, Kaye J, Kurlan R, Hulette C,
pathogenetic aspects distinct from Alzheimer disease. J Neuro- Kurland BF, Higdon R, Kukull W, Morris JC (2009) Neuropathol-
pathol Exp Neurol 68:774784 ogy of nondemented aging: presumptive evidence for preclinical
Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, Alzheimer disease. Neurobiol Aging 30:10261036
Castellani RJ, Crain BJ, Davies P, Del Tredici K, Duyckaerts C, Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP (2013)
Frosch MP, Haroutunian V, Hof PR, Hulette CM, Hyman BT, The global prevalence of dementia: a systematic review and
Iwatsubo T, Jellinger KA, Jicha GA, Kovari E, Kukull WA, metaanalysis. Alzheimers Dement 9:6375
Leverenz JB, Love S, Mackenzie IR, Mann DM, Masliah E, Purohit D, Batheja N, Haroutunian V, Sano M, Grossman H, Perl DP
McKee AC, Montine TJ, Morris JC, Schneider JA, Sonnen JA, (2008) A clinicopathological correlation study of cognitive status
Thal DR, Trojanowski JQ, Troncoso JC, Wisniewski T, Woltjer and senile plaques and neurofibrillary tangles in clinically well-
RL, Beach TG (2012) Correlation of Alzheimer disease neuro- characterized individuals of extreme old age (abstract). J Neuro-
pathologic changes with cognitive status: a review of the path Exp Neurol 67:494
literature. J Neuropathol Exp Neurol 71:362381 Rahimi J, Kovacs GG (2014) Prevalence of mixed pathologies in the
Nelson PT, Smith CD, Abner EL, Wilfred BJ, Wang WX, Neltner JH, aging brain. Alzheimer Res Ther (in press)
Baker M, Fardo DW, Kryscio RJ, Scheff SW, Jicha GA, Rauramaa T, Pikkarainen M, Englund E, Ince PG, Jellinger K, Paetau
Jellinger KA, Van Eldik LJ, Schmitt FA (2013) Hippocampal A, Alafuzoff I (2011) TAR-DNA binding protein-43 and
sclerosis of aging, a prevalent and high-morbidity brain disease. alterations in the hippocampus. J Neural Transm 118:683689
Acta Neuropathol 126:161177 Rauramaa T, Pikkarainen M, Englund E, Ince PG, Jellinger K, Paetau
Nolan KA, Lino MM, Seligmann AW, Blass JP (1998) Absence of A, Alafuzoff I (2013) Consensus recommendations on patho-
vascular dementia in an autopsy series from a dementia clinic. logic changes in the hippocampus: a postmortem multicenter
J Am Geriatr Soc 46:597604 inter-rater study. J Neuropathol Exp Neurol 72:452461
Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Richardson K, Stephan BC, Ince PG, Brayne C, Matthews FE, Esiri
Metherate R, Mattson MP, Akbari Y, LaFerla FM (2003) Triple- MM (2012) The neuropathology of vascular disease in the
transgenic model of Alzheimers disease with plaques and Medical Research Council Cognitive Function and Ageing Study
tangles: intracellular Abeta and synaptic dysfunction. Neuron (MRC CFAS). Curr Alzheimer Res 9:687696
39:409421 Riley KP, Snowdon DA, Markesbery WR (2002) Alzheimers
Oinas M, Polvikoski T, Sulkava R, Myllykangas L, Juva K, Notkola IL, neurofibrillary pathology and the spectrum of cognitive function:
Rastas S, Niinisto L, Kalimo H, Paetau A (2009) Neuropathologic findings from the nun study. Ann Neurol 51:567577
findings of dementia with Lewy bodies (DLB) in a population- Rincon F, Wright CB (2014) Current pathophysiological concepts in
based Vantaa 85? study. J Alzheimers Dis 18:677689 cerebral small vessel disease. Front Aging Neurosci 6:24
Pantoni L, Sarti C, Alafuzoff I, Jellinger K, Munoz DG, Ogata J, Robinson JL, Geser F, Corrada MM, Berlau DJ, Arnold SE, Lee VM,
Palumbo V (2006) Postmortem examination of vascular lesions Kawas CH, Trojanowski JQ (2011) Neocortical and hippocam-
in cognitive impairment: a survey among neuropathological pal amyloid-beta and tau measures associate with dementia in
services. Stroke 37:10051009 the oldest-old. Brain 134:37083715
Parkkinen L, Pirttila T, Tervahauta M, Alafuzoff I (2005) Widespread Roman GC (2008) The epidemiology of vascular dementia. In:
and abundant alpha-synuclein pathology in a neurologically Duyckaerts C, Litvan I (eds) Dementiashandbook of clinical
unimpaired subject. Neuropathology 25:304314 neurology, vol 89 (3rd series). Elsevier, Edinburgh, pp 639658
Parkkinen L, Pirttila T, Alafuzoff I (2008) Applicability of current Roman GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC,
staging/categorization of alpha-synuclein pathology and their Garcia JH, Amaducci L, Orgogozo JM, Brun A, Hofman A et al
clinical relevance. Acta Neuropathol 115:399407 (1993) Vascular dementia: diagnostic criteria for research
Perneczky R, Mosch D, Neumann M, Kretzschmar H, Muller U, studies. Report of the NINDS-AIREN international workshop.
Busch R, Forstl H, Kurz A (2005) The Alzheimer variant of Neurology 43:250260
Lewy body disease: a pathologically confirmed casecontrol Sachdev P, Kalaria R, OBrien J, Skoog I, Alladi S, Black SE,
study. Dement Geriatr Cogn Disord 20:8994 Blacker D, Blazer DG, Chen C, Chui H, Ganguli M, Jellinger K,
Petersen RC, Parisi JE, Dickson DW, Johnson KA, Knopman DS, Jeste DV, Pasquier F, Paulsen J, Prins N, Rockwood K, Roman
Boeve BF, Jicha GA, Ivnik RJ, Smith GE, Tangalos EG, Braak G, Scheltens P (2014) Diagnostic criteria for vascular cognitive
H, Kokmen E (2006) Neuropathologic features of amnestic mild disorders: a VASCOG statement. Alzheimer Dis Assoc Disord.
cognitive impairment. Arch Neurol 63:665672 doi:10.1097/WAD.0000000000000034
Petiet A, Delatour B, Dhenain M (2011) Models of neurodegenerative Santa-Maria I, Haggiagi A, Liu X, Wasserscheid J, Nelson PT, Dewar
diseaseAlzheimers anatomical and amyloid plaque imaging. K, Clark LN, Crary JF (2012) The MAPT H1 haplotype is
Methods Mol Biol 771:293308 associated with tangle-predominant dementia. Acta Neuropathol
Petrovitch H, Ross GW, Steinhorn SC, Abbott RD, Markesberry W, 124:693704
Davis DG, Nelson J, Hardman J, Masaki KH, Vogt MR, Launer Sarazin M, de Souza LC, Lehericy S, Dubois B (2012) Clinical and
LJ, White LR (2005) AD lesions and infarcts in demented and research diagnostic criteria for Alzheimers disease. Neuroim-
no-demented Japanese-American men. Ann Neurol 57:98103 aging Clin N Am 22:2332,viii
Polvikoski T, Sulkava R, Myllykangas L, Notkola IL, Niinisto L, Savva GM, Wharton SB, Ince PG, Forster G, Matthews FE, Brayne C
Verkkoniemi A, Kainulainen K, Kontula K, Perez-Tur J, Hardy (2009) Age, neuropathology, and dementia. N Engl J Med
J, Haltia M (2001) Prevalence of Alzheimers disease in very 360:23022309

123
520 K. A. Jellinger, J. Attems

Schmidt R, Schmidt H, Haybaeck J, Loitfelder M, Weis S, Cavalieri B, Morrison-Bogorad M, Wagster MV, Phelps CH (2011)
M, Seiler S, Enzinger C, Ropele S, Erkinjuntti T, Pantoni L, Toward defining the preclinical stages of Alzheimers disease:
Scheltens P, Fazekas F, Jellinger K (2011) Heterogeneity in age- recommendations from the National Institute on Aging-Alzhei-
related white matter changes. Acta Neuropathol 122:171185 mers Association workgroups on diagnostic guidelines for
Schmitt FA, Davis DG, Wekstein DR, Smith CD, Ashford JW, Alzheimers disease. Alzheimers Dement 7:280292
Markesbery WR (2000) Preclinical AD revisited: neuropa- Stankovic I, Krismer F, Jesic A, Antonini A, Benke T, Brown RG,
thology of cognitively normal older adults. Neurology Burn DJ, Holton JL, Kaufmann H, Kostic VS, Ling H, Meissner
55:370376 WG, Poewe W, Semnic M, Seppi K, Takeda A, Weintraub D,
Schneider JA, Wilson RS, Cochran EJ, Bienias JL, Arnold SE, Evans Wenning GK (2014) Cognitive impairment in multiple system
DA, Bennett DA (2003) Relation of cerebral infarctions to atrophy: a position statement by the neuropsychology task force
dementia and cognitive function in older persons. Neurology of the MDS multiple system atrophy (MODIMSA) study group.
60:10821088 Mov Disord. doi:10.1002/mds.25880
Schneider JA, Wilson RS, Bienias JL, Evans DA, Bennett DA (2004) Stephan BC, Matthews FE, Ma B, Muniz G, Hunter S, Davis D,
Cerebral infarctions and the likelihood of dementia from McKeith IG, Foster G, Ince PG, Brayne C (2012) Alzheimer and
Alzheimer disease pathology. Neurology 62:11481155 vascular neuropathological changes associated with different
Schneider JA, Arvanitakis Z, Bang W, Bennett DA (2007a) Mixed cognitive states in a non-demented sample. J Alzheimers Dis
brain pathologies account for most dementia cases in commu- 29:309318
nity-dwelling older persons. Neurology 69:21972204 Strozyk D, Dickson DW, Lipton RB, Katz M, Derby CA, Lee S,
Schneider JA, Boyle PA, Arvanitakis Z, Bienias JL, Bennett DA Wang C, Verghese J (2010) Contribution of vascular pathology
(2007b) Subcortical infarcts, Alzheimers disease pathology, and to the clinical expression of dementia. Neurobiol Aging
memory function in older persons. Ann Neurol 62:5966 31:17101720
Schneider JA, Aggarwal NT, Barnes L, Boyle P, Bennett DA (2009) Tanskanen M, Makela M, Myllykangas L, Rastas S, Sulkava R,
The neuropathology of older persons with and without dementia Paetau A (2012) Intracerebral hemorrhage in the oldest old: a
from community versus clinic cohorts. J Alzheimers Dis population-based study (Vantaa 85?). Front Neurol 3:103
18:691701 Thal DR, Ghebremedhin E, Rub U, Yamaguchi H, Del Tredici K,
Seltman RE, Matthews BR (2012) Frontotemporal lobar degenera- Braak H (2002a) Two types of sporadic cerebral amyloid
tion: epidemiology, pathology, diagnosis and management. CNS angiopathy. J Neuropathol Exp Neurol 61:282293
Drugs 26:841870 Thal DR, Rub U, Orantes M, Braak H (2002b) Phases of A beta-
Serrano-Pozo A, Qian J, Monsell SE, Frosch MP, Betensky RA, deposition in the human brain and its relevance for the
Hyman BT (2013) Examination of the clinicopathologic contin- development of AD. Neurology 58:17911800
uum of Alzheimer disease in the autopsy cohort of the national Thal DR, Papassotiropoulos A, Saido TC, Griffin WS, Mrak RE,
Alzheimer coordinating center. J Neuropathol Exp Neurol Kolsch H, Del Tredici K, Attems J, Ghebremedhin E (2010)
72:11821192 Capillary cerebral amyloid angiopathy identifies a distinct APOE
Shim YS, Roe CM, Buckles VD, Morris JC (2013) Clinicopathologic epsilon4-associated subtype of sporadic Alzheimers disease.
study of Alzheimers disease: Alzheimer mimics. J Alzheimers Acta Neuropathol 120:169183
Dis 35:799811 Thal DR, Grinberg LT, Attems J (2012) Vascular dementia: different
Shim YS, Roe CM, Benzinger TL, Cairns NJ, Xiong C, Galvin JE, forms of vessel disorders contribute to the development of
Coats MA, Yang D-W, Morris JC (2014) Pathological correlates dementia in the elderly brain. Exp Gerontol 47:816824
of white matter hyperintensities on MRI. Dement Geriatric Cogn Thies W, Bleiler L (2013) Alzheimers disease facts and figures.
Disord (in press) Alzheimers Dement 9:208245
Sinka L, Kovari E, Gold G, Hof PR, Herrmann FR, Bouras C, Toledo JB, Arnold SE, Raible K, Brettschneider J, Xie SX, Grossman
Giannakopoulos P (2010) Small vascular and Alzheimer disease- M, Monsell SE, Kukull WA, Trojanowski JQ (2013) Contribu-
related pathologic determinants of dementia in the oldest-old. tion of cerebrovascular disease in autopsy confirmed neurode-
J Neuropathol Exp Neurol 69:12471255 generative disease cases in the National Alzheimers
Smallwood A, Oulhaj A, Joachim C, Christie S, Sloan C, Smith AD, Coordinating Centre. Brain 136:26972706
Esiri M (2012) Cerebral subcortical small vessel disease and its Troncoso JC, Zonderman AB, Resnick SM, Crain B, Pletnikova O,
relation to cognition in elderly subjects: a pathological study in OBrien RJ (2008) Effect of infarcts on dementia in the
the Oxford project to investigate memory and ageing (OPTIMA) Baltimore longitudinal study of aging. Ann Neurol 64:168176
cohort. Neuropathol Appl Neurobiol 38:337343 Uchikado H, Lin WL, DeLucia MW, Dickson DW (2006) Alzheimer
Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, disease with amygdala Lewy bodies: a distinct form of alpha-
Markesbery WR (1997) Brain infarction and the clinical synucleinopathy. J Neuropathol Exp Neurol 65:685697
expression of Alzheimer disease. The nun study. JAMA Vanderstichele H, Bibl M, Engelborghs S, Le Bastard N, Lewczuk P,
277:813817 Molinuevo JL, Parnetti L, Perret-Liaudet A, Shaw LM, Teun-
Sonnen JA, Santa Cruz K, Hemmy LS, Woltjer R, Leverenz JB, issen C, Wouters D, Blennow K (2012) Standardization of
Montine KS, Jack CR, Kaye J, Lim K, Larson EB, White L, preanalytical aspects of cerebrospinal fluid biomarker testing for
Montine TJ (2011) Ecology of the aging human brain. Arch Alzheimers disease diagnosis: a consensus paper from the
Neurol 68:10491056 Alzheimers Biomarkers Standardization Initiative. Alzheimers
Sorbi S, Hort J, Erkinjuntti T, Fladby T, Gainotti G, Gurvit H, Dement 8:6573
Nacmias B, Pasquier F, Popescu BO, Rektorova I, Religa D, Wakisaka Y, Furuta A, Tanizaki Y, Kiyohara Y, Iida M, Iwaki T
Rusina R, Rossor M, Schmidt R, Stefanova E, Warren JD, (2003) Age-associated prevalence and risk factors of Lewy body
Scheltens P (2012) EFNS-ENS guidelines on the diagnosis and pathology in a general population: the Hisayama study. Acta
management of disorders associated with dementia. Eur J Neurol Neuropathol 106:374382
19:11591179 Weiner MW, Aisen PS, Jack CR Jr, Jagust WJ, Trojanowski JQ, Shaw
Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, L, Saykin AJ, Morris JC, Cairns N, Beckett LA, Toga A, Green
Iwatsubo T, Jack CR Jr, Kaye J, Montine TJ, Park DC, Reiman R, Walter S, Soares H, Snyder P, Siemers E, Potter W, Cole PE,
EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies Schmidt M (2010) The Alzheimers disease neuroimaging

123
Challenges of multimorbidity of the aging brain 521

initiative: progress report and future plans. Alzheimers Dement Wirth M, Villeneuve S, Haase CM, Madison CM, Oh H, Landau SM,
6(202211):e207 Rabinovici GD, Jagust WJ (2013) Associations between Alz-
White L (2009) Brain lesions at autopsy in older Japanese-American heimer disease biomarkers, neurodegeneration, and cognition in
men as related to cognitive impairment and dementia in the final cognitively normal older people. JAMA Neurol 70:15121519
years of life: a summary report from the Honolulu-Asia aging Zaccai J, Brayne C, McKeith I, Matthews F, Ince PG (2008) Patterns
study. J Alzheimers Dis 18:713725 and stages of alpha-synucleinopathy: relevance in a population-
White L, Petrovitch H, Hardman J, Nelson J, Davis DG, Ross GW, based cohort. Neurology 70:10421048
Masaki K, Launer L, Markesbery WR (2002) Cerebrovascular Zekry D, Duyckaerts C, Moulias R, Belmin J, Geoffre C, Herrmann F,
pathology and dementia in autopsied Honolulu-Asia aging study Hauw JJ (2002) Degenerative and vascular lesions of the brain
participants. Ann NY Acad Sci 977:923 have synergistic effects in dementia of the elderly. Acta
White L, Small BJ, Petrovitch H, Ross GW, Masaki K, Abbott RD, Neuropathol 103:481487
Hardman J, Davis D, Nelson J, Markesbery W (2005) Recent Zekry D, Duyckaerts C, Belmin J, Geoffre C, Herrmann F, Moulias R,
clinical-pathologic research on the causes of dementia in late Hauw JJ (2003a) The vascular lesions in vascular and mixed
life: update from the Honolulu-Asia aging study. J Geriatr dementia: the weight of functional neuroanatomy. Neurobiol
Psychiatry Neurol 18:224227 Aging 24:213219
Wills J, Jones J, Haggerty T, Duka V, Joyce JN, Sidhu A (2010) Zekry D, Duyckaerts C, Belmin J, Geoffre C, Moulias R, Hauw JJ
Elevated tauopathy and alpha-synuclein pathology in postmor- (2003b) Cerebral amyloid angiopathy in the elderly: vessel walls
tem Parkinsons disease brains with and without dementia. Exp changes and relationship with dementia. Acta Neuropathol
Neurol 225:210218 106:367373
Wilson RS, Yu L, Trojanowski JQ, Chen EY, Boyle PA, Bennett DA, Zheng L, Vinters HV, Mack WJ, Zarow C, Ellis WG, Chui HC (2013)
Schneider JA (2013) TDP-43 pathology, cognitive decline, and Cerebral atherosclerosis is associated with cystic infarcts and
dementia in old age. JAMA Neurol 70:14181424 microinfarcts but not Alzheimer pathologic changes. Stroke
Wimo A, Jonsson L, Bond J, Prince M, Winblad B (2013) The 44:28352841
worldwide economic impact of dementia 2010. Alzheimers
Dement 9(111):e13

123