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The purpose was to compare longitudinal cognitive changes in APP and PSEN1 gene mutation carriers and noncarriers from four autosomal-dominant Alzheimer's disease (ADAD) families across preclinical and early clinical stages of disease. Carriers (n = 34) with four different mutations (PSEN1M146V, PSEN1H163Y, APPSWE, and APPARC) and noncarriers (n = 41) were followed up longitudinally with repeated cognitive assessments starting many years before the expected clinical onset. The relationship between cognition and years to expected clinical onset, education, age, and type of mutation was analyzed using mixed-effects models. Results showed an education-dependent and time-related cognitive decline with linear and quadratic predictors in mutation carriers. Cognitive decline began close to the expected clinical onset and was relatively rapid afterward in PSEN1 mutation carriers, whereas decline was slower and started earlier than 10 years before expected clinical onset in APP mutation carriers. In noncarriers, the decline was minimal across time in accordance with normal aging. These results suggest that phenotypes for onset and rate of cognitive decline vary with PSEN1 and APP genes, suggesting a behavioral heterogeneity in ADAD.

We investigated whether subtypes of Alzheimer's disease (AD), that is, typical, limbic-predominant, hippocampal-sparing, and minimal atrophy AD, had a specific signature of small vessel disease and neurodegeneration. Four hundred twenty-three clinically diagnosed AD patients were included (161 typical, 121 limbic-predominant, 70 hippocampal-sparing, 71 minimal atrophy). One hundred fifty-six fulfilled a biomarkers-based AD diagnosis. White matter hyperintensities and cerebral microbleeds (CMB) had the highest prevalence in limbic-predominant AD, and the lowest prevalence in minimal atrophy AD. CMB existed evenly in lobar and deep brain areas in limbic-predominant, typical, and hippocampal-sparing AD. In minimal atrophy AD, CMB were mainly located in brain lobar areas. Perivascular spaces in the centrum semiovale were more prevalent in typical AD. Small vessel disease contributed to the prediction of Mini-Mental State Examination. Minimal atrophy AD showed highly pathological levels of cerebrospinal fluid As1-42, total tau, and phosphorylated tau, in the absence of overt brain atrophy. Cerebral amyloid angiopathy seems to have a stronger contribution to hippocampal-sparing and minimal atrophy AD, whereas hypertensive arteriopathy may have a stronger contribution to typical and limbic-predominant AD.

Butyrylcholinesterase (BuChE) activity is associated with activated astrocytes in Alzheimer's disease brain. The BuChE-K variant exhibits 30%-60% reduced acetylcholine (ACh) hydrolyzing capacity. Considering the increasing evidence of an immune-regulatory role of ACh, we investigated if genetic heterogeneity in BuChE affects cerebrospinal fluid (CSF) biomarkers of inflammation and cholinoceptive glial function. Alzheimer's disease patients (n = 179) were BCHE-K-genotyped. Proteomic and enzymatic analyses were performed on CSF and/or plasma. BuChE genotype was linked with differential CSF levels of glial fibrillary acidic protein, S100B, interleukin-1β, and tumor necrosis factor (TNF)-α. BCHE-K noncarriers displayed 100%-150% higher glial fibrillary acidic protein and 64%-110% higher S100B than BCHE-K carriers, who, in contrast, had 40%-80% higher interleukin-1β and 21%-27% higher TNF-α compared with noncarriers. A high level of CSF BuChE enzymatic phenotype also significantly correlated with higher CSF levels of astroglial markers and several factors of the innate complement system, but lower levels of proinflammatory cytokines. These individuals also displayed beneficial paraclinical and clinical findings, such as high cerebral glucose utilization, low β-amyloid load, and less severe progression of clinical symptoms. In vitro analysis on human astrocytes confirmed the involvement of a regulated BuChE status in the astroglial responses to TNF-α and ACh. Histochemical analysis in a rat model of nerve injury-induced neuroinflammation, showed focal assembly of astroglial cells in proximity of BuChE-immunolabeled sites. In conclusion, these results suggest that BuChE enzymatic activity plays an important role in regulating intrinsic inflammation and activity of cholinoceptive glial cells and that this might be of clinical relevance. The dissociation between astroglial markers and inflammatory cytokines indicates that a proper activation and maintenance of astroglial function is a beneficial response, rather than a disease-driving mechanism. Further studies are needed to explore the therapeutic potential of manipulating BuChE activity or astroglial functional status.

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.

The use of Alzheimer's disease (AD) biomarkers is supported in diagnostic criteria, but their maturity for clinical routine is still debated. Here, we evaluate brain fluorodeoxyglucose positron emission tomography (FDG PET), a measure of cerebral glucose metabolism, as a biomarker to identify clinical and prodromal AD according to the framework suggested for biomarkers in oncology, using homogenous criteria with other biomarkers addressed in parallel reviews. FDG PET has fully achieved phase 1 (rational for use) and most of phase 2 (ability to discriminate AD subjects from healthy controls or other forms of dementia) aims. Phase 3 aims (early detection ability) are partly achieved. Phase 4 studies (routine use in prodromal patients) are ongoing, and only preliminary results can be extrapolated from retrospective observations. Phase 5 studies (quantify impact and costs) have not been performed. The results of this study show that specific efforts are needed to complete phase 3 evidence, in particular comparing and combining FDG PET with other biomarkers, and to properly design phase 4 prospective studies as a basis for phase 5 evaluations.

Fifteen patients with Alzheimer's disease (AD) and 16 age-matched controls underwent skin vessel reactivity tests employing three vasodilating substances with different modes of action: acetylcholine (ACh), nitroprusside, and isoprenaline. The substances were iontophoresed into the skin and the results were mapped through a newly developed laser Doppler perfusion imager. The skin vascular responses of the patients to ACh and isoprenaline but not nitroprusside were significantly attenuated compared to those of the controls. The differences between patient and control groups concerning skin vessel reactivity might be due to receptor/signal transduction abnormalities but might in addition indicate an attenuated endothelium-dependent vasodilation in AD. The results of this study support the hypothesis that AD might be a systemic disease. They suggest that tests of skin vessel reactivity might be of help in the antemortem diagnosis of AD.

In Vitro Characterization Of Fibrillar Amyloid, Tau Deposits, And Activated Astrocytes In Arctic App And Sporadic Alzheimer's Disease Brain Using, 3H-Pib And 3H-Thk5117 And 3H-Deprenyl In Comparison To Immunostaining

In this study, we examined the relationship between various β-amyloid (Aβ) oligomer assemblies in autopsy brain with the levels of fibrillar Aβ and cholinergic synaptic function. Brain tissues obtained from the frontal cortex of 14 Alzheimer's disease (AD) patients grouped into early-onset AD (EOAD) and late-onset AD (LOAD) and 12 age-matched control subjects were used to extract and quantify Aβ oligomers in soluble (TBS), detergent soluble (TBST), and insoluble (GuHCl) fractions. The predominant oligomeric Aβ assemblies detected were dodecamers, decamers, and pentamers, and different patterns of expression were observed between EOAD and LOAD patients. There was no association between any of the detected Aβ oligomer assemblies and fibrillar Aβ levels measured by N-methyl[(3)H] 2-(40-methylaminophenyl)-6-hydroxy-benzothiazole ([(3)H]PIB) binding. Levels of pentamers in the soluble fraction significantly correlated with a reduction in choline acetyltransferase activity in AD patients. The number of nicotinic acetylcholine receptors negatively correlated with the total amount of Aβ oligomers in the insoluble fraction in EOAD patients, and with decamers in the soluble fraction in LOAD patients. These novel findings suggest that distinct Aβ oligomers induce impairment of cholinergic neurotransmission in AD pathogenesis.

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.

Recently, we reported that 3 of the known risk factors of Alzheimer's disease (AD), i.e., advanced age, apolipoprotein E (ApoE) ε4, and female gender, are associated with differential levels of ApoE proteins and butyrylcholinesterase (BuChE) in the cerebrospinal fluid (CSF) of AD patients. The ApoE ε4 allele and certain BuChE polymorphisms synergistically affect the conversion rate of mild cognitive impairment (MCI) to AD. Here, we investigated interrelationships between ApoE and BuChE levels, and pathological markers of AD in vivo. CSF from patients with probable AD, assessed for cerebral glucose metabolism (CMRglc; n = 50) and Pittsburgh compound B (PIB) retention (β-amyloid [Aβ] load, n = 29) by positron emission tomography (PET), was used for measurement of BuChE, ApoE, Aβ, tau, phosphorylated tau (P-tau) and interleukin-1β (IL-1β) levels. Levels of ApoE and BuChE strongly correlated with CMRglc (fluorodeoxyglucose [FDG]-PET, r = 0.54, p0.0001, n = 50), cerebral Aβ load (PIB retention, r = 0.73, p0.0001, n = 29), and CSF P-tau (r = 0.73, p0.0001, n = 33). High ApoE protein was tied to low CMRglc and high PIB retention and P-tau. BuChE levels had opposite relationships. Other CSF covariates were levels of interleukin-1β and Aβ(42) peptide. The pattern of the patients' cognitive Z-scores strongly supported these observations. High ApoE protein was also linked to changes in 3 of the biodynamic properties of BuChE. In vitro analysis indicated that high ApoE protein levels were related to an increased pool of dormant BuChE molecules with an abnormally high intrinsic catalytic rate in CSF, which was "turned on" by excess Aβ peptides. The findings suggest that abnormally high levels of ApoE may play a causative role in the pathological events of AD, particularly those involving the early cholinergic deficit in the AD brain, through modulation of cholinesterases activities, hence disturbing the acetylcholine-dependent activity of neurons and nonexcitable cells such as glial cells.

Six young related pre-symptomatic carriers of a His163Tyr mutation in the presenilin 1 gene who will develop early onset familial Alzheimer's disease (eoFAD), and a control group of 23 non-carriers underwent (18)F-fluorodeoxyglucose positron emission tomography (FDG PET). The mutation carriers were followed-up after 2 years. Multivariate analysis showed clear separation of carriers from non-carriers on both occasions, with the right thalamus being the region contributing most to group differentiation. Statistical parametric mapping (SPM) revealed in the carriers non-significantly lower thalamic cerebral glucose metabolism (CMRglc) at baseline and significantly decreased CMRglc in the right thalamus at follow-up. One mutation carrier was followed-up with FDG PET 10 years after baseline and showed reductions in cognition and CMRglc in the posterior cingulate and the frontal cortex. This subject was diagnosed with AD 1 year later and assessed with an additional FDG as well as an (11)C-PIB PET scan 12 years after baseline. Global cortical CMRglc and cognition were distinctly decreased. PIB binding was comparable with sporadic AD patterns but showing slightly higher striatal levels.

The apolipoprotein E (ApoE) e4 allele has consistently been established as an Alzheimer's disease (AD) risk factor, but its pathological contribution to AD is obscure. Certain butyrylcholinesterase (BuChE) polymorphisms together with the ApoE e4 allele synergistically increase the risk of AD. In addition, AD risk factors, i.e. advanced age, female gender and ApoE e4 are associated with different levels of CSF BuChE in AD patients, and BuChE protein attenuates Aβ fibrillization in vitro. Here we investigated the roles of ApoE and BuChE gene products as modulators of pathological features of AD in vivo. We found that AD risk factors were associated with different levels of ApoE protein in the CSF of AD patients (n=115). Women and ApoE e4 carriers had the highest levels of ApoE protein (up by 50-120%, p

It is of great clinical value to identify subjects at a high risk of developing AD. We previously found that the amyloid positron emission tomography (PET) tracer PIB showed a robust difference in retention in the brain between AD patients and healthy controls (HC). Twenty-one patients diagnosed with MCI (mean age 63.3+/-7.8 (S.D.) years) underwent PET studies with (11)C-PIB, and (18)F-fluoro-deoxy-glucose (FDG) to measure cerebral glucose metabolism, as well as assessment of cognitive function and CSF sampling. Reference group data from 27 AD patients and 6 healthy controls, respectively, were used for comparison. The mean cortical PIB retention for the MCI patients was intermediate compared to HC and AD. Seven MCI patients that later at clinical follow-up converted to AD (8.1+/-6.0 (S.D.) months) showed significant higher PIB retention compared to non-converting MCI patients and HC, respectively (ps0.01). The PIB retention in MCI converters was comparable to AD patients (p0.01). Correlations were observed in the MCI patients between PIB retention and CSF Abeta(1-42), total Tau and episodic memory, respectively.

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.