2825

One in 5 patients with stroke will end up demented shortly after a stroke, half with prior cognitive impairment and

half without. After recurrent stroke, more than a third will become demented.1 The mechanisms remain unclear beyond the fact that neurodegenerative and vascular mechanisms con-tribute to the cognitive decline.2 In this review, we explore experimental and clinical evidence of interaction between ischemia, amyloid deposition, and neuroinflammation and identify new potential therapeutic targets.

Evidence From Experimental StudiesClinical data clearly indicate that the coexistence of stroke and Alzheimer disease (AD) leads to exacerbated demen-tia,3 and experimental studies with animals have addressed the relationship between stroke and AD.4–9 Although human studies have also indicated that soluble parenchymal amyloid precursor protein and β-amyloid 1 to 42 (Aβ

1–42) accumulate

in patients with multi-infarct dementia,10,11 there are animal studies examining neurodegenerative mechanisms and cogni-tive impairment in global and focal experimental ischemia. Changes in neurotransmitter systems, trophic factors, and cell signaling and neuroinflammatory mechanisms have been well documented.12 Experimental animal models of cogni-tive impairment have demonstrated the presence of amyloid precursor protein in the area of ischemic damage.13 Studies in mice overexpressing mutated presenilin 1 or presenilin-knockout mice suggest that presenilin 1 mutations lead to enhanced neurodegeneration after focal ischemia or excitotox-icity.9,14 This may suggest that mutations leading to higher lev-els of Aβ may increase the sensitivity to ischemia. In another study, mice overexpressing amyloid precursor protein with middle cerebral artery occlusion were shown to have enlarged infarcts and a stronger reduction of blood flow after the arte-rial occlusion.15 These experiments, however, also showed that the vasodilatory effect of the endothelium-dependent vasodilator acetylcholine was significantly reduced in trans-genic mice, possibly suggesting that Aβ-induced disturbance in endothelium-dependent vascular reactivity may contribute

to the higher ischemia sensitivity. Our research group has conducted several studies directly examining the pathologi-cal, neuroinflammatory, and behavioral relationship of stroke and AD in rat and mouse models.4–7 In particular, these studies have focused on the potential synergism that would account for the clinical findings. A consequence of a chronic neuro-inflammatory response is perturbation of the cerebrovascu-lar system. Likewise, a perturbation of the cerebrovascular system will influence the degree of neuroinflammation after injury. A considerable body of evidence has demonstrated that AD is directly related to and has profound pathological changes in the cerebral microvasculature.16 Specific atten-tion has recently focused on changes within brain endothe-lial cells in AD and in response to exposure to Aβ.16 It has been hypothesized that during the onset of AD the breakdown of the blood–brain barrier results in an neuroinflammatory response leading to increased transport of soluble Aβ across the endothelium,17,18 the upregulation of inflammatory adhe-sion molecule expression in response to nuclear factor κB, and subsequent infiltration of inflammatory leukocytes into the brain.19 This hypothesis has been supported by data show-ing that Aβ exposure of the basal compartment of endothelial monolayers in culture results in increased monocyte transen-dothelial migration.20 Interestingly, this migration of mono-cytes was inhibited by antibodies to the putative Aβ receptor for advanced glycation end products and to the endothelial cell–cell adhesion molecule platelet endothelial cell adhesion molecule-1, suggesting a significant role of Aβ in mediating inflammatory responses in AD.20 Despite overwhelming evi-dence for an involvement of dysfunction of the microvascular endothelium in the onset of AD, surprisingly little is known about the particular changes that occur in the endothelium in response to Aβ exposure and in response to various vascular risk factors in animal models that mimic the aspects of AD, stroke, diabetes mellitus, and hypertension. Given the strong links between neuroinflammation and the microvasculature, there is a strong rationale for examining the role of the micro-vasculature in rodent models of AD and stroke.

Amyloid Burden, Neuroinflammation, and Links to Cognitive Decline After Ischemic Stroke

Alexander Thiel, MD; David F. Cechetto, PhD; Wolf-Dieter Heiss, MD; Vladimir Hachinski, MD; Shawn N. Whitehead, PhD

Received February 20, 2014; final revision received May 20, 2014; accepted June 3, 2014.From the Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada (A.T.); Vulnerable Brain Laboratory, Department

of Anatomy and Cell Biology (D.F.C., S.N.W.), and Department of Clinical Neurological Sciences, London Health Sciences Centre (V.H., S.N.W.), Western University, London, Ontario, Canada; and Max Planck Institute for Neurological Research, Cologne, Germany (W.-D.H.).

Correspondence to Shawn N. Whitehead, PhD, Vulnerable Brain Laboratory, Department of Anatomy and Cell Biology, Western University, Medical Sciences Building, Room 458, London, Ontario, Canada N6A 5C1. E-mail shawn.whitehead@schulich.uwo.ca

(Stroke. 2014;45:2825-2829.)© 2014 American Heart Association, Inc.

Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.114.004285

Topical ReviewSection Editors: Philip B. Gorelick, MD, MPH, and Leonardo Pantoni, MD, PhD

by guest on March 18, 2016http://stroke.ahajournals.org/Downloaded from

2826 Stroke September 2014

Neuroinflammation is a key component of the patholo-gies of both AD and stroke21–24 and involves proliferation of microglia and astrocytes,6 activation of the transcription fac-tor nuclear factor κB, upregulation of inflammatory cyto-kines such as tumor necrosis factor-α and interleukin-1β,4,7 release of prostaglandin E2 under the enzymatic control of cyclooxygenase-2,7 and release of reactive oxygen and nitro-gen species. Our previous work has demonstrated the follow-ing: (1) In a transgenic mouse model of AD (APP23 mice), small striatal infarcts induced with the vasoconstrictor endo-thelin-1 result in enhanced levels of inflammatory cytokines and AD-like pathology.7 (2) The combination of AD-like pathology induced by intracerebroventricular injections of the toxic 25 to 35 fragment of Aβ peptide (Aβ

25–35) and stroke

(unilateral endothelin-1 injections in the striatum) in the rat also resulted in enhanced neuroinflammatory responses and AD-like pathology in the neocortex and hippocampus and were correlated with memory deficits detected using the Barnes circular platform test.4–6 (3) Selective inhibition of the critical inflammatory transcription factor nuclear factor κB blocked the pathological and memory deficits associated with the rat AD model.25 (4) The neuroinflammatory, AD-like pathological changes and cognitive deficits in either the AD- or stroke-alone models were reduced with anti-inflammatory treatment, but not in the AD/stroke combined model.5,7 (5) This rat model of AD/stroke demonstrated progressive longer-term deterioration of cognitive function. In parallel, there was a progressive increase in the size of the infarct and the neuro-inflammatory response over time in the combined models of stroke and AD.6 Therefore, for stroke and AD, investigations indicate both conditions alone result in increased neuroinflam-mation that can be treated using anti-inflammatory agents. The combination of these 2 conditions elicited enhanced AD-like pathology, neuroinflammatory response, and memory deficits that are not ameliorated with anti-inflammatory treatment. This has led us to think that interactions between Aβ, stroke, and neuroinflammation may be occurring within the brains of some patients after a stroke, which may explain why they go on to develop dementia. Further work using innovative and sophisticated animal models needs to clearly demonstrate the timing between Aβ production, deposition, and the role of neuroinflammation after stroke and how this all related to the induction of cognitive decline. However, if this can be done, we can make the legitimate case for the concurrent use of anti-Aβ and anti-inflammatory therapies in human patients who suffered a stroke.

Evidence From Clinical and Epidemiological Studies

An association between ischemic stroke and poststroke cogni-tive decline or dementia has already been suggested in a sub-cohort of the Framingham Study26 and has been confirmed in prospective longitudinal studies.27–29 It was, however, not until the religious order study that an association between stroke, AD, or mild cognitive impairment and AD-specific pathology (parenchymal Aβ deposition) was described.30,31 Interestingly, subjects with subcortical infarcts had the highest risk of developing dementia and exhibited fewer AD pathologies

than those without infarcts,30 whereas subjects with AD alone and subjects with AD with infarcts show otherwise similar clinical and risk factor characteristics.32 Whether ischemic infarcts only accelerate a pre-existing cognitive impairment or whether infarcts pose a risk for developing cognitive decline also in cognitively normal subjects remains unclear. Although 2 population-based cohort studies seem to support the view that prestroke cognitive status is an independent risk factor for poststroke dementia,28,33 other studies found no such asso-ciation34 or only for nonamnestic mild cognitive impairment but not for amnestic mild cognitive impairment,35 which usu-ally is considered a prodromal state of AD. A recent longi-tudinal cohort study re-examining this question36 indicates that although higher levels of prestroke executive function are associated with lower risk for poststroke dementia (relative risk, 0.24; 95% confidence interval, 0.13–0.45), stroke was a disproportionate risk factor (relative risk, 4.4; 95% confidence interval, 1.35–14.63) for dementia in patients with high cogni-tive function. Based on these epidemiological studies and the results from animal experiments reviewed above, the follow-ing hypotheses explaining the relationship between stroke and AD pathology and poststroke cognitive decline have been put forward.

The Independence HypothesisThis view is mainly based on epidemiological studies and assumes that multiple cortical or even small subcortical ischemic events as well as microvascular disease in general2 cause either direct cortical neuronal loss or subcortical dam-age, leading to a reduction of anatomic connectivity and to a sudden decrease in cognitive function from which patients may recover to some extent (trajectory A in Figure 1A). In case of additional presence of AD pathology (trajectory D in Figure 1A), these vascular ischemic processes decrease the reserve capacity of the brain to compensate ongoing neurode-generation, thus preventing recovery of cognitive function.37 In this view, vascular processes are driving the poststroke cog-nitive impairment independently of the presence or absence of primary degenerative AD pathology.

The Interaction Hypothesis The fact that patients with more severe cognitive impairment at the time of stroke are at high risk for developing demen-tia even in the absence of recurrent stroke38 might suggest that ischemic stroke triggers ≥1 additional pathophysiologi-cal processes that may spark a secondary degenerative pro-cess (trajectory B in Figure 1A), which may interact with AD pathology and thus accelerate ongoing primary neurodegen-eration (trajectory C in Figure 1A).

One such process could be hypoperfusion/hypoxia. It has been shown that in demented patients with unilateral internal carotid artery stenosis, Aβ deposits are significantly higher in the hemisphere with the stenosis, suggesting that chronic hypoperfusion (in the sense of a chronic penumbra) may indeed favor Aβ deposition.39 It remains, however, unclear whether such persistent hypoperfusion states are occurring frequently enough after acute strokes to explain the rela-tively high incidence of poststroke decline. A more promising

by guest on March 18, 2016http://stroke.ahajournals.org/Downloaded from

Thiel et al Neuroinflammation and Links to Stroke 2827

pathophysiological process observed in conjunction with AD pathology as well as ischemic stroke is neuroinflamma-tion and has thus been regarded as one possible link between the 2 pathologies.40 Recent progress in brain imaging meth-ods, especially the combination of microglia imaging using positron emission tomography and diffusion tensor imaging using MRI,41 has demonstrated that persisting white matter inflammation after subcortical stroke can lead to the degen-eration of fiber tracts over a 6-month observation period,42,43 which can even occur trans-synaptically in callosal fibers not directly affected by the infarct.44 Which factors are respon-sible for maintaining the inflammatory response over several months remains to be investigated with vascular risk factors (hypertension, dyslipidemia, or diabetes mellitus) or genetic factors being obvious candidates. It thus seems not unreason-able to assume that similar mechanisms affecting association fibers may lead to a decline in cognitive function (Figure 1B).

Imaging Aβ deposition in vivo using positron emission tomo-graphic ligands is the third imaging component required to test these important hypothesis.45

To demonstrate the feasibility of such a multimodal imag-ing study that could test these hypotheses, 7 patients with stroke were investigated to determine the spatial and tempo-ral relationship between Aβ deposition, microglia activation, and cognitive performance. The 7 patients aged between 55 and 85 years with first supratentorial ischemic stroke under-went MRI scanning and the Montreal Cognitive Assessment (MoCA)46 <2 weeks and 5 to 7 months poststroke. Two posi-tron emission tomographic scans were performed between 5 and 7 months after the event to assess Aβ deposition with Pittsburg B compound (11C-PIB)47 and microglia activation with 11C-[R]-PK11195.48 Standardized uptake value ratios for 11C-PIB (SUVR

PIB) in global gray and white matter relative

to the cerebellum49 and uptake ratios for 11C-[R]-PK11195 (SUVR

PK) between the stroke-affected and -unaffected hemi-

sphere gray and white matter were analyzed.50

The cognitive performance at 5 to 7 months after stroke (MoCA2) was negatively correlated with gray matter Aβ deposition (SUVR

PIB; Figure 2). This relationship remained

significant even when initial cognitive performance (MoCA1) and age were entered as covariates into the analysis. A mul-tiple regression with MoCA1 and SUVR

PIB as independent

variables explained 98% of the variance in MoCA2 (adjusted R2=0.979; P<0.01). Microglia activation in the stroke-affected hemisphere (SUVR

PK) was mainly observed in white matter,

Aβ deposits in the gray matter of both hemispheres (Figure 3). No significant relationship was found between gray matter SUVR

PIB and SUVR

PK.

The results of this hypothesis-generating pilot sample data in human stroke show that the imaging modalities and tech-niques to test the proposed hypothesis are available and that it may be possible to differentiate separate pathomechanisms

A

B

Figure 1. A, Possible trajectories of poststroke cognitive decline. In the absence of parenchymal β-amyloid deposition, an isch-emic infarct may cause a transient decline in cognitive function, but full or partial recovery is possible (trajectory A) without further deterioration of cognitive status. If vascular and inflammatory processes trigger ongoing secondary neurodegeneration, post-stroke cognitive decline occurs (trajectory B). In the presence of amyloid, the ischemic lesion causes a loss of cognitive reserve preventing cognitive recovery (trajectory D), and cognitive decline may even be accelerated if secondary degeneration is trig-gered by inflammatory processes (trajectory C). MoCA indicates Montreal Cognitive Assessment. B, Summary of hypothetical pathomechanisms leading to poststroke cognitive decline.

Figure 2. Linear regression between Montreal Cognitive Assess-ment (MoCA) between 5 and 7 mo poststroke (MoCA2) and cortical β-amyloid depositions measured with positron emis-sion tomography and Pittsburg B compound (11C-PIB; SUVRPIB). Regression analysis demonstrates a highly significant positive linear relationship between cognitive status poststroke and tracer uptake. This relationship remained significant after entering age and initial cognitive status (MoCA1, 2 weeks after stroke) into the analysis. SUVR indicates standardized uptake value ratio.

by guest on March 18, 2016http://stroke.ahajournals.org/Downloaded from

2828 Stroke September 2014

explaining Aβ-dependent cortical and non–Aβ-dependent but neuroinflammation-related subcortical mechanisms. A clini-cal trial investigating Determinants of Dementia after Stroke (DEDEMAS) with an Aβ imaging component is currently under way.51 True multicenter, multimodal imaging studies informed by the results from animal experiments, however, are still missing. Testing hypotheses such as those summarized in Figure 1B is clinically relevant because poststroke cognitive function is a major risk factor for poor long-term functional outcome after stroke, and the proposed imaging techniques might be useful to guide clinical interventions in preventing poststroke cognitive decline by modulation of inflammation or Aβ deposition.

In summary, neurodegenerative and vascular processes often occur together, but are usually studied apart. Poststroke cognitive impairment offers a good model of interaction, given that acute ischemia sets up a chain of rapidly evolving pathogenic events that can be studied, blocked, and modified experimentally as a guide to potential poststroke therapy.

Disclosures None.

References 1. Pendlebury ST, Rothwell PM. Prevalence, incidence, and factors associ-

ated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis. Lancet Neurol. 2009;8:1006–1018.

2. Hachinski V, Munoz D. Vascular factors in cognitive impairment–where are we now? Ann N Y Acad Sci. 2000;903:1–5.

3. Whitehead SN, Hachinski VC, Cechetto DF. Interaction between a rat model of cerebral ischemia and beta-amyloid toxicity: inflammatory responses. Stroke. 2005;36:107–112.

4. Whitehead S, Cheng G, Hachinski V, Cechetto DF. Interaction between a rat model of cerebral ischemia and beta-amyloid toxicity: II. Effects of triflusal. Stroke. 2005;36:1782–1789.

5. Whitehead SN, Cheng G, Hachinski VC, Cechetto DF. Progressive increase in infarct size, neuroinflammation, and cognitive deficits in the presence of high levels of amyloid. Stroke. 2007;38:3245–3250.

6. Whitehead SN, Massoni E, Cheng G, Hachinski VC, Cimino M, Balduini W, et al. Triflusal reduces cerebral ischemia induced inflammation in a combined mouse model of Alzheimer’s disease and stroke. Brain Res. 2010;1366:246–256.

7. Grilli M, Goffi F, Memo M, Spano P. Interleukin-1beta and glutamate activate the NF-kappaB/Rel binding site from the regulatory region of the amyloid precursor protein gene in primary neuronal cultures. J Biol Chem. 1996;271:15002–15007.

8. Mattson MP, Zhu H, Yu J, Kindy MS. Presenilin-1 mutation increases neuronal vulnerability to focal ischemia in vivo and to hypoxia and glucose deprivation in cell culture: involvement of perturbed calcium homeostasis. J Neurosci. 2000;20:1358–1364.

9. Jendroska K, Hoffmann OM, Patt S. Amyloid beta peptide and precur-sor protein (APP) in mild and severe brain ischemia. Ann N Y Acad Sci. 1997;826:401–405.

10. Jendroska K, Poewe W, Daniel SE, Pluess J, Iwerssen-Schmidt H, Paulsen J, et al. Ischemic stress induces deposition of amyloid beta immunoreactivity in human brain. Acta Neuropathol. 1995;90:461–466.

11. Sarti C, Pantoni L. Experimental Models of Vascular Dementia: A Focus on White Matter Disease and Incomplete Infarction. New York: Oxford University Press; 2003.

12. Kalaria RN, Bhatti SU, Palatinsky EA, Pennington DH, Shelton ER, Chan HW, et al. Accumulation of the beta amyloid precursor protein at sites of ischemic injury in rat brain. Neuroreport. 1993;4:211–214.

13. Grilli M, Diodato E, Lozza G, Brusa R, Casarini M, Uberti D, et al. Presenilin-1 regulates the neuronal threshold to excitotoxicity both physiologically and pathologically. Proc Natl Acad Sci U S A. 2000;97:12822–12827.

14. Zhang F, Eckman C, Younkin S, Hsiao KK, Iadecola C. Increased sus-ceptibility to ischemic brain damage in transgenic mice overexpressing the amyloid precursor protein. J Neurosci. 1997;17:7655–7661.

15. Grammas P, Yamada M, Zlokovic B. The cerebromicrovasculature: a key player in the pathogenesis of Alzheimer’s disease. J Alzheimers Dis. 2002;4:217–223.

16. Pluta R, Misicka A, Barcikowska M, Spisacka S, Lipkowski AW, Januszewski S. Possible reverse transport of beta-amyloid peptide across the blood-brain barrier. Acta Neurochir Suppl. 2000;76:73–77.

17. Zlokovic BV. Vascular disorder in Alzheimer’s disease: role in patho-genesis of dementia and therapeutic targets. Adv Drug Deliv Rev. 2002;54:1553–1559.

18. Rhodin JA, Thomas T. A vascular connection to Alzheimer’s disease. Microcirculation. 2001;8:207–220.

19. Giri R, Selvaraj S, Miller CA, Hofman F, Yan SD, Stern D, et al. Effect of endothelial cell polarity on beta-amyloid-induced migration of mono-cytes across normal and AD endothelium. Am J Physiol Cell Physiol. 2002;283:C895–C904.

20. Arvin B, Neville LF, Barone FC, Feuerstein GZ. The role of inflammation and cytokines in brain injury. Neurosci Biobehav Rev. 1996;20:445–452.

21. Banati RB, Gehrmann J, Wiessner C, Hossmann KA, Kreutzberg GW. Glial expression of the beta-amyloid precursor protein (APP) in global ischemia. J Cereb Blood Flow Metab. 1995;15:647–654.

22. McGeer PL, McGeer EG. Inflammation, autotoxicity and Alzheimer dis-ease. Neurobiol Aging. 2001;22:799–809.

23. Stoll G, Jander S, Schroeter M. Inflammation and glial responses in isch-emic brain lesions. Prog Neurobiol. 1998;56:149–171.

24. Cheng G, Whitehead SN, Hachinski V, Cechetto DF. Effects of pyr-rolidine dithiocarbamate on beta-amyloid (25-35)-induced inflam-matory responses and memory deficits in the rat. Neurobiol Dis. 2006;23:140–151.

25. Kase CS, Wolf PA, Kelly-Hayes M, Kannel WB, Beiser A, D’Agostino RB. Intellectual decline after stroke: the Framingham Study. Stroke. 1998;29:805–812.

26. Desmond DW, Moroney JT, Sano M, Stern Y. Incidence of demen-tia after ischemic stroke: results of a longitudinal study. Stroke. 2002;33:2254–2260.

27. Gamaldo A, Moghekar A, Kilada S, Resnick SM, Zonderman AB, O’Brien R. Effect of a clinical stroke on the risk of dementia in a pro-spective cohort. Neurology. 2006;67:1363–1369.

28. Srikanth VK, Quinn SJ, Donnan GA, Saling MM, Thrift AG. Long-term cognitive transitions, rates of cognitive change, and predictors of incident dementia in a population-based first-ever stroke cohort. Stroke. 2006;37:2479–2483.

29. Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA. 1997;277:813–817.

Figure 3. Examples for multimodal positron emission tomo-graphic imaging in poststroke cognitive decline. Patient FDC (top) shows extensive β-amyloid (Aβ) depositions (left) but little to no microglia activation (right) together with a decrease in the Montreal Cognitive Assessment (MoCA1, 1 week; MoCA 2, 5–7 mo poststroke) scores. Patient BL exhibits persistent microg-lia activation 6 mo after the stroke but only little to no Aβ. She recovered cognitive function although not to normal levels.

by guest on March 18, 2016http://stroke.ahajournals.org/Downloaded from

Thiel et al Neuroinflammation and Links to Stroke 2829

30. Bennett DA, Schneider JA, Bienias JL, Evans DA, Wilson RS. Mild cog-nitive impairment is related to Alzheimer disease pathology and cerebral infarctions. Neurology. 2005;64:834–841.

31. Del Ser T, Hachinski V, Merskey H, Munoz DG. Alzheimer’s disease with and without cerebral infarcts. J Neurol Sci. 2005;231:3–11.

32. Srikanth VK, Anderson JF, Donnan GA, Saling MM, Didus E, Alpitsis R, et al. Progressive dementia after first-ever stroke: a community-based follow-up study. Neurology. 2004;63:785–792.

33. Reitz C, Bos MJ, Hofman A, Koudstaal PJ, Breteler MM. Prestroke cog-nitive performance, incident stroke, and risk of dementia: the Rotterdam Study. Stroke. 2008;39:36–41.

34. Knopman DS, Roberts RO, Geda YE, Boeve BF, Pankratz VS, Cha RH, et al. Association of prior stroke with cognitive function and cognitive impairment: a population-based study. Arch Neurol. 2009;66:614–619.

35. Dregan A, Wolfe CD, Gulliford MC. Does the influence of stroke on dementia vary by different levels of prestroke cognitive functioning?: a cohort study. Stroke. 2013;44:3445–3451.

36. Pendlebury ST. Dementia in patients hospitalized with stroke: rates, time course, and clinico-pathologic factors. Int J Stroke. 2012;7:570–581.

37. Rist PM, Chalmers J, Arima H, Anderson C, Macmahon S, Woodward M, et al. Baseline cognitive function, recurrent stroke, and risk of demen-tia in patients with stroke. Stroke. 2013;44:1790–1795.

38. Huang KL, Lin KJ, Ho MY, Chang YJ, Chang CH, Wey SP, et al. Amyloid deposition after cerebral hypoperfusion: evidenced on [(18)F]AV-45 positron emission tomography. J Neurol Sci. 2012;319:124–129.

39. Koistinaho M, Koistinaho J. Interactions between Alzheimer’s disease and cerebral ischemia–focus on inflammation. Brain Res Brain Res Rev. 2005;48:240–250.

40. Thiel A, Heiss WD. Imaging of microglia activation in stroke. Stroke. 2011;42:507–512.

41. Thiel A, Radlinska BA, Paquette C, Sidel M, Soucy JP, Schirrmacher R, et al. The temporal dynamics of poststroke neuroinflammation: a longi-tudinal diffusion tensor imaging-guided PET study with 11C-PK11195 in acute subcortical stroke. J Nucl Med. 2010;51:1404–1412.

42. Radlinska B, Ghinani S, Leppert IR, Minuk J, Pike GB, Thiel A. Diffusion tensor imaging, permanent pyramidal tract damage, and out-come in subcortical stroke. Neurology. 2010;75:1048–1054.

43. Radlinska BA, Blunk Y, Leppert IR, Minuk J, Pike GB, Thiel A. Changes in callosal motor fiber integrity after subcortical stroke of the pyramidal tract. J Cereb Blood Flow Metab. 2012;32:1515–1524.

44. Rowe CC, Villemagne VL. Amyloid imaging with PET in early Alzheimer disease diagnosis. Med Clin North Am. 2013;97:377–398.

45. Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, et al. The Montreal Cognitive Assessment, MoCA: a brief screen-ing tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53:695–699.

46. Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol. 2004;55:306–319.

47. Gerhard A, Neumaier B, Elitok E, Glatting G, Ries V, Tomczak R, et al. In vivo imaging of activated microglia using [11C]PK11195 and posi-tron emission tomography in patients after ischemic stroke. Neuroreport. 2000;11:2957–2960.

48. Lopresti BJ, Klunk WE, Mathis CA, Hoge JA, Ziolko SK, Lu X, et al. Simplified quantification of Pittsburgh Compound B amyloid imaging PET studies: a comparative analysis. J Nucl Med. 2005;46:1959–1972.

49. Thiel A, Radlinska BA, Paquette C, Sidel M, Soucy JP, Schirrmacher R, et al. The temporal dynamics of poststroke neuroinflammation: a longi-tudinal diffusion tensor imaging-guided PET study with 11C-PK11195 in acute subcortical stroke. J Nucl Med. 2010;51:1404–1412.

50. Wollenweber FA, Zietemann V, Rominger A, Opherk C, Bayer-Karpinska A, Gschwendtner A, et al. The Determinants of Dementia After Stroke (DEDEMAS) Study: protocol and pilot data. Int J Stroke. 2014;9:387–392.

51. Wagle J, Farner L, Flekkøy K, Bruun Wyller T, Sandvik L, Fure B, et al. Early post-stroke cognition in stroke rehabilitation patients pre-dicts functional outcome at 13 months. Dement Geriatr Cogn Disord. 2011;31:379–387.

KEY WORDS: amyloid ◼ inflammation ◼ stroke

by guest on March 18, 2016http://stroke.ahajournals.org/Downloaded from

WhiteheadAlexander Thiel, David F. Cechetto, Wolf-Dieter Heiss, Vladimir Hachinski and Shawn N.

StrokeAmyloid Burden, Neuroinflammation, and Links to Cognitive Decline After Ischemic

Print ISSN: 0039-2499. Online ISSN: 1524-4628 Copyright © 2014 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Stroke doi: 10.1161/STROKEAHA.114.004285

2014;45:2825-2829; originally published online July 8, 2014;Stroke. 

http://stroke.ahajournals.org/content/45/9/2825World Wide Web at:

The online version of this article, along with updated information and services, is located on the

  http://stroke.ahajournals.org//subscriptions/

is online at: Stroke Information about subscribing to Subscriptions: 

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

  document. Permissions and Rights Question and Answer process is available in the

Request Permissions in the middle column of the Web page under Services. Further information about thisOnce the online version of the published article for which permission is being requested is located, click

can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.Strokein Requests for permissions to reproduce figures, tables, or portions of articles originally publishedPermissions:

by guest on March 18, 2016http://stroke.ahajournals.org/Downloaded from