ABSTRACTTau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies (4RT), i... more ABSTRACTTau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies (4RT), including cortico-basal degeneration and progressive supranuclear palsy (PSP). Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4RTs, characterized not only by neuronal but also by astroglial and oligodendroglial tau accumulation. Here, we assessed whether connectivity drives 4R-tau spreading patterns by combining resting-state fMRI connectomics with both 2nd generation 18F- PI-2620 tau-PET in 46 patients with clinically diagnosed 4RTs and post-mortem cell-type- specific regional tau assessments from two independent PSP samples (n=97/96). We found that inter-regional connectivity was associated with higher inter-regional correlation of both tau- PET and post-mortem tau levels in 4RTs. In regional cell-type specific post-mortem tau assessments, this association was stronger for neuronal than for astroglial or oligode...
Journal of neural transmission (Vienna, Austria : 1996), Jan 8, 2015
Presenilin 1 (PSEN1) mutations are the major cause of autosomal dominant Alzheimer's disease ... more Presenilin 1 (PSEN1) mutations are the major cause of autosomal dominant Alzheimer's disease (ADAD). Here we report three novel PSEN1 mutations: Ile238_Lys239insIle, Ala246Pro and Ala164Val from patients who manifested in their twenties, forties and seventies, respectively, with variant clinical presentations of dementia. These cases exemplify the tremendous heterogeneity of clinical phenotypes and age of onset associated with PSEN1 mutations. The possibility of ADAD-not previously suspected in two of our patients-should always be considered in neurodegenerative conditions albeit they might neither exhibit the typical clinical picture of Alzheimer's disease nor early onset dementia, which is regarded the primary clinical sign of hereditary neurodegeneration.
Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition,... more Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10(-12)), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10(-8)), and 2p22 at SOS1 (rs963731; P=1.76 × 10(-7)). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10(-7)) and MAPT H1c (17q21; rs242557; P=7.91 × 10(-6)). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT a...
The objective was to characterize a rapidly progressive subtype of Alzheimer's disease (rpAD)... more The objective was to characterize a rapidly progressive subtype of Alzheimer's disease (rpAD). Multicenter (France, Germany, Japan, Spain) retrospective analyses of neuropathologically confirmed rpAD cases initially classified as prion disease due to their clinical phenotype were performed. Genetic properties, cerebrospinal fluid biomarkers, neuropathology, and clinical features were examined. Eighty-nine patients were included (median survival 10 months). APOE and PRNP codon 129 genotype distribution paralleled a healthy control group. APOE ε4 homozygosity was absent. Cerebrospinal fluid biomarkers were abnormal, but within a range as expected for classic AD, except for proteins 14-3-3, which were detectable in 42%. Thus, evidence of the existence of rpAD is accumulating. The APOE profile is intriguing, suggesting that this very rapid disease form might represent a distinct subtype of Alzheimer's disease.
The α-synuclein gene (SNCA) plays a major role in the aetiology of Lewy body disease (LBD) includ... more The α-synuclein gene (SNCA) plays a major role in the aetiology of Lewy body disease (LBD) including Parkinson's disease (PD). Point mutations and genetic alterations causing elevated gene expression are causally linked to familial PD. To what extent epigenetic changes play a role in the regulation of α-synuclein expression and may contribute to the aetiology of sporadic LBD is a matter of debate. We analysed the methylation state of the promoter region and a CpG-rich region of intron 1 of α-synuclein in several brain regions in sporadic LBD and controls using 454 GS-FLX-based high-resolution bisulphite sequencing. Our results indicate that there are significant differences in the level of methylation between different brain areas. The overall methylation levels in the promoter and intron 1 of α-synuclein are rather low in controls and-in contrast to previously reported findings-are not significantly different from LBD. However, single CpG analysis revealed significant hyper- and hypomethylation at different positions in various brain regions and LBD stages. A slight overall increase in methylation related to LBD patients' age was detected.
Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Br... more Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10(-3). We found significant previously unidentified signals (P < 5 × 10(-8)) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component.
Autopsy is the diagnostic gold standard for progressive supranuclear palsy (PSP). The National In... more Autopsy is the diagnostic gold standard for progressive supranuclear palsy (PSP). The National Institute of Neurological Disorders and Stroke and Society for Progressive Supranuclear Palsy (NINDS-SPSP) criteria for the clinical diagnosis of "probable" PSP are thought to possess high specificity and low sensitivity. The NINDS-SPSP criteria for "possible" PSP are considered to increase sensitivity at the expense of specificity. The Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS) criteria are intended to improve sensitivity while maintaining high specificity. The aim of this study was to conduct a clinicopathological evaluation of the NINDS-SPSP and NNIPPS criteria in tertiary neurological centers. Defined clinical features and their year of onset were recorded by chart review in neuropathologically diagnosed patients with PSP, Parkinsons's disease (PD), MSA parkinsonism and corticobasal degeneration from four European brain banks. Fulfillment of the clinical diagnostic criteria was verified for each year after disease onset and for the final antemortem record. We analyzed 98 PSP patients and 46 disease controls. The NINDS-SPSP "probable" criteria yielded shorter time to diagnosis, slightly higher specificity and positive predictive value (PPV), and similar sensitivity, compared with the NNIPPS criteria. Unexpectedly, the NINDS-SPSP "possible" criteria yielded the lowest sensitivity, specificity, and PPV. A combination of NINDS-SPSP possible and probable criteria yielded the highest sensitivity. We suggest that the NINDS-SPSP probable criteria might be preferred for recruitment of patients for clinical trials, where an early and specific diagnosis is important. For routine clinical care, where high sensitivity is crucial, a combination of NINDS possible and probable criteria might be preferred.
Journal of Neuropathology and Experimental Neurology, 2007
Animal studies suggest that adult bone marrow cells have the potential to migrate into the brain ... more Animal studies suggest that adult bone marrow cells have the potential to migrate into the brain and generate new neural cells. Because data on this physiologic repair mechanism in humans are lacking, we investigated bone marrow engraftment into the brain of bone marrow recipients after sex-mismatched transplantation. Brain sections of seven allogeneic female bone marrow recipients were examined. The Y-chromosome, which served as a natural marker of donor bone marrow-derived cells after male-to-female transplantation, was identified by in situ hybridization. The neural phenotype of Y-chromosome-positive cells was determined using neural nuclear protein (NeuN) immunohistochemistry. Y-chromosome-positive cells expressing NeuN were found within the first 3 months after transplantation in both the cerebrum and the cerebellum at a frequency of 0.003% to 0.013% of all neurons. These cells were observed only in patients with cerebral lymphocytic infiltration and graft-versus-host disease. Our data suggest that adult bone marrow cells are capable of generating cells that express the neural marker NeuN early after transplantation. Cells with this specific phenotype may contribute to tissue repair in brain regions remote from neurogenic zones.
Decreased levels of β-amyloid (Aβ) 1-42 in cerebrospinal fluid (CSF) are characteristic for Alzhe... more Decreased levels of β-amyloid (Aβ) 1-42 in cerebrospinal fluid (CSF) are characteristic for Alzheimer's disease (AD) and are also evident in Creutzfeldt-Jakob disease (CJD). Aβ plaques are thought to be responsible for this decrease in AD patients, whereas such Aβ plaques are rarely seen in CJD. To investigate the Aβ pattern in brain and CSF of neuropathologically confirmed CJD and AD patients we used an electrophoretic method to investigate Aβ peptide fractions which are not accessible to ELISA and immunohistochemistry. We analyzed Aβ peptides in the CSF of autopsy-confirmed CJD and AD patients and the corresponding brain homogenates using a quantitative urea-based Aβ electrophoresis immunoblot (Aβ-SDS-PAGE/immunoblot).The CSF Aβ1-42 decrease correlated with the brain Aβ load in AD, but not in CJD. There was no difference in the soluble fractions of brain homogenate in AD and CJD. We therefore conclude that different mechanisms in AD and CJD are responsible for the Aβ1-42 decrease in the CSF.
Journal of neuropathology and experimental neurology, 2011
α-Internexin (INA) has been proposed to be a surrogate marker for the 1p/19q codeletion in oligod... more α-Internexin (INA) has been proposed to be a surrogate marker for the 1p/19q codeletion in oligodendroglial tumors (OTs). We analyzed INA expression in 83 glioma and 21 oligodendroglial phenotype-mimicking tumors (OMT) to assess its usefulness in differential diagnosis and its correlation with 1p/19q status; in particular, INA expression in gliomas with isolated/partial 1p or 19q deletions was assessed. α-Internexin expression and 1p/19q codeletion were present in 92% (34/37) of codeleted tumors (p < 0.0001). By contrast, INA was found in only 20% of cases with isolated/partial 1p aberrations and 36% of cases without 1p/19q deletions; it was also foundin 63% (10/16) of cases with isolated/partial 19q aberrations. α-Internexin expression was more specific in high-grade than in low-grade gliomas (66% vs 31%). Notably, a subset of tumors (10/83) displayed a biphasic INA expression pattern that was significantly associated with proliferation rate, whereas all areas harbored the 1p/19...
To characterize clinical features, CSF biomarkers and genetic polymorphisms of patients suffering... more To characterize clinical features, CSF biomarkers and genetic polymorphisms of patients suffering from a rapidly progressing subtype of Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s dementia (rpAD). Retrospective analyses of 32 neuropathologically confirmed cases differentially diagnosed as AD out of a group with rapidly progressive dementia. CSF biomarkers (14-3-3, tau, beta-amyloid 1-42) and genetic markers (PRNP codon 129, apolipoprotein E, ApoE, polymorphism) were determined. Median survival was 26 months, age at onset 73 years. Biomarkers: mean beta-amyloid 1-42: 266 pg/ml, median tau: 491 pg/ml, 14-3-3 positive: 31%. Genetic polymorphisms showed a predominance of methionine homozygosity at PRNP codon 129 and a low frequency of ApoE4 (38%, no homozygous patients). Thirty-five symptoms were studied. Frequent symptoms were myoclonus (75%), disturbed gait (66%) and rigidity (50%). rpAD is associated with a diversity of neurological signs even able to mimic Creutzfeldt-Jakob disease. Biomarkers and genetic profile differ from those seen in classical AD. The findings on biomarkers, symptomatology and genetics may aid the differential diagnostic process.
ABSTRACTTau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies (4RT), i... more ABSTRACTTau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies (4RT), including cortico-basal degeneration and progressive supranuclear palsy (PSP). Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4RTs, characterized not only by neuronal but also by astroglial and oligodendroglial tau accumulation. Here, we assessed whether connectivity drives 4R-tau spreading patterns by combining resting-state fMRI connectomics with both 2nd generation 18F- PI-2620 tau-PET in 46 patients with clinically diagnosed 4RTs and post-mortem cell-type- specific regional tau assessments from two independent PSP samples (n=97/96). We found that inter-regional connectivity was associated with higher inter-regional correlation of both tau- PET and post-mortem tau levels in 4RTs. In regional cell-type specific post-mortem tau assessments, this association was stronger for neuronal than for astroglial or oligode...
Journal of neural transmission (Vienna, Austria : 1996), Jan 8, 2015
Presenilin 1 (PSEN1) mutations are the major cause of autosomal dominant Alzheimer's disease ... more Presenilin 1 (PSEN1) mutations are the major cause of autosomal dominant Alzheimer's disease (ADAD). Here we report three novel PSEN1 mutations: Ile238_Lys239insIle, Ala246Pro and Ala164Val from patients who manifested in their twenties, forties and seventies, respectively, with variant clinical presentations of dementia. These cases exemplify the tremendous heterogeneity of clinical phenotypes and age of onset associated with PSEN1 mutations. The possibility of ADAD-not previously suspected in two of our patients-should always be considered in neurodegenerative conditions albeit they might neither exhibit the typical clinical picture of Alzheimer's disease nor early onset dementia, which is regarded the primary clinical sign of hereditary neurodegeneration.
Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition,... more Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10(-12)), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10(-8)), and 2p22 at SOS1 (rs963731; P=1.76 × 10(-7)). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10(-7)) and MAPT H1c (17q21; rs242557; P=7.91 × 10(-6)). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT a...
The objective was to characterize a rapidly progressive subtype of Alzheimer's disease (rpAD)... more The objective was to characterize a rapidly progressive subtype of Alzheimer's disease (rpAD). Multicenter (France, Germany, Japan, Spain) retrospective analyses of neuropathologically confirmed rpAD cases initially classified as prion disease due to their clinical phenotype were performed. Genetic properties, cerebrospinal fluid biomarkers, neuropathology, and clinical features were examined. Eighty-nine patients were included (median survival 10 months). APOE and PRNP codon 129 genotype distribution paralleled a healthy control group. APOE ε4 homozygosity was absent. Cerebrospinal fluid biomarkers were abnormal, but within a range as expected for classic AD, except for proteins 14-3-3, which were detectable in 42%. Thus, evidence of the existence of rpAD is accumulating. The APOE profile is intriguing, suggesting that this very rapid disease form might represent a distinct subtype of Alzheimer's disease.
The α-synuclein gene (SNCA) plays a major role in the aetiology of Lewy body disease (LBD) includ... more The α-synuclein gene (SNCA) plays a major role in the aetiology of Lewy body disease (LBD) including Parkinson&amp;amp;amp;amp;#39;s disease (PD). Point mutations and genetic alterations causing elevated gene expression are causally linked to familial PD. To what extent epigenetic changes play a role in the regulation of α-synuclein expression and may contribute to the aetiology of sporadic LBD is a matter of debate. We analysed the methylation state of the promoter region and a CpG-rich region of intron 1 of α-synuclein in several brain regions in sporadic LBD and controls using 454 GS-FLX-based high-resolution bisulphite sequencing. Our results indicate that there are significant differences in the level of methylation between different brain areas. The overall methylation levels in the promoter and intron 1 of α-synuclein are rather low in controls and-in contrast to previously reported findings-are not significantly different from LBD. However, single CpG analysis revealed significant hyper- and hypomethylation at different positions in various brain regions and LBD stages. A slight overall increase in methylation related to LBD patients&amp;amp;amp;amp;#39; age was detected.
Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Br... more Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10(-3). We found significant previously unidentified signals (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 5 × 10(-8)) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component.
Autopsy is the diagnostic gold standard for progressive supranuclear palsy (PSP). The National In... more Autopsy is the diagnostic gold standard for progressive supranuclear palsy (PSP). The National Institute of Neurological Disorders and Stroke and Society for Progressive Supranuclear Palsy (NINDS-SPSP) criteria for the clinical diagnosis of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;probable&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; PSP are thought to possess high specificity and low sensitivity. The NINDS-SPSP criteria for &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;possible&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; PSP are considered to increase sensitivity at the expense of specificity. The Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS) criteria are intended to improve sensitivity while maintaining high specificity. The aim of this study was to conduct a clinicopathological evaluation of the NINDS-SPSP and NNIPPS criteria in tertiary neurological centers. Defined clinical features and their year of onset were recorded by chart review in neuropathologically diagnosed patients with PSP, Parkinsons&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (PD), MSA parkinsonism and corticobasal degeneration from four European brain banks. Fulfillment of the clinical diagnostic criteria was verified for each year after disease onset and for the final antemortem record. We analyzed 98 PSP patients and 46 disease controls. The NINDS-SPSP &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;probable&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; criteria yielded shorter time to diagnosis, slightly higher specificity and positive predictive value (PPV), and similar sensitivity, compared with the NNIPPS criteria. Unexpectedly, the NINDS-SPSP &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;possible&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; criteria yielded the lowest sensitivity, specificity, and PPV. A combination of NINDS-SPSP possible and probable criteria yielded the highest sensitivity. We suggest that the NINDS-SPSP probable criteria might be preferred for recruitment of patients for clinical trials, where an early and specific diagnosis is important. For routine clinical care, where high sensitivity is crucial, a combination of NINDS possible and probable criteria might be preferred.
Journal of Neuropathology and Experimental Neurology, 2007
Animal studies suggest that adult bone marrow cells have the potential to migrate into the brain ... more Animal studies suggest that adult bone marrow cells have the potential to migrate into the brain and generate new neural cells. Because data on this physiologic repair mechanism in humans are lacking, we investigated bone marrow engraftment into the brain of bone marrow recipients after sex-mismatched transplantation. Brain sections of seven allogeneic female bone marrow recipients were examined. The Y-chromosome, which served as a natural marker of donor bone marrow-derived cells after male-to-female transplantation, was identified by in situ hybridization. The neural phenotype of Y-chromosome-positive cells was determined using neural nuclear protein (NeuN) immunohistochemistry. Y-chromosome-positive cells expressing NeuN were found within the first 3 months after transplantation in both the cerebrum and the cerebellum at a frequency of 0.003% to 0.013% of all neurons. These cells were observed only in patients with cerebral lymphocytic infiltration and graft-versus-host disease. Our data suggest that adult bone marrow cells are capable of generating cells that express the neural marker NeuN early after transplantation. Cells with this specific phenotype may contribute to tissue repair in brain regions remote from neurogenic zones.
Decreased levels of β-amyloid (Aβ) 1-42 in cerebrospinal fluid (CSF) are characteristic for Alzhe... more Decreased levels of β-amyloid (Aβ) 1-42 in cerebrospinal fluid (CSF) are characteristic for Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD) and are also evident in Creutzfeldt-Jakob disease (CJD). Aβ plaques are thought to be responsible for this decrease in AD patients, whereas such Aβ plaques are rarely seen in CJD. To investigate the Aβ pattern in brain and CSF of neuropathologically confirmed CJD and AD patients we used an electrophoretic method to investigate Aβ peptide fractions which are not accessible to ELISA and immunohistochemistry. We analyzed Aβ peptides in the CSF of autopsy-confirmed CJD and AD patients and the corresponding brain homogenates using a quantitative urea-based Aβ electrophoresis immunoblot (Aβ-SDS-PAGE/immunoblot).The CSF Aβ1-42 decrease correlated with the brain Aβ load in AD, but not in CJD. There was no difference in the soluble fractions of brain homogenate in AD and CJD. We therefore conclude that different mechanisms in AD and CJD are responsible for the Aβ1-42 decrease in the CSF.
Journal of neuropathology and experimental neurology, 2011
α-Internexin (INA) has been proposed to be a surrogate marker for the 1p/19q codeletion in oligod... more α-Internexin (INA) has been proposed to be a surrogate marker for the 1p/19q codeletion in oligodendroglial tumors (OTs). We analyzed INA expression in 83 glioma and 21 oligodendroglial phenotype-mimicking tumors (OMT) to assess its usefulness in differential diagnosis and its correlation with 1p/19q status; in particular, INA expression in gliomas with isolated/partial 1p or 19q deletions was assessed. α-Internexin expression and 1p/19q codeletion were present in 92% (34/37) of codeleted tumors (p < 0.0001). By contrast, INA was found in only 20% of cases with isolated/partial 1p aberrations and 36% of cases without 1p/19q deletions; it was also foundin 63% (10/16) of cases with isolated/partial 19q aberrations. α-Internexin expression was more specific in high-grade than in low-grade gliomas (66% vs 31%). Notably, a subset of tumors (10/83) displayed a biphasic INA expression pattern that was significantly associated with proliferation rate, whereas all areas harbored the 1p/19...
To characterize clinical features, CSF biomarkers and genetic polymorphisms of patients suffering... more To characterize clinical features, CSF biomarkers and genetic polymorphisms of patients suffering from a rapidly progressing subtype of Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s dementia (rpAD). Retrospective analyses of 32 neuropathologically confirmed cases differentially diagnosed as AD out of a group with rapidly progressive dementia. CSF biomarkers (14-3-3, tau, beta-amyloid 1-42) and genetic markers (PRNP codon 129, apolipoprotein E, ApoE, polymorphism) were determined. Median survival was 26 months, age at onset 73 years. Biomarkers: mean beta-amyloid 1-42: 266 pg/ml, median tau: 491 pg/ml, 14-3-3 positive: 31%. Genetic polymorphisms showed a predominance of methionine homozygosity at PRNP codon 129 and a low frequency of ApoE4 (38%, no homozygous patients). Thirty-five symptoms were studied. Frequent symptoms were myoclonus (75%), disturbed gait (66%) and rigidity (50%). rpAD is associated with a diversity of neurological signs even able to mimic Creutzfeldt-Jakob disease. Biomarkers and genetic profile differ from those seen in classical AD. The findings on biomarkers, symptomatology and genetics may aid the differential diagnostic process.
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