Dynamic changes in PET amyloid and FDG imaging at different stages of Alzheimer's disease

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 [¹¹C] 2-(4-methylaminophenyl)-6-hydroxy-benzothiazole (¹¹C-PIB) and ¹⁸F-fluorodeoxyglucose (¹⁸F-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.     

Differential levels of apolipoprotein E and butyrylcholinesterase show strong association with pathological signs of Alzheimer's disease in the brain in vivo

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, p < 0.0001, n = 50), cerebral Aβ load (PIB retention, r = 0.73, p < 0.0001, n = 29), and CSF P-tau (r = 0.73, p < 0.0001, 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 Aβ₄₂ 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.     

Cerebrospinal fluid α-synuclein in neurodegenerative disorders-A marker of synapse loss?

The association of α-synuclein (α-syn) neuropathology with Parkinson's disease (PD) and several related disorders has led to an intense research effort to develop cerebrospinal fluid (CSF)- or blood-based α-syn biomarkers for these types of diseases. Recent studies show that α-syn is present in CSF and possible to measure using enzyme-linked immunosorbent assay (ELISA). Here, we describe a novel ELISA that allows for quantification of α-syn in CSF down to 50 pg/mL. The diagnostic value of the test was assessed using CSF samples from 66 Alzheimer's disease (AD) patients, 15 PD patients, 15 patients with dementia with Lewy bodies (DLB) and 55 cognitively normal controls. PD and DLB patients and controls displayed similar CSF α-syn levels. AD patients had significantly lower α-syn levels than controls (median [inter-quartile range] 296 [234–372] and 395 [298–452], respectively, p < 0.001). Moreover, AD patients with mini-mental state examination (MMSE) scores below 20 had significantly lower α-syn than AD patients with MMSE scores of 20 or higher (p = 0.02). There was also a tendency towards a negative correlation between α-syn levels and disease duration in the AD group (r = −0.247, p = 0.06). Altogether, our results speak against CSF α-syn as a reliable biomarker for PD and DLB. The lower α-syn levels in AD, as well as the association of α-syn reduction with AD severity, approximated by MMSE, suggests that it may be a general marker of synapse loss, a hypothesis that warrants further investigation.     

High Activities of BACE1 in Brains with Mild Cognitive Impairment

We recently discovered elevated β-secretase 1 (BACE1) activity in brains with sporadic Alzheimer disease (AD). Moreover, we also found high levels of BACE1 enzymatic activity in the cerebrospinal fluid from patients with both mild cognitive impairment (MCI) and AD. These results suggest that elevation of BACE1 enzymatic activity may occur early or may contribute to AD. We therefore examined whether BACE1 enzymatic activity was changed in MCI brains. BACE1 activity and tumor necrosis factor (TNF)-α levels were measured by enzymatic assay and ELISA in the temporal cortex from 18 patients with clinically well-characterized AD, 18 patients with MCI, and 18 healthy controls. We found a significant increase in BACE1 activity and protein level in brains of MCI and AD patients. Moreover, increased BACE1 activity correlated with plaque numbers and cognition status. We also found an increase in TNF-α in MCI brains. In vitro study revealed that TNF-α rather than other cytokines can up-regulate BACE1 protein expression. These findings suggest that BACE1 increase occurs early in MCI and is possibly induced by TNF-α and that BACE1 enzymatic activity may be important for conversion of MCI to AD.Searching the early events of Alzheimer disease (AD) is becoming critical for effective diagnosis and treatment. Neuritic plaques and neurofibrillary tangles are two major pathologic characteristics of AD and major targets for AD diagnosis. Amyloid β (Aβ) peptide is a major component of neuritic plaques. β-Secretase 1 (BACE1), also known as β-site amyloid precursor protein (APP) cleaving enzyme, is an aspartic protease, a critical enzyme to promote Aβ generation.^1–4 We originally discovered that BACE1 activity and protein expression are significantly increased in AD brains.^5,6 Because the signals from cerebrospinal fluid (CSF) reflect most of neuropathologic changes in AD, we have studied BACE1 activity in the CSF from patients with mild cognitive impairment (MCI) and AD and found elevated BACE1 activity in the CSF of both MCI and AD patients.^7,8 These results indicate that activation of BACE1 may play an important role in the early stage of AD when cognitive deficits are first observed and in progressive dementia associated with AD. However, whether BACE1 enzymatic activity and protein expression were altered in the brain as early as at the MCI stage was not known, possibly because of limits of sources of autopsied brain tissues. To examine whether BACE1 was activated in the brain during the early stages of AD (ie, MCI), we took advantage of the brain bank⁹ of rapidly autopsied MCI and AD brain tissues and biochemically measured BACE1 activity in brains of nondemented (ND) controls, MCI patients, and AD patients. We found that BACE1 enzymatic activity was significantly increased in both MCI and AD brains in the present study. Moreover, we also found that BACE1 activity was positively correlated with numbers of plaques and negatively correlated with Mini-Mental State Examination (MMSE) scores in MCI patients. Interestingly however, we also observed that there was no significant difference in BACE1 activity between MCI and AD patients. Because recent studies demonstrated that BACE1 may affect neuronal activity and brain metabolism,^10–13 we conclude that BACE1 activity precedes the clinical diagnosis of AD and could be an early indicator of neuronal dysfunction or disease in AD.     

Increased levels of CSF phosphorylated tau in apolipoprotein E epsilon4 carriers with mild cognitive impairment

We investigated the correlation between the apolipoprotein E varepsilon4 allele (apoE epsilon4) carrier status, a major risk factor of Alzheimer's disease (AD), and levels of tau protein phosphorylated at threonine 231 (P-tau(231P)) in cerebrospinal fluid (CSF) in predementia and clinical stages of AD and healthy controls (HC). Thirty-one subjects with mild cognitive impairment (MCI) who had converted to AD during follow-up were included, as well as 71 AD patients, and 29 HC subjects. In MCI, but not in AD and HC, CSF P-tau(231P) levels were significantly higher in apoE epsilon4 carriers compared to non-carriers (p<0.001). Controlling for disease duration, the apoE epsilon4 effect on P-tau(231P) remained significant. Our study indicates that the apoE epsilon4 carrier status should be considered when CSF P-tau(231P) is evaluated as biomarker candidate of AD in MCI subjects.     

Visual contrast sensitivity in Alzheimer’s disease,mild cognitive impairment,and older adults with cognitive complaints

Deficits in contrast sensitivity (CS) have been reported in Alzheimer’s disease (AD). However, the extent of these deficits in prodromal AD stages, including mild cognitive impairment (MCI) or even earlier, has not been investigated. In this study, CS was assessed using frequency doubling technology in older adults with AD (n = 10), amnestic MCI (n = 28), cognitive complaints without performance deficits (CC; n = 20), and healthy controls (HC; n = 29). The association between CS and cognition was also evaluated. Finally, the accuracy of CS measures for classifying MCI versus HC was evaluated. CS deficits were found in AD and MCI, while CC showed intermediate performance between MCI and HC. Upper right visual field CS showed the most significant difference among groups. CS was also associated with cognitive performance. Finally, CS measures accurately classified MCI versus HC. The CS deficits in AD and MCI, and intermediate performance in CC, indicate that these measures are sensitive to early AD-associated changes. Therefore, frequency doubling technology-based measures of CS may have promise as a novel AD biomarker.     

A link between sICAM-1, ACE and parietal blood flow in the aging brain

A connection between Alzheimer's disease (AD) and endothelium pathology has been inferred from measured decreases in both blood flow and metabolism in the parietal and temporal cortex. However, it is not known whether these alterations are seen in normal aging. We performed regional cerebral blood flow (rCBF) measurements in 22 AD patients and in 44 non-demented subjects during a simple test of information processing speed. Cerebrospinal fluid (CSF) levels of angiotensin-converting enzyme (ACE) and the soluble form of intercellular adhesion molecule-1 (sICAM-1) were analyzed in non-demented subjects. We found correlations between sICAM-1 and ACE (p = 0.004), and sICAM (but not ACE) and CSF/plasma albumin ratio (p < 0.0001). Higher concentrations of sICAM-1 (>893 ng/L) and ACE (>5.22 μg/L) were exclusively associated with lower parietal blood flow (p < 0.001). The rCBF patterns in the AD and non-demented subjects with biomarker levels above median showed similar reductions in the temporoparietal areas. Our findings provide evidence that elevated CSF sICAM-1 and ACE are associated with lower perfusion levels in the parietal cortex of cognitively intact elderly.     

Development of respiratory muscle contractile fatigue in the course of hyperpnoea

To assess the development of inspiratory and expiratory muscle fatigue during normocapnic hyperpnoea, we studied fourteen healthy men performing 8 min hyperpnoea, 6 min pause, 8 min hyperpnoea, etc., until task failure. Twitch transdiaphragmatic (P_di,tw) and gastric (P_ga,tw) pressures were measured during cervical and thoracic magnetic nerve stimulation, before hyperpnoea, after every 8 min of hyperpnoea, and at task failure (i.e., at 25.3 ± 4.7 min). P_di,tw decreased during the first 16 min (−28 ± 7%, p < 0.001) and P_ga,tw during the first 8 min (−20 ± 7%, p < 0.001) of hyperpnoea without further change until task failure. During inspiration, the pressure–time-product of oesophageal pressure (PTP_oes) increased relative to PTP_di during the first 16 min (+11 ± 21%, p < 0.05). Similarly, during expiration, PTP_oes increased relative to PTP_ga during the first 8 min (+10 ± 16%, p < 0.05). Also, blood lactate concentration and respiratory sensations significantly increased during the first 8 min (+1.0 ± 0.5 mmol l⁻¹, p < 0.001) and 16 min (breathlessness +1.6 ± 1.8 points, respiratory effort +5.9 ± 2.2 points, p < 0.001), respectively. We conclude that, during hyperpnoea, contractile fatigue of the diaphragm and abdominal muscles develops long before task failure and may trigger an increased recruitment of rib cage muscles.     

Magnetic resonance imaging of in vivo patellofemoral kinematics after total knee arthroplasty

Simulated partial weight bearing during magnetic resonance imaging of the knee was used to measure patellar tilt, medial–lateral patellar shift, and patellofemoral contact area in three groups of subjects; patients with posterior cruciate retaining (PCR) TKA, patients with bicruciate substituting (BCS) TKA, and healthy controls. Contact stress was also calculated based on the contact area and body weight-based estimates of contact force. Contact stress was significantly (p < 0.05) higher in PCR knees (2.5 ± 3.0 MPa) than in BCS knees (0.2 ± 0.1 MPa) when knees were fully extended, but this difference was not significant (3.7 ± 3.5 MPa for PCR knees vs. 1.4 ± 1.9 MPa for BCS knees; p > 0.05) in early flexion. The results also indicate that patellar tilt (normal = 2.4° ± 4.8°, BCS = 5.5° ± 5.5°, PCR = − 3.0° ± 6.9° change in lateral tilt when moving from full extension to early flexion) and contact area (full extension: normal = 267 ± 111 mm², BCS = 344 ± 201 mm², PCR = 83 ± 80 mm²; early flexion: normal = 723 ± 306 mm², BCS = 417 ± 290 mm², PCR = 246 ± 108 mm²) in BCS TKA mimic those in the normal knees more closely than PCR knees do. These results suggest that the patellar component in BCS TKA may be expected to experience less wear than the patellar component in PCR TKA over time.     

C9orf72 G4C2 repeat expansions in Alzheimer's disease and mild cognitive impairment

C9orf72 G₄C₂ repeat expansion is a major cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Its role in Alzheimer's disease (AD) is less clear. We assessed the prevalence of G₄C₂ pathogenic repeat expansions in Flanders-Belgian patients with clinical AD or mild cognitive impairment (MCI). In addition, we studied the effect of non-pathogenic G₄C₂ repeat length variability on susceptibility to AD, and on AD cerebrospinal fluid (CSF) biomarker levels. A pathogenic repeat expansion was identified in 5 of 1217 AD patients (frequency <1%). No pathogenic expansions were observed in patients with MCI (n = 200) or control individuals (n = 1119). Nonpathogenic repeat length variability was not associated with AD, risk of conversion to AD in MCI individuals, or CSF biomarker levels. We conclude that pathogenic C9orf72 G₄C₂ repeat expansions can be detected in clinical AD patients and could act as a contributor to AD pathogenesis. Non-pathogenic repeat length variability did not affect risk of AD or MCI, nor AD biomarker levels in CSF, indicating that C9orf72 is not a direct AD risk factor.