Vascular Dementia: A State Of Play . - Stroke Association
stroke.org.ukVascular Dementia:A state of playsummary reportand priorities forfuture research
Contents1. Introduction32. Overview/background of vascular dementia/stroke related dementia43. Pathophysiology and Classification of Vascular Dementia74. Clinical Trials for Treatment of VaD105. Pre-clinical models of vascular dementia156. Biomarkers187. Other key areas to focus on208. Research priorities219. Next Steps23Appendix 124Appendix 2252Vascular Dementia: A state of play summary report and priorities for future research
1. IntroductionVascular dementia has been highlighted as a research priorityin the Stroke Association’s 2014-2019 Research Strategydue to the devastating impact of the disease, the lack oftreatments or preventive measures to stop the progressionof the disease and the paucity of knowledge and research inthis area.Vascular dementia is of particular concern to the Stroke Association, as up to 30% of strokesurvivors will develop vascular dementia. Stroke doubles the risk of dementia and there is still adearth of knowledge around the pathology, risk factors, markers and other cross-contributoryfactors between stroke and dementia. The co-existence and co-development of these twoconditions presents a very complex picture.At the Stroke Association, we want to work in collaboration with researchers, other funders,patients and carers to identify the biggest issues that we can start to tackle with research. Ouraim is to lead a programme of work in this area. Firstly, to identify the difficulties, priorities andnext steps for research in this field, and to work in partnership with others to ensure we fund aprogramme that takes our knowledge and understanding forward in this research area.The Dementia UK report for the Alzheimer’s Society suggested that by 2025 there will be 250,000people living in the UK with vascular dementia. We must act now to make some long overdueprogress in the basic understanding of disease mechanisms, diagnostics, treatments andpreventive measures for this devastating condition.We convened a round table on 29 January 2015 to discuss the latest research and summarise thestate of play in this field: what we know, what we don’t know and the next priorities for research.Appendix 1 is the agenda from the January 29 roundtable and Appendix 2 is an attendance listfrom the day.The following sections 2-6 of this report provide a brief summary of the topics covered andthe current state of play in the research into vascular dementia. Recommendations for futureresearch priorities will be highlighted during the report where relevant. The overall priorities thatwere concluded from this report and those identified at the round table on 29 January 2015 arelisted in section 8. Finally, we outline the next steps for this programme of work in section 9.Vascular Dementia: A state of play summary report and priorities for future research3
2. Overview/background of vasculardementia/stroke related dementia(by Professor John O’Brien, University of Cambridge)Historical backgroundUp to the 1960s, “senile dementia” was thoughtto be due to cerebral arteriosclerosis, and waspreviously termed as arteriosclerotic dementia. By1968, Alzheimer’s Disease was recognised as themain cause of dementia in late life (1). In 1974 theterm ‘Multi-infarct dementia (MID)’ was coined (2).In the 1980s and 1990s, MID was recognised tobe just one of many causes of Vascular Dementia(VaD) and in 1993 consensus diagnostic criteriawere published for VaD (3). They outlined a set ofcriteria which emphasised: 1) the heterogeneityof vascular dementia syndromes; 2) the variabilityin clinical course, which may be static, remitting,or progressive; 3) specific clinical findings early inthe course (e.g. gait disorder, incontinence, moodand personality changes) that support a vascularrather than a degenerative cause; 4) the need toestablish a temporal relationship between strokeand dementia onset for a secure diagnosis; 5) theimportance of brain imaging to support clinicalfindings; 6) the value of neuropsychological testingto document impairments in multiple cognitivedomains; and 7) a protocol for neuropathologicevaluations and correlative studies of clinical,radiological, and neuropsychological features.These criteria were stratified by levels of certainty(definite, probable, and possible).4By 2003 the broader term Vascular CognitiveImpairment/ Disorders was preferred to dementia,including all subtypes, e.g. “vascular MCI” andvascular dementia. Further subtypes of vasculardementia are as follows: Multi-infarct dementia(Cortical VaD); Small vessel dementia (SubcorticalVaD); Strategic infarct dementia; Hypoperfusiondementia; Haemorrhagic dementia; Hereditaryvascular dementia (CADASIL); Alzheimer’s diseasewith CVD. In accord with the recent updates of theDSM V criteria, descriptions of mild and severevascular cognitive disorder have been proposed (4).A combination of mixed cases, pure VascularDementia and pure Alzheimer’s Disease has beenemerging more recently and a mixed pathology isrecognised as a very common dementia diagnosisin older people (results from the CognitiveFunction and Ageing Studies).Even so-called “pure” Alzheimer’s Disease (AD)is commonly associated with cerebrovascularpathology (white matter lesions on MRI, amyloidangiopathy up to approximately 100%), microinfarcts approximately 35%).Vascular Dementia: A state of play summary report and priorities for future research
Risk FactorsImaging changes proposed as consistent with VaDon MRI/CT:Several risk factors for vascular disease are alsorisk factors for “pure” AD, such as hypertension,smoking, APOE є4, IHD, raised cholesterol &homocysteine, diabetes, obesity and atrialfibrillation. Depression is a risk factor for VaDas well as for AD and for ‘all-cause’ dementia.Vascular risk factors for neurodegenerationare hypertension, diabetes, dyslipidemia,obesity, atherosclerosis, CHD, APOE є4 andhyperhomocystenaemia.1.2.3.One large vessel infarct is sufficient for Mild VCD,and 2 or more large vessel infarcts are generallynecessary for VaD (or Major VCD)An extensive or strategically placed singleinfarct, typically in the thalamus or basal gangliamay be sufficient for VaD (or Major VCD)Multiple lacunar infarcts (2) outside thebrainstem; 1-2 lacunes may be sufficient ifstrategically placed or in combination withextensive white matter lesionsExtensive and confluent white matter lesionsStrategically placed intracerebral haemorrhageor 2 or more intracerebral haemorrhagesA combination of the above.Vascular dementia is the second most commoncause of dementia (AD 60%, VaD 20%, DLB(Dementia with Lewy Bodies) 15%) and there issignificant vascular pathology in 1/3 dementiacases (5). Similar to AD, the rates of VaD rise withage (6); age is the strongest risk factor.4.5.Data from GWAS (Genome Wide AssociationStudies) is now starting to emerge to begin giving apicture of genetic predisposing factors (7).Dementia after stroke occurs in approximately15-30%. A further 20-25% will develop delayeddementia. The estimated incidence of new onsetdementia after stroke is 7% after 1 year and 48%after 25 years (8). Variable, especially for MID and strategic infarctdementia Major deficits are usually in attention, informationprocessing and executive function Tests such as verbal fluency, trails/maze, clockdrawing, reverse digits Memory, language and praxis variably affected Predominantly subserved by fronto-striatothalamic circuitsUpdate on Diagnostic CriteriaSeveral sets of diagnostic criteria have been publishedfor VaD since the 1960s. The continuing ambiguity indiagnostic criteria warranted a critical re-examination.The Vas-Cog study group began to address this anda broader, more inclusive set of changes/criteria havebeen established as diagnostic criteria, although this isstill yet to be validated in large cohorts.6.Cognitive Changes in VaD:In conclusion, the clinical diagnostic criteria arestill debated and still need further refinement andvalidation. However, they are robust enough forclinical studies/ trials to proceed, and AD markersalso have the potential to identify mixed cases.Vascular Dementia: A state of play summary report and priorities for future research5
Management strategies ofVascular Dementia to dateThe main strategy so far has been to use drugsdeveloped for Alzheimer’s disease. However,recent trials have shown that these are largelyineffective, the translation of AD treatmentsto VaD on the basis of shared neurochemicalmechanisms has failed.References:1.2.Other therapies have been used: Cerebrolysin;Antiplatelet agents; BP lowering; Lipid lowering;Calcium channel blockers. Trials with these will bementioned further in section 4.3.There is limited clinical research to date on VaD,and virtually none on non-cognitive features.Some drug trials have taken place and have failedto identify any treatment options, these aresummarised in section 4. We need trials of the besttreatment strategies to inform the best clinicalmanagement of patients. The UK can and shoulddo more to address this and develop an improvedstrategy for treatment of VaD.4.5.6.7.8.6Blessed, G., B. E. Tomlinson, et al. (1968). Theassociation between quantitative measures ofdementia and of senile change in the cerebralgrey matter of elderly subjects. British Journalof Psychiatry 114 (512): 797-811.Hachinski, V. C., N. A. Lassen, et al. (1974).Multi-infarct dementia. A cause of mentaldeterioration in the elderly. Lancet 2 (7874):207-210.Román G.C., Tatemichi T.K., et al. (1993)Vascular dementia: diagnostic criteria forresearch studies. Report of the NINDSAIREN International Workshop. Neurology 43(2):250-260.Sachdev P.,Kalaria, R., O’Brien J., et al. (2014)Diagnostic criteria for vascular cognitivedisorders: A VASCOG Statement. AlzheimerDisease and Associated Disorders 28 (3): 206218.Pathological correlates of late-onset dementiain a multicentre, community-based populationin England and Wales. Neuropathology Groupof the Medical Research Council CognitiveFunction and Ageing Study (MRC CFAS).(2001) Lancet. 20;357(9251):169-75.Jorm, A. F. and D. Jolley (1998). The incidenceof dementia: a meta-analysis. Neurology51(3): 728-733.Schrijvers EMC, Schürmann B, Koudstaal PJ, etal. (2012) Genome-wide association study ofvascular dementia. Stroke; 43: 315–9.Leys D., Hénon H., et al Lancet Neurology(2005);4:752-59.Vascular Dementia: A state of play summary report and priorities for future research
3. Pathophysiology and Classificationof Vascular Dementia(by Professor Raj Kalaria, Newcastle University)VaD assumes a clinically diagnosed dementiasyndrome comprising subtypes with predominantischaemic and haemorrhagic pathologies. Currentunderstanding of the pathophysiology of VaD isguided by knowledge of vascular disease risk factors(see above). These may affect both the systemic(extracranial) and cerebral vasculature. Degreesof cerebrovascular pathology may be influencedby demographic, atherosclerotic, stroke-relatedincluding metabolic syndrome, poor cerebralperfusion and genetic factors. In addition to these,other medical problems, including depression, maybe associated with vascular changes.Recent advances in neuroimaging andsystematic neuropathological examinationhave enabled better definitions of clinicallydiagnosed cerebrovascular disorders, whichcause cognitive impairment and result in VaD.Like AD, the definitive diagnosis of VaD requiresneuropathological examination. The systematicevaluation of potentially relevant clinical orphenotypic features with particular attentionto timing of events is important. However, it isoften difficult to define which neuropathologicalchanges are relevant and to what degree thesecontribute to VaD. This challenge arises becauseof the heterogeneous localisation of lesions andthe co-existence of other pathologies includingneurodegenerative changes, particularly thosecharacteristic of AD. The origin and type ofvascular occlusion, presence of haemorrhage,distribution of arterial territories, and the size ofvessels involved will define vascular dementia.Thus, many brain regions including the territoriesof the anterior, posterior and middle cerebralarteries, the angular gyrus, caudate and medialthalamus in the dominant hemisphere, theamygdala and hippocampus as well as thehippocampus have been implicated in VaD.Clinicopathological correlation studies haveenabled recognition of subtypes of VaD. Factorsthat define subtypes of VaD include multiplicity,size, anatomical location, laterality and age of thelesions besides genetic influences and previousexistence of systemic vascular disease. Subtypesof pathologically defined VaD can convenientlybe divided into three major types defined by theorigin of vascular disease, infarct site or sizeof the vasculature. Large vessel disease oftenrelated to cardiac atherothromboembolic eventscould involve atherosclerosis, plaque rupture,intraplaque hemorrhage, thrombotic occlusion,embolism, arterial dissection and dolichoectasia.Dementia resulting from large vessel obstructionor disease includes multiple infarcts (MID is a typeof VaD). Main clinical features include lateralizedsensorimotor changes and aphasia dependingon the location of infarction. Cerebral smallvessel disease may entail degrees of pathologicalchanges, mostly subcortical infarcts or lacunesand diffuse white matter disease, leading tosubcortical ischaemic VaD. Vascular changesinclude arteriolosclerosis, fibrinoid necrosis,microaneurysms, microatheromas, cerebralamyloid angiopathy and segmental arterialdisorganization. Subcortical ischaemic VaDinvolving predominantly the subcortical (below thecortex) structures is the most significant subtypeof VaD and is most frequent in elderly people whosurvive long periods. Small vessel disease is seenwith more subtle signs, including extrapyramidalsigns. However, there can also be considerableoverlap between the subtypes. For example,cerebral microinfarcts are apparent in both largeand small vessel disease. VaD may often have acombination of cortical and subcortical lesions,thereby may be called cortico-subcortical VaD. It israre for vascular lesions to be exclusively cortical.Vascular Dementia: A state of play summary report and priorities for future research7
Strategic infarct dementia or strategic VaDe.g. strokes occurring in thalamic or brainstemregions occurs less frequently and may involvesmall and large lesions. Irrespective, a definitivediagnosis of VaD should be supported by a burdenrelevant cerebrovascular pathology incorporatingmicrovascular and parenchymal (tissue) changes.There should be sufficient pathology attributedto vascular changes in the general absence ofneurofibrillary or neurodegenerative pathologyto explain the change in cognition(1).Vascular cognitive impairment (VCI) is sometimesregarded as the prodromal stage of VaD. Itincorporates conditions in any cognitive domain thathas a vascular origin or impaired brain perfusion.Therefore, early or mild neuropathological changessuch as small vessel disease or white matterrarefaction that can be linked to relevant cognitivedomains e.g. executive dysfunction, slowerprocessing speed or working memory deficits wouldconstitute VCI or mild vascular cognitive disorder(2). Relatively few prospective studies have validatedclinical criteria for VaD by assessing the same casesat post-mortem. The Oxford Project to InvestigateMemory and Ageing (OPTIMA) study has shown thatthe severity of SVD pathology was inversely relatedto cognitive scores and 43% of the cases with highSVD scores were designated to be demented (3). Itwas also proposed that arteriolosclerosis is the firstchange occurring in VaD and most severe VaD, i.e.stage VI, can bear multiple lesions including diffusewhite matter changes(4).Stroke or brain infarction may lead to VaD.Many stroke patients who are treated acutelye.g. with thrombolysis, or those who havesurgical interventions e.g. endarterectomy or otherrestorative management, may survive long enoughto eventually develop dementia more than theircounterparts who have not had stroke or vascularinterventions. Subjects with cerebral small vesseldisease may also survive long periods eventually tosuccumb to VaD. Incident dementia or post-strokedementia (PSD) may occur immediately after the8stroke, or be delayed after a stabilisation period ofa year or longer. In such cases, dementia can havea complex aetiology with varying combinations oflarge and small vessel disease, as well as non-vascularpathology. The pooled prevalence estimates of PSDless than one year after the stroke were calculatedto range from 7% in population-based studies to41% in hospital-based studies of recurrent stroke.Multiple lesions over time and the characteristicsand complications of the stroke are found to bemost strongly associated with PSD. In the NewcastleCOGFAST study(5), after a mean follow up period of3.8 years, 24% of elderly stroke survivors developeddementia and 76% remained alive without dementiaor had died without dementia. Neuroimaging studiesshow that the volume and site of infarcts, extentand location of WM lesions as well as brain atrophyincluding medial temporal atrophy, were importantdeterminants of PSD.Pathological examinations in this study, which isthe only study of its kind, showed that 75% of PSDcases were classified as VaD. Therefore, most of thedementia that develops in stroke survivors is VaD.A key pathological change that is important in VaDis microinfarction. Microinfarcts are widely acceptedto be small lesions visible only upon microscopyand may or may not involve a small vessel at itscentre but are foci with pallor, neuronal loss, axonaldamage (WM) and gliosis(6). They are estimated tooccur in thousands of severely demented cases.The neurochemistry of VaD is less clear. Variouscellular signalling and regulatory mechanismsincluding apoptosis, autophagy, oxidative stress andinflammation are associated with VaD by virtue oftheir involvement in cerebral ischaemia or oligaemia.Selective transmitter specific changes have alsobeen described. Choline acetyltransferase activityis reduced in MID and CADASIL. Other studies havereported deficits in monoamines including dopamineand 5-hydroxytryptamine (5HT) in the basal gangliaand neocortex in VaD. To compensate for the loss,5-HT(1A) and 5-HT(2A) receptors are apparentlyincreased in temporal cortex in MID but notsubcortical VaD. Glutamatergic synapses, assessedVascular Dementia: A state of play summary report and priorities for future research
by vesicular glutamate transporter 1, are reduced inthe temporal cortex but not in the frontal lobe.References:1.Medial temporal lobe atrophy is also associated withVaD in the general absence of neurodegenerativepathology. Even in small vessel disease the atrophycan be almost similar to that in AD. At the cellularlevel, atrophy of hippocampal pyramidal neurons(in CA1 and CA2) and of the dorsolateral prefrontalcortex, irrespective of the presence of anyneurodegenerative pathology, are seen as importantsubstrates of PSD and VaD(7). Thus, selectivehippocampal neuronal shrinkage is also an importantsubstrate for VaD. There is a clear vascular basis forhippocampal neurodegeneration and this concurswith the neuroimaging observations of hippocampalatrophy, even in population-based incident VaD. Thesimplest mechanistic explanation for the atrophyis that the neuronal or dendritic arbour results insubsequent loss in connectivity, which contributes tobrain structural and functional changes.In conclusion, current evidence frompathophysiological studies of VaD indicates thatsmall vessel disease is common to VaD and thatdementia after stroke is mostly VaD. Pathologicaldiagnosis of VaD is consistent with high burdenof vascular changes and sparse or mild amountof neurodegenerative pathology. Hereditarycerebral microangiopathies such as cerebralamyloid angiopathy, cerebral autosomal dominantarteriopathy with subcortica
Vascular dementia is of particular concern to the Stroke Association, as up to 30% of stroke survivors will develop vascular dementia. Stroke doubles the risk of dementia and there is still a factors between stroke and dementia. The co-existence and co-development of these two conditions presents a very complex picture.
2. Talking about dementia 6 3. Talking about people with dementia 8 4. Talking about the effects of dementia 10 Symptoms 11 The impact of dementia 13 5. Talking about people caring for a person with dementia 14 6. Glossary of preferred terms 17 7. Cultural awareness and dementia 20
brain become damaged. There are different types of dementia and it’s possible to have more than one. Vascular dementia is a common type of dementia. It happens when the blood supply to parts of your brain is cut off, so it doesn’t get the oxygen and nutrients that i
C: 8 MHz Vascular Probe Detection of peripheral vessels and calcified arteries D: EZ8 8 MHz Vascular Probe Easy location of vessels and maintain during cuff inflation or deflation E: 10 MHz Vascular Probe Detection of smaller vessels *Beam shape and depth for illustrative purposes only. 8 MHz Vascular Probe *EZ8 8 MHz Vascular Probe All XS High
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Dementia Frien Dly Communities: Key prinC iples Foreword This publication sets out the principles and the resources available to guide the development of dementia friendly communities. A second publication describes the development of dementia friendly communities around the world. Fostering the development of dementia friendly communities is a
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