| 1. |
- Gkanatsiou, Eleni, et al.
(författare)
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Characterization of monomeric and soluble aggregated A beta in Down's syndrome and Alzheimer's disease brains
- 2021
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Ingår i: Neuroscience Letters. - : Elsevier. - 0304-3940 .- 1872-7972. ; 754
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Tidskriftsartikel (refereegranskat)abstract
- The major characteristics of Alzheimer's disease (AD) are amyloid plaques, consisting of aggregated beta amyloid (A beta) peptides, together with tau pathology (tangles, neuropil treads and dystrophic neurites surrounding the plaques), in the brain. Down's syndrome (DS) individuals are at increased risk to develop AD-type pathology; most DS individuals have developed substantial pathology already at the age of 40. DS individuals have an extra copy of chromosome 21, harbouring the amyloid precursor protein gene (APP). Our aim was to investigate the A beta peptide pattern in DS and AD brains to investigate differences in their amyloid deposition and aggregation, respectively. Cortical tissue from patients with DS (with amyloid pathology), sporadic AD and controls were homogenized and fractionated into TBS (water soluble) and formic acid (water insoluble) fractions. Immunoprecipitation (IP) was performed using a variety of antibodies targeting different A beta species including oligomeric A beta. Mass spectrometry was then used to evaluate the presence of A beta species in the different patient groups. A large number of A beta peptides were identified including A beta 1-X, 2-X, 3-X, 4-X, 5-X, 11-X, and A beta peptides extended N terminally of the BACE1 cleavage site and ending at amino 15 in the A beta sequence APP/A beta(-X to 15), as well as peptides post-translationally modified by pyroglutamate formation. Most A beta peptides had higher abundance in AD and DS compared to controls, except the APP/A beta(-X to 15) peptides which were most abundant in DS followed by controls and AD. Furthermore, the abundancies of A?X-40 and A beta X-34 were increased in DS compared with AD. A beta 1-40, A beta 1-42, and A beta 4-42 were identified as the main constitutes of protofibrils (IP'd using mAb158) and higher relative A beta 1-42 signals were obtained compared with samples IP'd with 6E10 + 4G8, indicating that the protofibrils/oligomers were enriched with peptides ending at amino acid 42. All A? peptides found in AD were also present in DS indicating similar pathways of A beta peptide production, degradation and accumulation, except for APP/A beta(-X to 15). Likewise, the A beta peptides forming protofibrils/oligomers in both AD and DS were similar, implying the possibility that treatment with clinical benefit in sporadic AD might also be beneficial for subjects with DS.
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| 2. |
- Gkanatsiou, Eleni, et al.
(författare)
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Characterization of monomeric and soluble aggregated Aβ in Down's syndrome and Alzheimer's disease brains.
- 2021
-
Ingår i: Neuroscience letters. - : Elsevier BV. - 1872-7972 .- 0304-3940. ; 754
-
Tidskriftsartikel (refereegranskat)abstract
- The major characteristics of Alzheimer's disease (AD) are amyloid plaques, consisting of aggregated beta amyloid (Aβ) peptides, together with tau pathology (tangles, neuropil treads and dystrophic neurites surrounding the plaques), in the brain. Down's syndrome (DS) individuals are at increased risk to develop AD-type pathology; most DS individuals have developed substantial pathology already at the age of 40. DS individuals have an extra copy of chromosome 21, harbouring the amyloid precursor protein gene (APP). Our aim was to investigate the Aβ peptide pattern in DS and AD brains to investigate differences in their amyloid deposition and aggregation, respectively. Cortical tissue from patients with DS (with amyloid pathology), sporadic AD and controls were homogenized and fractionated into TBS (water soluble) and formic acid (water insoluble) fractions. Immunoprecipitation (IP) was performed using a variety of antibodies targeting different Aβ species including oligomeric Aβ. Mass spectrometry was then used to evaluate the presence of Aβ species in the different patient groups. A large number of Aβ peptides were identified including Aβ1-X, 2-X, 3-X, 4-X, 5-X, 11-X, and Aβ peptides extended N terminally of the BACE1 cleavage site and ending at amino 15 in the Aβ sequence APP/Aβ(-X to 15), as well as peptides post-translationally modified by pyroglutamate formation. Most Aβ peptides had higher abundance in AD and DS compared to controls, except the APP/Aβ(-X to 15) peptides which were most abundant in DS followed by controls and AD. Furthermore, the abundancies of AβX-40 and AβX-34 were increased in DS compared with AD. Aβ1-40, Aβ1-42, and Aβ4-42 were identified as the main constitutes of protofibrils (IP'd using mAb158) and higher relative Aβ1-42 signals were obtained compared with samples IP'd with 6E10+4G8, indicating that the protofibrils/oligomers were enriched with peptides ending at amino acid 42. All Aβ peptides found in AD were also present in DS indicating similar pathways of Aβ peptide production, degradation and accumulation, except for APP/Aβ(-X to 15). Likewise, the Aβ peptides forming protofibrils/oligomers in both AD and DS were similar, implying the possibility that treatment with clinical benefit in sporadic AD might also be beneficial for subjects with DS.
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| 3. |
- Johannesson, Malin, et al.
(författare)
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Elevated soluble amyloid beta protofibrils in Down syndrome and Alzheimer's disease
- 2021
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Ingår i: Molecular and Cellular Neuroscience. - : Elsevier. - 1044-7431 .- 1095-9327. ; 114
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Tidskriftsartikel (refereegranskat)abstract
- Down syndrome (DS) is caused by trisomy of chromosome 21, which leads to a propensity to develop amyloid beta (A beta) brain pathology in early adulthood followed later by cognitive and behavioral deterioration. Characterization of the A beta pathology is important to better understand the clinical deterioration of DS individuals and to identify interventive strategies. Brain samples from people with DS and Alzheimer's disease (AD), as well as nondemented controls (NDC), were analyzed with respect to different A beta species. Immunohistochemical staining using antibodies towards A beta was also performed. Elevated levels of soluble A beta protofibrils and insoluble A beta x-40 and A beta x-42 in formic acid brain extracts, and elevated immunohistochemical staining of A beta deposits were demonstrated with the antibody BAN2401 (lecanemab) in DS and AD compared with NDC. These data and the promising data in a large phase 2 CE clinical trial with lecanemab suggest that lecanemab may have the potential to preserve cognitive capacity in DS. Lecanemab is currently in a phase 3 CE clinical trial.
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| 4. |
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| 5. |
- Odergren, Tomas
(författare)
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Studies on pathophysiology and effects of botulinumtoxin in focal dystonia
- 1996
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The pathophysiology of focal dystonia, such as cervical dystonia (CD) and writer's cramp (WR) is far from determined and the development of effective treatment is thus impeded. The dystonia in WR is often action-specific, and most dystonic patients experience an action-induced worsening of the symptoms. Patients with CD and WR were studied at rest and during activity by different neurophysiological methods Intramuscular botulinum toxin (BTX) injection are increasingly utilized in the treatment of the focal dystonias. The effects of BTX in CD patients were studied with electromyography (EMG) and with measurements of clinical efficacy. Bursts of involuntary activity were recorded with EMG in CD patients' sternocleidomastoid muscles (SCMs), both at rest and during a slight muscle contraction Transcranial magnetic stimulation (TMS) induced motor evoked potentials (MEPs) with abnormally short latencies in the SCMs of CD patients. The onset of TMS induced suppression of EMG activity occurred abnormally late in the CD patients' SCMs. The CD patients' clinical signs were compatible with a unilateral central dysfunction, whereas the abnormal results of TMS were seen bilterally both at rest and during SCM contraction. Studies of precision grip function in patients with WR showed impaired abilities to coordinate grip and lift force trajectories, and to correct erroneously programmed grip force according to sensory feedback. The WR patients further ha abnormally large grip force increases in response to a sudden load increase. The findings in the EMG, TMS and precision grip studies suggest an impaired motor control in dystonia due to increased motoneuronal excitability and deficiencies of inhibitory regulation. Dystonic signs increased, and positron emission tomography showed increased regional cerebral blood flow (rCBF) in the left primary sensory-motor and premotor cortical areas, the left thalamus and the right cerebellum, as WR patients wrote for longer periods. These rCBF increases suggest an increased activation of a cerebro-cerebellar motor circuit in dystonia. The WR patients concurrently progressively decreased the rCBF in the left supramarginal and angular gyri. Control subjects had no progressive changes of rCBF during prolonged writing, but their rCBF changes during writing(compared to during drawing) resembled the WR patients' pattern of progressive rCBF changes during prolonged writing. The normal cerebral processes during writing seem thus to be exaggerated in WR, which may contribute to the task-specific dysfunction. Data from CD status scales according to Tsui and to Fahn correlated well with patient's rating of the BTX treatment effect. BTX injections improved but failed to normalize CD patients' quality of life. EMG of single motor units in SCMs repeatedly injected with BTX indicated persitent reduction of the number of size of functional muscle fibres, but otherwise restored functional neuromuscular organization when CD symptoms had relapsed.
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| 6. |
- Zingmark, Per-Henrik, et al.
(författare)
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Population pharmacokinetics of clomethiazole and its effect on the natural course of sedation in acute stroke patients
- 2003
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 56:2, s. 173-183
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: This analysis was performed to investigate the population pharmacokinetics of clomethiazole and its effect on the natural course of sedation in acute stroke patients using a nonlinear mixed effects modelling approach. METHODS: One thousand five hundred and forty-six acute stroke patients (774 on active treatment) from 166 centres were included in three randomized, double-blind, placebo-controlled phase III efficacy and safety studies. A total dose of 68 mg kg(-1) clomethiazole edisilate was given as a three-phase i.v.-infusion over 24 h. Three blood samples were drawn from all patients to characterize the pharmacokinetics. Sedation was monitored throughout the entire treatment period and the degree of sedation was measured on a discrete ordinal scale with six levels. Models were fitted to the data using the software NONMEM. RESULTS: Clomethiazole was characterized by a two-compartment pharmacokinetic model with interindividual variability in all structural parameters. For a patient weighing 75 kg, the average CL, V1, Q, and V2 was estimated to be 52.7 l h(-1), 82.5 l, 167 l h(-1) and 335 l, respectively. The interindividual variability in CL, V1, Q and V2 was estimated to be 48%, 53%, 42% and 54%, respectively. Increasing body weight and concomitant administration of liver enzyme inducing drugs were found to increase clearance (by 0.5 l h(-1) kg(-1) and 40%, respectively). Increasing weight also increased the volume of distribution (1.1 l kg(-1) for V1 and 4.7 l kg(-1) for V2). A six-category proportional odds model with a component including the natural course of sedation following placebo administration, a drug component (present or absent) and an interindividual variability component described the degree of sedation. Stroke severity as measured on the NIH-stroke scale on admission and drug treatment were the most important predictors of sedation, but a nonlinear increase in sedation with increasing age was also found. Increasing body weight increased the sedative drug effect. CONCLUSIONS: The pharmacokinetics of clomethiazole were characterized in acute stroke patients and the analysis excluded several possible covariates of interest in drug development. The time course of sedation could be quantitatively described during the first 24 h following an acute stroke in the presence or absence of clomethiazole treatment.
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