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1.  Antibodies against phosphorylcholine are not altered in plasma of patients with Alzheimer’s disease 
BMC Neurology  2015;15:8.
Phosphorylcholine is one of the major epitopes of oxidised low density lipoprotein. Low levels of IgM antibodies against phosphorylcholine (anti-PC) are associated with development of myocardial infarction and stroke. It has been shown that patients with Alzheimer’s disease and other dementias have significantly lower serum anti-PC levels compared to controls, suggesting that low levels of atheroprotective anti-PC may play a role in AD and dementia.
We quantified levels of anti-PC levels using an ELISA in plasma from 176 controls, 125 patients with Alzheimer’s disease, 19 patients with vascular dementia and 63 patients with other dementias.
We observed similar plasma anti-PC levels in controls, patients with Alzheimer’s disease, and other dementias.
Our data suggests that anti-PC is not useful as a biomarker for Alzheimer’s disease.
PMCID: PMC4324431  PMID: 25651913
Anti-phosphorylcholine; Alzheimer’s disease; Dementia; Biomarker
2.  Prediction of Falls and/or Near Falls in People with Mild Parkinson’s Disease 
PLoS ONE  2015;10(1):e0117018.
To determine factors associated with future falls and/or near falls in people with mild PD.
The study included 141 participants with PD. Mean (SD) age and PD-duration were 68 (9.7) and 4 years (3.9), respectively. Their median (q1–q3) UPDRS III score was 13 (8-18). Those >80 years of age, requiring support in standing or unable to understand instructions were excluded. Self-administered questionnaires targeted freezing of gait, turning hesitations, walking difficulties in daily life, fatigue, fear of falling, independence in activities of daily living, dyskinesia, demographics, falls/near falls history, balance problems while dual tasking and pain. Clinical assessments addressed functional balance performance, retropulsion, comfortable gait speed, motor symptoms and cognition. All falls and near falls were subsequently registered in a diary during a six-month period. Risk factors for prospective falls and/or near falls were determined using logistic regression.
Sixty-three participants (45%) experienced ≥1 fall and/or near fall. Three factors were independent predictors of falls and/or near falls: fear of falling (OR = 1.032, p<0.001) history of near falls (OR = 3.475, p = 0.009) and retropulsion (OR = 2.813, p = 0.035). The strongest contributing factor was fear of falling, followed by a history of near falls and retropulsion.
Fear of falling seems to be an important issue to address already in mild PD as well as asking about prior near falls.
PMCID: PMC4311993  PMID: 25635687
3.  SNAP-25 is a promising novel cerebrospinal fluid biomarker for synapse degeneration in Alzheimer’s disease 
Synaptic degeneration is an early pathogenic event in Alzheimer’s disease, associated with cognitive impairment and disease progression. Cerebrospinal fluid biomarkers reflecting synaptic integrity would be highly valuable tools to monitor synaptic degeneration directly in patients. We previously showed that synaptic proteins such as synaptotagmin and synaptosomal-associated protein 25 (SNAP-25) could be detected in pooled samples of cerebrospinal fluid, however these assays were not sensitive enough for individual samples.
We report a new strategy to study synaptic pathology by using affinity purification and mass spectrometry to measure the levels of the presynaptic protein SNAP-25 in cerebrospinal fluid. By applying this novel affinity mass spectrometry strategy on three separate cohorts of patients, the value of SNAP-25 as a cerebrospinal fluid biomarker for synaptic integrity in Alzheimer’s disease was assessed for the first time. We found significantly higher levels of cerebrospinal fluid SNAP-25 fragments in Alzheimer’s disease, even in the very early stages, in three separate cohorts. Cerebrospinal fluid SNAP-25 differentiated Alzheimer’s disease from controls with area under the curve of 0.901 (P < 0.0001).
We developed a sensitive method to analyze SNAP-25 levels in individual CSF samples that to our knowledge was not possible previously. Our results support the notion that synaptic biomarkers may be important tools for early diagnosis, assessment of disease progression, and to monitor drug effects in treatment trials.
Electronic supplementary material
The online version of this article (doi:10.1186/1750-1326-9-53) contains supplementary material, which is available to authorized users.
PMCID: PMC4253625  PMID: 25418885
Alzheimer’s disease; Biomarker; Cerebrospinal fluid; SNAP-25; SNARE proteins; Mass spectrometry; Immunopurification; Selected reaction monitoring
4.  Levels of cerebrospinal fluid α-synuclein oligomers are increased in Parkinson’s disease with dementia and dementia with Lewy bodies compared to Alzheimer’s disease 
The objective was to study whether α-synuclein oligomers are altered in the cerebrospinal fluid (CSF) of patients with dementia, including Parkinson disease with dementia (PDD), dementia with Lewy bodies (DLB), and Alzheimer disease (AD), compared with age-matched controls.
In total, 247 CSF samples were assessed in this study, including 71 patients with DLB, 30 patients with PDD, 48 patients with AD, and 98 healthy age-matched controls. Both total and oligomeric α-synuclein levels were evaluated by using well-established immunoassays.
The levels of α-synuclein oligomers in the CSF were increased in patients with PDD compared with the controls (P < 0.05), but not in patients with DLB compared with controls. Interestingly, the levels of α-synuclein oligomers in the CSF were also significantly higher in patients with PDD (P < 0.01) and DLB (P < 0.05) compared with patients with AD. The levels of CSF α-synuclein oligomers and the ratio of oligomeric/total-α-synuclein could distinguish DLB or PDD patients from AD patients, with areas under the curves (AUCs) of 0.64 and 0.75, respectively. In addition, total-α-synuclein alone could distinguish DLB or PDD patients from AD patients, with an AUC of 0.80.
The levels of α-synuclein oligomers were increased in the CSF from α-synucleinopathy patients with dementia compared with AD cases.
PMCID: PMC4075410  PMID: 24987465
5.  Changes in cerebrospinal fluid and blood plasma levels of IGF-II and its binding proteins in Alzheimer’s disease: an observational study 
BMC Neurology  2014;14:64.
The Insulin-like Growth Factor (IGF)-related system is implicated in neuroregeneration and cell repair, as well as regulating lifespan. IGF-II, one component of this system, has also been found to affect memory functions in a rat model. In this study we explored changes in the IGF-related system in patients with Alzheimer’s disease (AD), including changes in IGF-II levels.
We measured blood plasma and cerebrospinal fluid (CSF) levels of IGF-I, IGF-II, IGFBP-2 and IGFBP-3 in 72 healthy controls and 92 patients with AD.
We found significantly lower blood plasma levels of IGF-II and IGFBP-3 in patients with AD, compared with controls. The levels of IGF-II and IGFBP-2 were significantly elevated in the CSF from patients with AD. We also found correlations between established CSF biomarkers for AD (tau and P-tau) and components of the IGF system.
CSF and blood plasma levels of IGF-II and some of its binding proteins are changed in patients with AD. Further investigation into this area may unravel important clues to the nature of this disease.
PMCID: PMC3973836  PMID: 24685003
Alzheimer Disease; Dementia; Cerebrospinal fluid; Blood plasma; IGF-I; IGF-II; IGFBP-2; IGFBP-3; Insulin
6.  Factors associated with fear of falling in people with Parkinson’s disease 
BMC Neurology  2014;14:19.
This study aimed to comprehensibly investigate potential contributing factors to fear of falling (FOF) among people with idiopathic Parkinson’s disease (PD).
The study included 104 people with PD. Mean (SD) age and PD-duration were 68 (9.4) and 5 (4.2) years, respectively, and the participants’ PD-symptoms were relatively mild. FOF (the dependent variable) was investigated with the Swedish version of the Falls Efficacy Scale, i.e. FES(S). The first multiple linear regression model replicated a previous study and independent variables targeted: walking difficulties in daily life; freezing of gait; dyskinesia; fatigue; need of help in daily activities; age; PD-duration; history of falls/near falls and pain. Model II included also the following clinically assessed variables: motor symptoms, cognitive functions, gait speed, dual-task difficulties and functional balance performance as well as reactive postural responses.
Both regression models showed that the strongest contributing factor to FOF was walking difficulties, i.e. explaining 60% and 64% of the variance in FOF-scores, respectively. Other significant independent variables in both models were needing help from others in daily activities and fatigue. Functional balance was the only clinical variable contributing additional significant information to model I, increasing the explained variance from 66% to 73%.
The results imply that one should primarily target walking difficulties in daily life in order to reduce FOF in people mildly affected by PD. This finding applies even when considering a broad variety of aspects not previously considered in PD-studies targeting FOF. Functional balance performance, dependence in daily activities, and fatigue were also independently associated with FOF, but to a lesser extent. Longitudinal studies are warranted to gain an increased understanding of predictors of FOF in PD and who is at risk of developing a FOF.
PMCID: PMC3904169  PMID: 24456482
Fear of falling; Physical therapy; Parkinson’s disease; Postural Balance; Rehabilitation
7.  Cerebrospinal Fluid (CSF) 25-Hydroxyvitamin D Concentration and CSF Acetylcholinesterase Activity Are Reduced in Patients with Alzheimer's Disease 
PLoS ONE  2013;8(11):e81989.
Little is known of vitamin D concentration in cerebrospinal fluid (CSF) in Alzheimer´s disease (AD) and its relation with CSF acetylcholinesterase (AChE) activity, a marker of cholinergic function.
A cross-sectional study of 52 consecutive patients under primary evaluation of cognitive impairment and 17 healthy controls. The patients had AD dementia or mild cognitive impairment (MCI) diagnosed with AD dementia upon follow-up (n = 28), other dementias (n = 12), and stable MCI (SMCI, n = 12). We determined serum and CSF concentrations of calcium, parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHD), and CSF activities of AChE and butyrylcholinesterase (BuChE).
CSF 25OHD level was reduced in AD patients (P < 0.05), and CSF AChE activity was decreased both in patients with AD (P < 0.05) and other dementias (P < 0.01) compared to healthy controls. None of the measured variables differed between BuChE K-variant genotypes whereas the participants that were homozygous in terms of the apolipoprotein E (APOE) ε4 allele had decreased CSF AChE activity compared to subjects lacking the APOE ε4 allele (P = 0.01). In AD patients (n=28), CSF AChE activity correlated positively with CSF levels of total tau (T-tau) (r = 0.44, P < 0.05) and phosphorylated tau protein (P-tau) (r = 0.50, P < 0.01), but CSF activities of AChE or BuChE did not correlate with serum or CSF levels of 25OHD.
In this pilot study, both CSF 25OHD level and CSF AChE activity were reduced in AD patients. However, the lack of correlations between 25OHD levels and CSF activities of AChE or BuChE might suggest different mechanisms of action, which could have implications for treatment trials.
PMCID: PMC3843721  PMID: 24312390
9.  Prediagnostic body fat and risk of death from amyotrophic lateral sclerosis 
Neurology  2013;80(9):829-838.
The aim of this study was to investigate for the first time the association between body fat and risk of amyotrophic lateral sclerosis (ALS) with an appropriate prospective study design.
The EPIC (European Prospective Investigation into Cancer and Nutrition) study included 518,108 individuals recruited from the general population across 10 Western European countries. At recruitment, information on lifestyle was collected and anthropometric characteristics were measured. Cox hazard models were fitted to investigate the associations between anthropometric measures and ALS mortality.
Two hundred twenty-two ALS deaths (79 men and 143 women) occurred during the follow-up period (mean follow-up = 13 years). There was a statistically significant interaction between categories of body mass index and sex regarding ALS risk (p = 0.009): in men, a significant linear decrease of risk per unit of body mass index was observed (hazard ratio = 0.93, 95% confidence interval 0.86–0.99 per kg/m2); among women, the risk was more than 3-fold increased for underweight compared with normal-weight women. Among women, a significant risk reduction increasing the waist/hip ratio was also evident: women in the top quartile had less than half the risk of ALS compared with those in the bottom quartile (hazard ratio = 0.48, 95% confidence interval 0.25–0.93) with a borderline significant p value for trend across quartiles (p = 0.056).
Increased prediagnostic body fat is associated with a decreased risk of ALS mortality.
PMCID: PMC3598455  PMID: 23390184
10.  Body mass index is associated with biological CSF markers of core brain pathology of Alzheimer’s disease 
Neurobiology of Aging  2011;33(8):1599-1608.
Weight changes are common in aging and Alzheimer’s disease (AD) and post-mortem findings suggested a relation between lower body mass index (BMI) and increased AD brain pathology. In the current multicenter study, we tested whether lower BMI is associated with higher core AD brain pathology as assessed by cerebrospinal fluid (CSF) based biological markers of AD in 751 living subjects: 308 patients with AD, 296 subjects with amnestic mild cognitive impairment (MCI), and 147 elderly healthy controls (HC). Based upon a priori cutoff values on CSF concentration of total tau and beta-amyloid (Aβ1-42), subjects were binarized into a group with abnormal CSF biomarker signature (CSF+) and those without (CSF−). Results showed that BMI was significantly lower in the CSF+ when compared to the CSF− group (F = 27.7, df = 746, p < 0.001). There was no interaction between CSF signature and diagnosis or ApoE genotype. In conclusion, lower BMI is indicative of AD pathology as assessed with CSF-based biomarkers in demented and non-demented elderly subjects.
PMCID: PMC3208117  PMID: 21684041
Alzheimer’s disease; body mass index; cerebrospinal fluid; tau protein; Aβ1-42
11.  Fluid biomarkers in Alzheimer’s disease – current concepts 
The diagnostic guidelines of Alzheimer’s disease (AD) have recently been updated to include brain imaging and cerebrospinal fluid (CSF) biomarkers, with the aim of increasing the certainty of whether a patient has an ongoing AD neuropathologic process or not. The CSF biomarkers total tau (T-tau), hyperphosphorylated tau (P-tau) and the 42 amino acid isoform of amyloid β (Aβ42) reflect the core pathologic features of AD, which are neuronal loss, intracellular neurofibrillary tangles and extracellular senile plaques. Since the pathologic processes of AD start decades before the first symptoms, these biomarkers may provide means of early disease detection. The updated guidelines identify three different stages of AD: preclinical AD, mild cognitive impairment (MCI) due to AD and AD with dementia. In this review, we aim to summarize the CSF biomarker data available for each of these stages. We also review results from blood biomarker studies. In summary, the core AD CSF biomarkers have high diagnostic accuracy both for AD with dementia and to predict incipient AD (MCI due to AD). Longitudinal studies on healthy elderly and recent cross-sectional studies on patients with dominantly inherited AD mutations have also found biomarker changes in cognitively normal at-risk individuals. This will be important if disease-modifying treatment becomes available, given that treatment will probably be most effective early in the disease. An important prerequisite for this is trustworthy analyses. Since measurements vary between studies and laboratories, standardization of analytical as well as pre-analytical procedures will be essential. This process is already initiated. Apart from filling diagnostic roles, biomarkers may also be utilized for prognosis, disease progression, development of new treatments, monitoring treatment effects and for increasing the knowledge about pathologic processes coupled to the disease. Hence, the search for new biomarkers continues. Several candidate biomarkers have been found in CSF, and although biomarkers in blood have been harder to find, some recent studies have presented encouraging results. But before drawing any major conclusions, these results need to be verified in independent studies.
PMCID: PMC3691925  PMID: 23800368
Alzheimer’s disease; Cerebrospinal fluid; Blood; Biomarker; Amyloid β; Total tau; Phosphorylated tau; Diagnosis; Disease stages
12.  Evaluating Amyloid-β Oligomers in Cerebrospinal Fluid as a Biomarker for Alzheimer’s Disease 
PLoS ONE  2013;8(6):e66381.
The current study evaluated amyloid-β oligomers (Aβo) in cerebrospinal fluid as a clinical biomarker for Alzheimer’s disease (AD). We developed a highly sensitive Aβo ELISA using the same N-terminal monoclonal antibody (82E1) for capture and detection. CSF samples from patients with AD, mild cognitive impairment (MCI), and healthy controls were examined. The assay was specific for oligomerized Aβ with a lower limit of quantification of 200 fg/ml, and the assay signal showed a tight correlation with synthetic Aβo levels. Three clinical materials of well characterized AD patients (n = 199) and cognitively healthy controls (n = 148) from different clinical centers were included, together with a clinical material of patients with MCI (n = 165). Aβo levels were elevated in the all three AD-control comparisons although with a large overlap and a separation from controls that was far from complete. Patients with MCI who later converted to AD had increased Aβo levels on a group level but several samples had undetectable levels. These results indicate that presence of high or measurable Aβo levels in CSF is clearly associated with AD, but the overlap is too large for the test to have any diagnostic potential on its own.
PMCID: PMC3682966  PMID: 23799095
13.  Assessment of Global and Regional Diffusion Changes along White Matter Tracts in Parkinsonian Disorders by MR Tractography 
PLoS ONE  2013;8(6):e66022.
The aim of the study was to determine the usefulness of diffusion tensor tractography (DTT) in parkinsonian disorders using a recently developed method for normalization of diffusion data and tract size along white matter tracts. Furthermore, the use of DTT in selected white matter tracts for differential diagnosis was assessed.
We quantified global and regional diffusion parameters in major white matter tracts in patients with multiple system atrophy (MSA), progressive nuclear palsy (PSP), idiopathic Parkinson’s disease (IPD) and healthy controls). Diffusion tensor imaging data sets with whole brain coverage were acquired at 3 T using 48 diffusion encoding directions and a voxel size of 2×2×2 mm3. DTT of the corpus callosum (CC), cingulum (CG), corticospinal tract (CST) and middle cerebellar peduncles (MCP) was performed using multiple regions of interest. Regional evaluation comprised projection of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and the apparent area coefficient (AAC) onto a calculated mean tract and extraction of their values along each structure.
There were significant changes of global DTT parameters in the CST (MSA and PSP), CC (PSP) and CG (PSP). Consistent tract-specific variations in DTT parameters could be seen along each tract in the different patient groups and controls. Regional analysis demonstrated significant changes in the anterior CC (MD, RD and FA), CST (MD) and CG (AAC) of patients with PSP compared to controls. Increased MD in CC and CST, as well as decreased AAC in CG, was correlated with a diagnosis of PSP compared to IPD.
DTT can be used for demonstrating disease-specific regional white matter changes in parkinsonian disorders. The anterior portion of the CC was identified as a promising region for detection of neurodegenerative changes in patients with PSP, as well as for differential diagnosis between PSP and IPD.
PMCID: PMC3681971  PMID: 23785466
14.  NG2 cells, a new trail for Alzheimer’s disease mechanisms? 
Neuron Glial 2 (NG2) cells are glial cells known to serve as oligodendrocyte progenitors as well as modulators of the neuronal network. Altered NG2 cell morphology and up-regulation as well as increased shedding of the proteoglycan NG2 expressed on the cell surface have been described in rodent models of brain injury. Here we describe alterations in the human NG2 cell population in response to pathological changes characteristic of Alzheimer’s disease (AD).
Immunohistological stainings of postmortem brain specimens from clinically diagnosed and postmortem verified AD patients and non-demented controls revealed reduced NG2 immunoreactivity as well as large numbers of NG2 positive astrocytes in individuals with high amyloid beta plaque load. Since fibrillar amyloid beta (Aβ)1-42 is the major component of AD-related senile plaques, we exposed human NG2 cells to oligomer- and fibril enriched preparations of Aβ1-42. We found that both oligomeric and fibrillar Aβ1-42 induced changes in NG2 cell morphology. Further, in vitro exposure to fibrillar Aβ1-42 decreased the NG2 concentrations in both cell lysates and supernatants. Interestingly, we also found significantly decreased levels of soluble NG2 in the cerebrospinal fluid (CSF) from clinically diagnosed AD patients compared to non-demented individuals. Additionally, the CSF NG2 levels were found to significantly correlate with the core AD biomarkers Aß1-42, T-tau and P-tau.
Our results demonstrate major alterations in the NG2 cell population in relation to AD pathology which highlights the NG2 cell population as a new attractive research target in the search for cellular mechanisms associated with AD pathogenesis.
Electronic supplementary material
The online version of this article (doi:10.1186/2051-5960-1-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4046664  PMID: 24252600
NG2 cells; Alzheimer’s disease; Amyloid beta; Cerebrospinal fluid; Brain tissue; Cell culture
15.  Proinflammatory Cytokines Are Elevated in Serum of Patients with Multiple System Atrophy 
PLoS ONE  2013;8(4):e62354.
Despite several lines of evidence from preclinical and post-mortem studies suggesting that inflammation is involved in Multiple System Atrophy (MSA), no previous studies have measured peripheral indices of inflammation in MSA patients.
We measured C-reactive protein, interleukin (IL)-6, soluble IL-2 receptor and tumor necrosis factor (TNF)-α in blood samples from MSA patients (n = 14) and healthy controls (n = 40).
IL-6 and TNF-α were significantly elevated in MSA patients compared to healthy controls. After controlling for the potentially confounding effects of age, gender, and somatic co-morbidities, a diagnosis of MSA was still significantly associated with high levels of TNF-α. Higher TNF-α levels were associated with less severe motor symptoms and earlier disease stage.
Our findings are in line with the hypothesis that inflammation might be involved at an early stage of MSA pathophysiology.
PMCID: PMC3633844  PMID: 23626805
16.  Tau Pathology and Parietal White Matter Lesions Have Independent but Synergistic Effects on Early Development of Alzheimer's Disease 
White matter lesions (WMLs) are a common finding in patients with dementia. This study investigates the relationship between WMLs, hyperphosphorylated tau (P-tau) in cerebrospinal fluid (CSF) and apolipoprotein E (APOE) ε4 genotype in prodromal Alzheimer's disease (AD).
Baseline levels of tau, P-tau and β-amyloid 1-42 in CSF, the presence of WMLs in the brain, and the APOE genotype were ascertained in 159 patients with mild cognitive impairment (MCI) and 38 cognitively healthy controls.
After 5.7 years, 58 patients had developed AD. In this group, patients with normal levels of CSF P-tau had higher levels of WMLs in the parietal regions than those with pathological P-tau levels (p < 0.05). Also, patients without APOE ε4 alleles had more WMLs in the parietal lobes than those with at least one allele (p < 0.05). MCI patients with pathological P-tau levels and parietal WMLs showed a greater risk of developing AD than those with just one of the two pathological parameters.
We suggest that WMLs in parietal lobes and tau pathology likely have independent but synergistic effects on the reduction of the cognitive reserve capacity of the brain. In patients with a more low-grade AD pathology, WMLs in the parietal lobes might increase the risk of developing dementia.
PMCID: PMC3656673  PMID: 23687506
Alzheimer's disease; Dementia; Cerebrospinal fluid; White matter lesions; Follow-up studies

17.  Low CSF Levels of Both α-Synuclein and the α-Synuclein Cleaving Enzyme Neurosin in Patients with Synucleinopathy 
PLoS ONE  2013;8(1):e53250.
Neurosin is a protease that in vitro degrades α-synuclein, the main constituent of Lewy bodies found in brains of patients with synucleinopathy including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Several studies have reported reduced cerebrospinal fluid (CSF) levels of α-synuclein in synucleinopathy patients and recent data also proposes a significant role of α-synuclein in the pathophysiology of Alzheimer's disease (AD). To investigate potential links between neurosin and its substrate α-synuclein in vivo we used a commercially available sandwich ELISA and an in-house developed direct ELISA to quantify CSF levels of α-synuclein and neurosin in patients diagnosed with DLB, PD and PD dementia (PDD) versus AD patients and non-demented controls. We found that patients with synucleinopathy displayed lower CSF levels of neurosin and α-synuclein compared to controls and AD patients. In contrast, AD patients demonstrated significantly increased CSF α-synuclein but similar neurosin levels compared to non-demented controls. Further, CSF neurosin and α-synuclein concentrations were positively associated in controls, PD and PDD patients and both proteins were highly correlated to CSF levels of phosphorylated tau in all investigated groups. We observed no effect of gender or presence of the apolipoprotein Eε4 allele on neither neurosin or α-synuclein CSF levels. In concordance with the current literature our study demonstrates decreased CSF levels of α-synuclein in synucleinopathy patients versus AD patients and controls. Importantly, decreased α-synuclein levels in patients with synucleinopathy appear linked to low levels of the α-synuclein cleaving enzyme neurosin. In contrast, elevated levels of α-synuclein in AD patients were not related to any altered CSF neurosin levels. Thus, altered CSF levels of α-synuclein and neurosin in patients with synucleinopathy versus AD may not only mirror disease-specific neuropathological mechanisms but may also serve as fit candidates for future biomarker studies aiming at identifying specific markers of synucleinopathy.
PMCID: PMC3540093  PMID: 23308173
18.  No Diagnostic Value of Plasma Clusterin in Alzheimer's Disease 
PLoS ONE  2012;7(11):e50237.
There is an urgent need for biomarkers to enable early diagnosis of Alzheimer's disease (AD). It has recently been shown that a variant within the clusterin gene is associated with increased risk of AD and plasma levels of clusterin have been found to be associated with the risk of AD. We, therefore, investigated the diagnostic value of clusterin by quantifying clusterin using an ELISA in plasma from 171 controls, 127 patients with AD, 82 patients with other dementias and 30 patients with depression. We observed similar plasma clusterin levels in controls, AD patients and patients with other dementias, suggesting that plasma clusterin levels have no diagnostic value for AD. There was a slight, but significant, increase in plasma clusterin in patients with depression compared to all other groups tested, which may warrant further investigation.
PMCID: PMC3509147  PMID: 23209684
19.  Non-Motor Symptoms in Patients with Parkinson’s Disease – Correlations with Inflammatory Cytokines in Serum 
PLoS ONE  2012;7(10):e47387.
Parkinson’s Disease (PD) is the second most common neurodegenerative disorder of the central nervous system. Motor symptoms are the focus of pharmacotherapy, yet non-motor features of the disease (e.g. fatigue, mood disturbances, sleep disturbances and symptoms of anxiety) are both common and disabling for the patient. The pathophysiological mechanisms behind the non-motor symptoms in PD are yet to be untangled. The main objective of this study was to investigate associations between pro-inflammatory substances and non-motor symptoms in patients with PD.
Methods and Materials
We measured C-reactive protein, interleukin (IL)-6, soluble IL-2 receptor (sIL-2R) and tumor necrosis factor-α (TNF-α) in blood samples from PD patients (n = 86) and healthy controls (n = 40). Symptoms of fatigue, depression, anxiety and sleeping difficulties were assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT), the Hospital Anxiety and Depression Scale (HAD), and the Scales for Outcome in PD-Sleep Scale respectively.
IL-6 was significantly higher in PD patients than in healthy controls. Compared to healthy controls, PD patients displayed significantly higher mean scores on HAD and lower scores on FACIT, thus indicating more severe symptoms as measured with these scales. Within the PD sample, high levels of both sIL-2R and TNF-α were significantly associated with more severe symptoms assessed by means of FACIT and HAD (depression and anxiety subscales). SIL-2-R levels were able to significantly predict FACIT and HAD scores after the effects of age, gender, anti-parkinsonian medications, and severity of motor symptoms were controlled for.
We suggest that non-motor symptoms in PD patients, such as fatigue and depressive symptoms, might be generated via inflammatory mechanisms. This knowledge might contribute to the development of novel treatment options in PD, specifically targeting non-motor symptoms.
PMCID: PMC3474801  PMID: 23082161
20.  Comparison of Brief Cognitive Tests and CSF Biomarkers in Predicting Alzheimer’s Disease in Mild Cognitive Impairment: Six-Year Follow-Up Study 
PLoS ONE  2012;7(6):e38639.
Early identification of Alzheimer’s disease (AD) is needed both for clinical trials and in clinical practice. In this study, we compared brief cognitive tests and cerebrospinal fluid (CSF) biomarkers in predicting conversion from mild cognitive impairment (MCI) to AD.
At a memory clinic, 133 patients with MCI were followed until development of dementia or until they had been stable over a mean period of 5.9 years (range 3.2–8.8 years). The Mini-Mental State Examination (MMSE), the clock drawing test, total tau, tau phosphorylated at Thr181 (P-tau) and amyloid-β1–42 (Aβ42) were assessed at baseline.
During clinical follow-up, 47% remained cognitively stable and 53% developed dementia, with an incidence of 13.8%/year. In the group that developed dementia the prevalence of AD was 73.2%, vascular dementia 14.1%, dementia with Lewy bodies (DLB) 5.6%, progressive supranuclear palsy (PSP) 4.2%, semantic dementia 1.4% and dementia due to brain tumour 1.4%. When predicting subsequent development of AD among patients with MCI, the cognitive tests classified 81% of the cases correctly (AUC, 0.85; 95% CI, 0.77–0.90) and CSF biomarkers 83% (AUC, 0.89; 95% CI, 0.82–0.94). The combination of cognitive tests and CSF (AUC, 0.93; 95% CI 0.87 to 0.96) was significantly better than the cognitive tests (p = 0.01) and the CSF biomarkers (p = 0.04) alone when predicting AD.
The MMSE and the clock drawing test were as accurate as CSF biomarkers in predicting future development of AD in patients with MCI. Combining both instruments provided significantly greater accuracy than cognitive tests or CSF biomarkers alone in predicting AD.
PMCID: PMC3382225  PMID: 22761691
21.  CCL2 Is Associated with a Faster Rate of Cognitive Decline during Early Stages of Alzheimer's Disease 
PLoS ONE  2012;7(1):e30525.
Chemokine (C-C motif) receptor 2 (CCR2)-signaling can mediate accumulation of microglia at sites affected by neuroinflammation. CCR2 and its main ligand CCL2 (MCP-1) might also be involved in the altered metabolism of beta-amyloid (Aβ) underlying Alzheimer's disease (AD). We therefore measured the levels of CCL2 and three other CCR2 ligands, i.e. CCL11 (eotaxin), CCL13 (MCP-4) and CCL26 (eotaxin-3), in the cerebrospinal fluid (CSF) and plasma of 30 controls and 119 patients with mild cognitive impairment (MCI) at baseline. During clinical follow-up 52 MCI patients were clinically stable for five years, 47 developed AD (i.e. cases with prodromal AD at baseline) and 20 developed other dementias. Only CSF CCL26 was statistically significantly elevated in patients with prodromal AD when compared to controls (p = 0.002). However, in patients with prodromal AD, the CCL2 levels in CSF at baseline correlated with a faster cognitive decline during follow-up (rs = 0.42, p = 0.004). Furthermore, prodromal AD patients in the highest tertile of CSF CCL2 exhibited a significantly faster cognitive decline (p<0.001) and developed AD dementia within a shorter time period (p<0.003) compared to those in the lowest tertile. Finally, in the entire MCI cohort, CSF CCL2 could be combined with CSF Tau, P-tau and Aβ42 to predict both future conversion to AD and the rate of cognitive decline. If these results are corroborated in future studies, CCL2 in CSF could be a candidate biomarker for prediction of future disease progression rate in prodromal AD. Moreover, CCR2-related signaling pathways might be new therapeutic targets for therapies aiming at slowing down the disease progression rate of AD.
PMCID: PMC3268759  PMID: 22303443
22.  Evaluation of a Previously Suggested Plasma Biomarker Panel to Identify Alzheimer's Disease 
PLoS ONE  2012;7(1):e29868.
There is an urgent need for biomarkers in plasma to identify Alzheimer's disease (AD). It has previously been shown that a signature of 18 plasma proteins can identify AD during pre-dementia and dementia stages (Ray et al, Nature Medicine, 2007). We quantified the same 18 proteins in plasma from 174 controls, 142 patients with AD, and 88 patients with other dementias. Only three of these proteins (EGF, PDG-BB and MIP-1δ) differed significantly in plasma between controls and AD. The 18 proteins could classify patients with AD from controls with low diagnostic precision (area under the ROC curve was 63%). Moreover, they could not distinguish AD from other dementias. In conclusion, independent validation of results is important in explorative biomarker studies.
PMCID: PMC3261152  PMID: 22279551
23.  Cerebrospinal Fluid Levels of sAPPα and sAPPβ in Lewy Body and Alzheimer's Disease: Clinical and Neurochemical Correlates 
We measured cerebrospinal fluid (CSF) levels of the soluble isoforms of amyloid precursor protein (APP; sAPPα sAPPβ) and other CSF biomarkers in 107 patients with Alzheimer's disease (AD), dementia with Lewy body dementia (DLB), Parkinson's disease dementia (PDD), and normal controls (NC) using commercial kits. DLB and PDD were combined in a Lewy body dementia group (LBD). No differences were observed in sAPPα and sAPPβ levels between the groups. Significant correlations were observed between sAPPα and sAPPβ and between sAPPβ and Mini-Mental State Examination scores in the total group analysis as well as when LBD and AD groups were analyzed separately. sAPPα and sAPPβ levels correlated with Aβ38, Aβ40, Aβ42, and Tau in the LBD group. In AD, sAPPα correlated with p-Tau and sAPPβ with Aβ40. The differential association between sAPPα and sAPPβ with Aβ and Tau species between LBD and AD groups suggests a possible relationship with the underlying pathologies in LBD and AD.
PMCID: PMC3182340  PMID: 21966597
24.  Discriminatory Analysis of Biochip-Derived Protein Patterns in CSF and Plasma in Neurodegenerative Diseases 
The role of biomarkers in neurodegenerative diseases has been emphasized by recent research. Future clinical demands for identifying diseases at an early stage may render them essential. The aim of this pilot study was to test the analytical performance of two multiplex assays of cerebral markers on a well-defined clinical material consisting of patients with various neurodegenerative diseases. We measured 10 analytes in plasma and cerebrospinal fluid (CSF) from 60 patients suffering from Alzheimer's disease (AD), vascular dementia, frontotemporal dementia, dementia with Lewy bodies, or mild cognitive impairment, as well as 20 cognitively healthy controls. We used the Randox biochip-based Evidence Investigator™ system to measure the analytes. We found it possible to measure most analytes in both plasma and CSF, and there were some interesting differences between the diagnostic groups, although with large overlaps. CSF heart-type fatty acid-binding protein was increased in AD. Glial fibrillary acidic protein and neutrophil gelatinase-associated lipocalin in CSF and D-dimer in plasma were elevated in patients with cerebrovascular disease. A multivariate statistical analysis revealed that the pattern of analytes could help to differentiate the conditions, although more studies are required to verify this.
PMCID: PMC3057441  PMID: 21442044
neurodegenerative diseases; Alzheimer; fatty acid-binding protein; biochip
25.  Aβ40 Oligomers Identified as a Potential Biomarker for the Diagnosis of Alzheimer's Disease 
PLoS ONE  2010;5(12):e15725.
Alzheimer's Disease (AD) is the most prevalent form of dementia worldwide, yet the development of therapeutics has been hampered by the absence of suitable biomarkers to diagnose the disease in its early stages prior to the formation of amyloid plaques and the occurrence of irreversible neuronal damage. Since oligomeric Aβ species have been implicated in the pathophysiology of AD, we reasoned that they may correlate with the onset of disease. As such, we have developed a novel misfolded protein assay for the detection of soluble oligomers composed of Aβ x-40 and x-42 peptide (hereafter Aβ40 and Aβ42) from cerebrospinal fluid (CSF). Preliminary validation of this assay with 36 clinical samples demonstrated the presence of aggregated Aβ40 in the CSF of AD patients. Together with measurements of total Aβ42, diagnostic sensitivity and specificity greater than 95% and 90%, respectively, were achieved. Although larger sample populations will be needed to confirm this diagnostic sensitivity, our studies demonstrate a sensitive method of detecting circulating Aβ40 oligomers from AD CSF and suggest that these oligomers could be a powerful new biomarker for the early detection of AD.
PMCID: PMC3012719  PMID: 21209907

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