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					        Intensive Blood Pressure lowering
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         increases Cerebral Blood Flow in
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         older subjects with Hypertension
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      Tryambake D, He J, Firbank M, O’Brien JT, Blamire A ,

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                            Ford GA

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               Institute for Ageing and Health

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                 Magnetic Resonance Centre

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                     Newcastle University

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Supported by the NIHR Biomedical Research Centre for Ageing and Age-related disease award
               to the Newcastle upon Tyne Hospitals NHS Foundation Trust
         Hypertension in Older People
• Optimum BP target in older people with hypertension is unclear


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• BP treatment is well tolerated in older people recruited into

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  trials (target BP < 140/90)

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• Clinical practice and observational series suggest BP lowering
  drugs may produce adverse events due to hypotension

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• Rapid initiation BP treatment may produce hypoperfusion if BP

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  goes below lower limit of CBF autoregulation modified by
  hypertension
                                   Ruland, S. et al. Hypertension 2007;49:977
      Cerebral blood flow in hypertension
Cross- sectional studies :

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• Cognitively normal subjects with HTN have decreased rCBF in the

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  putamen, globus pallidus, bilaterally, and in the left hippocampus

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  compared with normotensives. -ASL                 Dai W, et al, 2008



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• Higher resting SBP or DBP was associated with lower levels of


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  cerebral perfusion in otherwise healthy older men- SPECT


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                                            Waldstein SR, et al, 2010




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•  10 out of 33 young Indian patients deminstrted reduced CBF

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  measured by SPECT,                         Mishra SA, et al, 2006



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• 133 Xe inhalation - reduced global and regional CBF in untreated

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  hypertensive subjects, lesser reductions in treated hypertensives

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  compared to normotensives

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                                             Nobili F, et al 199




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• Significant reduction in CBF in temporal, parietal frontal and


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  posterior cingulated cortices in AD subjects Alsop DC, et al, 2000
Longitudinal studies
• Cerebral blood flow as a marker of cognitive decline. 3 y follow-


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  up. PET                                              Kitagawa K, 2010



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• Antihypertensive therapy increases MCA velocity and carotid

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  distensibility in hypertensive elderly subjects. Lipsitz LA,et al, 2005.


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• Olmesartan restores brain hypoperfusion in elderly and


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  hypertensive patients without organic damage. SPECT, Nagata R, et


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   al, 2010
• HTN group shows greater rCBF decreases in prefrontal, anterior

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  cingulate, and occipital areas over 7 years, suggesting that these


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  regions are more susceptible to hypertension-related dysfunction


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  with advancing age –PET Beason-Held LL, et al, 2007

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• Improvement in mean cerebral blood flow in patients with HT

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  and chronic cerebral infarction after treatment with doxazosin.


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   Usuda K, et al, 2009
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Hypothesis
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More intensive BP lowering in older
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subjects increases cerebral blood
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flow compared to usual BP lowering.
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Cerebral blood flow measurement
• PET, SPECT, Xenon, TCD
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• ASL
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   Non-invasive and effective way of measuring
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  CBF
  No use of contrastke
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  Validated by numerous experience in
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  animals and humans      Noguchi T YT, et al,2007


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  Close correlation with PET
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                                             Ye et al, 2000




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  Over 200 studies published
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                  ASL: fMRI of Blood Flow


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                z (=B0)                            inversion
                                                   slab


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                   excitation         blood


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                inversion                               imaging


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                                                        plane


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•

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  Generate quantitative blood flow maps using water as an endogenous label
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  Acquire control or univerted IMAGE of inflowing arterial blood


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• Magnetically Label through inversion inflowing arterial blood


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• Acquisition of tag or inverted IMAGE

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•

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  Difference in magnetization between control and tag conditions is
  proportional to regional cerebral blood flow
• IMAGErCBF = IMAGEcontrol – IMAGEtag
NEUROIMAGING WITH ASL PERFUSION MRI




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Inclusion criteria:
• Essential hypertension with baseline systolic BP >150 mmHg
• Age >70 yrs


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• Taking none or one BP lowering drug


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• Able to give written informed consent


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Exclusion criteria:


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• Terminal health condition e.g. malignancy


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• Dementia



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• Diabetes


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• Recurrent falls


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• Contraindication to more than one class BP lowering drugs: thiazide


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   diuretics, beta blockers, ACE inhibitors, ARBs, calcium channel blockers,


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   alpha blockers


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• Previous cardiovascular events: TIA, angina, MI, CHF, PVD

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• Contraindication to MR perfusion (i.e. metallic foreign body)

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            Assessments and Methods
• Screening and Consent
• Baseline              Seated BP (mean 2nd/3rd readings)


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                        24 hr ambulatory BP recording

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                        Active stand BP

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                        MR perfusion (arterial spin labelling)
                        Arterial stiffness (Sphygmocor)

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                        Cognitive Function (CDR battery / exec function)

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                        Balance Confidence Scale and QoL


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• 2 weekly visits       Monitor BP and assess adverse events


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• 12 weeks              Repeat baseline assessments


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• 2 weekly visits       Monitor BP and assess adverse events

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• 6 months              Repeat assessments but no MR or 24 hr amb BP


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Treatment protocol:     Randomised to:

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       Usual (Target < 140/85 mmHg, 6 weekly treatment change) vs.


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       Intensive (Target < 130/80 mm Hg, 2 weekly treatment change)


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Drugs: Amlodipine (5-10mg)                Lisinopril (5-20mg)
       Bendroflumethazide (2.5mg)          Doxazosin/Atenolol/Spiro
MRI Methods:

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•   2 MRI – o months & 3 months

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    T1 weighted anatomical
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    dm, m, t1, cbf, FLAIR,UTE

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•   dm- perfusion image- blood as contrast

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•   t1- intrinsic tissue characteristics
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    FLAIR- white mater intensities

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•   UTE- developmental technique ( white matter
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    and myelin )
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Methods (cont.)
• Mapping the anatomical images of all subjects
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  into ‘standard Talairach space’ to allow group

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  analysis.

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• Apply the transformation to CBF, FLAIR, UTE,
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  T1 map into standard space
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• A range of paired t test (inter, intra group and

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  individual) performed on dm, t1,cbf map.

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• ROI analysis-MARSBAR-40 regions studied.
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  Further paired t test on dm, t1, cbf of these
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  regions
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               Baseline Demographics

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                                 Usual        Intensive    Comparison Usual vs.



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                                (n=17)          (n=20)         Intensive
                                                                P value


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Age (years)                     74 (3)         75 (4)              0.3


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Sex (F)                          11              11                0.7


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BP Systolic (mmHg)             155 (13)       149 (13)             0.2



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BP Diastolic (mmHg)             84 (9)         87 (10)             0.4


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24 hr amb BP systolic (mmHg)   131 (12)       128 (10)             0.5


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24hr amb BP diastolic (mmHg)    71 (8)         69 (7)              0.5


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Grey matter CBF                76 (15)         74 (14)             0.6


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(ml/min/100g)


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                 BP changes over 12 weeks

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            155              Usual 155/84 →140/79



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140   149                                                140




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                                                               Usual (SBP)




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100                                                            Usual (DBP)




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                           Intensive 149/87→123/70             Intensive(SBP)
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                                                               Intensive (DBP)

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Cerebral Blood Flow Changes
     76→73                74→81(P<0.05)


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            Whole grey matter- t1
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y = .877x +.203                 Y = .944 + .092

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Regional cerebral blood flow

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                    Changes in BP and CBF

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                                           Usual        Intensive  Comparison usual


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                                                                     vs. intensive



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                                                                        P Value
Systolic BP                             -15 (14) **    -26 (14) **       0.018


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Diastolic BP                              -5 (7) *      -17 (9) **      < 0.001


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24hr amb BP systolic (mmHg)               -2 (10)       -12 (7) **       0.002



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24hr amb BP diastolic (mmHg)               -1 (6)        -6 (5) **       0.005


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Grey matter CBF (ml/min/100g)              -3 (9)        7 (11) *        0.008


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  Asterisks indicate a significant change within the group


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  Paired t test * p < 0.05 ** p < 0.01


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Change in BP and Cerebral Blood Flow


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                    Conclusions
• Intensive BP lowering in older people with
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  hypertension increases cerebral blood flow.

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• Suggests hypertension in older people shifts the

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  autoregulatory CBF curve rightwards and downwards

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  and is reversible with BP lowering.

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• Intensive BP lowering may protect the brain against

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  development of white matter lesions if white matter

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  blood flow is increased.

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              CBF




                           BP
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