Publications (11)70.45 Total impact
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Article: Encapsulated cell biodelivery of nerve growth factor to the Basal forebrain in patients with Alzheimer's disease.
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ABSTRACT: Degeneration of cholinergic neurons in the basal forebrain correlates with cognitive decline in patients with Alzheimer's disease (AD). Targeted delivery of exogenous nerve growth factor (NGF) has emerged as a potential AD therapy due to its regenerative effects on the basal forebrain cholinergic neurons in AD animal models. Here we report the results of a first-in-man study of encapsulated cell (EC) biodelivery of NGF to the basal forebrain of AD patients with the primary objective to explore safety and tolerability. This was an open-label, 12-month study in 6 AD patients. Patients were implanted stereotactically with EC-NGF biodelivery devices targeting the basal forebrain. Patients were monitored with respect to safety, tolerability, disease progression and implant functionality. All patients were implanted successfully with bilateral single or double implants without complications or signs of toxicity. No adverse events were related to NGF or the device. All patients completed the study, including removal of implants at 12 months. Positive findings in cognition, EEG and nicotinic receptor binding in 2 of 6 patients were detected. This study demonstrates that surgical implantation and removal of EC-NGF biodelivery to the basal forebrain in AD patients is safe, well tolerated and feasible.Dementia and Geriatric Cognitive Disorders 02/2012; 33(1):18-28. · 2.14 Impact Factor -
Article: Dynamic changes in PET amyloid and FDG imaging at different stages of Alzheimer's disease.
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ABSTRACT: In this study 5 patients with mild cognitive impairment (MCI) and 9 Alzheimer's disease (AD) patients underwent respectively 3- and 5-year follow-up positron emission tomography (PET) studies with N-methyl [(11)C] 2-(4-methylaminophenyl)-6-hydroxy-benzothiazole ((11)C-PIB) and (18)F-fluorodeoxyglucose ((18)F-FDG) to understand the time courses in AD disease processes. Significant increase in PIB retention as well as decrease in regional cerebral metabolic rate of glucose (rCMRglc) was observed at group level in the MCI patients while no significant change was observed in cognitive function. At group level the AD patients showed unchanged high PIB retention at 5-year follow-up compared with baseline. At the individual level, increased, stable, and decreased PIB retention were observed while disease progression was reflected in significant decrease in rCMRglc and cognition. In conclusion, after a long-term follow-up with PET, we observed an increase in fibrillar amyloid load in MCI patients followed by more stable level in clinical AD patients. The rCMRglc starts to decline in MCI patients and became more pronounced in clinical stage which related to continuous decline in cognition.Neurobiology of aging 01/2012; 33(1):198.e1-14. · 5.94 Impact Factor -
Article: Positron emission tomography imaging and clinical progression in relation to molecular pathology in the first Pittsburgh Compound B positron emission tomography patient with Alzheimer's disease.
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ABSTRACT: The accumulation of β-amyloid in the brain is an early event in Alzheimer's disease. This study presents the first patient with Alzheimer's disease who underwent positron emission tomography imaging with the amyloid tracer, Pittsburgh Compound B to visualize fibrillar β-amyloid in the brain. Here we relate the clinical progression, amyloid and functional brain positron emission tomography imaging with molecular neuropathological alterations at autopsy to gain new insight into the relationship between β-amyloid accumulation, inflammatory processes and the cholinergic neurotransmitter system in Alzheimer's disease brain. The patient underwent positron emission tomography studies with (18)F-fluorodeoxyglucose three times (at ages 53, 56 and 58 years) and twice with Pittsburgh Compound B (at ages 56 and 58 years), prior to death at 61 years of age. The patient showed a pronounced decline in cerebral glucose metabolism and cognition during disease progression, while Pittsburgh Compound B retention remained high and stable at follow-up. Neuropathological examination of the brain at autopsy confirmed the clinical diagnosis of pure Alzheimer's disease. A comprehensive neuropathological investigation was performed in nine brain regions to measure the regional distribution of β-amyloid, neurofibrillary tangles and the levels of binding of (3)H-nicotine and (125)I-α-bungarotoxin to neuronal nicotinic acetylcholine receptor subtypes, (3)H-L-deprenyl to activated astrocytes and (3)H-PK11195 to microglia, as well as butyrylcholinesterase activity. Regional in vivo (11)C-Pittsburgh Compound B-positron emission tomography retention positively correlated with (3)H-Pittsburgh Compound B binding, total insoluble β-amyloid, and β-amyloid plaque distribution, but not with the number of neurofibrillary tangles measured at autopsy. There was a negative correlation between regional fibrillar β-amyloid and levels of (3)H-nicotine binding. In addition, a positive correlation was found between regional (11)C-Pittsburgh Compound B positron emission tomography retention and (3)H-Pittsburgh Compound B binding with the number of glial fibrillary acidic protein immunoreactive cells, but not with (3)H-L-deprenyl and (3)H-PK-11195 binding. In summary, high (11)C-Pittsburgh Compound B positron emission tomography retention significantly correlates with both fibrillar β-amyloid and losses of neuronal nicotinic acetylcholine receptor subtypes at autopsy, suggesting a closer involvement of β-amyloid pathology with neuronal nicotinic acetylcholine receptor subtypes than with inflammatory processes.Brain 01/2011; 134(Pt 1):301-17. · 9.46 Impact Factor -
Article: Long-term effects of galantamine treatment on brain functional activities as measured by PET in Alzheimer's disease patients.
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ABSTRACT: The effects of galantamine (16 to 24 mg/day) treatment on brain functional activities (blood flow and glucose metabolism) were examined in 18 patients with mild Alzheimer's disease (AD) in relation to brain acetylcholinesterase (AChE) activity and nicotinic receptors and cognitive function. The study consisted of an initial double-blind phase of three months (short-term) followed by an open-label phase until twelve months after the beginning of the study (long-term). The AD patients underwent positron emission tomography (PET) studies with the tracers [15O]-H2O for measurement of regional cerebral blood flow (rCBF) at baseline, 3 weeks, 3 and 12 months treatment, and [18F]-fluoro-deoxyglucose (FDG) for measurement of regional cerebral metabolic rate for glucose (rCMRglc) at baseline and 12 months. A battery of neuropsychological assessments was performed on each patient in order to follow changes in cognition during the treatment period. Throughout the study, different cortical areas showed significant increases in rCBF after galantamine treatment. rCBF positively correlated with AChE activity, nicotinic receptors and cognition. In addition to these positive changes, an increase in rCMRglc in the frontal brain region and stabilization in other cortical areas was observed after 12 months galantamine treatment. This stabilization in rCMRglc was also correlated with a stabilization of cognition. Our results ultimately suggest that treatment with galantamine has a long-term positive effect on brain perfusion and rCMRglc and stabilizes cognition.Journal of Alzheimer's disease: JAD 12/2010; 24(1):109-23. · 3.74 Impact Factor -
Article: Target-specific PET probes for neurodegenerative disorders related to dementia.
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ABSTRACT: Dementia is a highly prevalent problem causing considerable disability and mortality and exacting great costs to individuals, their families, and society. The 4 most common neurodegenerative disorders that cause dementia-Alzheimer disease, frontotemporal dementia, dementia with Lewy bodies, and dementia in Parkinson disease-have different underlying etiologies and pathogenetic mechanisms. There is a great need for early diagnostic markers; functional brain imaging may therefore assist in the detection and differential diagnosis of dementia due to neurodegenerative diseases. Functional imaging such as PET allows in vivo imaging of functional brain activity indicating cerebral blood flow and cerebral glucose metabolism, and PET allows imaging of neurotransmitter activity, including that of the cholinergic, dopaminergic, and serotonergic systems. New PET neuroimaging tracers are being developed for detecting pathologic parameters such as amyloid plaque and microglial activity. The development of molecular imaging is important for early diagnosis of dementia, selection of patients for therapies, and evaluation of therapies.Journal of Nuclear Medicine 09/2010; 51(9):1418-30. · 6.38 Impact Factor -
Article: The use of PET in Alzheimer disease.
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ABSTRACT: In Alzheimer disease (AD), which is the most common cause of dementia, the underlying disease pathology most probably precedes the onset of cognitive symptoms by many years. Thus, efforts are underway to find early diagnostic markers as well as disease-modifying treatments for this disorder. PET enables various brain systems to be monitored in living individuals. In patients with AD, PET can be used to investigate changes in cerebral glucose metabolism, various neurotransmitter systems, neuroinflammation, and the protein aggregates that are characteristic of the disease, notably the amyloid deposits. These investigations are helping to further our understanding of the complex pathophysiological mechanisms that underlie AD, as well as aiding the early and differential diagnosis of the disease in the clinic. In the future, PET studies will also be useful for identifying new therapeutic targets and monitoring treatment outcomes. Amyloid imaging could be useful as early diagnostic marker of AD and for selecting patients for anti-amyloid-beta therapy, while cerebral glucose metabolism could be a suitable PET marker for monitoring disease progression. For the near future, multitracer PET studies are unlikely to be used routinely in the clinic for AD, being both burdensome and expensive; however, such studies are very informative in a research context.Nature Reviews Neurology 02/2010; 6(2):78-87. · 12.46 Impact Factor -
Article: Effect of phenserine treatment on brain functional activity and amyloid in Alzheimer's disease.
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ABSTRACT: 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. 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. 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. Phenserine treatment was associated with an improvement in cognition and an increase in rCMRglc.Annals of Neurology 06/2008; 63(5):621-31. · 11.09 Impact Factor -
Article: Effect of phenserine treatment on brain functional activity and amyloid in Alzheimer's disease
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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 (30mg/day) and 10 patients the placebo. Three to 6 months was an open-label extension phase, during which the placebo group received donepezil (5mg/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 (18F-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.ResultsStatistically 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 β-amyloid 40 (Aβ40). Cortical Pittsburgh Compound B retention correlated negatively with CSF Aβ40 levels and the ratio Aβ/β-secretase–cleaved amyloid precursor protein. In CSF, Aβ40 correlated positively with the attention domain of cognition.InterpretationPhenserine treatment was associated with an improvement in cognition and an increase in rCMRglc. Ann Neurol 2008Annals of Neurology 04/2008; 63(5):621 - 631. · 11.09 Impact Factor -
Article: Effect of phenserine treatment on brain functional activity and amyloid in Alzheimer's disease
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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 Alz-heimer'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 (30mg/day) and 10 patients the placebo. Three to 6 months was an open-label extension phase, during which the placebo group received donepezil (5mg/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 (18 F-FDG) and amyloid load (11 C-PIB) at baseline and after 3 and 6 months of the treatment. Neuropsy-chological 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 -amyloid 40 (A40). Cortical Pittsburgh Compound B retention correlated negatively with CSF A40 levels and the ratio A/-secretase–cleaved amyloid precursor protein. In CSF, A40 correlated positively with the attention domain of cognition. Interpretation: Phenserine treatment was associated with an improvement in cognition and an increase in rCMRglc.Ann Neurol. 01/2008; 63:621-631. -
Article: Changes in brain 11C-nicotine binding sites in patients with mild Alzheimer's disease following rivastigmine treatment as assessed by PET.
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ABSTRACT: 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. 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. Ten mild AD patients received rivastigmine for 12 months. A dual-tracer PET model with administration of (15)O-water and (S)(-)(11)C-nicotine was used to assess (11)C-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. The (11)C-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 (11)C-nicotine binding. The (11)C-nicotine binding positively correlated with attentional task at the 12-month follow-up. Changes in the (11)C-nicotine binding during rivastigmine treatment might represent remodeling of the cholinergic and related neuronal network.Psychopharmacologia 06/2007; 191(4):1005-14. · 4.08 Impact Factor -
Article: PET imaging of cortical 11C-nicotine binding correlates with the cognitive function of attention in Alzheimer's disease.
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ABSTRACT: Patients suffering from Alzheimer's disease (AD) experience a marked reduction in cortical nicotinic acetylcholine receptors (nAChRs). In particular, selective loss of the alpha4beta2 nAChR subtype was observed in postmortem AD brain tissue. The alpha4 and alpha7 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. To investigate the relationship between measures of cognitive function and in vivo 11C-nicotine binding in mild AD brain as assessed by PET. Twenty-seven patients with mild AD were recruited in this study. A dual tracer model with administration of 15O-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. Mean cortical 11C-nicotine binding significantly correlated with the results of attention tests [Digit Symbol test (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. Cortical nicotinic receptors in vivo in mild AD patients are robustly associated with the cognitive function of attention.Psychopharmacologia 12/2006; 188(4):509-20. · 4.08 Impact Factor
Top co-authors
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Institutions
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2006–2012
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Karolinska University Hospital
Stockholm, Stockholm, Sweden
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2007–2011
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Karolinska Institutet
- Institutionen för neurobiologi, vårdvetenskap och samhälle - NVS
Solna, Stockholm, Sweden
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2008
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Stockholm University
Stockholm, Stockholm, Sweden
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