The validation status of blood biomarkers of amyloid and phospho-tau assessed with the 5-phase development framework for AD biomarkers.

PURPOSE: The development of blood biomarkers that reflect Alzheimer's disease (AD) pathophysiology (phosphorylated tau and amyloid-ß) has offered potential as scalable tests for dementia differential diagnosis and early detection. In 2019, the Geneva AD Biomarker Roadmap Initiative included blood biomarkers in the systematic validation of AD biomarkers. METHODS: A panel of experts convened in November 2019 at a two-day workshop in Geneva. The level of maturity (fully achieved, partly achieved, preliminary evidence, not achieved, unsuccessful) of blood biomarkers was assessed based on the Biomarker Roadmap methodology and discussed fully during the workshop which also evaluated cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers. RESULTS: Plasma p-tau has shown analytical validity (phase 2 primary aim 1) and first evidence of clinical validity (phase 3 primary aim 1), whereas the maturity level for Aß remains to be partially achieved. Full and partial achievement has been assigned to p-tau and Aß, respectively, in their associations to ante-mortem measures (phase 2 secondary aim 2). However, only preliminary evidence exists for the influence of covariates, assay comparison and cut-off criteria. CONCLUSIONS: Despite the relative infancy of blood biomarkers, in comparison to CSF biomarkers, much has already been achieved for phases 1 through 3 - with p-tau having greater success in detecting AD and predicting disease progression. However, sufficient data about the effect of covariates on the biomarker measurement is lacking. No phase 4 (real-world performance) or phase 5 (assessment of impact/cost) aim has been tested, thus not achieved.

2020 update on the clinical validity of cerebrospinal fluid amyloid, tau, and phospho-tau as biomarkers for Alzheimer's disease in the context of a structured 5-phase development framework.

PURPOSE: In the last decade, the research community has focused on defining reliable biomarkers for the early detection of Alzheimer's disease (AD) pathology. In 2017, the Geneva AD Biomarker Roadmap Initiative adapted a framework for the systematic validation of oncological biomarkers to cerebrospinal fluid (CSF) AD biomarkers-encompassing the 42 amino-acid isoform of amyloid-ß (Aß42), phosphorylated-tau (P-tau), and Total-tau (T-tau)-with the aim to accelerate their development and clinical implementation. The aim of this work is to update the current validation status of CSF AD biomarkers based on the Biomarker Roadmap methodology. METHODS: A panel of experts in AD biomarkers convened in November 2019 at a 2-day workshop in Geneva. The level of maturity (fully achieved, partly achieved, preliminary evidence, not achieved, unsuccessful) of CSF AD biomarkers was assessed based on the Biomarker Roadmap methodology before the meeting and presented and discussed during the workshop. RESULTS: By comparison to the previous 2017 Geneva Roadmap meeting, the primary advances in CSF AD biomarkers have been in the area of a unified protocol for CSF sampling, handling and storage, the introduction of certified reference methods and materials for Aß42, and the introduction of fully automated assays. Additional advances have occurred in the form of defining thresholds for biomarker positivity and assessing the impact of covariates on their discriminatory ability. CONCLUSIONS: Though much has been achieved for phases one through three, much work remains in phases four (real world performance) and five (assessment of impact/cost). To a large degree, this will depend on the availability of disease-modifying treatments for AD, given these will make accurate and generally available diagnostic tools key to initiate therapy.

Clinical validity of increased cortical uptake of [18F]flortaucipir on PET as a biomarker for Alzheimer's disease in the context of a structured 5-phase biomarker development framework.

PURPOSE: In 2017, the Geneva Alzheimer's disease (AD) Biomarker Roadmap initiative adapted the framework of the systematic validation of oncological diagnostic biomarkers to AD biomarkers, with the aim to accelerate their development and implementation in clinical practice. With this work, we assess the maturity of [18F]flortaucipir PET and define its research priorities. METHODS: The level of maturity of [18F]flortaucipir was assessed based on the AD Biomarker Roadmap. The framework assesses analytical validity (phases 1-2), clinical validity (phases 3-4), and clinical utility (phase 5). RESULTS: The main aims of phases 1 (rationale for use) and 2 (discriminative ability) have been achieved. [18F]Flortaucipir binds with high affinity to paired helical filaments of tau and has favorable kinetic properties and excellent discriminative accuracy for AD. The majority of secondary aims of phase 2 were fully achieved. Multiple studies showed high correlations between ante-mortem [18F]flortaucipir PET and post-mortem tau (as assessed by histopathology), and also the effects of covariates on tracer binding are well studied. The aims of phase 3 (early detection ability) were only partially or preliminarily achieved, and the aims of phases 4 and 5 were not achieved. CONCLUSION: Current literature provides partial evidence for clinical utility of [18F]flortaucipir PET. The aims for phases 1 and 2 were mostly achieved. Phase 3 studies are currently ongoing. Future studies including representative MCI populations and a focus on healthcare outcomes are required to establish full maturity of phases 4 and 5.

Regional binding of tau and amyloid PET tracers in Down syndrome autopsy brain tissue.

INTRODUCTION: Tau pathology is a major age-related event in Down syndrome with Alzheimer's disease (DS-AD). Although recently, several different Tau PET tracers have been developed as biomarkers for AD, these tracers showed different binding properties in Alzheimer disease and other non-AD tauopathies. They have not been yet investigated in tissue obtained postmortem for DS-AD cases. Here, we evaluated the binding characteristics of two Tau PET tracers (3H-MK6240 and 3H-THK5117) and one amyloid (3H-PIB) ligand in the medial frontal gyrus (MFG) and hippocampus (HIPP) in tissue from adults with DS-AD and DS cases with mild cognitive impairment (MCI) compared to sporadic AD. METHODS: Tau and amyloid autoradiography were performed on paraffin-embedded sections. To confirm respective ligand targets, adjacent sections were immunoreacted for phospho-Tau (AT8) and stained for amyloid staining using Amylo-Glo. RESULTS: The two Tau tracers showed a significant correlation with each other and with AT8, suggesting that both tracers were binding to Tau deposits. 3H-MK6240 Tau binding correlated with AT8 immunostaining but to a lesser degree than the 3H-THK5117 tracer, suggesting differences in binding sites between the two Tau tracers. 3H-THK5117, 3H-MK6240 and 3H-PIB displayed dense laminar binding in the HIPP and MFG in adult DS brains. A regional difference in Tau binding between adult DS and AD was observed suggesting differential regional Tau deposition in adult DS compared to AD, with higher THK binding density in the MFG in adult with DS compared to AD. No significant correlation was found between 3H-PIB and Amylo-Glo staining in adult DS brains suggesting that the amyloid PIB tracer binds to additional sites. CONCLUSIONS: This study provides new insights into the regional binding distribution of a first-generation and a second-generation Tau tracer in limbic and neocortical regions in adults with DS, as well as regional differences in Tau binding in adult with DS vs. those with AD. These findings provide new information about the binding properties of two Tau radiotracers for the detection of Tau pathology in adults with DS in vivo and provide valuable data regarding Tau vs. amyloid binding in adult DS compared to AD.

Longitudinal changes of tau PET imaging in relation to hypometabolism in prodromal and Alzheimer's disease dementia.

The development of tau-specific positron emission tomography (PET) tracers allows imaging in vivo the regional load of tau pathology in Alzheimer's disease (AD) and other tauopathies. Eighteen patients with baseline investigations enroled in a 17-month follow-up study, including 16 with AD (10 had mild cognitive impairment and a positive amyloid PET scan, that is, prodromal AD, and six had AD dementia) and two with corticobasal syndrome. All patients underwent PET scans with [18F]THK5317 (tau deposition) and [18F]FDG (glucose metabolism) at baseline and follow-up, neuropsychological assessment at baseline and follow-up and a scan with [11C]PIB (amyloid-ß deposition) at baseline only. At a group level, patients with AD (prodromal or dementia) showed unchanged [18F]THK5317 retention over time, in contrast to significant decreases in [18F]FDG uptake in temporoparietal areas. The pattern of changes in [18F]THK5317 retention was heterogeneous across all patients, with qualitative differences both between the two AD groups (prodromal and dementia) and among individual patients. High [18F]THK5317 retention was significantly associated over time with low episodic memory encoding scores, while low [18F]FDG uptake was significantly associated over time with both low global cognition and episodic memory encoding scores. Both patients with corticobasal syndrome had a negative [11C]PIB scan, high [18F]THK5317 retention with a different regional distribution from that in AD, and a homogeneous pattern of increased [18F]THK5317 retention in the basal ganglia over time. These findings highlight the heterogeneous propagation of tau pathology among patients with symptomatic AD, in contrast to the homogeneous changes seen in glucose metabolism, which better tracked clinical progression.

Harmonized diagnostic criteria for Alzheimer's disease: recommendations.

BACKGROUND: Two major sets of criteria for the clinical diagnosis of Alzheimer's disease (AD) recently have been published, one from an International Working Group (IWG) and the other from working groups convened by the National Institute on Aging (NIA) and the Alzheimer's Association (AA) in the United States. These criteria both aim to support a clinical diagnosis with in vivo evidence of AD pathology, using imaging methods and detection of biofluid biomarkers, and emphasize an aetiological diagnosis even in the prodromal stages of the disorder. Nonetheless, there are substantial differences in these two sets of criteria. METHODS: An international group of investigators with experience in the clinical diagnosis of AD met at the Key Symposium in Stockholm, Sweden on 6 & 7 December 2012, to develop recommendations to harmonize these criteria. The group was led by individuals who were integral to the development of both the IWG and the NIA-AA criteria. The similarities and differences between the two sets of criteria were identified and open discussion focused on ways to resolve the differences and thus yield a harmonized set of criteria. RESULTS: Based on both published evidence as well as the group's collective clinical experience, the group was tasked with achieving consensus, if not unanimity, as it developed recommendations for harmonized clinical diagnostic criteria for AD. CONCLUSION: The recommendations are to: (i) define AD as a brain disorder, regardless of clinical status; (ii) refer to the clinically expressed disorder, including its prodromal stages, as symptomatic AD; (iii) after the successful completion of standardization efforts, consider incorporating biomarkers into diagnostic algorithms for AD; and (iv) allow nonamnestic, atypical presentations to be included as symptomatic AD, especially when there is supportive biomarker evidence.

Comparison of MRI based and PET template based approaches in the quantitative analysis of amyloid imaging with PIB-PET.

RATIONALE: [(11)C]Pittsburgh compound-B (PIB) has been the most widely used positron emission tomography (PET) imaging agent for brain amyloid. Several longitudinal studies evaluating the progression of Alzheimer's disease (AD), and numerous therapeutic intervention studies are underway using [(11)C]PIB PET as an AD biomarker. Quantitative analysis of [(11)C]PIB data requires the definition of regional volumes of interest. This investigation systematically compared two data analysis routes both using a probabilistic brain atlas with 11 bilateral regions. Route 1 used individually segmented structural magnetic resonance images (MRI) for each subject while Route 2 used a standardised [(11)C]PIB PET template. METHODS: A total of 54 subjects, 20 with probable Alzheimer's disease (AD), 14 with amnestic Mild Cognitive Impairment (MCI) and 20 age-matched healthy controls, were scanned at two imaging centres either in London (UK) or in Turku (Finland). For all subjects structural volumetric MRI and [(11)C]PIB PET scans were acquired. Target-to-cerebellum ratios 40 min to 60 min post injection were used as outcome measures. Regional read outs for grey matter target regions were generated for both routes. Based on a composite neocortical, frontal, posterior cingulate, combined posterior cingulate and frontal cortical regions, scans were categorised into either 'PIB negative' (PIB-) or 'PIB positive' (PIB+) using previously reported cut-off target-to-cerebellar ratios of 1.41, 1.5 and 1.6, respectively. RESULTS: Target-to-cerebellum ratios were greater when defined with a [(11)C]PIB PET template than with individual MRIs for all cortical regions regardless of diagnosis. This difference was highly significant for controls (p<0.001, paired samples t-test), less significant for MCIs and borderline for ADs. Assignment of subjects to raised or normal categories was the same with both routes with a 1.6 cut-off while with lower cut off using frontal cortex, and combined frontal cortex and posterior cingulate demonstrated similar results, while posterior cingulate alone demonstrated significantly higher proportion of controls as amyloid positive by Route 2. CONCLUSIONS: Definition of cortical grey matter regions is more accurate when individually segmented MRIs (Route 1) were used rather than a population-based PET template (Route 2). The impact of this difference depends on the grey-to-white matter contrast in the PET images; specifically seen in healthy controls with high white matter and low grey matter uptake. When classifying AD, MCI and control subjects as normal or abnormal using large cortical regions; discordance was found between the MRI and template approach for those few subjects who presented with cortex-to-cerebellum ratios very close to the pre-assigned cut-off. However, posterior cingulate alone demonstrated significant discordance in healthy controls using template based approach. This study, therefore, demonstrates that the use of a [(11)C]PIB PET template (Route 2) is adequate for clinical diagnostic purposes, while MRI based analysis (Route 1) remains more appropriate for clinical research.

Speech problems affect more than one in two children with cerebral palsy: Swedish population-based study.

AIM: To describe speech ability in a population-based study of children with cerebral palsy (CP), in relation to CP subtype, motor function, cognitive level and neuroimaging findings. METHODS: A retrospective chart review of 129 children (66 girls, 63 boys) with CP, born in 1999-2002, was carried out. Speech ability and background information, such as type of CP, motor function, cognitive level and neuroimaging data, were collected and analysed. RESULTS: Speech disorders were found in 21% of the children and were present in all types of CP. Forty-one per cent of the children with speech disorders also had mental retardation, and 42% were able to walk independently. A further 32% of the children were nonverbal, and maldevelopment and basal ganglia lesions were most common in this group. The remaining 47% had no speech disorders, and this group was most likely to display white matter lesions of immaturity. CONCLUSION: More than half of the children in this CP cohort had a speech disorder (21%) or were nonverbal (32%). Speech ability was related to the type of CP, gross motor function, the presence of mental retardation and the localization of brain maldevelopment and lesions. Neuroimaging results differed between the three speech ability groups.

Life cycle assessment of energy self-sufficiency systems based on agricultural residues for organic arable farms.

The agricultural industry today consumes large amounts of fossil fuels. This study used consequential life cycle assessment (LCA) to analyse two potential energy self-sufficient systems for organic arable farms, based on agricultural residues. The analysis focused on energy balance, resource use and greenhouse gas (GHG) emissions. A scenario based on straw was found to require straw harvest from 25% of the farm area; 45% of the total energy produced from the straw was required for energy carrier production and GHG emissions were reduced by 9% compared with a fossil fuel-based reference scenario. In a scenario based on anaerobic digestion of ley, the corresponding figures were 13%, 24% and 35%. The final result was sensitive to assumptions regarding, e.g., soil carbon content and handling of by-products.

High PIB retention in Alzheimer's disease is an early event with complex relationship with CSF biomarkers and functional parameters.

BACKGROUND: New in vivo amyloid PET imaging tracers, such as (11)C-PIB, provide possibilities to deeper understand the underlying pathological processes in Alzheimer's disease (AD). In this study we investigated how (11)C-PIB retention is related to cerebral glucose metabolism, episodic memory and CSF biomarkers. METHOD: Thirty-seven patients with mild AD and 21 patients with mild cognitive impairment (MCI) underwent PET examinations with the amyloid tracer (11)C-PIB, (18)F-FDG for measurement of regional cerebral metabolic rate of glucose (rCMRglc), assessment of episodic memory and assay of cerebral spinal fluid (CSF) levels of amyloid-beta (Abeta(1-42)), total tau and phosphorylated tau respectively. Analyses were performed using Statistical Parametric Mapping (SPM) and regions of interest (ROIs). RESULTS: Pooled data from AD and MCI patients showed strong correlations between (11)C-PIB retention, levels of CSF biomarkers (especially Abeta(1-42)), rCMRglc and episodic memory. Analysis of the MCI group alone revealed significant correlations between (11)C-PIB retention and CSF biomarkers and between CSF biomarkers and episodic memory respectively. A strong correlation was observed in the AD group between rCMRglc and episodic memory as well as a significant correlation between (11)C-PIB retention and rCMRglc in some cortical regions. Regional differences were observed as sign for changes in temporal patterns across brain regions. CONCLUSIONS: A complex pattern was observed between pathological and functional markers with respect to disease stage (MCI versus AD) and brain regions. Regional differences over time were evident during disease progression. (11)C-PIB PET and CSF Abeta(42) allowed detection of prodromal stages of AD. Amyloid imaging is useful for early diagnosis and evaluation of new therapeutic interventions in AD.

Pittsburgh compound-B and Alzheimer's disease biomarkers in CSF, plasma and urine: An exploratory study.

BACKGROUND: The positron emission tomography (PET) radiotracer Pittsburgh Compound-B (PIB) is an in vivo ligand for measuring beta-amyloid (Abeta) load. Associations between PET PIB and cerebrospinal fluid (CSF) Abeta1-42 and apolipoprotein E epsilon4 (APOE epsilon4) have been observed in several studies, but the relations between PIB uptake and other biomarkers of Alzheimer's disease (AD) are less investigated. METHOD: PET PIB, PET 18Fluoro-2-deoxy-D-glucose and different AD biomarkers were measured twice in CSF, plasma and urine 12 months apart in 10 patients with a clinical diagnosis of mild to moderate AD. RESULTS: PIB retention was constant over 1 year, inversely related to low CSF Abeta1-42 (p = 0.01) and correlated positively to the numbers of the APOE epsilon4 allele (0, 1 or 2) (p = 0.02). There was a relation between mean PIB retention and CSF ApoE protein (r = -0.59, p = 0.07), and plasma cystatin C (r = -0.56, p = 0.09). CONCLUSION: PIB retention is strongly related to CSF Abeta1-42, and to the numbers of the APOE epsilon4 allele.

Safety of lumbar puncture procedures in patients with Alzheimer's disease.

Changes in cerebrospinal fluid (CSF) biomarkers are representative of biochemical changes in the brain. Collection of CSF by lumbar puncture (LP) is essential for biomarker analysis, which is important for research in neurodegenerative disorders. However, LP for research purposes has been controversial due to a reported high incidence of severe LP headache when using standard 18g or 20g Quincke needles with a beveled cutting tip. A procedural safety analysis was performed using the database of a multicenter, 13-week study of CSF cholinesterase activity. A 24g Sprotte atraumatic needle was used to collect CSF at baseline and at Week 13 from 63 older patients with mild to moderate Alzheimer's disease. There was a < 2% LP headache incidence, and a favorable safety profile was reported. In conclusion, LP performed with a 24g Sprotte atraumatic needle (blunt, "bullet" tip) was a well tolerated procedure, with good acceptability.

Ammonia, a selective agent for methane production by syntrophic acetate oxidation at mesophilic temperature.

In biogas processes, methane production from acetate proceeds by either aceticlastic methanogenesis or through syntrophic acetate oxidation (SAO). In the present study, the pathway for methane production from acetate was analysed; i) during a gradual increase of the ammonia concentration (final concentration 7 g NH(4)(+) -N/L) in a semi-continuous lab-scale anaerobic digester (4.3 L), operating at mesophilic temperature (37 degrees C) or ii) in diluted enrichment cultures (100 ml) experiencing a gradual increase in ammonia, sodium, potassium and propionic acid. The pathway for methane formation was determined by calculating the (14)CO(2)/(14)CH(4) ratio after incubating samples with (14)C-2-acetate. In the anaerobic digester, as well as in the enrichment cultures, the (14)CO(2)/(14)CH4 ratio clearly increased with increasing ammonium-nitrogen concentration, i.e. as the ammonia concentration increased, a shift from the aceticlastic mechanism to the syntrophic pathway occurred. The shift was very distinct and occurred as the NH(4)(+) -N concentration rose above 3 g/l. No shift in pathway was seen during increasing concentrations of sodium, potassium or propionic acid. The shift to SAO in the biogas digester resulted in a twofold decrease in the specific gas and methane yield.

Transgenic mice overexpressing human acetylcholinesterase and the Swedish amyloid precursor protein mutation: effect of nicotine treatment.

Acetylcholinesterase (AChE) is shown to promote deposition of beta-amyloid (Abeta) peptides and to enhance Abeta toxicity. Tg2576 (transgenic mice carrying the Swedish mutation of amyloid precursor protein, APPswe) mice and mice overexpressing human synaptic acetylcholinesterase (AChE-S) were crossed (hAChE-Tg//APPswe), to study the effects of brain Abeta, from 1 to 10 months of age, under the constant influence of AChE-S. The effect of nicotine treatment was also evaluated in these mice since we have previously shown that nicotine dramatically decreases Abeta levels in single transgenic APPswe mice. Already at 1 and 3 months, hAChE-Tg// APPswe mice showed increased levels of cortical insoluble Abeta1-40 and Abeta1-42 compared with APPswe mice, whereas APPswe mice displayed increased soluble Abeta1-40. Abeta plaques were detected at 7 months, thus before onset of plaque formation in APPswe mice. No differences were found in [125I]alpha-bungarotoxin binding sites or hippocampal glial fibrillary acidic protein (GFAP) immunoreactivity between hAChE-Tg//APPswe, and APPswe mice at either 1 or 10 months of age. L(-)-Nicotine (final dose 0.45 mg/kg) treatment twice daily for 10 days to 14-month-old hAChE-Tg// APPswe mice increased cortical insoluble Abeta1-40 levels, while both L(-)- and D(+)-nicotine (final dose 0.45 mg/kg) increased soluble Abeta1-42. L(-)-Nicotine reduced hippocampal GFAP immunoreactivity both in hAChE-Tg//APPswe mice and non-transgenic controls, while D(+)-nicotine caused a decrease only in hAChE-Tg//APPswe mice. Moreover, D(+)-nicotine increased the [125I]alpha-bungarotoxin binding sites in the hippocampus, and cortex of the hAChE-Tg//APPswe mice. In conclusion, already at a very young age, hAChE-Tg// APPswe mice exhibit increased levels of aggregated Abeta compared with APPswe mice, due to the possible interaction between Abeta and AChE-S, whereas APPswe mice exhibit increased soluble Abeta. The interaction between Abeta and AChE-S may also explain the different effect of nicotine on Abeta pathology in the hAChE-Tg//APPswe mice. The results in this study emphasize the importance of using different transgenic mouse models for evaluating the effect of new drug candidates for the treatment of Alzheimer's disease.

Age-dependent decline of neprilysin in Alzheimer's disease and normal brain: inverse correlation with A beta levels.

Brain deposition of amyloid-beta (A beta) is a pathological hallmark of Alzheimer disease (AD) but A beta is also detected in non-demented elderly individuals. Neprilysin has been shown to be an important enzyme to degrade A beta in brain. We investigated whether decreased neprilysin levels contributes to the accumulation of A beta in AD and in normal aging. No difference in neprilysin protein and mRNA levels were found between AD subjects and age-matched controls. Protein levels of neprilysin were reduced with age in the temporal and frontal cortex of AD and normal brain. A significant positive correlation between insoluble A beta 40 and A beta 42 with age was found in cortex of normal brain whereas in AD brain the correlation between age and A beta was weaker. Our findings of an inverse correlation between neprilysin and insoluble A beta levels in both groups suggest that neprilysin is involved in the clearance of A beta. The observed age-dependent decline in neprilysin may be related to the increased A beta levels during normal aging. The similar rate of decline in neprilysin with age may not be the major cause of the high levels of A beta associated with AD but is likely to be a trigger of AD pathology.

Inhibition of acetylcholinesterase in CSF versus brain assessed by 11C-PMP PET in AD patients treated with galantamine.

The relationship between acetylcholinesterase (AChE) activity in the CSF and brain of patients with Alzheimer's disease (AD) was investigated in 18 mild AD patients following galantamine treatment. The first 3 months of the study had a randomized double-blind placebo-controlled design, during which 12 patients received galantamine (16-24 mg/day) and six patients placebo. This was followed by 9 months galantamine treatment in all patients. Activities and protein levels of both the "read-through" AChE (AChE-R) and the synaptic (AChE-S) variants in CSF were assessed in parallel together with the regional brain AChE activity by (11)C-PMP and PET. The AChE-S inhibition was 30-36% in CSF, which correlated well with the in vivo AChE inhibition in the brain. No significant AChE inhibition was observed in the placebo group. The increased level of the AChE-R protein was 16% higher than that of AChE-S. Both the AChE inhibition and the increased level of AChE-R protein positively correlated with the patient's performance in cognitive tests associated with visuospatial ability and attention. In conclusion, AChE levels in CSF closely mirror in vivo brain AChE levels prior to and after treatment with the cholinesterase inhibitors. A positive cognitive response seems to dependent on the AChE inhibition level, which is balanced by an increased protein level of the AChE-R variant in the patients.

PET imaging of the in vivo brain acetylcholinesterase activity and nicotine binding in galantamine-treated patients with AD.

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 (16-24mg/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 ((11)C-PMP) and (11)C-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 (11)C-nicotine binding was observed during the study. (11)C-Nicotine binding, however, positively correlated with plasma galantamine concentration. Both the changes of AChE activity and (11)C-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 (11)C-nicotine binding were associated with changes in the attention domain of cognition rather than episodic memory.

[(11)C]-PIB imaging in patients with Parkinson's disease: preliminary results.

[(11)C]-PIB positron emission tomography ([(11)C]-PIB PET) is a sensitive marker of amyloid in Alzheimer's disease (AD), but its specificity has not been fully evaluated. Vascular amyloid-beta deposition is common in Parkinson's disease (PD) and alpha-synuclein, the major component of the Lewy bodies in PD, forms amyloid fibrils. We investigated five apparently cognitively normal PD patients with [(11)C]-PIB PET. The results were compared to 16 patients with AD and six healthy controls from a previous study. [(11)C]-PIB retention was not significantly increased in our patients who all had early stage PD. Further studies of more advanced PD patients are warranted.

Vertebral fractures fixation with composite patch fibre reinforced adhesives.

PURPOSE: The aim is to investigate fixation of cervical vertebral fractures by patching it with a composite laminate of adhesive and fibres, in comparison with use of only adhesives. MATERIAL AND METHODS: The composite fixation was tested on bonded roe deer vertebrae. 25 specimens were sawed in two halves, creating a generic fracture, and thereafter bonded. The adhesives used were a dental system, Scotchbond XT, and a cyanoacrylate, M-bond 200. The fibres used were unidirectional carbon fibres and randomly distributed E-glass fibres. The composites were applied as a 7 mm wide patch circumferential along the induced fracture. Reference specimens for comparison were also made. The ultimate tensile strength was tested in an Instron 5567. The failure site was examined with a microscope. Strain vectors were tracked using Digital Speckle Analysis. RESULTS: Scotchbond XT + E-glass fibres gave best results, with a tensile strength of 3.5 N/mm circumferential length (24.3% of reference). All composites had lower stiffness than cortical bone. The dental adhesive fibre composites gave better results than the cyanoacrylate fibre composites. In all cases fibre reinforced adhesive composite gave better results than adhesive without fibre reinforcement. CONCLUSION: Fibre-adhesive composite is a promising technique for fixating cervical vertebral fractures.