Cholinergic Dysfunction after Cholinergic Dysfunction after Traumatic Brain Injury – A PET Traumatic Brain Injury – A PET

Study Study

Anna Östberg Anna Östberg 11, Jere Virta, Jere Virta22, Juha Rinne, Juha Rinne22, Vesa , Vesa OikonenOikonen22, Pauliina Luoto, Pauliina Luoto22, Olli Tenovuo*, Olli Tenovuo*11

11Department of Neurology, University of Turku, Department of Neurology, University of Turku, Finland,Finland, 2 2Turku PET Centre, FinlandTurku PET Centre, Finland

**presenting author presenting author

IntroductionIntroduction

• Several lines of evidence suggest that the Several lines of evidence suggest that the cholinergic system plays an important role in cholinergic system plays an important role in a significant portion of TBI-related cognitive a significant portion of TBI-related cognitive deficits.deficits.

• Numerous studies have suggested that Numerous studies have suggested that cholinergic stimulation may be beneficial in cholinergic stimulation may be beneficial in chronic cognitive TBI sequels.chronic cognitive TBI sequels.

ObjectivesObjectives

• To test the hypothesis of cholinergic dysfunction To test the hypothesis of cholinergic dysfunction after TBI by examining the after TBI by examining the in vivoin vivo cholinergic cholinergic system with positron emission tomography (PET), system with positron emission tomography (PET), and by comparing patients with chronic cognitive and by comparing patients with chronic cognitive TBI sequels with healthy controls.TBI sequels with healthy controls.

• To assess whether the acetylcholinesterase (AChE) To assess whether the acetylcholinesterase (AChE) activity of those TBI patients who have responded activity of those TBI patients who have responded to a central AChE inhibitor differ from those who to a central AChE inhibitor differ from those who have failed to respond.have failed to respond.

Subjects Subjects

Inclusion criteria:Inclusion criteria:• chronic sequels of TBI with the presence of all four chronic sequels of TBI with the presence of all four

core symptoms: memory problems, fatigue, core symptoms: memory problems, fatigue, decreased initiation, and attention deficitsdecreased initiation, and attention deficits

• more than one year post-injury more than one year post-injury • mainly diffuse injury mechanism without large (> 1 mainly diffuse injury mechanism without large (> 1

cm3) local contusions cm3) local contusions • an earlier treatment trial with rivastigmine with a an earlier treatment trial with rivastigmine with a

minimum duration of one week and a minimum minimum duration of one week and a minimum daily dose of 3 mgdaily dose of 3 mg

Subjects Subjects

• 38 subjects from the TBI database fulfilled the 38 subjects from the TBI database fulfilled the criteria of the study, 19 of them agreed to criteria of the study, 19 of them agreed to participate.participate.

• Two persons discontinued the study. Thus, the Two persons discontinued the study. Thus, the final study group consisted of 17 subjects, ten of final study group consisted of 17 subjects, ten of them having shown subjective treatment them having shown subjective treatment response to rivastigmine, and seven of them response to rivastigmine, and seven of them having been non-respondents.having been non-respondents.

• 12 healthy volunteers as controls12 healthy volunteers as controls

TABLE 1. The characteristics of the study subjects.TABLE 1. The characteristics of the study subjects.

RespondentsRespondentsNon-Non-respondentsrespondents ControlsControls

n = 10n = 10 n = 7n = 7 n = 12n = 12

AgeAge 44.5 ± 12.044.5 ± 12.0 43.4 ± 14.143.4 ± 14.1 48.4±13.948.4±13.9

TBI severityTBI severity11

moderatemoderate 2 (20 %)2 (20 %) 2 (29 %)2 (29 %)

severesevere 5 (50 %)5 (50 %) 4 (57 %)4 (57 %)

very severevery severe 3 (30 %)3 (30 %) 1 (14 %)1 (14 %)

Injury mechanismInjury mechanism

traffictraffic 9 (90 %)9 (90 %) 5 (72 %)5 (72 %)

fallfall 1 (10 %)1 (10 %) 2 (28 %)2 (28 %)

Years from TBIYears from TBI 12.0 ± 7.612.0 ± 7.6 6.3 ± 3.56.3 ± 3.5

11 Assessed according to the duration of posttraumatic amnesia, Assessed according to the duration of posttraumatic amnesia, moderate 1 – 7 days, severe 1 – 4 weeks, very severe > 4 weeksmoderate 1 – 7 days, severe 1 – 4 weeks, very severe > 4 weeks

Methods Methods • 1111C-MP4A C-MP4A (acetylcholine analog with high AChE (acetylcholine analog with high AChE

specificity) PET imaging scan specificity) PET imaging scan

• The subjects with TBI were scanned twice - for the The subjects with TBI were scanned twice - for the four weeks preceding the scan they had been either four weeks preceding the scan they had been either without any centrally acting drugs or had taken without any centrally acting drugs or had taken rivastigmine at a dose of 1.5 mg b.i.drivastigmine at a dose of 1.5 mg b.i.d

• ROIs were delineated bilaterally on the frontal ROIs were delineated bilaterally on the frontal cortex (FCX), lateral temporal cortex (LTC), medial cortex (FCX), lateral temporal cortex (LTC), medial temporal lobe (MTL), inferior part of the parietal temporal lobe (MTL), inferior part of the parietal lobe (LPI), occipital cortex (OCC), posterior lobe (LPI), occipital cortex (OCC), posterior cingulatum (PC) and putamencingulatum (PC) and putamen

Results – SPM analyses Results – SPM analyses

• The baseline AChE activity (= without The baseline AChE activity (= without medication) was significantly lower in TBI medication) was significantly lower in TBI subjects than in controls in several areas of the subjects than in controls in several areas of the neocortexneocortex

Results – SPM analyses Results – SPM analyses

• A significant difference between the A significant difference between the respondents and non-respondents was seen respondents and non-respondents was seen bilaterally in the frontal cortex, the respondents bilaterally in the frontal cortex, the respondents having significantly lower AChE activityhaving significantly lower AChE activity

Results – SPM analyses Results – SPM analyses

• The SPM analysis showed a widely significant The SPM analysis showed a widely significant lowering of the AChE activity in the neocortex lowering of the AChE activity in the neocortex after rivastigmine, in both respondents and non-after rivastigmine, in both respondents and non-respondents without any significant difference respondents without any significant difference between them.between them.

Results – ROI analyses Results – ROI analyses

• AChE activity in the non-respondent group did AChE activity in the non-respondent group did not differ significantly from the controls except not differ significantly from the controls except in the inferior part of the parietal lobein the inferior part of the parietal lobe (-8.4 ± 2.6 (-8.4 ± 2.6 %, p = 0.050) and the occipital cortex (-12.6 ± 6.8 %, p = 0.050) and the occipital cortex (-12.6 ± 6.8 %, p = 0.013).%, p = 0.013).

Results – ROI analyses Results – ROI analyses

• In the respondents, the AChE activity was In the respondents, the AChE activity was significantly reduced in several cortical areas, significantly reduced in several cortical areas, including the lateral frontal cortex (-10.9 ± 9.0%, including the lateral frontal cortex (-10.9 ± 9.0%, p = 0.003), lateral temporal cortex (-8.4 ± 6.4%, p p = 0.003), lateral temporal cortex (-8.4 ± 6.4%, p = 0.032), inferior part of the parietal cortex (-= 0.032), inferior part of the parietal cortex (-10.9 ± 10.0%, p = 0.007), occipital cortex (-9.0 ± 10.9 ± 10.0%, p = 0.007), occipital cortex (-9.0 ± 21.8 %, p = 0.047), anterior cingulate cortex (-8.3 21.8 %, p = 0.047), anterior cingulate cortex (-8.3 ± 4.6 %, p = 0.014), and posterior cingulate ± 4.6 %, p = 0.014), and posterior cingulate cortex (-13.6 ± 7.8 %, p = 0.001)cortex (-13.6 ± 7.8 %, p = 0.001)

Results – ROI analyses Results – ROI analyses

• Within the subjects with TBI, those responding Within the subjects with TBI, those responding to rivastigmine treatment showed significantly to rivastigmine treatment showed significantly lower AChE activity compared to the non-lower AChE activity compared to the non-respondents in the lateral frontal cortex (-9.4 ± respondents in the lateral frontal cortex (-9.4 ± 9.2 %, p = 0.023).9.2 %, p = 0.023).

Conclusions Conclusions

• The main finding was a widely lowered cortical The main finding was a widely lowered cortical AChE activity in TBI subjects compared to AChE activity in TBI subjects compared to controls.controls.

• A more profound cholinergic dysfunction in the A more profound cholinergic dysfunction in the respondents contrast to non-respondents when respondents contrast to non-respondents when compared to controls supports the concept that compared to controls supports the concept that AChE-inhibitors may be beneficial for some AChE-inhibitors may be beneficial for some patients with chronic TBI sequelspatients with chronic TBI sequels

Conclusions Conclusions

• Our study also shows that the respondents have Our study also shows that the respondents have a significantly lower AChE activity in the lateral a significantly lower AChE activity in the lateral frontal cortex in direct comparison with the non-frontal cortex in direct comparison with the non-respondents. As frontal dysfunction often lies respondents. As frontal dysfunction often lies behind the most disabling symptoms of TBI, the behind the most disabling symptoms of TBI, the finding of a more profound frontal cholinergic finding of a more profound frontal cholinergic dysfunction in the respondents suits nicely into dysfunction in the respondents suits nicely into this entirety.this entirety.