| 1. |
- Kadir, Ahmadul, et al.
(author)
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Changes in brain 11C-nicotine binding sites in patients with mild Alzheimer's disease following rivastigmine treatment as assessed by PET
- 2007
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In: Psychopharmacology. - : Springer Science and Business Media LLC. - 0033-3158 .- 1432-2072. ; 191:4, s. 1005-1014
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Journal article (peer-reviewed)abstract
- Rationale Marked reduction in the cortical nicotinic acetylcholine receptors is observed in the brain of patients suffering from Alzheimer’s disease (AD). Although cholinesterase inhibitors are used for symptomatic treatment of mild to moderate AD patients, numerous long-term treatment studies indicate that they might stabilize or halt the progression of the disease by restoring the central cholinergic neurotransmission. Thus, we used positron emission tomography (PET) technique as a sensitive approach to assess longitudinal changes in the nicotine binding sites in the brains of patients with AD. Objective To evaluate changes in brain nicotinic binding sites in relation to inhibition level of cholinesterases in cerebrospinal fluid (CSF) and plasma and changes in cognitive performance of the patients in different neuropsychological tests after rivastigmine treatment. Materials and methods Ten mild AD patients received rivastigmine for 12 months. A dual-tracer PET model with administration of 15O–water and (S)(–)11C–nicotine was used to assess 11C–nicotine binding sites in the brain at baseline and after 3 and 12 months of the treatment. Cholinesterase activities in CSF and plasma were assessed colorimetrically. Results The 11C–nicotine binding sites were significantly increased 12–19% in several cortical brain regions after 3 months compared with baseline, while the increase was not significant after 12 months of the treatment. After 3 months treatment, low enzyme inhibition in CSF and plasma was correlated with higher cortical 11C–nicotine binding. The 11C–nicotine binding positively correlated with attentional task at the 12-month follow-up. Conclusion Changes in the 11C–nicotine binding during rivastigmine treatment might represent remodeling of the cholinergic and related neuronal network.
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| 2. |
- Kadir, Ahmadul, et al.
(author)
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Effect of phenserine treatment on brain functional activity and amyloid in Alzheimer's disease.
- 2008
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In: Annals of neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 63:5, s. 621-31
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Journal article (peer-reviewed)abstract
- OBJECTIVE: The effects of (-)-phenserine (phenserine) and placebo/donepezil treatment on regional cerebral metabolic rate for glucose (rCMRglc) and brain amyloid load were investigated by positron emission tomography in 20 patients with mild Alzheimer's disease in relation to cerebrospinal fluid (CSF) and plasma biomarkers, and cognitive function. METHODS: The first 3 months of the study was a randomized, double-blind, placebo-controlled phase, during which 10 patients received phenserine (30 mg/day) and 10 patients the placebo. Three to 6 months was an open-label extension phase, during which the placebo group received donepezil (5 mg/day) and the phenserine group remained on phenserine. After 6 months, all patients received phenserine treatment up to 12 months. The patients underwent positron emission tomography examinations to measure rCMRglc (8F-FDG) and amyloid load (11C-PIB) at baseline and after 3 and 6 months of the treatment. Neuropsychological and biomarker data were collected at the three times of positron emission tomography imaging. RESULTS: Statistically significant effects on a composite neuropsychological test score were observed in the phenserine-treated group compared with the placebo and donepezil group at 3 and 6 months, respectively. Values of rCMRglc were significantly increased in several cortical regions after 3 months of phenserine treatment, compared with baseline, and correlated positively with cognitive function and CSF beta-amyloid 40 (Abeta40). Cortical Pittsburgh Compound B retention correlated negatively with CSF Abeta40 levels and the ratio Abeta/beta-secretase-cleaved amyloid precursor protein. In CSF, Abeta40 correlated positively with the attention domain of cognition. INTERPRETATION: Phenserine treatment was associated with an improvement in cognition and an increase in rCMRglc.
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| 3. |
- Kadir, Ahmadul
(author)
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Functional brain activity in Alzheimer patients as studied by multi-tracer positron emission tomography : effects of treatment with cholinesterase inhibitors
- 2007
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Doctoral thesis (other academic/artistic)abstract
- Alzheimer’s disease (AD) is a progressive neurodegenerative disease accompanied by cognitive impairment and disturbances in several neurotransmitter systems, especially the cholinergic system. Studies have correlated the cognitive impairment observed in AD patients with a deficit in central cholinergic neurotransmission. The most successful therapeutic agents for symptomatic treatment of AD patients are cholinesterase inhibitors (ChEIs), e.g. donepezil, rivastigmine and galantamine, which are targeted towards enhancing cholinergic neurotransmission. One of the most valuable tools for evaluating cholinergic neurotransmission in AD patients is positron emission tomography (PET). PET with high spatial resolution, has successfully been used in the early diagnosis, differential diagnosis and evaluation of drug treatment in patients suffering from AD. The overall aim of this thesis was to utilize the multi-tracer PET technique to measure brain glucose metabolism, nicotinic acetylcholine receptor (nAChR) density, acetylcholinesterase (AChE) activity and amyloid load of patients with mild AD. These brain functional aspects were measured during the natural course of the disease or during treatment with ChEIs and/or anti-amyloid therapy in conjunction with assessment of changes in CSF biomarkers, ChE activity as well as with cognitive performance of the patients. In this thesis, it was demonstrated that cortical nAChRs as assessed by a dual tracer PET model with administration of 15O-water and (S)(-)11C-nicotine in mild AD patients (n = 27) are associated with the cognitive function of attention rather than with episodic memory. The effect of different ChEIs on cortical nAChRs was also evaluated in this thesis. Rivastigmine treated mild AD patients (n = 10) showed a significant increase of nAChRs in several cortical brain regions after 3 months compared with baseline, while the increase was not significant after 12 months of treatment. In a randomized double-blind placebo-controlled study, mild AD patients (n = 18) treated with galantamine demonstrated no change in cortical nAChRs after both short- (3 months) and long-term (12 months) treatment. However, it should be noted that individual subjects with higher plasma galantamine levels also demonstrated an increase in cortical nAChR binding. Additionally, patients treated with galantamine for 12 months demonstrated a 30–40% decrease in cortical AChE activity (as assessed by 11C-PMP-PET) and a 30-36% decrease in CSF AChEsynaptic activity. In addition to rivastigmine and galantamine, the effects of (-)-phenserine, a new ChEI, were evaluated in mild AD patients (n = 20) in a randomized double-blind placebo-controlled study. Phenserine is a tentative AD drug that demonstrates an additional mechanism of action as an inhibitor of the formation of beta-amyloid precursor protein (beta-APP). Mild AD patients treated with (-)-phenserine demonstrated an increase in cerebral glucose metabolism as evaluated by 18F-FDGPET after 3 months compared with baseline. We also observed that cortical amyloid load, measured by 11C-PIB-PET, was inversely correlated with CSF beta-amyloid (Abeta) levels, suggesting that (-)- phenserine treatment influenced both brain and CSF amyloid. After treatment with galantamine and (-)-phenserine we observed the highest level of improvement of cognitive performance up to 3 to 6 months, and maintenance of cognitive performance was observed after 12 months’ treatment, indicating stabilization of the disease. Attention was shown to be the main cognitive domain improved by the treatment. Positive correlations were also observed between the changes in number of cortical nicotinic receptors, AChE inhibition and changes in cognitive measures of attention. In conclusion, the present findings demonstrate that utilizing the multi-tracer PET method is important in the investigation of functional activity, neurotransmitters and pathology in the brains of patients with AD, in conjunction with measures of cognitive function, to evaluate the efficacy of the currently available ChEI treatments and future treatment strategies.
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| 4. |
- Kadir, Ahmadul, et al.
(author)
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PET imaging of cortical 11C-nicotine binding correlates with the cognitive function of attention in Alzheimer´s disease.
- 2006
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In: Psychopharmacology. - : Springer Science and Business Media LLC. - 0033-3158 .- 1432-2072. ; 188:4, s. 509-520
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Journal article (peer-reviewed)abstract
- Rationale: Patients suffering from Alzheimer's disease (AD) experience a marked reduction in cortical nicotinic acetylcholine receptors (nAChRs). In particular, selective loss of the α-sub-4β-sub-2 nAChR subtype was observed in postmortem AD brain tissue. The α-sub-4 and α-sub-7 nAChR subunits were suggested to play an important role in cognitive function. Positron emission tomography (PET) has so far been used to visualize neuronal nAChRs in vivo by 11C-nicotine binding. Objectives: To investigate the relationship between measures of cognitive function and in vivo 11C-nicotine binding in mild AD brain as assessed by PET. Materials and methods: Twenty-seven patients with mild AD were recruited in this study. A dual tracer model with administration of 1-sup-5O-water for regional cerebral blood flow and (S)(-)11C-nicotine was used to assess nicotine binding sites in the brain by PET. Cognitive function was assessed using neuropsychological tests of global cognition, episodic memory, attention, and visuospatial ability. Results: Mean cortical 11C-nicotine binding significantly correlated with the results of attention tests (r = -0.44 and p = 0.02) and Trail Making Test A (TMT-A) (r = 0.42 and p = 0.03)]. No significant correlation was observed between 11C-nicotine binding and the results of tests of episodic memory or visuospatial ability. Regional analysis showed that 11C-nicotine binding in the frontal and parietal cortex, which are the main areas for attention, correlated significantly with the Digit Symbol test and TMT-A results. Conclusion: Cortical nicotinic receptors in vivo in mild AD patients are robustly associated with the cognitive function of attention.
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| 5. |
- Kadir, Ahmadul, et al.
(author)
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PET imaging of the in vivo brain acetylcholinesterase activity and nicotine binding in galantamine-treated patients with AD
- 2008
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In: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 29:8, s. 1204-1217
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Journal article (peer-reviewed)abstract
- The effect of galantamine treatment on cortical acetylcholinesterase (AChE) activity and nicotinic receptor binding was investigated by positron emission tomography (PET) in 18 patients with mild Alzheimer's disease (AD) in relation to galantamine concentration and the patients’ cognitive performances. The first 3 months of the study was of a randomized double-blind placebo-controlled design, during which 12 patients received galantamine (16–24 mg/day) and 6 patients the placebo, and this was followed by 9 months’ galantamine treatment in all patients. The patients underwent PET examinations to measure cortical AChE activity (11C-PMP) and 11C-nicotine binding. Neuropsychological tests were performed throughout the study. Inhibition (30–40%) of cortical AChE activity was observed after 3 weeks to 12 months of galantamine treatment. No significant change in mean cortical 11C-nicotine binding was observed during the study. 11C-Nicotine binding, however, positively correlated with plasma galantamine concentration. Both the changes of AChE activity and 11C-nicotine binding correlated positively with the results of a cognitive test of attention. In conclusion, galantamine caused sustained AChE inhibition for up to 12 months. At the individual level, the in vivo cortical AChE inhibition and 11C-nicotine binding were associated with changes in the attention domain of cognition rather than episodic memory.
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