review of existing studies on ASL in dementia Marion Smits, MD PhD

review of existing studies on ASL in dementia Marion Smits, MD PhD Associate Professor of Neuroradiology Department of Radiology, Erasmus MC, Rotterdam (NL) Alzheimer Centre South-West Netherlands, Rotterdam (NL) source: depositphotos.com 1&

frontotemporal&demen2a& HIV&demen2a& Cor2cobasal&degenera2on& Parkinson s&demen2a& Lewy&Body&demen2a& Alzheimer s+disease+ Seman2c&demen2a& mul2system&atrophy& Primary&progressive&aphasia& Creutzfeld;Jakob&disease& Pick s&disease& Vascular&demen2a& Progressive&supranuclear&palsy& Alzheimer s Association 2013: www.alz.org 2&

Alzheimer s,disease,is,not,, just,memory,loss,,alzheimer s,kills, Alzheimer s Association 2013: www.alz.org Biomarker development! Therapeutic interventions most effective in early stages! maybe even in the preclinical stage early disease detection required.! Need for quantitative outcome measures in clinical trials disease monitoring required. 3&

Molecular biomarkers PiB-PET (amyloid deposition). CSF Aβ 1-42 (amyloid deposition). CSF tau protein (neuronal degeneration).! high sensitivity to early disease and histological measures of pathology.! limited sensitivity to clinical status and capacity to track disease progression. Functional biomarkers! Reflect synaptic activity more sensitive to disease activity.! Quantification allows for longitudinal measurements of drug effects. FDG-PET (glucose metabolism). ASL-MRI (cerebral blood flow). 4&

Alzheimer frontotemporal vascular THE DEMENTIAS 5&

Alzheimer s disease Clinical presentation! progressive memory impairment.! loss of episodic memory.! disorientation in time and place.! disturbance of executive and visuospatial function, praxis.! later: focal neurological deficits aphasia. Pathology! atrophy enlargement of ventricles and sulci.! entorhinal cortex limbic system higher order cortex.! neurofibrillary tangles and neuritic plaques. 6&

hippocampal atrophy temporal atrophy parietal atrophy global atrophy ASL in Alzheimer s disease! Regional hypoperfusion (~ regional hypometabolism)! posterior cingulate cortex (PCC)! precuneus! inferior parietal lobe! lateral prefrontal cortex.! Global hypoperfusion Asslani et al. J Cereb Blood Flow Metab 2008;28:725. 7&

ASL for early diagnosis of dementia * p<0.01 ** p<0.001 Regions involved in dementia Regions spared in dementia Steketee et al. submitted Hypoperfusion and atrophy! Hypoperfusion commonly exceeds atrophy precedes tissue loss.! Discordant regions! hippocampus! anterior cingulate cortex. Alsop et al. Neuroimage 2008;42:1267 8&

hypoperfusion atrophy Alsop et al. Neuroimage 2008;42:1267 hypoperfusion atrophy Alsop et al. Neuroimage 2008;42:1267 9&

The hippocampus Hyper perfusion! decoupling with vascular compromise! local inflammation! plastic remodelling! compensatory response! methodology? Hypo perfusion! before PVE correction Binnewijzend et al. Radiology 2013;267:221 Often not imaged. Alsop et al. Neuroimage 2008;42:1267 Comparison of ASL with FDG-PET! 15 AD vs 19 controls.! High concordance with simultaneous ASL and FDG-PET.! Comparable diagnostic accuracy (AUC)! ASL 0.94 (0.77-0.99)! PET 0.92 (0.76-0.99). Chen et al. Neurology 2011;77:1977 10&

ASL in prodromal AD: MCI! Important target population for disease modifying therapeutics.! Regional hypoperfusion (consistent with FDG-PET & AD)! PCC! precuneus! parietal regions! to lesser extent than in AD.! Also hyperperfusion Dai et al. Radiology 2009;250:856! hippocampus! amygdala! striatum. Correlation with disease severity! Studies are scarce.! Generally correlated with MMSE (crude!).! Regional hypoperfusion! (lateral) parietal and parieto-occipital cortices! early stage AD or MCI: PCC. 11&

AD converters precuneus middle cingulum inferior parietal lobe middle frontal cortex Predictors of decline precuneus (selective attention, activities of daily living, dementia score) inferior parietal lobe (dementia score) middle cingulum (dementia score) Chao et al. Alzheimer Dis Assoc Disord 2010;24:19 large patient population 71 AD patients 31 MCI patients 70 subjective complaints (SC) correlation with MMSE parietal cortex precuneus PCC Binnewijzend et al. Radiology 2013;267:221 12&

Task-related ASL MRI in early AD! MCI versus controls Xu et al. Neurology 2007;69:1650! resting CBF in precuneus! extent of hypoperfusion in precuneus PCC during memory encoding task! CBF in MTL with task compared with rest in controls CBF.! APOE-ε4 carriers Fleisher et al. Neurobiol Aging 2009;30:1737! resting CBF in the MTL! blunted increase during face-name memory encoding task. Task-related ASL accentuates group differences. Frontotemporal dementia Incidence! 5-10% of cases of dementia! family history (1 st degree) positive in 40% Clinical presentation! psychiatric symptoms: depression, behavioural and personality changes! memory deficits! later: language impairment (progressive mutism) Subtypes! behavioural variant FTD: bvftd! semantic dementia: SD! progressive nonfluent aphasia: PNFA 13&

temporal and frontal atrophy asymmetrical left sided temporal lobe atropy Semantic dementia 14&

ASL in FTD! Studies are scarce.! Regional hypoperfusion! prefrontal cortex! insula.! No studies on specific subtypes. Semantic dementia marked hypoperfusion bilateral insula left >> right hyperfusion temporal lobe 15&

Hu et al. Neurology 2010;75:881 FTD<controls FTD>AD regional hypoperfusion regional hyperperfusion Du et al. Neurology 2006;67:1215 16&

FTD versus controls concordance atrophy with CBF - R prefrontal cortex - medial frontal lobe discordance atrophy without CBF - premotor cortex Shimizu et al. Brain Im&Beh 2010;4:46 Vascular dementia Incidence! most common cause of dementia after Alzheimer disease! association with vascular risk factors Clinical presentation! more sudden onset than Alzheimer disease! stepwise pattern with sudden onsets of deterioration! more commonly small vessel disease with gradual deterioration 17&

multiple lacunar infarcts carotid occlusion frontal and parietal infarcts in the dominant hemisphere ASL in vascular dementia (VaD)! Largely un(der)explored.! No coherent regional metabolic/perfusion pattern described! preferential changes in frontal lobes have been reported! generally no PVE correction in PET/SPECT studies! disruption of (frontal) cortical-subcortical connections.! ASL may show tissue at risk for future infarcts! resting CBF! reactivity measurements of cerebrovascular reserve.! ASL may establish diagnosis: perfusion (rest/challenge). 18&

Alzheimer s disease vascular dementia Hendrikse et al. NeuroImaging Clin N Am 2012;22:259 ASL in vascular dementia CBF irrespective of atrophy in both AD (n=14) and VaD (n=8) in frontal > parietal lobes in VaD > AD Inverse correlation of CBF with white matter lesion load in frontal > parietal lobes in VaD > AD ( ) VaD ( ) AD ( ) controls Schuff et al. Alzheimers Dement 2009;5:454 19&

high incidence of dementia post-stroke (15-30%) patient population 39 patients (>75y) 6 years post-stroke - 8 with dementia 17 AD patients 29 healthy controls large vessel vascular dementia Firbank et al. Neurology 2011;76:1478 control AD AD: parietal & prefrontal cortex post-stroke no dementia post-stroke: global CBF reduction post-stroke dementia CBF AD > poststroke dementia: global & precentral gyrus Firbank et al. Neurology 2011;76:1478 20&

Presenile dementia Patient 63y language & memory deficit Ddx: AD / FTD? Presenile dementia Behandeling! Disease onset < 65 years.! Alzheimer s disease most common cause! often with atypical presentation: language, vision, praxis! memory deficits not/less present! no/minor hippocampal atrophy.! Frontotemporal dementia second most common! important differential diagnosis! may be indistinguishable from early AD. 21&

Presenile dementia Cholinesterase inhibitors (Reminyl, Exelon )! may positively influence AD disease course! most effective in the early stage of the disease! may negatively influence FTD! may have serious side effects 25-30% discontinue treatment. Prognosis Prognosis is worse in FTD compared with AD! poorer life expectancy (4.2 versus 6.0 years)! faster loss of activities of daily living! faster decline on MMSE (-6.7 versus -2.3) Rascovsky et al. Neurology 2005;65:397 22&

ASL for early diagnosis of presenile dementia Patient 63y Control 63y Steketee et al. submitted from group studies to THE PATIENT 23&

From group to patient! 13 AD patients, 19 healthy controls! Overall accuracy 70%! Inter-rater reliability κ = 0.7! exceeds structural imaging rating. Raji et al. AJNR 2010;31:847 From group to patient: presenile dementia Threshold CBF values! Thalamus! 42.2 ml/100cc GM/min! sensitivity = 78%! specificity = 65%.! PCC! 52.0 ml/100cc GM/min! sensitivity = 72%! specificity = 70%. Steketee et al. submitted 24&

From group to patient Clinical reading of FDG-PET versus ASL-MRI! 2 readers (expert nuclear medicine physicians)! moderate to moderate-strong intermodality agreement (κ = 0.45-0.61)! sensitivity and specificity comparable between modalities! difference in interobserver agreement! FDG-PET κ = 0.74! ASL-MRI κ = 0.48. Musiek et al. Alzheimers Dement 2012;8:51 From group to patient Clinical reading of FDG-PET versus ASL-MRI.! 9 young (mean 59y) patients! FDG-PET rated by 2 nuclear medicine physicians! ASL-MRI rated by 2 neuroradiologists.! High intra- and intermodality agreement (κ=0.85-0.86)! Diagnostic accuracy (p>0.05)! FDG-PET: 78%! ASL-MRI: 67%. Weyts et al. ESMRMB 2013 25&

Clinical&informa2on& 46&y.o.&female& progressive&neurocogni2ve&deteriora2on& MRI&&&FDG;PET:&?&Alzheimer s&disease& FDG&PET&(27;05;2011)& C/Alzheimer s+disease+ &L&temporal&lobe& &posterior&cingulate& 26&

ASL&MRI&(24;05;2011)& C/Normal+ Normal&L&temporal&lobe& Normal&posterior&cingulate& Diagnosis& Paraneoplas2c&limbic&encephali2s& an2;nmda;receptor&encephali2s& Structural&MRI& ~50%&normal& mild&t2;hyperintensi2es&(medial)&temporal&lobes& leptomeningeal&enhancement.& Perfusion& focal&hyperperfusion&(?&related&to&seizures).& FDG&PET& focal&hyper;&and&hypometabolism&& temporal&lobes,&posterior&cingulate.& 27&

Conclusions! Published studies mainly on AD! generally small sample size! longitudinal studies lacking! generally established disease stage.! Early stage AD MCI! regional hypoperfusion in PCC and precuneus! accentuated with task-based ASL.! Generally concordance with FDG-PET (glucose metabolism) findings! limited direct comparision of diagnostic accuracy.! Conflicting findings in the hippocampus/mtl.! Gap group individual patient level still needs to be bridged. E+marion.smits@erasmusmc.nl+ T+@MarionSmits+ Curr&Opin&Neurol&2012;25:421& + + Acknowledgments& UCL,+London,+UK+ Prof.&Dr.&X.&Golay& M.&Grade+ + + + + GE+Healthcare& & Dr.&G.C.&Houston& & Porto+University,+PT& & Dr.&A.&Bastos&Leite& & & & AMC,+Amsterdam,+NL& Dr.&A.J.&Nederveen& H.J.&Mutsaerts& Erasmus+MC,+RoEerdam,+NL& R.M.E.&Steketee& E.E.&Bron& 28&