Cerebrospinal fluid myelin basic protein is elevated in multiple system atrophy

IntroductionParkinson's disease (PD) and multiple system atrophy (MSA) have overlapping symptoms, challenging an early diagnosis. Diagnostic accuracy is important because PD and MSA have a different prognosis and response to treatment. Here, we aimed to evaluate the diagnostic value of brain-specific structural proteins in cerebrospinal fluid (CSF) of PD and MSA patients, as well as their association with cognitive decline.MethodsCSF samples were collected from patients with clear signs of parkinsonism, but with uncertain diagnosis at the time of inclusion. Clinical diagnoses of PD (n = 55) and MSA (n = 22) were established after 3 and 10 years of follow-up and re-evaluated after 12 years, according to the most updated clinical criteria. CSF from controls (n = 118) was studied for comparison. Neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), S100 calcium-binding protein B (S100B) and myelin basic protein (MBP) levels in CSF were measured using ELISA. Protein levels were also correlated with cognitive decline, i.e. worsening of the mini mental state examination (MMSE) over a period of three years.ResultsMBP concentrations were increased in MSA compared to PD and controls (p < 0.005) and could differentiate MSA and PD with high accuracy (AUC = 0.781; p < 0.001). Concentrations of MPB, GFAP and S100B, but not NSE, were significantly elevated in PD patients compared to controls (p = 0.05). None of the brain-specific structural proteins correlated with MMSE progression.ConclusionsOur results demonstrate that MBP differentiates PD from MSA at early stages of the disease, indicating that demyelination and axonal damage may already occur in early stages of MSA.     

Cerebrospinal fluid analysis differentiates multiple system atrophy from Parkinson's disease.

We investigated whether cerebrospinal fluid (CSF) analysis discriminates between idiopathic Parkinson's disease (PD; n = 35) and multiple system atrophy (MSA; n = 30). The median CSF concentration of the neurotransmitter metabolites 5-hydroxyindolacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) was reduced significantly (49-70%) in MSA compared to PD. In contrast, several brain-specific proteins (tau, neuron-specific enolase, myelin basic protein) were elevated (130-230%) in MSA compared with those in PD. A combination of CSF tau and MHPG discriminated PD from MSA (adjusted odds ratios: tau, 27.2; MHPG, 0.14). Our data suggest that the more progressive and widespread neurodegenerative nature of MSA, as compared with PD, is reflected in the composition of CSF. We propose that CSF analysis may become part of the diagnostic work-up of patients with parkinsonian syndromes.     

CSF α-synuclein and UCH-L1 levels in Parkinson's disease and atypical parkinsonian disorders

IntroductionThere is an unmet need for biomarkers for Parkinson's disease (PD) and atypical parkinsonian disorders (APD). α-Synuclein, linked to the pathogenesis of PD, is a promising biomarker candidate in need of further investigation. The ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), a pivotal component of the ubiquitin proteasome system which seems to be disturbed in PD, may also be involved in the pathogenesis of this disorder.MethodsWe investigated cerebrospinal fluid (CSF) α-synuclein and UCH-L1 levels from 22 healthy controls, 52 patients with PD, 34 with multiple system atrophy (MSA), 32 with progressive supranuclear palsy, and 12 with corticobasal degeneration.Resultsα-Synuclein levels were significantly decreased in PD and in MSA compared with controls, and in synucleinopathies compared with tauopathies. UCH-L1 levels were significantly decreased in PD, MSA as well as PSP compared with controls, and in PD compared with APD (p < 0.001). Both markers discriminated PD well from controls (p < 0.0001; area under the curve [AUC] = 0.82 and 0.89, respectively). Additionally, CSF α-synuclein separated patients with synucleinopathies from those with tauopathies (p = 0.015; AUC = 0.63), whereas CSF UCH-L1 discriminated between PD and APD (p = 0.0003; AUC = 0.69). Interestingly, α-synuclein and UCH-L1 levels were strongly correlated in PD and synucleinopathies, and weakly in tauopathies. No correlation was found in controls.ConclusionsCSF levels of α-synuclein and UCH-L1 show distinct patterns in parkinsonian syndromes. Their combined determination may be useful in the differential diagnosis of parkinsonian disorders and provide key to understanding their pathoetiology and clinical course. Further large studies are needed to validate our findings.     

Cerebrospinal fluid tau and phosphorylated tau protein are elevated in corticobasal syndrome

Differentiating corticobasal syndrome (CBS) from progressive supranuclear palsy (PSP) and idiopathic Parkinson's disease (PD) can be difficult. To investigate the additional value of cerebrospinal fluid (CSF) biomarkers in the diagnostic differentiation of parkinsonism, we analyzed the CSF concentrations of total protein, lactate and brain specific proteins amyloid‐β₄₂ protein, tau protein (t‐tau), and tau protein phosphorylated at Thr181 (p‐tau), in CSF samples from patients with PSP (n = 21), CBS (n = 12), and PD (n = 28). CBS patients demonstrated higher concentrations of t‐tau and p‐tau compared with PSP and PD patients. In discriminating CBS and PD, t‐tau offered the best combination of sensitivity (75%) and specificity (90.9%), followed by p‐tau (sensitivity 87.5% and specificity 75%). The p‐tau/t‐tau ratio resulted in sensitivity of 84.2% and specificity of 66.7% in discriminating PSP and CBS. In conclusion, our results suggest that CSF parameters are of additional value in the diagnostic differentiation of CBS and PD. © 2010 Movement Disorder Society     

Diagnostic performance of iodine-123-metaiodobenzylguanidine scintigraphy in differential diagnosis between Parkinson's disease and multiple-system atrophy: a systematic review and a meta-analysis

Background and purpose

This study was designed to review the diagnostic performance of iodine-123-metaiodobenzylguanidine (MIBG) scintigraphy in differential diagnosis between Parkinson's disease (PD) and multiple-system atrophy (MSA).

Methods

A comprehensive computer literature search of studies published through March 2011 regarding MIBG scintigraphy in patients with PD and MSA was performed in PubMed/MEDLINE and Embase databases. Only studies in which MIBG scintigraphy was performed for differential diagnosis between PD and MSA were selected. Pooled sensitivity and specificity of MIBG scintigraphy were presented with a 95% confidence interval (CI). The area under the ROC curve was calculated to measure the accuracy of MIBG scintigraphy in differential diagnosis between PD and MSA.

Results

Ultimately, we identified 12 studies comprising a total of 1226 patients (593 patients with PD, 117 patients with other Lewy body disease, 129 patients with MSA, and 387 patients with other diseases). The pooled sensitivity of MIBG scintigraphy to detect PD was 89% (95% CI: 86-91%); the pooled specificity of MIBG scintigraphy to discriminate between PD and MSA was 77% (95% CI: 68-84%). The area under the ROC curve was 0.93.

Conclusions

MIBG scintigraphy is an accurate test for PD detection and differential diagnosis between PD and MSA; this method shows high sensitivity and adequate specificity in this field. Nevertheless, possible causes of false negative and false positive findings should be considered when interpreting the scintigraphic results.     

Tau/α‐synuclein ratio and inflammatory proteins in Parkinson's disease: An exploratory study

Background : No CSF or plasma biomarker has been validated for diagnosis or progression of PD. Objectives : To assess whether the CSF and plasma levels of proteins associated with PD neuropathological inclusions and with neuroinflammation might have value in the diagnosis of PD or in relation to disease severity. Methods : CSF levels of α‐synuclein, amyloid‐ß1‐42, total tau, and threonine‐181 phosphorylated tau, as well as CSF and plasma levels of cytokines (interleukin‐1ß, interleukin‐2, interleukin, interferon‐γ, and tumor necrosis factor α) were studied in 40 PD patients and 40 healthy controls. Plasma levels of cytokines were measured in 51 patients and 26 aditional controls. We also explored the Parkinson's Progression Markers Initiative data set as a replication cohort. Results : CSF levels of α‐synuclein, amyloid‐ß1‐42, and tumor necrosis factor α were lower in patients than in controls, and the total tau/α‐synuclein, phosphorylated tau/α‐synuclein, total tau/amyloid‐ß1‐42+α‐synuclein, and phosphorylated tau/amyloid‐ß1‐42+α‐synuclein ratios were higher in patients. The best area under the curve value was obtained for the phosphorylated tau/α‐synuclein ratio alone (0.86) and also when this was combined with tumor necrosis factor α in CSF (0.91; sensitivity 92.9%, specificity 75% for a cut‐off value of ≤ 0.71). Phosphorylated tau/α‐synuclein and phosphorylated tau/amyloid‐ß1‐42+α‐synuclein were higher in patients than in controls of the Parkinson's Progression Markers Initiative database. Plasma cytokines did not differ between groups, although interleukin‐6 levels were positively correlated with UPDRS‐I, ‐II, and ‐III scores. Conclusions : The CSF phosphorylated tau/α‐synuclein ratio alone, and in combination with tumor necrosis factor α and plasma interleukin‐6 levels, might serve as biomarkers to diagnose PD and monitor its severity. © 2017 International Parkinson and Movement Disorder Society     

Neurofilament heavy-chain NfH(SMI35) in cerebrospinal fluid supports the differential diagnosis of Parkinsonian syndromes.

We aimed to evaluate the potential of the cerebrospinal fluid (CSF) axonal damage biomarker NfH(SMI35) in the laboratory-supported differential diagnosis of parkinsonian syndromes. Patients with idiopathic Parkinson's disease (PD; n = 22), multiple-system atrophy (MSA; n = 21), progressive supranuclear palsy (PSP; n = 21), corticobasal degeneration (CBD; n = 6), and age-matched controls (n = 45) were included. CSF levels of NfH(SMI35) were measured using ELISA. Levels of CSF NfH(SMI35) were elevated in PSP compared to PD and controls (P < 0.05 each). They were also significantly higher in MSA than in PD and controls (P < 0.05 each). NfH(SMI35) differentiated PD from PSP with a sensitivity of 76.5% and a specificity of 94.4%. Axonal damage as measured by CSF NfH(SMI35) is most prominent in the more rapidly progressive syndromes PSP and MSA as compared to PD or CBD. CSF NfH(SMI35) may therefore be of some value for the laboratory-supported differential diagnosis of atypical parkinsonian syndromes.     

Differentiating Parkinson's disease from multiple system atrophy by [123I] meta-iodobenzylguanidine myocardial scintigraphy and olfactory test

We aimed to study whether either [¹²³l] myocardial meta-iodobenzylguanidine (MIBG) myocardial scintigraphy or the odor stick identification test for Japanese (OSIT-J) is effective in differentiating Parkinson’s disease (PD) from multiple system atrophy (MSA). We compared the MIBG accumulation and olfactory score between 42 PD and 42 MSA (19 MSA-P and 23 MSA-C) patients in the early stages. [¹²³l] MIBG myocardial scintigraphy showed higher sensitivity and the olfactory test higher specificity in differentiating PD from MSA. There were significant differences between PD and MSA-C (p = 0.0019) instead of MSA-P (p > 0.05) in the MIBG accumulation, while there were significant differences between PD and MSA-P (p = 0.0003) or MSA-C (p = 0.0003) in the OSIT-J score. Our data suggest that the olfactory test can be useful as a clinical tool with its higher specificity in differentiating PD from MSA in the early stages and, moreover, support the discrimination of PD from MSA-P.     

Diagnostic value of CSF protein profile in a Portuguese population of sCJD patients

The clinical diagnosis of sporadic Creutzfeldt–Jakob disease (sCJD) is difficult, and reliable markers are highly desired. In this work we assess the value of several cerebrospinal fluid (CSF) markers for sCJD diagnosis. Within the framework of the Portuguese Epidemiological Surveillance Program for Human Prion Diseases, CSF samples from 71 patients with clinically suspected sCJD, 30 definite sCJD and 41 non-CJD patients, were analysed for the presence of 14-3-3 protein. CSF levels of tau (t-tau), and phosphorylated tau (p-tau181), S-100b and β amyloid (Aβ42) proteins were determined. The influence of clinical and genetic characteristics on CSF markers sensitivity was also evaluated. Protein 14-3-3 was detected in 29/30 sCJD patients and 9/41 non-CJD patients. Extremely elevated t-tau and S-100b protein levels were found in sCJD patients, while p-tau181 levels were only slightly elevated and Aβ42 showed no differences compared to controls. 14-3-3 was the most sensitive parameter (97%), but its specificity was low (78%); sensitivity/specificity for other proteins were: S-100b—93/93%, t-tau—93/95%, with maximum accuracy being obtained by a combination of tests (14-3-3 combined with either t-tau or S-100b, or combining S-100b with t-tau/Aβ42 or p-tau/t-tau ratios). The sensitivity of 14-3-3, as well as of p-tau181/t-tau ratio, was decreased in younger patients with long disease duration, with the PrP-2 isotype and MV genotype. Both 14-3-3, t-tau and S-100b are sensitive markers for sCJD, but 14-3-3 specificity seems to be lower in this special clinical setting of rapidly progressing dementias. We propose that in cases with a 14-3-3 weak positive result, or in young patients with long disease duration, a second CSF marker would be valuable for the diagnosis of sCJD.     

Heart rate circadian profile in the differential diagnosis between Parkinson disease and multiple system atrophy

Clinical diagnostic criteria indicate presence of autonomic features as the primary hallmark of Multiple System Atrophy (MSA). However involvement of the autonomic system is also a recognized feature of Parkinson's Disease (PD), yielding a broad clinical overlap between the two diseases. Laboratory assessments may help in the differential diagnosis between PD and MSA. Ambulatory Monitoring of Blood Pressure (AMBP) is a suitable tool to study the circadian rhythm of blood pressure (BP) and heart rate (HR). Different studies reported a reduction of physiological BP nocturnal dipping in PD and MSA patients, but failed to identify a distinctive pattern discriminating the two diseases. On the other hand, HR nocturnal behavior has not been exhaustively analyzed. In the present study we compared the profiles of HR circadian rhythm in 61 PD and 19 MSA patients who underwent 24 h AMBP.We found higher nocturnal HR (nHR) (71.5 beats/min ± 7.4) in MSA compared with PD (63.8 beats/min ± 9.6) as well as significantly lower nocturnal decline of HR (ndHR) in MSA (7.3% ± 8.2) vs. PD (14% ± 7.5). At a Receiver Operating Curve analysis nHR and ndHR significantly discriminated MSA from PD. nHR showed a sensitivity of 84.2% and a specificity of 62.3% (AUC 0.76; 95% IC 0.65–0.85); ndHR showed a sensitivity of 68% of and a specificity of 77% (AUC 0.72; 95% IC 0.61–0.82).According to our findings, nHR is increased and ndHR is reduced in MSA compared to PD. Moreover, these two indices discriminate between the two diseases with acceptable accuracy.     

Cerebrospinal fluid levels of neurofilament light chain in multiple system atrophy relative to Parkinson’s disease: a meta-analysis

As a biomarker of axonal injury, neurofilament light chain (NFL) in multiple system atrophy (MSA) patients and Parkinson’s disease (PD) patients has been investigated by numerous studies. However, cerebrospinal fluid (CSF) NFL changes are conflicting in MSA patients relative to PD patients to date. Therefore, the current study was carried out to find out possible heterogeneity sources. Furthermore, “Neurofilament”, “Neurofilament light chain” and “Multiple system atrophy” were employed to search “PubMed”, “Springer” and “Medline” databases until August 2016 with standard mean difference (Std.MD) being calculated. In addition, subgroup analysis and meta-regression were performed to assess possible heterogeneity sources. Nine studies were pooled, in which 212 MSA patients and 373 PD patients were involved. Moreover, CSF NFL in MSA patients was higher than that in PD patients [pooled Std.MD = 1.56, 95% CI (1.12, 2.00), p < 0.00001] with significant heterogeneity (I ² = 76%). Besides, population variations, sample size, the difference in CSF phosphorylated tau (p-tau) levels between MSA patients and PD patients, and Hoehn–Yahr staging of PD patients were the main heterogeneity sources. As shown by meta-regression, Hedges’s g of CSF NFL was correlated with CSF Std.MD of α-synuclein between MSA patients and healthy controls (r = ?1.34824, p = 0.00025). Therefore, CSF NFL increased in MSA patients relative to PD patients. Meta-regression showed that NFL was associated with α-synuclein in CSF of MSA patients relative to healthy controls. Due to the influence of heterogeneity sources, more prospective large sample studies are still needed to assess CSF NFL changes in MSA patients relative to PD patients.     

CSF tau, Aβ42, and MHPG differentiate dementia with Lewy bodies from Alzheimer's disease

Differentiating dementia with Lewy bodies (DLB) from Alzheimer's Disease (AD) can be difficult because of the substantial overlap in clinical features. Since deficits in serotonergic and dopaminergic pathways seem more pronounced in DLB patients, we investigated whether cerebrospinal fluid (CSF) analysis of neurotransmitter metabolites, in addition to brain-specific proteins, may improve the differentiation between DLB and AD. We retrospectively compared CSF concentrations of the neurotransmitter metabolites homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and the brain-specific proteins total tau (t-tau), phosphorylated tau protein (p-tau), and amyloid-β42 (Aβ42) in 45 patients with AD (mean age 71.6 years; 34 (76%) men; 44 probable AD, 1 definite) and 23 patients with DLB (mean age 71.6 years; 18 (78%) men; 6 possible DLB, 16 probable, 1 definite). The concentrations of all neurotransmitter metabolites, as well as those for t-tau and p-tau protein, were significantly lower in DLB compared to AD, irrespective of the diagnostic certainty (i.e., possible or probable). The currently used combination of Aβ42, p-tau, and t-tau yielded a sensitivity of 92.9% and a specificity of 90%. The addition of MHPG resulted in an increased sensitivity of 97.6% and a specificity of 95% for the discrimination between DLB and AD. In conclusion, the combination of MHPG and the brain specific proteins t-tau, p-tau, and Aβ42 in CSF were associated with the clinical diagnosis of DLB and discriminated between AD and DLB with high diagnostic accuracy, suggesting this combination as a potential biomarker for DLB.     

CSF markers of neurodegeneration in Parkinson’s disease

Parkinson’s disease (PD) is a chronic, progressive, neurodegenerative disease with a multifactorial etiology. Protein accumulation is speculated by some to play a prominent role in the pathogenesis of PD. The severity of neurodegeneration should correlate with cerebrospinal fluid (CSF) levels of these neurodegenerative markers (NDMs). The aims of the study were to assess the CSF levels of tau protein, beta-amyloid (1–42), cystatin C, and clusterin in patients suffering from PD and in a control group, to compare the CSF levels between the two groups and to correlate them to PD duration. NDMs in the CSF were assessed in 32 patients suffering from PD and in a control group (CG) of 30 patients. The following statistically significant differences in the CSF were found: higher tau protein (p = 0.045) and clusterin levels (p = 0.004) in PD patients versus CG; higher tau protein levels (p = 0.033), tau protein/beta-amyloid (1–42) ratio (p = 0.011), and clusterin (p = 0.044) in patients suffering from PD for <2 years versus patients suffering PD for more than 2 years. No differences between beta-amyloid (1–42) and cystatin C CSF levels were found in the CG and PD patients groups. Significantly higher tau protein and clusterin CSF levels in the group of PD patients with disease duration of <2 years probably reflect the fact that most neurodegenerative changes in PD patients occur in the initial stage of disease.     

Combined assessment of tau and neuronal thread protein in Alzheimer's disease CSF

OBJECTIVE: Comparative study of CSF levels of tau and AD7C-neuronal thread protein (NTP) in patients with AD and control subjects. BACKGROUND: AD is characterized by neurofibrillary tangles composed of the abnormally hyperphosphorylated microtubule-associated protein tau. AD7C-NTP is a proposed AD marker expressed at early stages of neurofibrillary degeneration. METHODS: Enzyme-linked immunosorbent assays specific for tau and AD7C-NTP. CSF samples were obtained from 35 demented patients (25 with antemortem clinical diagnosis of probable AD, 5 with neuropathologic diagnosis of definite AD, 5 with Lewy body pathology), 29 nondemented patients with PD, and 16 elderly healthy control subjects. Receiver operating characteristics (ROC) and multivariate discriminant analysis for AD versus controls. Correlational analysis of CSF tau and AD7C-NTP and of each marker with Mini-Mental State Examination (MMSE) scores was performed. RESULTS: Levels of both tau and AD7C-NTP were significantly elevated in the AD patients compared with control subjects. ROC analysis showed that CSF tau distinguished between patients with AD and nondemented control subjects with 63% sensitivity and 89% specificity, AD7C-NTP with 70% sensitivity and 87% specificity. Combined evaluation of both markers with discriminant analysis raised the specificity to 93% at a 63% sensitivity level. Both markers positively correlated with each other within the AD group, but not among control subjects. CSF levels of AD7C-NTP, but not of tau, showed a small but significant inverse correlation (r = -0.43) with MMSE scores of AD patients. CONCLUSIONS: CSF levels of tau and AD7C-NTP may be useful biomarkers for AD.     

A prospective study of CSF markers in 250 patients with possible Creutzfeldt-Jakob disease

OBJECTIVE: To investigate various cerebrospinal fluid (CSF) markers that could assist in the clinical diagnosis of Creutzfeldt-Jakob disease (CJD). METHODS: CSF samples were analysed for the presence of 14-3-3 protein, microtubule associated protein tau, and beta amyloid in 250 patients with possible CJD. Densitometric analysis was used to quantify the level of 14-3-3 in all patients. RESULTS: Analysis of the clinical data showed that cerebellar signs or myoclonus combined with progressive dementia were the main features leading to a clinical suspicion of CJD. While 14-3-3 detection had a sensitivity of 100% and a specificity of 92%, tau determination using a threshold of 1300 pg/ml had a sensitivity of 87% and a specificity of 97%. If the protocol for the analysis of 14-3-3 was modified (using densitometric analysis) a higher specificity (97%) could be obtained, but with a lower sensitivity (96%). Maximum sensitivity, specificity, and positive predictive value were obtained with a combination of 14-3-3 and beta amyloid determinations. The concentrations of 14-3-3 and tau in the CSF were reduced in CJD patients with a long duration of disease (more than one year; p < 0.05). The concentrations of 14-3-3 or tau were lowest at the onset or at the end stage of the disease, while the beta amyloid concentration remained low throughout the course of the disease. CONCLUSIONS: Both 14-3-3 and tau protein are sensitive and specific biomarkers for CJD. The combination of 14-3-3 and beta amyloid analysis resulted in the maximum sensitivity, specificity, and positive predictive value. When these biomarkers are used in the diagnosis of CJD, the phase of the disease in which the CSF sample was obtained should be taken into account. Disease duration, dependent on the PrP genotype, also has a significant influence on the level of 14-3-3 and tau in the CSF.     

Detection of biomarkers with a multiplex quantitative proteomic platform in cerebrospinal fluid of patients with neurodegenerative disorders

Biomarkers are needed to assist in the diagnosis and medical management of various neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy body (DLB). We have employed a multiplex quantitative proteomics method, iTRAQ (isobaric Tagging for Relative and Absolute protein Quantification), in conjunction with multidimensional chromatography, followed by tandem mass spectrometry (MS/MS), to simultaneously measure relative changes in the proteome of cerebrospinal fluid (CSF) obtained from patients with AD, PD, and DLB compared to healthy controls. The diagnosis of AD and DLB was confirmed by autopsy, whereas the diagnosis of PD was based on clinical criteria. The proteomic findings showed quantitative changes in AD, PD, and DLB as compared to controls; among more than 1,500 identified CSF proteins, 136, 72, and 101 of the proteins displayed quantitative changes unique to AD, PD, and DLB, respectively. Eight unique proteins were confirmed by Western blot analysis, and the sensitivity at 95% specificity was calculated for each marker alone and in combination. Several panels of unique makers were capable of distinguishing AD, PD and DLB patients from each other as well as from controls with high sensitivity at 95% specificity. Although these preliminary findings must be validated in a larger and different population of patients, they suggest that a roster of proteins may be generated and developed into specific biomarkers that could eventually assist in clinical diagnosis and monitoring disease progression of AD, PD and DLB.     

Value of CSF beta-amyloid1-42 and tau as predictors of Alzheimer's disease in patients with mild cognitive impairment

Subjects with mild cognitive impairment (MCI) are at a high risk of developing clinical Alzheimer's disease (AD). We asked to what extent the core biomarker candidates cerebro-spinal fluid (CSF) beta-amyloid(1-42) (Abeta(1-42)) and CSF tau protein concentrations predict conversion from MCI to AD. We studied 52 patients with MCI, 93 AD patients, and 10 healthy controls (HC). The MCI group was composed of 29 patients who had converted to AD during follow-up, and of 23 patients who showed no cognitive decline. CSF Abeta(1-42) and tau protein levels were assessed at baseline in all subjects, using enzyme-linked immunosorbent assays. For assessment of sensitivity and specificity, we used independently established reference values for CSF Abeta(1-42) and CSF tau. The levels of CSF tau were increased, whereas levels of Abeta(1-42) were decreased in MCI subjects. Abeta(1-42) predicted AD in converted MCI with a sensitivity of 59% and a specificity of 100% compared to HC. Tau yielded a greater sensitivity of 83% and a specificity of 90%. In a multiple Cox regression analysis within the MCI group, low baseline levels of Abeta(1-42), but not other predictor variables (tau protein, gender, age, apolipoprotein E epsilon4 carrier status, Mini Mental Status Examination score, observation time, antidementia therapy), correlated with conversion status (P<0.05). Our findings support the notion that CSF tau and Abeta(1-42) may be useful biomarkers in the early identification of AD in MCI subjects.     

Differential pattern of brain‐specific CSF proteins tau and amyloid‐beta in Parkinsonian syndromes

To evaluate cerebrospinal fluid (CSF) proteins reflecting processes of neurodegeneration and glial activation in progressive supranuclear palsy (PSP; Richardson's syndrome, n = 20; PSP‐Parkinsonism, n = 7) and multiple system atrophy (MSA, n = 25), we analyzed tau, phosphorylated tau, amyloid‐beta_1–42 (Aβ1–42), Aβ1–40, glial fibrillary acidic protein (GFAP), and CSF routine variables. Individuals with PSP‐Parkinsonism and MSA had elevated tau levels when compared with Richardson's syndrome, Parkinson's disease (PD), and age‐matched controls (P ≤ 0.001). Ratios of P‐tau/T‐tau were significantly different in Parkinsonian syndromes. CSF Aβ1–42 was decreased only in patients with Richardson's syndrome. In a subset of Parkinsonian syndromes, we found elevated GFAP concentrations and increased CSF/serum albumin ratios. There were no correlations between biomarker concentrations and clinical scores in any of the diseases. In conclusion, this preliminary data show that changes in CSF tau and Aβ1–42 may indicate different protein processing in PSP patients and might, therefore, be relevant in the differentiation of PSP subtypes. © 2010 Movement Disorder Society     

Biomarkers to detect central dopamine deficiency and distinguish Parkinson disease from multiple system atrophy

ObjectiveBiomarkers are increasingly important to diagnose and test treatments of neurodegenerative diseases such as Parkinson disease (PD). This study compared neuroimaging, neurochemical, and olfactory potential biomarkers to detect central dopamine (DA) deficiency and distinguish PD from multiple system atrophy (MSA).MethodsIn 77 PD, 57 MSA, and 87 control subjects, radioactivity concentrations in the putamen (PUT), caudate (CAU), occipital cortex (OCC), and substantia nigra (SN) were measured 2 h after 6-[¹⁸F]fluorodopa injection, septal myocardial radioactivity measured 8 min after 6-[¹⁸F]fluorodopamine injection, CSF and plasma catechols assayed, or olfaction tested (University of Pennsylvania Smell Identification Test (UPSIT)). Receiver operating characteristic curves were constructed, showing test sensitivities at given specificities.ResultsPUT:OCC, CAU:OCC, and SN:OCC ratios of 6-[¹⁸F]fluorodopa-derived radioactivity were similarly low in PD and MSA (p < 0.0001, p < 0.0001, p = 0.003 compared to controls), as were CSF dihydroxyphenylacetic acid (DOPAC) and DOPA concentrations (p < 0.0001, each). PUT:SN and PUT:CAU ratios were lower in PD than in MSA (p = 0.004; p = 0.005). CSF DOPAC correlated positively with PUT:OCC ratios (r = 0.61, p < 0.0001). Myocardial 6-[¹⁸F]fluorodopamine-derived radioactivity distinguished PD from MSA (83% sensitivity at 80% specificity, 100% sensitivity among patients with neurogenic orthostatic hypotension). Only PD patients were anosmic; only MSA patients had normal olfaction (61% sensitivity at 80% specificity).ConclusionsPD and MSA feature low PUT:OCC ratios of 6-[¹⁸F]fluorodopa-derived radioactivity and low CSF DOPAC and DOPA concentrations, cross-validating the neuroimaging and neurochemical approaches but not distinguishing the diseases. PUT:SN and PUT:CAU ratios of 6-[¹⁸F]fluorodopa-derived radioactivity, cardiac 6-[¹⁸F]fluorodopamine-derived radioactivity, and olfactory testing separate PD from MSA.     

The arginine growth hormone stimulation test in bradykinetic‐rigid parkinsonisms

The arginine growth hormone (GH) stimulation test differentiates the Parkinsonian variant of multiple system atrophy (MSA‐P) from idiopathic Parkinson's disease (PD). Our aim was to evaluate the accuracy of the arginine GH stimulation test in distinguishing between PSP, MSA‐P, and PD. We measured the GH response to arginine in serum samples of 26 MSA‐P, 23 PSP, and 26 PD patients, and in 80 healthy controls. We used ANOVA followed by the Bonferroni test to compare GH values and peaks among groups. We used receiver operating characteristic curve analysis to establish the arginine cut‐off level that best differentiated between MSA‐P, PSP, and PD. The GH peak was significantly lower (P < 0.01) in MSA‐P (1.46 ± 0.29 μg/L) than in both PD (8.74 ± 0.98 μg/L) and PSP (6.64 ± 0.82 μg/L) patients, and controls (8.59 ± 0.44 μg/L). Growth hormone peaked later in PSP patients than in PD patients and controls. At a cut‐off level of 4 μg/L, arginine test distinguished MSA‐P from PD with a sensitivity of 92% and a specificity of 96%, and MSA‐P from PSP with a sensitivity of 78% and a specificity of 96%. The GH response to arginine differentiates MSA‐P from PD and PSP with a good diagnostic accuracy. The neuroendocrine response to arginine of PSP patients differed from that of MSA‐P patients, but was not identical to that of normal controls and PD patients. Our results suggest that the impairment of the central mechanisms modulating GH release differs between PSP and MSA‐P. © 2007 Movement Disorder Society