Rrecent studies have highlighted a group of 4-repeat (4R) tauopathies that are characterised neur... more Rrecent studies have highlighted a group of 4-repeat (4R) tauopathies that are characterised neuropathologically by widespread, globular glial inclusions (GGIs). Tau immunohistochemistry reveals 4R immunore-active globular oligodendroglial and astrocytic inclusions and the latter are predominantly negative for Gallyas silver staining. These cases are associated with a range of clinical presentations, which correlate with the severity and distribution of underlying tau pathology and neurodegeneration. Their heterogeneous clinicopathological features combined with their rarity and under-recognition have led to cases characterised by GGIs being described in the literature using various and redundant terminologies. In this report, a group of neuropathologists form a consensus on the terminology and classification of cases with GGIs. After studying microscopic images from previously reported cases with suspected GGIs (n = 22), this panel of neuropathologists with extensive experience in the diagnosis of neurodegenerative diseases and a documented record of previous experience with at least one case with GGIs, agreed that (1) GGIs were present in all the cases reviewed; (2) the morphology of globular astrocytic inclusions was different to tufted astrocytes and finally that (3) the cases represented a number of different neuropathological subtypes. They also agreed that the different morphological subtypes are likely to be part of a spectrum of a distinct disease entity, for which they recommend that the overarching term globular glial tauopathy (GGT) should be used. Type I cases typically present with frontotemporal dementia, which correlates with the fronto-temporal distribution of pathology. Type II cases are characterised by pyramidal features reflecting motor cortex involvement and corticospinal tract degeneration. Type III cases can present with a combination of frontotemporal dementia and motor neuron disease with fronto-temporal cortex, motor cortex and corticospinal tract being severely affected. extrapyramidal features can be present in Type II and III cases and significant degeneration of the white matter is a feature of all GGT subtypes. Improved detection and classification will be necessary for the establishment of neuropathological and clinical diagnostic research criteria in the future.
In Neuropathology and Applied Neurobiology Blackwell Publishing, 2009
Mutations in the glucocerebrosidase gene (GBA) are associated with Gaucher's disease, the most co... more Mutations in the glucocerebrosidase gene (GBA) are associated with Gaucher's disease, the most common lysosomal storage disorder. Parkinsonism is an established feature of Gaucher's disease and an increased frequency of mutations in GBA has been reported in several different ethnic series with sporadic Parkinson's disease. In this study, we evaluated the frequency of GBA mutations in British patients affected by Parkinson's disease. We utilized the DNA of 790 patients and 257 controls, matched for age and ethnicity, to screen for mutations within the GBA gene. Clinical data on all identified GBA mutation carriers was reviewed and analysed. Additionally, in all cases where brain material was available, a neuropathological evaluation was performed and compared to sporadic Parkinson's disease without GBA mutations. The frequency of GBA mutations among the British patients (33/790 = 4.18%) was significantly higher (P = 0.01; odds ratio = 3.7; 95% confidence interval = 1.12-12.14) when compared to the control group (3/257 = 1.17%). Fourteen different GBA mutations were identified, including three previously undescribed mutations, K7E, D443N and G193E. Pathological examination revealed widespread and abundant a-synuclein pathology in all 17 GBA mutation carriers, which were graded as Braak stage of 5-6, and had McKeith's limbic or diffuse neocortical Lewy bodytype pathology. Diffuse neocortical Lewy body-type pathology tended to occur more frequently in the group with GBA mutations compared to matched Parkinson's disease controls. Clinical features comprised an early onset of the disease, the presence of hallucinations in 45% (14/31) and symptoms of cognitive decline or dementia in 48% (15/31) of patients. This study demonstrates that GBA mutations are found in British subjects at a higher frequency than any other known Parkinson's disease gene. This is the largest study to date on a non-Jewish patient sample with a detailed genotype/phenotype/pathological analyses which strengthens the hypothesis that GBA mutations represent a significant risk factor for the development of Parkinson's disease and suggest that to date, this is the most common genetic factor identified for the disease.
Previous studies suggested that olfaction is normal in progressive supranuclear palsy (PSP). We a... more Previous studies suggested that olfaction is normal in progressive supranuclear palsy (PSP). We applied the University of Pennsylvania Smell Identification Test (UPSIT) to 36 patients with PSP who scored more than 18 on the Mini Mental State Examination (MMSE), 140 patients with nondemented Parkinson's disease (PD) and 126 controls. Mean UPSIT scores in PSP were lower than in controls (P < 0.001) but higher than in PD (P < 0.001) after adjusting for age, gender, and smoking history. For patients with PSP, UPSIT scores correlated with MMSE (r 5 0.44, P 5 0.006) but not disease duration (P 5 0.6), motor subscale of the Unified Parkinson's Disease Rating Scale (P 5 0.2), or Frontal Assessment Battery (P 5 0.5). The brains of six of the patients with PSP were examined postmortem and all revealed neurofibrillary tangles and tau accumulation in the rhinencephalon, although only three had hyposmia. Further prospective studies including patients with early PSP and PSP-P with postmortem confirmation might help clarify if smell tests could be useful when the differential diagnosis lies between PD and PSP.
The 2 major types of neurodegeneration with brain iron accumulation (NBIA) are the pantothenate k... more The 2 major types of neurodegeneration with brain iron accumulation (NBIA) are the pantothenate kinase type 2 (PANK2)-associated neurodegeneration (PKAN) and NBIA2 or infantile neuroaxonal dystrophy (INAD) due to mutations in the phospholipase A2, group VI (PLA2G6) gene. We have recently demonstrated clinical heterogeneity in patients with mutations in the PLA2G6 gene by identifying a poorly defined subgroup of patients who present late with dystonia and parkinsonism. We report the clinical and genetic features of 7 cases with PLA2G6 mutations. Brain was available in 5 cases with an age of death ranging from 8 to 36 years and showed widespread alpha-synuclein-positive Lewy pathology, which was particularly severe in the neocortex, indicating that the Lewy pathology spread corresponded to Braak stage 6 and was that of the "diffuse neocortical type". In 3 cases there was hyperphosphorylated tau accumulation in both cellular processes as threads and neuronal perikarya as pretangles and neurofibrillary tangles. Later onset cases tended to have less tau involvement but still severe alpha-synuclein pathology. The clinical and neuropathological features clearly represent a link between PLA2G6 and parkinsonian disorders.
We identified a case of Alzheimer's disease with a deletion of the lysine residue at codon 280 (Δ... more We identified a case of Alzheimer's disease with a deletion of the lysine residue at codon 280 (ΔK280) in exon 10-encoded microtubule-binding repeat domain of the tau gene (MAPT). This mutation was originally identified in a sporadic case of frontotemporal dementia (FTD) with a family history of Parkinson's disease. In the original report, the authors were careful in their assessment of the pathogenicity and suggested one could not be sure whether the mutation was pathogenic or not. The mutation has always presented a conundrum because it is the only known mutation, of assumed pathogenicity, which increases the proportion of 3-repeat tau mRNA in in vitro assays. Here we present the clinical and pathological features of a new case with this mutation and discuss whether the mutation is indeed pathogenic.
Two hereditary conditions, familial British dementia (FBD) and familial Danish dementia (FDD), ar... more Two hereditary conditions, familial British dementia (FBD) and familial Danish dementia (FDD), are associated with amyloid deposition in the central nervous system and neurodegeneration. The two amyloid proteins, ABri and ADan, are degradation products of the same precursor molecule BriPP bearing different genetic defects, namely a Stop-to-Arg mutation in FBD and a ten-nucleotide duplication-insertion immediately before the stop codon in FDD. Both de novo created amyloid peptides have the same length (34 amino acids) and the same post-translational modification (pyroglutamate) at their N-terminus. Neurofibrillary tangles containing the classical paired helical filaments as well as neuritic components in many instances co-localize with the amyloid deposits. In both disorders, the pattern of hyperphosphorylated tau immunoreactivity is almost indistinguishable from that seen in Alzheimer&amp;amp;#39;s disease. These issues argue for the primary importance of the amyloid deposits in the mechanism(s) of neuronal cell loss. We propose FBD and FDD, the chromosome 13 dementia syndromes, as models to study the molecular basis of neurofibrillary degeneration, cell death and amyloid formation in the brain.
The histological features of familial cerebral amyloid angiopathy (British type) with non-neuriti... more The histological features of familial cerebral amyloid angiopathy (British type) with non-neuritic amyloid plaque formation (FAB) include deposition of amyloid, (supposedly associated with the C-terminal fragments of both αand β-tubulin), in small cerebral and spinal arteries, hippocampal amyloid plaques and neurofibrillary tangles (NFTs) as well as ischaemic white matter changes. In the present study we report on the cytoskeletal pathology that occurs in association with FAB. Sections from the hippocampus and cerebellum of three cases from three unrelated families were stained with silver impregnation methods and antibodies to antigens including tau, neurofilaments, ubiquitin and glial fibrillary acidic protein. Electron microscopic examination of the hippocampus was carried out in one case. All hippocampal subregions contained large numbers of NFTs and neuropil threads (NT), which were stained with both phosphorylation-dependent and phosphorylation-independent tau antibodies and ultrastructurally were found to be composed of paired helical filaments (PHFs). Although the majority of the amyloid plaques were of the non-neuritic type, distended PHF-containing and tau-positive neurites were seen in close proximity of a minority of the hippocampal plaques. The perivascular amyloid deposits of the cerebellum contained numerous ubiquitin-positive granular elements similar to those seen in cerebellar Aβ amyloid plaques in Alzheimer's disease. In FAB severe cytoskeletal pathology is present in areas most affected by amyloid plaque deposits, thus suggesting a localised neurotoxic effect of the poorly characterised amyloidogenic peptide characteristic of this condition.
Although previous studies have shown that the lesions of multiple sclerosis may involve the cereb... more Although previous studies have shown that the lesions of multiple sclerosis may involve the cerebral cortex, there is little published research on the prevalence and distribution of such lesions. Using neuropathological techniques and MRI, a series of studies has been undertaken in order to assess this, in particular to identify their relationship to cortical veins. A serial MRI study showed that the use of gadolinium proffered an increase in cortical lesion detection of 140% and showed that 26% of active lesions arose within or adjacent to the cortex. In a post-mortem study, MRI under-reported lesions subsequently analysed neuro
Conflict of interest statement We declare that we have no conflict of interest. the study and had... more Conflict of interest statement We declare that we have no conflict of interest. the study and had final responsibility for the decision to submit for publication. References 1 Bonifati V, Oostra BA, Heutink P. Unraveling the pathogenesis of Parkinson's disease-the contribution of monogenic forms.
Summary Although previous studies have shown that the lesions of multiple sclerosis may involve t... more Summary Although previous studies have shown that the lesions of multiple sclerosis may involve the cerebral cortex, there is little published research on the prevalence and distribution of such lesions. Using neuropathological techniques and MRI, a series of studies has been undertaken in order to assess this, in particular to identify their relationship to cortical veins. A serial MRI study
A patient is described who presented with cervical cord compression. The imaging and operative fi... more A patient is described who presented with cervical cord compression. The imaging and operative findings were typical of a neurofibroma of the right third cervical root. However, histological studies confirmed that the tumour was a B-cell lymphoma. Isolated spinal lymphomas can therefore occur and may present as nerve sheath tumours.
Frontotemporal lobar degeneration (FTLD) with mutations in the tau gene (MAPT) causes familial fr... more Frontotemporal lobar degeneration (FTLD) with mutations in the tau gene (MAPT) causes familial frontotemporal dementia with tau pathology. Many of these mutations result in morphological phenotypes resembling sporadic tauopathies, although, to date, no such cases mimicking argyrophilic grain disease (AgD) have been documented. We now present a case with a novel S305I MAPT mutation and a morphological phenotype showing resemblance to AgD. At the age of 39, the patient developed behavioural and personality changes and lack of verbal Xuency with later poor performance on naming tasks and rigidity in the extremities. After a short disease course of 1.5 years, the patient died. A unique neuropathological phenotype with neuronal diVuse cytoplasmic tau immunoreactivity, oligodendroglial-coiled bodies, argyrophilic grains, and non-argyrophilic, but tau-immunopositive and ubiquitin-immunonegative pre-grains were
This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License New... more This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License Newcastle University ePrints-eprint.ncl.ac.uk
Rrecent studies have highlighted a group of 4-repeat (4R) tauopathies that are characterised neur... more Rrecent studies have highlighted a group of 4-repeat (4R) tauopathies that are characterised neuropathologically by widespread, globular glial inclusions (GGIs). Tau immunohistochemistry reveals 4R immunore-active globular oligodendroglial and astrocytic inclusions and the latter are predominantly negative for Gallyas silver staining. These cases are associated with a range of clinical presentations, which correlate with the severity and distribution of underlying tau pathology and neurodegeneration. Their heterogeneous clinicopathological features combined with their rarity and under-recognition have led to cases characterised by GGIs being described in the literature using various and redundant terminologies. In this report, a group of neuropathologists form a consensus on the terminology and classification of cases with GGIs. After studying microscopic images from previously reported cases with suspected GGIs (n = 22), this panel of neuropathologists with extensive experience in the diagnosis of neurodegenerative diseases and a documented record of previous experience with at least one case with GGIs, agreed that (1) GGIs were present in all the cases reviewed; (2) the morphology of globular astrocytic inclusions was different to tufted astrocytes and finally that (3) the cases represented a number of different neuropathological subtypes. They also agreed that the different morphological subtypes are likely to be part of a spectrum of a distinct disease entity, for which they recommend that the overarching term globular glial tauopathy (GGT) should be used. Type I cases typically present with frontotemporal dementia, which correlates with the fronto-temporal distribution of pathology. Type II cases are characterised by pyramidal features reflecting motor cortex involvement and corticospinal tract degeneration. Type III cases can present with a combination of frontotemporal dementia and motor neuron disease with fronto-temporal cortex, motor cortex and corticospinal tract being severely affected. extrapyramidal features can be present in Type II and III cases and significant degeneration of the white matter is a feature of all GGT subtypes. Improved detection and classification will be necessary for the establishment of neuropathological and clinical diagnostic research criteria in the future.
In Neuropathology and Applied Neurobiology Blackwell Publishing, 2009
Mutations in the glucocerebrosidase gene (GBA) are associated with Gaucher's disease, the most co... more Mutations in the glucocerebrosidase gene (GBA) are associated with Gaucher's disease, the most common lysosomal storage disorder. Parkinsonism is an established feature of Gaucher's disease and an increased frequency of mutations in GBA has been reported in several different ethnic series with sporadic Parkinson's disease. In this study, we evaluated the frequency of GBA mutations in British patients affected by Parkinson's disease. We utilized the DNA of 790 patients and 257 controls, matched for age and ethnicity, to screen for mutations within the GBA gene. Clinical data on all identified GBA mutation carriers was reviewed and analysed. Additionally, in all cases where brain material was available, a neuropathological evaluation was performed and compared to sporadic Parkinson's disease without GBA mutations. The frequency of GBA mutations among the British patients (33/790 = 4.18%) was significantly higher (P = 0.01; odds ratio = 3.7; 95% confidence interval = 1.12-12.14) when compared to the control group (3/257 = 1.17%). Fourteen different GBA mutations were identified, including three previously undescribed mutations, K7E, D443N and G193E. Pathological examination revealed widespread and abundant a-synuclein pathology in all 17 GBA mutation carriers, which were graded as Braak stage of 5-6, and had McKeith's limbic or diffuse neocortical Lewy bodytype pathology. Diffuse neocortical Lewy body-type pathology tended to occur more frequently in the group with GBA mutations compared to matched Parkinson's disease controls. Clinical features comprised an early onset of the disease, the presence of hallucinations in 45% (14/31) and symptoms of cognitive decline or dementia in 48% (15/31) of patients. This study demonstrates that GBA mutations are found in British subjects at a higher frequency than any other known Parkinson's disease gene. This is the largest study to date on a non-Jewish patient sample with a detailed genotype/phenotype/pathological analyses which strengthens the hypothesis that GBA mutations represent a significant risk factor for the development of Parkinson's disease and suggest that to date, this is the most common genetic factor identified for the disease.
Previous studies suggested that olfaction is normal in progressive supranuclear palsy (PSP). We a... more Previous studies suggested that olfaction is normal in progressive supranuclear palsy (PSP). We applied the University of Pennsylvania Smell Identification Test (UPSIT) to 36 patients with PSP who scored more than 18 on the Mini Mental State Examination (MMSE), 140 patients with nondemented Parkinson's disease (PD) and 126 controls. Mean UPSIT scores in PSP were lower than in controls (P < 0.001) but higher than in PD (P < 0.001) after adjusting for age, gender, and smoking history. For patients with PSP, UPSIT scores correlated with MMSE (r 5 0.44, P 5 0.006) but not disease duration (P 5 0.6), motor subscale of the Unified Parkinson's Disease Rating Scale (P 5 0.2), or Frontal Assessment Battery (P 5 0.5). The brains of six of the patients with PSP were examined postmortem and all revealed neurofibrillary tangles and tau accumulation in the rhinencephalon, although only three had hyposmia. Further prospective studies including patients with early PSP and PSP-P with postmortem confirmation might help clarify if smell tests could be useful when the differential diagnosis lies between PD and PSP.
The 2 major types of neurodegeneration with brain iron accumulation (NBIA) are the pantothenate k... more The 2 major types of neurodegeneration with brain iron accumulation (NBIA) are the pantothenate kinase type 2 (PANK2)-associated neurodegeneration (PKAN) and NBIA2 or infantile neuroaxonal dystrophy (INAD) due to mutations in the phospholipase A2, group VI (PLA2G6) gene. We have recently demonstrated clinical heterogeneity in patients with mutations in the PLA2G6 gene by identifying a poorly defined subgroup of patients who present late with dystonia and parkinsonism. We report the clinical and genetic features of 7 cases with PLA2G6 mutations. Brain was available in 5 cases with an age of death ranging from 8 to 36 years and showed widespread alpha-synuclein-positive Lewy pathology, which was particularly severe in the neocortex, indicating that the Lewy pathology spread corresponded to Braak stage 6 and was that of the "diffuse neocortical type". In 3 cases there was hyperphosphorylated tau accumulation in both cellular processes as threads and neuronal perikarya as pretangles and neurofibrillary tangles. Later onset cases tended to have less tau involvement but still severe alpha-synuclein pathology. The clinical and neuropathological features clearly represent a link between PLA2G6 and parkinsonian disorders.
We identified a case of Alzheimer's disease with a deletion of the lysine residue at codon 280 (Δ... more We identified a case of Alzheimer's disease with a deletion of the lysine residue at codon 280 (ΔK280) in exon 10-encoded microtubule-binding repeat domain of the tau gene (MAPT). This mutation was originally identified in a sporadic case of frontotemporal dementia (FTD) with a family history of Parkinson's disease. In the original report, the authors were careful in their assessment of the pathogenicity and suggested one could not be sure whether the mutation was pathogenic or not. The mutation has always presented a conundrum because it is the only known mutation, of assumed pathogenicity, which increases the proportion of 3-repeat tau mRNA in in vitro assays. Here we present the clinical and pathological features of a new case with this mutation and discuss whether the mutation is indeed pathogenic.
Two hereditary conditions, familial British dementia (FBD) and familial Danish dementia (FDD), ar... more Two hereditary conditions, familial British dementia (FBD) and familial Danish dementia (FDD), are associated with amyloid deposition in the central nervous system and neurodegeneration. The two amyloid proteins, ABri and ADan, are degradation products of the same precursor molecule BriPP bearing different genetic defects, namely a Stop-to-Arg mutation in FBD and a ten-nucleotide duplication-insertion immediately before the stop codon in FDD. Both de novo created amyloid peptides have the same length (34 amino acids) and the same post-translational modification (pyroglutamate) at their N-terminus. Neurofibrillary tangles containing the classical paired helical filaments as well as neuritic components in many instances co-localize with the amyloid deposits. In both disorders, the pattern of hyperphosphorylated tau immunoreactivity is almost indistinguishable from that seen in Alzheimer&amp;amp;#39;s disease. These issues argue for the primary importance of the amyloid deposits in the mechanism(s) of neuronal cell loss. We propose FBD and FDD, the chromosome 13 dementia syndromes, as models to study the molecular basis of neurofibrillary degeneration, cell death and amyloid formation in the brain.
The histological features of familial cerebral amyloid angiopathy (British type) with non-neuriti... more The histological features of familial cerebral amyloid angiopathy (British type) with non-neuritic amyloid plaque formation (FAB) include deposition of amyloid, (supposedly associated with the C-terminal fragments of both αand β-tubulin), in small cerebral and spinal arteries, hippocampal amyloid plaques and neurofibrillary tangles (NFTs) as well as ischaemic white matter changes. In the present study we report on the cytoskeletal pathology that occurs in association with FAB. Sections from the hippocampus and cerebellum of three cases from three unrelated families were stained with silver impregnation methods and antibodies to antigens including tau, neurofilaments, ubiquitin and glial fibrillary acidic protein. Electron microscopic examination of the hippocampus was carried out in one case. All hippocampal subregions contained large numbers of NFTs and neuropil threads (NT), which were stained with both phosphorylation-dependent and phosphorylation-independent tau antibodies and ultrastructurally were found to be composed of paired helical filaments (PHFs). Although the majority of the amyloid plaques were of the non-neuritic type, distended PHF-containing and tau-positive neurites were seen in close proximity of a minority of the hippocampal plaques. The perivascular amyloid deposits of the cerebellum contained numerous ubiquitin-positive granular elements similar to those seen in cerebellar Aβ amyloid plaques in Alzheimer's disease. In FAB severe cytoskeletal pathology is present in areas most affected by amyloid plaque deposits, thus suggesting a localised neurotoxic effect of the poorly characterised amyloidogenic peptide characteristic of this condition.
Although previous studies have shown that the lesions of multiple sclerosis may involve the cereb... more Although previous studies have shown that the lesions of multiple sclerosis may involve the cerebral cortex, there is little published research on the prevalence and distribution of such lesions. Using neuropathological techniques and MRI, a series of studies has been undertaken in order to assess this, in particular to identify their relationship to cortical veins. A serial MRI study showed that the use of gadolinium proffered an increase in cortical lesion detection of 140% and showed that 26% of active lesions arose within or adjacent to the cortex. In a post-mortem study, MRI under-reported lesions subsequently analysed neuro
Conflict of interest statement We declare that we have no conflict of interest. the study and had... more Conflict of interest statement We declare that we have no conflict of interest. the study and had final responsibility for the decision to submit for publication. References 1 Bonifati V, Oostra BA, Heutink P. Unraveling the pathogenesis of Parkinson's disease-the contribution of monogenic forms.
Summary Although previous studies have shown that the lesions of multiple sclerosis may involve t... more Summary Although previous studies have shown that the lesions of multiple sclerosis may involve the cerebral cortex, there is little published research on the prevalence and distribution of such lesions. Using neuropathological techniques and MRI, a series of studies has been undertaken in order to assess this, in particular to identify their relationship to cortical veins. A serial MRI study
A patient is described who presented with cervical cord compression. The imaging and operative fi... more A patient is described who presented with cervical cord compression. The imaging and operative findings were typical of a neurofibroma of the right third cervical root. However, histological studies confirmed that the tumour was a B-cell lymphoma. Isolated spinal lymphomas can therefore occur and may present as nerve sheath tumours.
Frontotemporal lobar degeneration (FTLD) with mutations in the tau gene (MAPT) causes familial fr... more Frontotemporal lobar degeneration (FTLD) with mutations in the tau gene (MAPT) causes familial frontotemporal dementia with tau pathology. Many of these mutations result in morphological phenotypes resembling sporadic tauopathies, although, to date, no such cases mimicking argyrophilic grain disease (AgD) have been documented. We now present a case with a novel S305I MAPT mutation and a morphological phenotype showing resemblance to AgD. At the age of 39, the patient developed behavioural and personality changes and lack of verbal Xuency with later poor performance on naming tasks and rigidity in the extremities. After a short disease course of 1.5 years, the patient died. A unique neuropathological phenotype with neuronal diVuse cytoplasmic tau immunoreactivity, oligodendroglial-coiled bodies, argyrophilic grains, and non-argyrophilic, but tau-immunopositive and ubiquitin-immunonegative pre-grains were
This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License New... more This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License Newcastle University ePrints-eprint.ncl.ac.uk
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