Spreading of pathology in neurodegenerative diseases: a focus on human studies

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Neurodegenerative diseases are a major cause of dis-ability and premature death among older people world-wide13. Although these diseases, for which there arecurrently no disease-modifying therapies, show a greatdiversity of clinical phenotypes, they share a commonpathological hallmark the accumulation of charac-teristic proteins into insoluble aggregates in or amongselectively vulnerable neurons and glial cells.

Aggregates of the phosphorylated microtubule-associated protein tau in neurofibrillary tangles andneuropil threads, together with deposits of amyloid-(A), are characteristic of sporadic Alzheimer disease(AD). Tau pathology alone also characterizes a subgroup

of cases of frontotemporal lobar degeneration (FTLD),which is designated as FTLD-tau, as well as other raretauopathies47. Moreover, neuronal accumulations of-synuclein in Lewy bodies and Lewy neurites are thepathological signatures of sporadic Parkinson disease(PD) and PD with dementia, as well as of dementia withLewy bodies8. Furthermore, almost all cases of amyo-trophic lateral sclerosis (ALS) and a further subgroupof cases of FTLD (FTLD-TDP) are characterized byaggregates of TAR DNA-binding protein 43 (TDP43)9.

The disease-related proteins are transformed fromtheir normal conformation into fibrillar or multimericspecies that function as seeds and templates to drive

non-pathological protein counterparts to adopt a simi-lar structural alteration (BOX 1) . In a self-perpetuatingprocess that has been likened to that observed in priondiseases10, progressive seeded aggregation of confor-mationally altered proteins spreads to interconnectedneurons and adjacent glial cells. Based on converginglines of evidence from human tissue, cell culture andanimal model studies1113, the paradigm of pathologicalprotein propagation in neurodegenerative diseases isnow firmly established.

This Review links experimental evidence of themolecular mechanisms of protein propagation in AD(involving tau and A), FTLD-tau (involving tau),

PD (involving -synuclein), and ALS and FTLD-TDP(both of which involve TDP43) to what is known fromstudies in humans regarding vulnerable types of neu-rons and glial cells and the pathways by which disease-protein pathology might spread through the CNS. Wefocus on studies of neuropathology but also underlinethe importance of novel protein-specific neuroimagingmarkers that offer the opportunity to validate the pos-sibility ofsequential spreading that has been implicatedby human pathology studies. Finally, we discuss howthe unifying pathological principle of protein propa-gation may offer new disease-modifying therapeuticapproaches to treating neurodegenerative diseases.

Spreading of pathology inneurodegenerative diseases:a focus on human studies

Johannes Brettschneider 1,2 , Kelly Del Tredici 2 , Virginia M.-Y. Lee 1,3 and John Q. Trojanowski 1,3

Abstract | The progression of many neurodegenerative diseases is thought to be driven by

the template-directed misfolding, seeded aggregation and cellcell transmission ofcharacteristic disease-related proteins, leading to the sequential dissemination ofpathological protein aggregates. Recent evidence strongly suggests that the anatomicalconnections made by neurons in addition to the intrinsic characteristics of neurons, suchas morphology and gene expression profile determine whether they are vulnerable todegeneration in these disorders. Notably, this common pathogenic principle opens upopportunities for pursuing novel targets for therapeutic interventions for theseneurodegenerative disorders. We review recent evidence that supports the notion ofneuronneuron protein propagation, with a focus on neuropathological and positronemission tomography imaging studies in humans.

1Center for Neuro-degenerative DiseaseResearch, Perelman School ofMedicine at the University ofPennsylvania, 3rd FloorMaloney Building,3400 Spruce Street,Philadelphia, Pennsylvania19104, USA.2Clinical NeuroanatomySection, Department ofNeurology, Center forBiomedical Research,University of Ulm,

Helmholtzstrasse 8/1,89081 Ulm, Germany.3Department of Pathologyand Laboratory Medicine,Perelman School of Medicineat the University ofPennsylvania, 3rd FloorMaloney Building,3400 Spruce Street,Philadelphia, Pennsylvania19104, USA.Correspondence to J.Q.T.e-mail: [email protected]:10.1038/nrn3887Published online15 January 2015

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Chronic traumaticencephalopathyA form of neurodegenerationthat occurs in individuals whohave sustained multipleconcussions or injuries to thebrain.

fibrillar -synuclein and wild-type TDP43 can be trans-ported through the axon anterogradely as well as retro-gradely 39,6163 (and the transport of tau has recently beensummarized in detail64). In transgenic mice expressingmutant human tau or mutant human -synuclein, injec-tion of tau or -synuclein preformed fibrils, respectively,into the brain caused aggregates in anatomical structuresthat were relatively distant from the original injection sites,whereas no aggregates formed at the injection site28,42, thusimplying that neuronal connections are probably involvedin disease protein propagation and disease spread. In addi-tion, intramuscular injection of mutant -synuclein in twomouse strains one of which expressed mutant human

-synuclein and the other of which expressed wild-typehuman -synuclein caused intraneuronal -synucleinpathology in the brain and the spinal cord65.

Evidence from studies in humansIn this section, we review evidence from post-mortemand positron emission tomography (PET) studies ofhuman tissue, and explain how these studies supportthe concept that neurodegenerative disease progression(in the disorders discussed here) probably reflects thecellcell propagation of non-prion disease proteins.

Stereotypical patterns of pathology progression. Neuropathological studies have identified that stereotypi-cal patterns of pathology occur in various neurodegen-erative diseases over time, and that progression of thesepatterns is associated with increasing severity of the clini-cal phenotype, thus enabling the development of stagingsystems for these diseases. These studies noted that patho-logical lesions develop at different CNS sites sequentially,and that disease progression is associated with an increase

in the size of aggregates and an increase in the numberof cells showing pathological inclusions at these sites66,67.Such a stereotypical pathology pattern was first estab-lished for AD, in which tau aggregates are found first inthe locus coeruleus of the pontine tegmentum68 and thenin the transentorhinal cortex of the anteromedial tempo-ral lobe (FIG. 2a,b) . Subsequently, lesions are found in otherparts of the temporal lobe, including the entorhinal andhippocampal areas, with lesions next becoming detectablein the basal temporal lobe and the insular cortex, beforefinally developing in the neocortex66,69. Stereotypical pat-terns of tau pathology are not restricted to AD; tau lesionsin chronic traumatic encephalopathy can originate close toperivascular spaces within the depths of cortical sulci70 and become subsequently detectable in large regions ofthe neocortex and allocortex, diencephalon, basal ganglia,brainstem and spinal cord7. Thus, even though tau pathol-ogy characterizes both AD and chronic traumatic enceph-alopathy, the overall directions in which this pathologyprogresses in these diseases are different.

In contrast to the dissemination of tau, patternsof A plaques in AD follow essentially the oppositedirection: plaques are initially found in the cortex andthen, at later disease stages, spread to the brainstem71 (FIG. 2c,d) . Indeed, studies have shown that A plaques areobserved first in the neocortex and then in allocortical,diencephalic and basal ganglial structures before being

found in cases with the highest burden of pathology in the brainstem and cerebellum66,71,72. Why thesetwo major disease proteins of AD show such funda-mentally different patterns is incompletely understood.Although tau and A are likely to exert toxicity via sepa-rate mechanisms73, observations from in vitro and in vivo models indicate that A may drive the formation of taupathology 74 and that tau may mediate A toxicity 7577.Furthermore, these proteins could have synergistic del-eterious effects on, for instance, mitochondrial func-tion78. Future studies of possible interactions betweenthese key players of AD pathology are needed to explaintheir divergent spreading patterns in AD79.

Box 2 | Neurodegenerative disease proteins: prions or not?

Prions arise from an abnormal version of the cell membrane prion protein PrP C, calledPrPSc, which misfolds and may aggregate into plaques. The name was coined by Prusinerin 1982 when he suggested that the scrapie agent be designated a proteinaciousinfectious particle or prion (REF. 14) . Prions isolated from different sources (such assheep, deer and cattle) target different brain areas, induce unique symptoms and havevaried incubation times, indicating that prions exist in different conformational variants

so-called strains160 ,161

. Prions are by definition infectious, and have causedepidemics 162. Accordingly, infectivity is one of the essential components of thedefinition of prions. The infectious transmission of prions between species is not trivialand thus justifies categorizing infectious prion diseases as zoonoses. This wasdramatically evidenced by the spread of bovine spongiform encephalopathy (whichkilled almost 200,000 cattle) to humans in the form of CreutzfeldtJakob disease, whichcaused more than 200 human deaths 162.

Prionoids (also called prion-like proteins to emphasize their similarities to prions, ornon-prion proteins to underline differences) is a term coined by Aguzzi 10 to refer todisease proteins that seem to spread from cell to cell, possibly underlying theprogression of non-prion neurodegenerative diseases such as Alzheimer disease andParkinson disease 11 ,13. Evidence from animal model studies and cell culture experimentsindicates that misfolding, cellcell propagation and spreading of prionoids withinregions probably occurs in non-prion neurodegenerative diseases, and there isincreasing evidence to indicate that these disease proteins can also exist as different

strains 2931 . However, although misfolded variants of these proteins from one diseasedanimal can, when injected at high concentrations into the brains of unaffected animals,spread in the recipient, they cannot be termed prions because they are neitherinfectious nor zoonoses in the way prion diseases are 161,163. There are no epidemiologicaldata to support an infectious spread of tauopathies and synucleinopathies throughblood transfusions, organ transplants or other means. Indeed, we found no evidence ofinter-individual transmission of any of these diseases in a cohort of more than 7,000middle-aged and older individuals who, as children, had been treated with dailysystemic injections of human growth hormone extracted from post-mortem humanpituitaries, whereas 24 cases of prion PrP Sc disease occurred 163.

An even more notable difference between prions and other transmissibleneurodegenerative disease proteins, again with respect to infectivity, comes from dataon the very high prevalence of readily transmissible or infectious prion diseases insheep, cattle, moose, elk and other animals for which there is just no counterpart fortauopathies or synucleinopathies. Nothing comparable to the epidemic of, for instance,bovine spongiform encephalopathy has occurred for tauopathies or synucleinopathiesin livestock, and nor is anything likely to occur, because there is no reservoir ofinfectious human proteinopathies in livestock or other mammals. These clinical andepidemiological differences are important for human medicine, and suggest that priondiseases and neurodegenerative diseases caused by non-prion neurodegenerativedisease proteins or prionoids should not be grouped together. In agreement withAguzzi 161, and to avoid unfounded public health concerns about whether Alzheimerdisease, Parkinson disease and other non-prion neurodegenerative diseases may beinfectious, we do not recommend referring to these other disease proteins as prions.Instead, we think it is preferable to refer to these non-prion neurodegenerative diseaseproteins by their long-accepted traditional names pathological amyloid- , tau and-synuclein rather than as amyloid- , tau and -synuclein prionoids.

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RigidityStiffness and resistance to limbmovement due to increasedmuscle tone. It is a key clinicalsymptom of Parkinson diseaseand can be uniform (known aslead-pipe rigidity) or ratchety(known as cogwheel rigidity).

HyposmiaA reduced ability to smell anddetect odours. This deficit canbe due to any of a wide rangeof causes, includingneurodegenerative diseasessuch as Parkinson disease orAlzheimer disease.

Dual-hit theoryThe proposal that -synucleinpathology in Parkinson diseasestarts in two different locations:the lower brainstem (dorsalmotor nucleus of the vagusnerve) and the olfactory bulb.

Although tau pathology in AD is first found incaudal areas and then later in rostral regions, and Aplaque pathology is detected in increasingly caudalareas with disease progression, -synuclein-containingLewy bodies and Lewy neurites in PD, PD with demen-tia, and dementia with Lewy bodies are first detectedin ventral areas and subsequently in more dorsal brainregions69,71,80. The earliest lesions in PD and in dementiawith Lewy bodies can be detected in the olfactory bulband anterior olfactory nucleus, as well as in the dorsalmotor nucleus of the vagus nerve in the medulla oblon-gata. In PD and in dementia with Lewy bodies, withincreasing burden of pathology, -synuclein aggregatepathology is found in the pons and midbrain beforebeing found in the basal forebrain and, ultimately, inthe neocortex8085 (FIG. 2e,f) . Thus, only in more advancedstages of PD does -synuclein aggregation cause theloss of midbrain dopaminergic neurons in the parscompacta of the substantia nigra80. It is this specific cellloss that has been linked to the classic motor symptomsof PD, including rigidity , resting tremor and bradykin-esia. The accumulation of -synuclein aggregates in theanterior olfactory nucleus86 and olfactory bulb is clini-cally reflected byhyposmia , which is frequently observedbefore the onset of motor symptoms in PD87.

Intriguingly, in individuals with early PD,-synuclein pathology has also been detected outsidethe CNS, in neurons of Auerbachs and Meissners plex-uses of the enteric nervous system (ENS)88,89, as wellas in autonomic nerves of the submandibular gland90.This distribution of -synuclein pathology couldexplain other early symptoms of PD, such as dyspha-gia and constipation91, and has prompted speculationabout the possible spread of early -synuclein pathol-ogy between the closely connected ENS and the dorsalmotor nucleus of the vagus nerve. However, it currentlyremains unclear whether it is the olfactory bulb, theENS or the lower brainstem that is the earliest focus of

-synuclein pathology 9294. Indeed, the appearance ofthe initial pathology in these separate locations gaverise to the dual-hit theory of PD95.

Our group recently proposed four sequential stagesof TDP43 pathology in ALS, whereby the proteinpathology initially seems to spread rostrally and cau-dally from the motor neocortex and towards the spinalcord and brainstem, and then to frontal, parietal and,ultimately, anteromedial temporal lobes at later stages96 (FIG. 2g,h) . Moreover, other studies show stereotypicalpatterns of TDP43 pathology that are suggestive ofsequential spreading in other neurodegenerative dis-eases. Indeed, TDP43 aggregates have frequently beenobserved in addition to tau pathology and A plaquesin AD97102. In such cases, TDP43 aggregates have beenreported to first appear in the amygdala and, withincreasing burden of pathology, to be subsequentlydetected in the entorhinal and hippocampal areas, theoccipitotemporal and inferior temporal cortical areasand, finally, the frontal cortex and basal ganglia103.Similarly, in FTLD-TDP presenting as behavioural variant FTD, a stereotypical distribution pattern sug-gestive of a sequential spreading of TDP43 aggregatesalong a fronto-occipital gradient was observed, with thefirst lesions developing in orbitofrontal areas and the

amygdala, and other lesions appearing later in premo-tor, primary motor, parietal and, finally, occipital areasof the cortex104. In chronic traumatic encephalopathy,TDP43 pathology has been observed among widespreadcortical regions (as in FTLD-TDP), as well as in the spi-nal cord, although no clear regional spreading patternhas been described7. It is therefore possible that TDP43pathology spreads along different pathways in differentneurodegenerative diseases.

Vulnerable types of neurons. Human tissue studies andanimal model experiments indicate that the spatiotem-poral patterns of neurodegenerative disease protein

Table 1 | Summary of evidence supporting the propagation and transmission of non-prion neurodegenerative disease proteins

Pathogenicprotein

Associateddiseases in humans

Main localization of protein Studies in humantissue supportingsequential spread

References supporting neuronneuron transmission

Wild-type Pathological Cell culture Animal models

-synuclein PD, DLB and MSA Presynaptic Cytoplasmic PD 80 and MSA 105 39,40,62,177 178 4144

Amyloid- AD Transmembrane

(APP)

Extracellular AD 66,71 179 23,31,180182

Mutant huntingtin HD Nuclear Nuclear 60

Mutant superoxidedismutase 1

ALS Cytoplasmic Cytoplasmic 56

RNA-bindingprotein FUS

ALS and FTLD-FUS Nuclear Cytoplasmic

Tau AD, FTLD-tau(including PiD, PSPand CBD) and CTE

Cytoplasmic Cytoplasmic AD 66 and CTE 7 50,55 25,183

TDP43 ALS and FTLD-TDP Nuclear Cytoplasmic ALS 96, FTLD-TDP104 and AD 103*

48,49

AD, Alzheimer disease; ALS, amyotrophic lateral sclerosis; APP, amyloid precursor protein (a transmembrane precursor protein whose proteolysis generatesamyloid- ); CBD, corticobasal degeneration; CTE, chronic traumatic encephalopathy; DLB, dementia with Lewy bodies; FTLD, frontotemporal lobar degeneration;HD, Huntington disease; MSA, multiple system atrophy; PD, Parkinson disease; PiD, Pick disease; PSP, progressive supranuclear palsy; TDP43, TAR DNA-binding

protein 43. *Although AD is primarily characterized by tau and amyloid- pathology, TDP43 pathology is observed in up to 57% of cases.

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pathology are highly selective. Only a small number of themany neuronal types are prone to developing the abnor-mal aggregations, with the remainder often directlyin the vicinity of the affected neurons remainingfunctionally and morphologically normal. For instance,-synuclein pathology in early multiple system atrophy isobserved in neurons of the inferior olive in the medulla

oblongata105, whereas the dorsal motor nuclei of the vagusnerve and the hypoglossal nerves remain virtually free of-synuclein aggregates (except in patients with severeoverall pathology). The reasons underlying this selec-tive vulnerability of distinct neuronal populations areunknown. Neuronal vulnerability could be determinedby inherent biochemical and structural characteristics thatwould render neurons more prone to developing aggre-gates, and/or by the location and connectivity of thesecells. Glial cells, particularly oligodendrocytes, exhibit-synuclein inclusions early in multiple system atrophy 105;however, the mechanisms of possible spread between glialcells and neurons remain largely unknown(BOX 4) .

Several studies have noted that neurons affectedby the aggregation of -synuclein, tau or TDP43 havespecific anatomical characteristics. In PD, the neuronsfound to be particularly vulnerable to -synucleinaggregation belong to the class of projection neurons80.Specifically, projection neurons with axons that were very long exhibited a pronounced tendency to develop-synuclein inclusions. By contrast, projection neu-

rons with short axons (such as the pyramidal cells ofneocortical layers II and IV, the neurons of the pre-subicular parvocellular layer of the hippocampus andlocal-circuit neurons with short axons) were generallyresistant to -synuclein aggregation80. Furthermore,projection neurons with long and thin axons that wereonly sparsely myelinated or unmyelinated were vulner-able to -synuclein aggregates, whereas neurons withlong, but thickly myelinated axons with large diameterswere resistant to the formation of such aggregates80,106.

It has been suggested that projection neurons withsparsely myelinated axons would require prodigiousenergy expenditure to maintain axonal function andtransport 107, and that such high energy demands wouldresult in continuously high levels of oxidative stressthat could increase neuron vulnerability to -synucleinaggregation in PD108111. In the final stages of PD (when-synuclein aggregates can be found in the neocortex),the cortical areas that myelinate ontogenetically last andtherefore have thinly myelinated axons develop severe-synuclein pathology, whereas thickly myelinatedaxons in primary cortices are comparatively imperviousto -synuclein aggregation112. Intriguingly, a highly simi-lar pattern can be noted in AD: the first tau aggregatesappear in the sparsely myelinated temporal mesocortex,whereas heavily myelinated primary cortical fields arethe last to exhibit such pathology 113.

Moreover, motor neurons are very large with verylong axons that require high levels of mitochondrialactivity compared with other neurons, and this couldmake them more vulnerable in ALS114. Importantly,however, neuronal susceptibility to TDP43 aggrega-tion in ALS is not confined to motor neurons but alsoincludes non-motor neurons such as the pyramidallayer II or III cells of large (non-motor) areas of theneocortex, especially in frontal areas96. By contrast, somemotor neurons for example, the motor neurons of thecranial nerves III, IV and VI that innervate the extrinsiceye muscles are not (or are only at very late stages ofdisease) affected by TDP43 lesions96.

Figure 1 | Hypothetical molecular mechanisms ofprion-like disease protein transmission inneurodegenerative diseases. In template-directedmisfolding, the deposited pathological disease proteinsare transformed from their normal conformation, viaintermediates, into fibrillar species. These species havethe properties of amyloid (for instance, a fibrillarultrastructure that consists of sheets of -strands) andserve as templates to drive normal physiological versionsof the protein to adopt similar structural alterations 13.In a self-perpetuating process, the progressive seededaggregation of conformationally changed proteinsresults in intracellular aggregates that fragment intodaughter seeds. Finally, in cellcell transmission,pathological proteins spread to anatomicallyinterconnected neurons and adjacent glial cells viaan autocatalytic chain-reaction-like process 11.

Normal protein

Pathologicalmisfoldedprotein

Pathologicalmisfoldedprotein brillarultrastructure

Aggregate

Template-directedmisfolding

Release

Extracellularspace

Uptake

Fragmentationinto further seeds

Seededaggregation

Cell-to-cellspreading

Neighbouring

neuron or glial cell

Further seededaggregation

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PretanglesEarly intracellular aggregatesof hyperphosphorylated tauprotein that develop intofilamentous neurofibrillarytangles.

Routes and pathways. Imaging studies of patients withFTD or AD suggest that the differential vulnerability ofbrain regions to neurodegenerative changes is correlatedwith the strength of neuronal connections among theinvolved areas115,116. For example, brain regions withintense neuronal connectivity as determined byfunctional MRI correlated with foci of brain atrophyin patients with behavioural variant FTD or other neu-rodegenerative diseases115. Neuropathology studies ofALS, PD and AD also provide evidence to suggest thatneurodegenerative protein pathologies may spread vianeuronal connections.

In ALS, the vulnerability of subcortical neuronsto developing TDP43 aggregates seems to be deter-mined by the presence of direct cortical connectionsfrom already affected areas. Post-mortem analysis ofALS brain tissue revealed that areas that receive directprojections from the cortex develop TDP43 inclusionsonce the corresponding area of cortex is affected96.By contrast, neurons that receive no relevant corticalinput such as the motor nuclei of the extrinsic eyemuscles remain resistant to TDP43 lesions until latein the disease96.

In PD, the detection of -synuclein pathology in the vagal dorsal motor nucleus in cases with early disease is

intriguing because this nucleus is a synaptic relay stationof the parasympathetic nervous system, which includesthe ENS, and Lewy body and Lewy neurite patholo-gies have been repeatedly observed in neurons of theENS89,117119. The mechanisms that trigger misfoldingof -synuclein in the ENS remain unresolved, althoughlocal inflammation, oxidative stress and the crossing ofexternal pathogens through the mucosal barrier to theENS are all proposed triggers112,119.

In individuals with AD, or PD and concomitant AD,glial tau pathology is rare, but all of the brain regionsand neuronal types that do exhibit tau pathology areanatomically interconnected. This pattern indicates that

physical contacts, axonal transport and/or transynap-tic transmission between involved regions could playa key role in the pathogenesis of AD120122. The locuscoeruleus the initial site of tau pathology in AD is anatomically distant from the cortical transentorhi-nal region, the second site in which pretangles (andsubsequently, neurofibrillary tangles) develop in AD.Tau aggregates are at first confined to isolated corticalpyramidal cells that are located chiefly in the transen-torhinal region11,25,120,123,124; however, axonal projectionsfrom the coeruleus project to this region, suggestingthat these projections may mediate the propagation oftau pathology.

Some nuclei within the brainstem (including the locuscoeruleus), midbrain, basal forebrain and hypothalamussend long and extensively ramifying projections to theolfactory bulb, many subcortical nuclei, the entire cer-ebral cortex, the cerebellum and the spinal cord. Suchnuclei, in contrast to specific thalamic nuclei (the neu-rons of which project and relay data to specific corticalregions), belong to a functionally unified group called thenon-thalamic nuclei with diffuse cortical projections, andthese projections are assumed to have a more generalizedeffect on cortical regions125. Even at early stages of AD, allof these diffusely projecting non-thalamic nuclei display

some degree of tau pathology 126128.Phylogenetic influences may also be partially

responsible for the spread of tau pathology from thelocus coeruleus to cortical neurons in the transen-torhinal region in AD. The transentorhinal region is aninterface between the basal temporal neocortex (whichdevelops late, both phylogenetically and ontogeneticallyspeaking) and the portions of the entorhinal region thatare close to the neocortex. Among primates, humanshave the largest transentorhinal region and the transen-torhinal region that shows the highest degree of lami-nar differentiation129. The most evolutionarily recentportions of the locus coeruleus project to and synapse

Box 3 | Evidence from animal model studies of spreading via neuronal connections

If the vulnerability of neurons to protein pathology were determined solely by inherent neuronal characteristics, onewould expect the same types of neurons to be affected, independently of the location of the initial focus. However,animal models in which the initial focus of pathology is varied have shown that depending on where preformed fibrils(PFFs) are injected, different neuronal populations are sequentially affected 25 ,28,42,44,124, implying that neuronalconnectivity could be an important clue to understanding neuronal vulnerability to protein aggregation inneurodegenerative diseases. For example, injections of human tau PFFs into the striatum of PS19 human mutant tau

transgenic mice induced tau aggregation in regions interconnected with the striatum, including the substantia nigraand thalamus, whereas after PFFs were injected into the hippocampus, aggregates first spread to the entorhinalcortex and contralateral hippocampus 28.

Furthermore, as inclusion pathology can spread to anatomically distant structures while neurons closer to theinjection site are spared, the transmission of protein pathology in these diseases might not simply occur by diffusionamong neighbouring cells but rather occur via axonal connections 25 ,28 ,42 ,124 . A recent study in mice expressing humanmutant tau indicated that tau seeded aggregates, similar to prions and amyloid- aggregates, can reach the CNSfrom the periphery 164 . Recently, the hypothesis that intestinal -synuclein spreads to the CNS via postganglionicenteric neurons and the vagus nerve was strengthened by the observation that human Parkinson disease brainlysates injected into the intestinal wall of wild-type SpragueDawley rats cause -synuclein pathology in the dorsalmotor nucleus of the vagus after ~144 hours 165 . Although mechanisms such as glial cellglial cell or glial cellneuronspreading, migration through interstitial fluids and/or cerebrospinal fluid, or blood-cell-mediated transport of tauamyloid pathology 166 cannot be eliminated, the patterns of pathology in animal models and human tissue studiesmake the idea of neuronal connection-mediated propagation particularly attractive, at least for pathological tauand -synuclein 154 .

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in the transentorhinal region. The fact that this con-nection is evolutionarily recent may partially explainwhy neurons from these two areas develop the earliestAD-associated tau lesions within the CNS68,122,130.

PET studies. Human tissue pathology-staging studies arelimited by the relative lack of early (that is, prodromal)cases, because most patients die as a consequence of theneurodegenerative disease. Furthermore, these studiesare limited by the fact that the resulting neuropathologi-cal data are by definition cross-sectional, and can proposea sequential order of involvement only by correlatingfindings with clinical phenotype and disease duration.

Although experimental evidence from animal studiessuggests a similar spreading in humans is most likely, thiscannot be proven in any given individual autopsy case.

To validate the sequential involvement of differentCNS regions proposed by human autopsy studies, imag-ing biomarkers specific to the different disease proteinsare necessary because they should enable thein vivo detection and monitoring of any spreading of proteinpathology in longitudinal studies. Currently, the mostpromising markers are PET ligands. Such markers havebeen developed to visualize A pathology in individualswith AD, and PET ligands for pathological tau are alsoemerging131,132.

Figure 2 | Sequential topographical dissemination of non-prion proteins in neurodegenerative diseases. In allpanels, the pathology is first detected in areas delineated by darker colours and subsequently in regions shown inlighter colours. a , b | In Alzheimer disease, tau aggregates develop in the locus coeruleus (LC), then in thetransentorhinal and entorhinal regions and subsequently in the hippocampal formation and in broad areas of theneocortex (NC) 69. c, d | In contrast to tau pathology, amyloid- deposits in Alzheimer disease are first observed in theNC and are then detected in allocortical, diencephalic and basal ganglia structures (in a caudal direction) and inthe brainstem, and occasionally in the cerebellum (CB) 71. e , f | The progression of -synuclein-immunoreactive Lewybody and Lewy neurite pathology in Parkinson disease follows an ascending pattern from the brainstem to the

telencephalon80

. The earliest lesions can be detected in the olfactory bulb (OB), as well as in the dorsal motornucleus of the vagus nerve (DMX) in the medulla oblongata. At later stages, the -synuclein aggregate pathology isfound more rostrally through the brainstem via the pons and midbrain, in the basal forebrain and, ultimately, in theNC. g, h | In amyotrophic lateral sclerosis cases with a low burden of TAR DNA-binding protein 43 (TDP43) pathology,TDP43 inclusions are seen in the agranular motor cortex (AGN), in the brainstem motor nuclei of cranial nerves XIIX,VII and V, and in -motor neurons in the spinal cord. Later stages of disease are characterized by the presence ofTDP43 pathology in the prefrontal neocortex (PFN), brainstem reticular formation, precerebellar nuclei, pontine greyand the red nucleus. Subsequently, prefrontal and postcentral neocortices, as well as striatal neurons, are affected bypathological TDP43, before the pathology is found in anteromedial portions of the temporal lobe, including thehippocampus 96. AC, allocortex; BFB, basal forebrain; BN, brainstem nuclei; BSM, brainstem somatomotor nuclei;ENT, entorhinal cortex; MTC, mesiotemporal cortex; SC9, spinal cord grey-matter lamina IX; SN, substantia nigra;TH, thalamus. Part f reprinted from Neurobiology of Aging , 24 , Braak, H. et al. Staging of brain pathology related tosporadic Parkinsons disease, 197211, 2003, with permission from Elsevier.

Alzheimer disease: tau

Parkinson disease: -synuclein Amyotrophic lateral sclerosis: TDP43

a bNC

BFB

LCENT

NC

BFB

e f

OBBFB

BFB

BNSN

DMXDMX

Alzheimer disease: amyloid-

c d

g h

TH

CBAC

BNBN CB

BSM

SC9

TH

PFN

AGN

PFNAGN

BSM

SC9

MTC

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The PET tracer that is most widely used for imag-

ing A is C-6-OH-BTA-1, which is also known asC-Pittsburgh compound B (C-PiB), which wasdeveloped by Klunk and colleagues133. C-PiB PET-imaging trials in humans have shown that tracer uptakein the neocortical brain regions of patients with AD issubstantially greater than in those of individuals with-out dementia133. Moreover, trial data have shown thattracer uptake is predictive of conversion of mild cogni-tive impairment to AD134 and correlates with A depo-sition (as determined post-mortem) 133,135. Individualscarrying rare autosomal-dominant AD mutationsshowed elevated C-PiB levels in nearly every corticalregion and also in subcortical grey-matter structures

15 years before the estimated age of dementia onset136.In addition to C-PiB, several studies have used theF-labelled A-targeting tracers flutemetamol137, flor-betapir138 and florbetaben139. Flutemetamol showedgood discrimination between AD and controls137, andflorbetapir showed close correlation of F uptake inPET with post-mortem A pathology 138. Furthermore,florbetaben showed a higher tracer uptake in individ-uals with AD than in age-matched normal controls,especially in neocortical regions (particularly the pos-terior cingulate gyrus)139. Moreover, there was a loweruptake of an A-specific PET ligand within the hip-pocampus than in neocortical brain areas, and this mayclosely reflect the more prominent A pathology inneocortical areas than in allocortical areas, as reportedin post-mortem neuropathology studies 71. A caveat,however, is that A-specific PET tracers may bind tofibrillar rather than to early-stage diffuse A plaques;therefore, the earliest deposits of A may not be visual-ized by these imaging ligands. In addition,11C-PiB andthe 18F-labelled PET tracers bind with greater affinity to

-sheet (fibrillar) A than to diffuse plaques140.Several PET markers that are highly specific to neurofi-

brillary tangles and other types of tau pathology (includ-ing glial tau pathology) have recently been developed,such as the 18F-labelled tracers 18F-THK5105(REF. 184) ,18F-THK523 (REF. 132) , 18F-T807 (REF. 141) , 18F-T808(REF. 142) and the 11C-labelled tracer 11C-PBB3(REF. 143) .In vitro studies in AD brain homogenates have shown thatTHK5105 and T808 have an affinity for tau fibrils that is2527-fold higher than that for A fibrils144. In a groupof eight individuals with late-stage AD, the18F-THK5105PET tracer was substantially enriched in the medial andinferior temporal lobe (as compared with cognitivelynormal age-matched controls)145, thus reflecting the earlyeffects of tau neurofibrillary tangle pathology on theseareas in AD69. In addition, 18F-THK5105 retention wasstrongly associated with decreases in cognitive param-eters and with reduced hippocampal and whole-braingrey-matter volumes. All of these associations are con-sistent with findings from previous post-mortem studiesthat showed marked correlations between neurofibrillarytangle density and dementia severity or neuronal loss69.

A notable feature of the tau tracers is that they havedifferent sensitivities to different types of tau lesionsdepending on the underlying disease. Tau exists in sixisoforms: three three-repeat (3R) isoforms and threefour-repeat (4R) isoforms. Thus, tau deposits can con-

tain 3R tau, 4R tau or a mixture of 3R and 4R tau iso-forms, depending on the specific disease6. The 18F-tracerTHK523 exclusively labels neurofibrillary tangles(which contain a mixture of 3R and 4R isoforms)that are present in AD, but not the 3R tau lesions thatoccur in Pick disease or the 4R tau lesions that occurin corticobasal degeneration and progressive supra-nuclear palsy, whereas11C-PBB3 seems to detect all ofthese tau lesions143. Thus, these tracers possess differ-ent clinical applications, either as general markers ofAD and related tauopathies (for instance, in the case of11C-PBB3) or for the differential diagnosis to distinguishbetween tauopathies (for example,18F-THK523).

Box 4 | Do glia contribute to protein propagation?

There is now abundant evidence to support a prominent role of astrocytes, microgliaand oligodendrocytes in the initiation and progression of differentneurodegenerative diseases (recently summarized in REFS 167170 ). By contrast,little is known about how glia could specifically contribute to protein propagation.

Some initial studies on the role of glia in protein propagation exist forsynucleinopathies. Here, both monomeric and aggregated -synuclein released from

neuronal cells were shown to be endocytosed by astrocytes in a co-culture of primaryastrocytes with a neuronal cell line overexpressing -synuclein 171. This neuron-to-astroglia transfer of -synuclein led to changes in the expression of genes related toneuroinflammatory response 171. The glial accumulation of misfolded -synucleinthrough transmission of the neuronal protein was also demonstrated in transgenicmice expressing human -synuclein 171. These results indicate that astroglial-synuclein pathology observed in Parkinson disease and dementia with Lewy bodiescould be caused by a direct transmission of neuronal -synuclein to astroglia, andcould result in inflammatory responses, including microglial activation 172. Suppressionof this subsequent microglial activation extended mouse survival.

To replicate the prominent pathological effects on oligodendroglia in multiplesystem atrophy, several transgenic mouse models that express human wild-type-synuclein under the control of oligodendroglia-specific promoters have beendeveloped. These models reproduce the accumulation of -synuclein in glialcytoplasmic inclusions and these mice exhibit various levels of motor

impairment 173 ,174 . Indeed, Yazawa et al. 174 described -synuclein pathology in axons oftransgenic mice overexpressing wild-type human -synuclein specifically inoligodendrocytes that at the time was difficult to explain, but that in retrospect mayhave signified the transfer of -synuclein pathology from oligodendrocytes to axons.In addition, oligodendrocytes in cell culture were shown to internalize -synucleinmonomers, oligomers and fibrils. Furthermore, in the brains of rats thatoverexpressed human -synuclein, a transfer of human -synuclein to ratoligodendroglia that had been grafted into the striatum was observed 175 . Thesefindings support the notion of neuron-to-oligodendrocyte transfer of -synuclein, amechanism that could have a crucial role in the propagation of -synuclein pathologyin multiple system atrophy.

For tauopathies, Clavaguera et al. 26 showed the induction of tau pathology inoligodendrocytes and astrocytes following injection of progressive supranuclearpalsy, corticobasal degeneration and argyrophilic grain disease brain lysates into thebrains of mice expressing wild-type tau. This demonstrates that tau pathology canspread to these cells, but does not explain the potential role of glia in taupropagation.

Finally, with regard to amyloid- , both in cases of Alzheimer disease and transgenicmice, the expression of -secretase 1 and amyloid- were not restricted to neuronsbut to also occur in astroglia 176 , indicating that astrocytes may contribute to thegeneration of amyloid- aggregates in vivo .

Thus, although the current evidence from cell culture studies and animal models islimited, it is plausible that pathological aggregates may be induced not only inneurons, but also (to a variable extent) in glial cells, and that pathological diseaseproteins may be transferred between neurons and glia. Therefore, future studies thatmore specifically examine the role of glial cells in protein propagation are necessary.

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A current limitation of PET studies is their relativelylow spatial resolution, which makes it difficult to ade-quately detect neurofibrillary tangles within subcorti-cal regions and small anatomical structures such as thelocus coeruleus (which is where, according to neuro-pathological staging models, tau pathology first occursin AD69). Thus, compared with autopsy staging studiesthat can focus on individual lesions and involved cells,PET studies can only provide an assessment of regionaleffects. In addition, the majority of PET studies havebeen cross-sectional; to show a sequential spread ofpathology, additional longitudinal studies are necessarythat should also compare their findings to those frompost-mortem pathology analyses. Finally, there are stillno specific neuroimaging markers for synucleinopathiesor TDP43 proteinopathies, although the developmentof such ligands is the focus of intense ongoing research.Indeed, for these latter diseases, we are currently limitedto indirect approaches that monitor the neuronal andaxonal loss that is associated with potentially spread-ing pathology. Given the close relationship between

the presence of protein deposits and neuronal loss (asseen in pathology studies of tau in AD or TDP43 inALS and in FTLD-TDP69,96,104) in certain regions, serialanalyses of changes in brain connectivity 115 and of pro-gressive damage to fibre tracts could help to delineatespreading pathways in proteinopathies for which nospecific in vivo marker yet exists. For example, wedemonstrated that ALS-induced axonal loss in white-matter tracts as measured by diffusion tensor imag-ing affected the same regions as seen in our stagingstudy of TDP43 pathology 146, and we are currentlyimplementing this diffusion tensor imaging-basedapproach in a prospective study. However, prospec-tive studies that implement serial fibre-tract and con-nectivity analyses are still rare and have been limited toAD147. Moreover, these prospective studies have mostlyincluded small numbers of individuals and have notcompared their findings with data from post-mortemanalysis of protein pathology.

Therapeutic implicationsTo date, no disease-modifying therapy exists for the neu-rodegenerative diseases discussed here, and neuroprotec-tive and anti-inflammatory therapies have largely provedunsatisfactory. Template-directed replication and subse-quent cellcell transmission of pathology-associated pro-teins provides a common molecular pathway that could

be targeted by novel therapeutic strategies with the aimof disrupting or delaying propagation.

As template-directed misfolding is likely to be a veryearly event in the pathological cascade of the non-prionneurodegenerative diseases discussed here, one thera-peutic approach could be to stabilize the wild-type pro-teins in their normal conformation, ideally renderingthem resistant to template-directed conformationalchange while not interfering with their normal cellularfunction13. This approach has already been applied withsome success to the treatment of transthyretin amy-loidosis148. In this disease, the transthyretin tetramermust first dissociate into monomers to form amyloid.

Ligands that stabilize the tetramer can prevent amy-loidosis, and a drug with that effect (tafamidis) hasbeen approved by the European Medicines Agencyfor the treatment of a familial form of transthyretinamyloidosis148.

Moreover, agents that interfere with the release oruptake of neurodegenerative disease proteins couldprevent transmission of pathology to neighbouringneurons. For example, specific antibodies could cap-ture protein seeds in the extracellular space as theyare in transit between neurons149, or target receptorsor other cellular proteins needed for the uptake orrelease of pathogenic proteins10,13,17,40,50,150,151. However,such immunological interventions in humans wouldface the formidable obstacles of the bloodbrain bar-rier and the bloodcerebrospinal fluid barrier, bothof which limit the passage of extrathecally adminis-tered antibodies into the CNS152. Similarly, interferingwith protein transmission by nonspecifically enhanc-ing cell membrane stability, inhibiting endocytosis orinhibiting exosomal protein secretion would prob-

ably interfere with the homeostasis of other cellularproteins and thus entail unacceptable adverse effects.However, these therapeutic strategies are worthy offurther exploration.

Open questions and future directionsAlthough the propagation of disease proteins offersa unifying pathophysiological concept of neurodegen-erative diseases, several key issues need to be resolved.The specific molecular mechanisms that trigger theinitial conversion of normally soluble proteins intofilamentous or aggregated polymers remain unknown.Understanding the initial event or events in the protein-misfolding cascade would be valuable for identifyingtherapeutic targets that could be modulated beforepotentially irreversible spreading of protein pathologyand neuron loss.

Furthermore, it will be crucial to determine thespecific biochemical characteristics of protein speciesthat are transmissible. For instance, it remains to bedetermined whether pre-fibrillar protein species, suchas oligomers, are more detrimental to cells than arefibrillar forms153. Many mechanistic aspects of cellcelltransmission require clarification. Although the uptakeand release of pathological proteins via different typesof endocytosis and exocytosis processes can explainpathological protein transmission in cell culture mod-

els, they can only partially account for the spreadingof disease proteins over considerable anatomical dis-tances as observed in animal models and human tis-sue studies62,154. An understanding of the pathways anddirectionality of spreading would be facilitated by thedefinition of primary (early) foci of protein pathologyin the human disease. However, for some diseases, suchas PD, the initial focus is still being discussed95, and forothers, such as ALS, it has not been determined96. Thisis attributable partly to the limitations of neuropatho-logical studies, which analyse selected and often onlysmall blocks of tissue (obviously, with the aim of pre-serving invaluable human material) that do not allow

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detailed analysis of pathology in large regions or acrossdifferent regions of the CNS. Thus, comprehensivepathology studies performed on entire cortical regionsor entire hemispheres, the brainstem and the full lengthof the spinal cord may be necessary to more reliablydefine the early foci of protein pathology.

Finally, many neurodegenerative diseases are likely tobe non-cell autonomous, with an important part playedby astroglia, oligodendroglia and microglia. For exam-ple, in multiple system atrophy, -synuclein pathologychiefly presents as cytoplasmic inclusions in oligoden-drocytes (although it is also observed to a much lesser

extent in neurons) 105. The relevance and extent of glialcontributions to the transmission of protein pathologyin neurodegenerative diseases remain unclear.

Considerable effort will be needed to resolve eachof these problems and to make progress towards effec-tive therapies for neurodegenerative diseases. Indeed,any progress in resolving the key issues outlined in thisReview is likely to advance our understanding of each ofthese diseases substantially, and future strategies that tar-get the transmission of any of these pathological proteinswill most probably constitute a fundamental step forwardin treating neurodegenerative diseases.

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AcknowledgementsThe authors thank H. Braak for reviewing the manuscript andM. Leonhard for help with designing the figures.

Competing interests statementThe authors declare no competing interests.

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Spreading of pathology in neurodegenerative diseases: a focus on human studies

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