Foudil Lamari

Cerebrospinal fluid biomarkers in the differential diagnosis of Alzheimer's disease from other cortical dementias

Background Considering that most semantic dementia (SD) and frontotemporal dementia (FTD) patients show no post-mortem Alzheimers disease (AD) pathology, cerebrospinal fluid (CSF) biomarkers may be of value for distinguishing these patients from those with AD. Additionally, biomarkers may be useful for identifying patients with atypical phenotypic presentations of AD, such as posterior cortical atrophy (PCA) and primary progressive non-fluent or logopenic aphasia (PNFLA). Methods The authors investigated CSF biomarkers (beta-amyloid 1–42 (Aβ42), total tau (T-tau) and phosphorylated tau (P-tau)) in 164 patients with AD (n=60), PCA (n=15), behavioural variant FTD (n=27), SD (n=19), PNFLA (n=26) and functional cognitive disorders (FCD, n=17). The authors then examined the diagnostic value of these CSF biomarkers in distinguishing these patients from those with AD. Results The P-Tau/Aβ42 ratio was found to be the best biomarker for distinguishing AD from FTD and SD, with a sensitivity of 91.7% and 98.3%, respectively, and a specificity of 92.6% and 84.2%, respectively. As expected, biomarkers were less effective in differentiating AD from PNFLA and PCA, as significant proportions of PCA and PNFLA patients (60% and 61.5%, respectively) had concurrent alterations of both T-tau/Aβ42 and P-Tau/Aβ42 ratios. None of the FCD patients had a typical AD CSF profile or abnormal T-tau/Aβ42 or P-Tau/Aβ42 ratios. Conclusion The P-Tau/Aβ42 ratio is a useful tool to distinguish AD from both FTD and SD, which are known to involve pathological processes distinct from AD. Biomarkers could be useful for identifying patients with an atypical AD phenotype that includes PNFLA and PCA.

Similar amyloid-β burden in posterior cortical atrophy and Alzheimer's disease

While the clinical presentation of posterior cortical atrophy is clearly distinct from typical Alzheimers disease, neuropathological studies have suggested that most patients with posterior cortical atrophy have Alzheimers disease with an atypical visual presentation. We analysed in vivo pathophysiological markers of Alzheimers disease such as cerebrospinal fluid biomarkers and positron emission tomography imaging with ¹¹C-labelled Pittsburgh compound-B in posterior cortical atrophy to determine whether biochemical profile and fibrillar amyloid-β burden topography are associated with the clinical presentation. Nine patients with posterior cortical atrophy and nine with typical Alzheimers disease individually matched for age, duration and severity of the disease and 10 cognitively normal age-matched controls were included. ¹¹C-labelled Pittsburgh compound-B images were analysed both using volumes of interest and on a voxel-wise basis using statistical parametric mapping, taking into account the individual regional cortical atrophy. Cerebrospinal fluid biomarkers did not differ between posterior cortical atrophy and patients with Alzheimers disease. Compared with normal controls, both posterior cortical atrophy and Alzheimers disease groups showed increased ¹¹C-labelled Pittsburgh compound-B uptake. No significant difference was found in regional or global ¹¹C-labelled Pittsburgh compound-B binding between posterior cortical atrophy and Alzheimers disease groups with both volumes of interest and voxel-wise basis using statistical parametric mapping methods. Our findings demonstrate that cerebrospinal fluid biomarkers and positron emission tomography imaging with ¹¹C-labelled Pittsburgh compound-B may be useful in identifying an atypical visual form of Alzheimers disease. The similar topography of fibrillar amyloid-β deposition between typical Alzheimers disease and posterior cortical atrophy groups suggests that, although amyloid-β accumulation plays a critical role in the pathogenesis of Alzheimers disease, other factors such as neurofibrillary tangles may contribute to the different clinical features observed in posterior cortical atrophy.

CSF tau markers are correlated with hippocampal volume in Alzheimer's disease

Hippocampal atrophy as assessed by magnetic resonance imaging (MRI) and abnormal cerebrospinal fluid (CSF) biomarkers are supportive features for the diagnosis of Alzheimers disease (AD) and are assumed to be indirect pathological markers of the disease. In AD patients, antemortem MRI hippocampal volumes (HVs) correlate with the density of neurofibrillary tangles (but not with senile plaques) at autopsy suggesting that HVs may better correlate with CSF tau and hyperphosphorylated tau (P-tau) levels than CSF amyloid beta protein (Aβ)(42) level. Here, we tested this hypothesis in a well-defined AD group. Patients were selected according to the New Research Criteria for AD, including specific episodic memory deficit and CSF AD profile (defined as abnormal ratio of Aβ(42):tau). MRI was performed within 6 months of lumbar puncture. HVs were obtained using automated segmentation software. Thirty-six patients were included. Left HV correlated with CSF tau (R = -0.53) and P-tau (R = -0.56) levels. Mean HVs correlated with the CSF P-tau level (R = -0.52). No correlation was found between any brain measurement and CSF Aβ(42) level. The CSF tau and P-tau levels, but not the CSF Aβ(42) level, correlated with HV, suggesting that CSF tau markers reflect the neuronal loss associated with the physiopathological process of AD.

Two distinct amnesic profiles in behavioral variant frontotemporal dementia.

BACKGROUND Whether or not episodic memory deficit is a characteristic of behavioral variant frontotemporal dementia (bvFTD) is a crucial question for its diagnosis and management. METHODS We compared the episodic memory performance profile of bvFTD patients with healthy control subjects and patients with Alzheimers disease (AD) as defined by clinical and biological criteria. Episodic memory was assessed with the Free and Cued Selective Reminding Test, which controls for effective encoding and identifies memory storage ability resulting from consolidation processing. One hundred thirty-four participants were evaluated: 56 patients with typical clinical presentation of AD and pathophysiological evidence as defined by cerebrospinal fluid AD biomarker profile and/or significant amyloid retention on Pittsburgh Compound B positron emission tomography; 56 patients diagnosed with bvFTD with no evidence of AD-cerebrospinal fluid biomarkers when a profile was available (28/56), including 44 progressive (bvFTD) and 12 nonprogressive (phenocopies) patients; and 22 control subjects with negative amyloid imaging. RESULTS Memory scores could not differentiate bvFTD from AD patients (sensitivity and specificity <50%). Taking into account the individual distribution of Free and Cued Selective Reminding Test scores, half of bvFTD patients had a deficit of free recall, total (free + cued) recall, and delayed recall as severe as AD patients. The other half had subnormal scores similar to phenocopies and a delayed recall score similar to control subjects. CONCLUSIONS We observed two distinct amnesic profiles in bvFTD patients that could reflect two types of hippocampal structure and Papez circuit involvement. These findings on episodic memory profiles could contribute to discussions on the recent international consensus criteria for bvFTD.

Is Hippocampal Volume a Good Marker to Differentiate Alzheimer's Disease from Frontotemporal Dementia?

BACKGROUND Previous studies analyzed the ability of hippocampal volumes (HV) to differentiate Alzheimers disease (AD) from frontotemporal dementia (FTD). However, these studies did not include patients selected according to clinico-biological criteria, using pathophysiological biomarkers. OBJECTIVE To analyze the effectiveness of hippocampal volumetric measures to distinguish AD from behavioral variant FTD (bvFTD), using strict inclusion criteria based on clinical and pathophysiological markers. METHODS Seventy-two participants were included: 31 AD patients with predominant and progressive episodic memory deficits associated with typical AD cerebrospinal fluid (CSF) profile and/or positive amyloid imaging (PET with 11C-labeled Pittsburgh Compound B [PiB]), 26 bvFTD patients diagnosed according to consensual clinical criteria and with no AD CSF profile, and 15 healthy controls without amyloid retention on PiB-PET exam. HV were segmented with an automated method and were normalized to total intracranial volume (nHV). RESULTS Significant reductions in HV were found in both AD and bvFTD patients compared with controls, but there were no significant difference between AD and bvFTD patients. Mean nHV distinguished normal controls from either AD or bvFTD with high sensitivity (80.6% and 76.9%, respectively) and specificity (93.3% for both), but it was inefficient in differentiating AD from bvFTD (9.7% specificity). There was no difference in the clinical and neuropsychological profiles according to HV in bvFTD and AD patients. CONCLUSIONS When considered alone, measures of HV are not good markers to differentiate AD from bvFTD. Hippocampal sclerosis associated with FTD may explain the high degree of overlap in nHV between both groups.

Neurofilament light chain: a biomarker for genetic frontotemporal dementia

To evaluate cerebrospinal fluid (CSF) and serum neurofilament light chain (NfL) levels in genetic frontotemporal dementia (FTD) as a potential biomarker in the presymptomatic stage and during the conversion into the symptomatic stage. Additionally, to correlate NfL levels to clinical and neuroimaging parameters.

Multicenter validation of CSF neurofilaments as diagnostic biomarkers for ALS

Abstract OBJECTIVE: Neurofilaments are leading neurochemical biomarkers for amyotrophic lateral sclerosis (ALS). Here, we investigated the effect of preanalytical factors on neurofilament concentrations in cerebrospinal fluid (CSF) in a “reverse” round-robin with 15 centers across Europe/U.S. METHODS: Samples from ALS and control patients (5/5 each center, n = 150) were analyzed for phosphorylated neurofilament heavy chain (pNfH) and neurofilament light chain (NfL) at two laboratories. RESULTS: CSF pNfH was increased (p < 0.05) in ALS in 10 out of 15 centers and NfL in 5 out of 12 centers. The coefficient of variation (CV%) of pNfH measurements between laboratories was 18.7 ± 19.1%. We calculated a diagnostic cut-off of >568.5 pg/mL for pNfH (sensitivity 78.7%, specificity 93.3%) and >1,431pg/mL for NfL (sensitivity 79.0%, specificity 86.4%). CONCLUSION: Values in ALS patients are already comparable between most centers, supporting eventual implementation into clinical routine. However, continuous quality control programs will be necessary for inclusion in the diagnostic work-up.

The AD-CSF-index discriminates Alzheimer's disease patients from healthy controls: a validation study.

BACKGROUND Cerebrospinal fluid (CSF) biomarkers of Alzheimers disease (AD) show an acceptable diagnostic sensitivity and specificity; however, their interpretation and ease of use is far from optimal. OBJECTIVE To study and validate the diagnostic accuracy of an easy-to-use normalized CSF biomarker index, the AD-CSF-index, in different European populations. METHODS A total of 342 subjects, 103 healthy controls and 239 AD patients, from four European memory clinics were included. The AD-CSF-index was constructed from the addition of normalized values between the minimum and maximum of amyloid and tau protein levels. The diagnostic accuracy, receiver operating characteristic, and regression analysis of the AD-CSF-index and other composite indices were evaluated in this study. RESULTS AD patients presented a significantly higher AD-CSF-index than healthy subjects (control = 0.5204; AD = 1.2272; p < 0.001). The AD-CSF-index obtained a sensitivity of 88.6% at 85% specificity and also showed a significantly higher diagnostic power (p < 0.05) than the individual CSF biomarkers and other studied indices. The performance of the AD-CSF-index was very similar between ELISA and MesoScale measurements. Cut-off values of approximately 0.75 provided the lowest achievable overall classification errors and a cut-off point of about 0.95 consistently provided specificities above 85%. CONCLUSION The AD-CSF-index represents a novel approach, combining normalized CSF values, for the biological diagnosis of AD. The AD-CSF-index presents an optimal AUC with high sensitivity and specificity and seems to be a simple and intuitive way to interpret AD CSF biomarker results even from different analytical platforms.

HS3ST2 expression is critical for the abnormal phosphorylation of tau in Alzheimer's disease-related tau pathology

Heparan sulphate (glucosamine) 3-O-sulphotransferase 2 (HS3ST2, also known as 3OST2) is an enzyme predominantly expressed in neurons wherein it generates rare 3-O-sulphated domains of unknown functions in heparan sulphates. In Alzheimers disease, heparan sulphates accumulate at the intracellular level in disease neurons where they co-localize with the neurofibrillary pathology, while they persist at the neuronal cell membrane in normal brain. However, it is unknown whether HS3ST2 and its 3-O-sulphated heparan sulphate products are involved in the mechanisms leading to the abnormal phosphorylation of tau in Alzheimers disease and related tauopathies. Here, we first measured the transcript levels of all human heparan sulphate sulphotransferases in hippocampus of Alzheimers disease (n = 8; 76.8 ± 3.5 years old) and found increased expression of HS3ST2 (P < 0.001) compared with control brain (n = 8; 67.8 ± 2.9 years old). Then, to investigate whether the membrane-associated 3-O-sulphated heparan sulphates translocate to the intracellular level under pathological conditions, we used two cell models of tauopathy in neuro-differentiated SH-SY5Y cells: a tau mutation-dependent model in cells expressing human tau carrying the P301L mutation hTau(P301L), and a tau mutation-independent model in where tau hyperphosphorylation is induced by oxidative stress. Confocal microscopy, fluorescence resonance energy transfer, and western blot analyses showed that 3-O-sulphated heparan sulphates can be internalized into cells where they interact with tau, promoting its abnormal phosphorylation, but not that of p38 or NF-κB p65. We showed, in vitro, that the 3-O-sulphated heparan sulphates bind to tau, but not to GSK3B, protein kinase A or protein phosphatase 2, inducing its abnormal phosphorylation. Finally, we demonstrated in a zebrafish model of tauopathy expressing the hTau(P301L), that inhibiting hs3st2 (also known as 3ost2) expression results in a strong inhibition of the abnormally phosphorylated tau epitopes in brain and in spinal cord, leading to a complete recovery of motor neuronal axons length (n = 25; P < 0.005) and of the animal motor response to touching stimuli (n = 150; P < 0.005). Our findings indicate that HS3ST2 centrally participates to the molecular mechanisms leading the abnormal phosphorylation of tau. By interacting with tau at the intracellular level, the 3-O-sulphated heparan sulphates produced by HS3ST2 might act as molecular chaperones allowing the abnormal phosphorylation of tau. We propose HS3ST2 as a novel therapeutic target for Alzheimers disease.

Distinct brain perfusion pattern associated with CSF biomarkers profile in primary progressive aphasia

Objective A new classification of primary progressive aphasia (PPA) was recently proposed to differentiate between non-fluent aphasia (NF-PPA), semantic variant of PPA (S-PPA) and logopenic aphasia (LPA) by their phenotypic presentations. CSF biomarkers (BM) may differentiate PPA with atypical Alzheimers disease (AD) that presents with LPA from PPA with frontotemporal lobe degeneration that presents with either NF-PPA or S-PPA. Single photon emission computed tomography (SPECT) was used to investigate brain hypoperfusion differences among PPA subtypes according to their CSF AD profiles. Methods 34 PPA patients underwent lumbar puncture and brain perfusion SPECT. PPA patients were classified into two subgroups according to theAβ42:tau ratio: PPA BM positive (with an AD CSF profile) and PPA BM negative (not having an AD CSF profile). The biological classification was made while blind to the phenotypical presentation. The brain perfusion profiles of the PPA subgroups were compared with those of 24 healthy subjects. Results PPA BM positive patients had left-side predominant hypoperfusion in the temporoparietal cortex that extended to the dorsolateral prefrontal cortex and perisylvian region while PPA BM negative patients had hypoperfusion that was predominant in the temporal poles (p<10−4 corrected). Conclusion Distinct hypoperfusion patterns in PPA BM positive and PPA BM negative patients were observed, similar to those that have been described for S-PPA and LPA. These results support using CSF biomarkers to classify PPA.