Evaluating the Impact of Physical Exercise on Mild Alzheimer's Disease in a Randomized Clinical Trial: Quantification With 18F -FDG and 11C- AcAc PET Imaging
Phase: NA
Conditions: Alzheimer's Disease
Sponsor: Université de Sherbrooke

English version – august 2017 
 
Evaluating the impact of physical exercise on mild 
Alzheimer's disease in a randomized clinical trial: 
quantification with 18F-FDG and 11C-AcAc PET 
imaging  
 
 
 
PROTOCOLE: 
#CHUS 09-043 / CIMS-2009-02 / #CSSS-IUGS 2010-212 
 
 
 
 
 PRINCIPAL INVESTIGATORS and CO-INVESTIGATORS: 
Stephen Cunnane, PhD 
Nancy Paquet, MD, FRCPC  
Christian Bocti, MD, FRCPC 
Guy Lacombe, MD, FRCPC 
Hélène Imbault, PhD  
 
 
CONTRIBUTORS 
Éric Lavallée, tim 
Stéphanie Dubreuil, research assistant 
Maxime Gravel, MD 
Eric Turcotte, MD, FRCPC 
Tamas, Fulop, MD  
Dionne, Isabelle, PhD 
Catherine Brodeur, MD, FRCPC 
Marie-Maxime Lavallée, student 
Christian-Alexandre Castellano, PhD, research assistant  
Mathieu Maltais, kinesiologist 
Mélanie Fortier, research assistant 
Esteban Espinosa,  nuclear medicine technologist 
Etienne Croteau, PhD, nuclear medicine technologist  
Christine Brodeur-Dubreuil, research nurse 
 
Centre d’imagerie moléculaire de Sherbrooke (CIMS) ; Centre de recherche clinique (CRC) ; Centre 
Hospitalier Universitaire de Sherbrooke (CHUS) ; Centre de recherche sur le vieillissement (CDRV) ; 
Centre de santé et de service sociaux – Institut universitaire de gériatrie de Sherbooke (CSSS-IUGS) 
 
 
 
 

English version – august 2017 
 
Participants 
This study was conducted with the informed written consent of all the participants and was 
approved by the appropriate ethics committees (Health and Social Services Center – Sherbrooke 
University Geriatrics Institute and the Centre hospitalier universitaire de Sherbrooke). The 
original research protocol included two groups: a Walking group and a sedentary Control group.  
Patients were diagnosed as having probable or possible AD dementia using conventional 
NINCDS-ADRDA criteria. They were referred to this study by a geriatrician or a neurologist 
from the Memory Disorders Clinic at Health and Social Services Center – Sherbrooke University 
Geriatrics Institute or a physician from the Sherbrooke University Hospital Center (CIUSSS de 
l’Estrie - CHUS) between January, 2010 and September, 2015. All prospective participants had to 
normally be sedentary e.g. not following a structured physical activity or training more than 30 
min twice a week. Exclusion criteria included an MMSE score <20/30, drug addiction, alcohol 
use disorder, depression, smoking, diabetes, evidence of overt heart, liver or renal disease, and 
uncontrolled hypertension, dyslipidemia, or thyroid disease. All participants were taking an 
acetylcholinesterase inhibitor (Donepezil, Galantamine or Rivastigmine) for at least 3 months 
prior to study enrollment. Six were medicated for hypothyroid disorder (Levothyroxine) and eight 
for dyslipidemia (Pravastatin, Simvastatin, Rosuvastatin or Atorvastatin).  
 
Walking program 
Participants were trained to walk on motorized treadmills 3 days/wk for 12 weeks. Most of the 
walking sessions were conducted at the exercise facility at the Research Centre on Aging, under 
the supervision of a kinesiologist. For 3 participants, some training sessions were conducted from 
home, in which case a Polar FT2 watch with T31 heart rate sensor strap (Polar Electro, Kempele, 
Finland) was used to monitor exercise intensity and duration. The walking program was divided 
into two phases: phase one lasted 6 wks and consisted of a gradual increase of the duration of the 
training from 15 min per session in Week 1, to 40 min per session in Week 6 (adding 5 min 
weekly); phase two lasted 6 wks and consisted of 40 min training sessions. The objective of each 
training session was to achieve 60% of maximum heart rate (pulse of 120 beats/min [bpm]) and a 
perceived exertion at level 12-14 on the Borg scale, e.g. mild shortness of breath while still being 
able to speak during exercise. Heart rate reserve was determined during the pre-intervention visit. 
  
 

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Neuroimaging protocol 
To measure brain 18F-FDG and 11C-AcAc uptake, a previously described dynamic PET imaging 
protocol was chosen. Participants underwent a T1-weighted magnetic resonance image (MRI; 
scan duration = 9.14 min, TR = 16.00 ms, TE = 4.68 ms, field of view = 256 x 240 x 192 mm, 
matrix size = 256 x 256 x 164, flip angle = 20° and 1 mm isotropic voxels) on a 1.5 Tesla scanner 
(Sonata, Siemens Medical Solutions, Erlangen, Germany). All participants also underwent a brain 
dynamic acquisition (2 mm isotropic voxels, field of view = 25 cm and axial field = 18 cm) on a 
dual PET-CT Philips Gemini TF scanner (Philips Medical System, Eindhoven, The Netherlands). 
The PET scans were done twice, once at the beginning (Baseline) and once at the end of the 3-
month aerobic training period (Walking). Briefly, for each scan, after a fasting period of 6-7 h 
after breakfast, the participant was positioned in the PET-CT scanner in the early afternoon in a 
dark quiet environment. After intravenous administration of 248 ± 89 MBq of 11C-AcAc via a 
forearm vein catheter, dynamic scans were obtained over a total duration of 10 min (time frames 
12 x 10 sec, 8 x 30 seconds, and 1 x 4 minutes). After a 60 min wash-out period, an IV dose of 
189 ± 26 MBq of 18F-FDG was administered and PET images were acquired over 60 min (time 
frames = 12 х 10 sec, 8 х 30 s sec, 6 х 4 min, and 3 х 10 min).  
 
Quantification of cerebral acetoacetate and glucose consumption 
Cerebral 11C-AcAc and 18F-FDG PET images were analyzed using PMOD 3.7 (PMOD 
Technologies Ltd., Zurich, Switzerland) as previously described. Briefly, cerebral metabolic rate 
(CMR; [µmoles/100 g/min]) of acetoacetate and glucose (CMRacac and CMRglu, respectively) 
were quantified according to the graphical analysis method developed by Patlak et al.[26] based 
on the plasma time-activity curves determined from the blood samples obtained during the 11C-
AcAc and 18F-FDG PET scans. The following equation was used: CMR = K*Cp/LC , where K is 
the rate constant for net uptake of the tracer, Cp is the plasma tracer, and LC is the lumped 
constant ; The LC of CMRacac and CMRglu were set to 1.0 and 0.8, respectively[18, 27]. Brain 
segmentation was defined by Freesurfer parcellation labels (Freesurfer Suite 5.0). Brain 3D 
projections of parametric maps of CMRacac and CMRglu were visualized using MIM Neuro 
(MIM Software Inc., Cleveland, OH, USA). 
 
 
 

English version – august 2017 
 
Biochemical analysis 
Most plasma metabolites were measured using an automated clinical chemistry analyzer 
(Dimension Xpand Plus; Siemens Healthcare Diagnostics, Deerfield, IL, USA). Plasma 
concentrations of homocysteine were analyzed by high performance liquid chromatography 
(Agilent technologies Santa Clara, CA, USA). Plasma insulin was analyzed by commercial 
enzyme-linked immunosorbent assay (Alpco, Salem, NH, USA) with a Victor X4 multi-label 
plate reader (Perkin Elmer, Woodbridge, ON, Canada). The homeostasis model assessment 
method was used to estimate insulin resistance (HOMA-IR) from fasting plasma glucose and 
insulin. 
 
Statistical methods 
We established from our previous work and from others that with an increase of blood ketones of 
2-fold, a sample size of n=10 would provide the required 80% power (p < 0.05) to detect a pre- to 
post-walking difference in the primary outcome - global CMRacac. Data are presented as mean ± 
SD. All statistical analyses were carried out using SPSS 24.0 software (SPSS Inc, Chicago, IL, 
USA). A Wilcoxon signed rank test was used to compare difference between the pre- and the 
post-walking measurements with a statistical threshold of p ≤ 0.05. 
 
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