An expanded hexanucleotide repeat in the C9orf72 gene is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). We now report the first description of a homozygous patient and compare it to a series of heterozygous cases. The patient developed early-onset frontotemporal dementia without additional features. Neuropathological analysis showed c9FTD/ALS characteristics, with abundant p62-positive inclusions in the frontal and temporal cortices, hippocampus and cerebellum, as well as less abundant TDP-43-positive inclusions. Overall, the clinical and pathological features were severe, but did not fall outside the usual disease spectrum. Quantification of C9orf72 transcript levels in post-mortem brain demonstrated expression of all known C9orf72 transcript variants, but at a reduced level. The pathogenic mechanisms by which the hexanucleotide repeat expansion causes disease are unclear and both gain- and loss-of-function mechanisms may play a role. Our data support a gain-of-function mechanism as pure homozygous loss of function would be expected to lead to a more severe, or completely different clinical phenotype to the one described here, which falls within the usual range. Our findings have implications for genetic counselling, highlighting the need to use genetic tests that distinguish C9orf72 homozygosity.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-013-1147-0) contains supplementary material, which is available to authorized users.
C9orf72; ALS; FTD
We report a British family with young-onset Parkinson’s disease (PD) and a G51D SNCA mutation that segregates with the disease. Family history was consistent with autosomal dominant inheritance as both the father and sister of the proband developed levodopa-responsive parkinsonism with onset in their late thirties. Clinical features show similarity to those seen in families with SNCA triplication and to cases of A53T SNCA mutation. Post-mortem brain examination of the proband revealed atrophy affecting frontal and temporal lobes in addition to the caudate, putamen, globus pallidus and amygdala. There was severe loss of pigmentation in the substantia nigra and pallor of the locus coeruleus. Neuronal loss was most marked in frontal and temporal cortices, hippocampal CA2/3 subregions, substantia nigra, locus coeruleus and dorsal motor nucleus of the vagus. The cellular pathology included widespread and frequent neuronal α-synuclein immunoreactive inclusions of variable morphology and oligodendroglial inclusions similar to the glial cytoplasmic inclusions of multiple system atrophy (MSA). Both inclusion types were ubiquitin and p62 positive and were labelled with phosphorylation-dependent anti-α-synuclein antibodies In addition, TDP-43 immunoreactive inclusions were observed in limbic regions and in the striatum. Together the data show clinical and neuropathological similarities to both the A53T SNCA mutation and multiplication cases. The cellular neuropathological features of this case share some characteristics of both PD and MSA with additional unique striatal and neocortical pathology. Greater understanding of the disease mechanism underlying the G51D mutation could aid in understanding of α-synuclein biology and its impact on disease phenotype.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-013-1096-7) contains supplementary material, which is available to authorized users.
Parkinson’s disease; Multiple system atrophy; α-Synuclein; SNCA
To test whether the synucleinopathies Parkinson’s disease and multiple system atrophy (MSA) share a common genetic etiology, we performed a candidate single nucleotide polymorphism (SNP) association study of the 384 most associated SNPs in a genome-wide association study of Parkinson’s disease in 413 MSA cases and 3,974 control subjects. The 10 most significant SNPs were then replicated in additional 108 MSA cases and 537 controls. SNPs at the SNCA locus were significantly associated with risk for increased risk for the development of MSA (combined p = 5.5 × 1012; odds ratio 6.2).
Chronic thromboembolic pulmonary hypertension (CTEPH) is a disabling condition that is being increasingly recognised. It is unique as a cause of pulmonary hypertension in that it is surgically curable. We wish to highlight the importance of recognition and early referral of any patient who may have CTEPH even in the absence of resting pulmonary hypertension as excellent results can be achieved by restoring pulmonary vascular anatomy, reducing exercise-induced pulmonary hypertension, and reducing dead-space ventilation. We present a case that illustrates these points and discuss our experience as a referral centre for CTEPH.
Neuronal intermediate filament inclusion disease and atypical frontotemporal lobar degeneration are rare diseases characterized by ubiquitin-positive inclusions lacking transactive response DNA-binding protein-43 and tau. Recently, mutations in the fused in sarcoma gene have been shown to cause familial amyotrophic lateral sclerosis and fused in sarcoma-positive neuronal inclusions have subsequently been demonstrated in neuronal intermediate filament inclusion disease and atypical frontotemporal lobar degeneration with ubiquitinated inclusions. Here we provide clinical, imaging, morphological findings, as well as genetic and biochemical data in 14 fused in sarcoma proteinopathy cases. In this cohort, the age of onset was variable but included cases of young-onset disease. Patients with atypical frontotemporal lobar degeneration with ubiquitinated inclusions all presented with behavioural variant frontotemporal dementia, while the clinical presentation in neuronal intermediate filament inclusion disease was more heterogeneous, including cases with motor neuron disease and extrapyramidal syndromes. Neuroimaging revealed atrophy of the frontal and anterior temporal lobes as well as the caudate in the cases with atypical frontotemporal lobar degeneration with ubiquitinated inclusions, but was more heterogeneous in the cases with neuronal intermediate filament inclusion disease, often being normal to visual inspection early on in the disease. The distribution and severity of fused in sarcoma-positive neuronal cytoplasmic inclusions, neuronal intranuclear inclusions and neurites were recorded and fused in sarcoma was biochemically analysed in both subgroups. Fused in sarcoma-positive neuronal cytoplasmic and intranuclear inclusions were found in the hippocampal granule cell layer in variable numbers. Cortical fused in sarcoma-positive neuronal cytoplasmic inclusions were often ‘Pick body-like’ in neuronal intermediate filament inclusion disease, and annular and crescent-shaped inclusions were seen in both conditions. Motor neurons contained variable numbers of compact, granular or skein-like cytoplasmic inclusions in all fused in sarcoma-positive cases in which brainstem and spinal cord motor neurons were available for study (five and four cases, respectively). No fused in sarcoma mutations were found in any cases. Biochemically, two major fused in sarcoma species were found and shown to be more insoluble in the atypical frontotemporal lobar degeneration with ubiquitinated inclusions subgroup compared with neuronal intermediate filament inclusion disease. There is considerable overlap and also significant differences in fused in sarcoma-positive pathology between the two subgroups, suggesting they may represent a spectrum of the same disease. The co-existence of fused in sarcoma-positive inclusions in both motor neurons and extramotor cerebral structures is a characteristic finding in sporadic fused in sarcoma proteinopathies, indicating a multisystem disorder.
frontotemporal lobar degeneration; FUS; clinical presentation; neuropathology; biochemistry
Microtubule-associated protein tau (MAPT) mutations have been shown to underlie frontotemporal dementia and a variety of additional sporadic tauopathies. We identified a rare p.A152T variant in MAPT exon 7 in two (of eight) patients with clinical presentation of parkinsonism and postmortem finding of neurofibrillary tangle pathology. Two siblings of one patient also carried the p.A152T variant, and both have progressive cognitive impairment. Further screening identified the variant in two other cases: one with pathologically confirmed corticobasal degeneration and another with the diagnosis of Parkinson's disease with dementia. The balance of evidence suggests this variant is associated with disease, but the very varied phenotype of the cases with the mutation is not consistent with it being a fully penetrant pathogenic mutation. Interestingly, this variation results in the creation of a new phosphorylation site that could cause reduced microtubule binding. We suggest that the A152T variant is a risk factor associated with the development of atypical neurodegenerative conditions with abnormal tau accumulation.
MAPT; Parkinsonism; Corticobasal degeneration; Genetics; Postencephalitic parkinsonism
MAPT has been repeatedly linked with Parkinson's disease (PD) in association studies. Although tau deposition may be seen in PD, its relevance to the pathogenesis of the condition remains unclear. The presence of tau-positive inclusions is, however, the defining feature of progressive supranuclear palsy (PSP), which may often be clinically misdiagnosed as idiopathic PD. On a genetic level, variants in MAPT are the strongest risk factor for PSP. These facts raise the question whether the MAPT association in PD results from contamination with unrecognized cases of PSP. Using only neuropathologically proven PD, we show that the MAPT association remains and is independent of the PSP Association.
Genetics; Association study; Parkinson's disease; MAPT; Tau; Progressive supranuclear palsy; PD; PSP
An expanded hexanucleotide repeat in the C9ORF72 gene has recently been identified as a major cause of familial frontotemporal lobar degeneration and motor neuron disease, including cases previously identified as linked to chromosome 9. Here we present a detailed retrospective clinical, neuroimaging and histopathological analysis of a C9ORF72 mutation case series in relation to other forms of genetically determined frontotemporal lobar degeneration ascertained at a specialist centre. Eighteen probands (19 cases in total) were identified, representing 35% of frontotemporal lobar degeneration cases with identified mutations, 36% of cases with clinical evidence of motor neuron disease and 7% of the entire cohort. Thirty-three per cent of these C9ORF72 cases had no identified relevant family history. Families showed wide variation in clinical onset (43–68 years) and duration (1.7–22 years). The most common presenting syndrome (comprising a half of cases) was behavioural variant frontotemporal dementia, however, there was substantial clinical heterogeneity across the C9ORF72 mutation cohort. Sixty per cent of cases developed clinical features consistent with motor neuron disease during the period of follow-up. Anxiety and agitation and memory impairment were prominent features (between a half to two-thirds of cases), and dominant parietal dysfunction was also frequent. Affected individuals showed variable magnetic resonance imaging findings; however, relative to healthy controls, the group as a whole showed extensive thinning of frontal, temporal and parietal cortices, subcortical grey matter atrophy including thalamus and cerebellum and involvement of long intrahemispheric, commissural and corticospinal tracts. The neuroimaging profile of the C9ORF72 expansion was significantly more symmetrical than progranulin mutations with significantly less temporal lobe involvement than microtubule-associated protein tau mutations. Neuropathological examination in six cases with C9ORF72 mutation from the frontotemporal lobar degeneration series identified histomorphological features consistent with either type A or B TAR DNA-binding protein-43 deposition; however, p62-positive (in excess of TAR DNA-binding protein-43 positive) neuronal cytoplasmic inclusions in hippocampus and cerebellum were a consistent feature of these cases, in contrast to the similar frequency of p62 and TAR DNA-binding protein-43 deposition in 53 control cases with frontotemporal lobar degeneration–TAR DNA-binding protein. These findings corroborate the clinical importance of the C9ORF72 mutation in frontotemporal lobar degeneration, delineate phenotypic and neuropathological features that could help to guide genetic testing, and suggest hypotheses for elucidating the neurobiology of a culprit subcortical network.
frontotemporal lobar degeneration; motor neuron disease; neurodegenerative disorders; neuroimaging; genetics
Amyloid precursor protein gene (APP) duplications have been identified in screens of selected probands with early onset familial Alzheimer's disease (FAD). A causal role for copy number variation (CNV) in the prion protein gene (PRNP) in prion dementias is not known. We aimed to determine the prevalence of copy number variation in APP and PRNP in a large referral series, test a screening method for detection of the same, and expand knowledge of clinical phenotype. We used a 3-tiered screening assay for APP and PRNP duplication (exonic real-time quantitative polymerase chain reaction [exon-qPCR], fluorescent microsatellite quantitative PCR [fm-q-PCR], and Illumina array [Illumina Inc., San Diego, CA, USA]) for analysis of a heterogeneous referral series comprising 1531 probands. Five of 1531 probands screened showed APP duplication, a similar prevalence to APP missense mutation. Real-time quantitative PCR and fluorescent microsatellite quantitative PCR were similar individually but are theoretically complementary; we used Illumina arrays as our reference assay. Two of 5 probands were from an autosomal dominant early onset Alzheimer's disease (familial Alzheimer's disease) pedigree. One extensive, noncontiguous duplication on chromosome 21 was consistent with an unbalanced translocation not including the Down's syndrome critical region. Seizures were prominent in the other typical APP duplications. A range of imaging, neuropsychological, cerebrospinal fluid, and pathological findings are reported that extend the known phenotype. APP but not PRNP duplication is a significant cause of early onset dementia in the UK. The recognized phenotype may be expanded to include the possibility of early seizures and apparently sporadic disease which, in part, may be due to different mutational mechanisms. The pros and cons of our screening method are discussed.
APP; Duplication; PRNP; Prion; Chromosome 21; Dementia
Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common being 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 PSP cases and 3,247 controls (Stage 1) followed up by a second stage where 1,051 cases and 3,560 controls were genotyped for Stage 1 SNPs that yielded P ≤ 10−3. We found significant novel 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.
Parkinson's disease (PD) is a complex neurodegenerative disease which is clinically heterogeneous and pathologically consists of loss of dopaminergic neurons in the substantia nigra and intracytoplasmic neuronal inclusions containing alpha-synuclein aggregations known as Lewy bodies. Although the majority of PD is idiopathic, pathogenic mutations in several mendelian genes have been successfully identified through linkage analyses. To identify susceptibility loci for idiopathic PD, several genome-wide association studies (GWAS) within different populations have recently been conducted in both idiopathic and familial forms of PD. These analyses have confirmed SNCA and MAPT as loci harboring PD susceptibility. In addition, the GWAS identified several other genetic loci suggestively associated with the risk of PD; among these, only one was replicated by two different studies of European and Asian ancestries. Hence, we investigated this novel locus known as PARK16 for coding mutations in a large series of idiopathic pathologically proven PD cases, and also conducted an association study in a case–control cohort from the United Kingdom. An association between a novel RAB7L1 mutation, c.379-12insT, and disease (P-value=0.0325) was identified. Two novel coding variants present only in the PD cohort were also identified within the RAB7L1 (p.K157R) and SLC41A1 (p.A350V) genes. No copy number variation analyses have yet been performed within this recently identified locus. We concluded that, although both coding variants and risk alleles within the PARK16 locus seem to be rare, further molecular analyses within the PARK16 locus and within different populations are required in order to examine its biochemical role in the disease process.
PARK16 locus; genetics; association studies
Relating clinical symptoms to neuroanatomical profiles of brain damage and ultimately to tissue pathology is a key challenge in the field of neurodegenerative disease and particularly relevant to the heterogeneous disorders that comprise the frontotemporal lobar degeneration spectrum. Here we present a retrospective analysis of clinical, neuropsychological and neuroimaging (volumetric and voxel-based morphometric) features in a pathologically ascertained cohort of 95 cases of frontotemporal lobar degeneration classified according to contemporary neuropathological criteria. Forty-eight cases (51%) had TDP-43 pathology, 42 (44%) had tau pathology and five (5%) had fused-in-sarcoma pathology. Certain relatively specific clinicopathological associations were identified. Semantic dementia was predominantly associated with TDP-43 type C pathology; frontotemporal dementia and motoneuron disease with TDP-43 type B pathology; young-onset behavioural variant frontotemporal dementia with FUS pathology; and the progressive supranuclear palsy syndrome with progressive supranuclear palsy pathology. Progressive non-fluent aphasia was most commonly associated with tau pathology. However, the most common clinical syndrome (behavioural variant frontotemporal dementia) was pathologically heterogeneous; while pathologically proven Pick's disease and corticobasal degeneration were clinically heterogeneous, and TDP-43 type A pathology was associated with similar clinical features in cases with and without progranulin mutations. Volumetric magnetic resonance imaging, voxel-based morphometry and cluster analyses of the pathological groups here suggested a neuroanatomical framework underpinning this clinical and pathological diversity. Frontotemporal lobar degeneration-associated pathologies segregated based on their cerebral atrophy profiles, according to the following scheme: asymmetric, relatively localized (predominantly temporal lobe) atrophy (TDP-43 type C); relatively symmetric, relatively localized (predominantly temporal lobe) atrophy (microtubule-associated protein tau mutations); strongly asymmetric, distributed atrophy (Pick's disease); relatively symmetric, predominantly extratemporal atrophy (corticobasal degeneration, fused-in-sarcoma pathology). TDP-43 type A pathology was associated with substantial individual variation; however, within this group progranulin mutations were associated with strongly asymmetric, distributed hemispheric atrophy. We interpret the findings in terms of emerging network models of neurodegenerative disease: the neuroanatomical specificity of particular frontotemporal lobar degeneration pathologies may depend on an interaction of disease-specific and network-specific factors.
frontotemporal dementia; frontotemporal lobar degeneration; voxel-based morphometry; MRI; neural network
Cerebral amyloid angiopathy (CAA) is increasingly recognized as a major contributor of Alzheimer’s disease (AD) pathogenesis. To date, vascular deposits and not parenchymal plaques appear more sensitive predictors of dementia. Amyloid deposition in and around cerebral blood vessels plays a central role in a series of response mechanisms that lead to changes in the integrity of the blood-brain barrier, extravasations of plasma proteins, edema formation, release of inflammatory mediators and matrix metalloproteases which, in turn, produce partial degradation of the basal lamina with the potential to develop hemorrhagic complications. The progressive buildup of amyloid deposits in and around blood vessels chronically limits blood supply and causes focal deprivation of oxygen, triggering a secondary cascade of metabolic events several of which involve the generation of nitrogen and oxygen free radicals with consequent oxidative stress and cell toxicity. Many aspects of CAA in early- and late-onset AD –the special preference of Aβ40 to deposit in the vessel walls, the favored vascular compromise associated with many Aβ genetic variants, the puzzling observation that some of these vasculotropic variants solely manifest with recurrent hemorrhagic episodes while others are mainly associated with dementia– await clarification. Non-Aβ cerebral amyloidoses reinforce the viewpoint that plaque burden is not indicative of dementia while highlighting the relevance of nonfibrillar lesions and vascular involvement in the disease pathogenesis. The lessons learned from the comparative study of Aβ and non-Aβ cerebral amyloidosis provide new avenues and alternative models to study the role of amyloid in the molecular basis of neurodegeneration.
Amyloid molecules harboring pyroglutamate (pGlu) residue at the N-termini are considered to be important for the development of cerebral amyloidosis such as Alzheimer’s disease and thought to be either spontaneously generated or being catalyzed by glutaminyl cyclase. Familial British dementia (FBD) is an autosomal dominant form of dementia neuropathologically characterized by parenchymal amyloid and preamyloid deposits, extensive cerebral amyloid angiopathy, and neurofibrillary tangles. FBD is caused by a stop to Arg mutation in the BRI2 gene, generating de novo created amyloid molecule ABri which accumulates in FBD brains but is not present in the normal population. Soluble ABri molecules present in the circulation of carriers of the BRI2 mutation are 34 amino acids long exclusively harboring Glu residue at the N-termini (ABri1-34E), whereas water- and formic acid-soluble ABri molecules extracted from FBD brains have abundant ABri species bearing pGlu residue (ABri1-34pE), suggesting that pyroglutamate formation occurs at the site of deposition. In order to further clarify the mechanism (s) of ABri deposition, we studied whether pyroglutamate formation indeed occurs outside the central nervous system taking advantage that FBD is also a systemic amyloidosis. Soluble and fibrillar ABri molecules extracted from systemic organs and analyzed biochemically using a combination of immunoprecipitation, mass spectrometry, and western blot analysis were oligomeric in size and contained a large proportion of ABri1-34pE. The data indicate that pyroglutamate formation at the N-termini of ABri molecules is an early step in the process of FBD amyloid deposition, and its formation is not restricted to the central nervous system.
familial British dementia; ABri; pyroglutamate; amyloid; post-translational modification
Urinary frequency, urgency and nocturia are common complaints in Parkinson’s disease (PD). The hypothesis most widely proposed to explain neurogenic bladder symptoms in PD is that cell loss in the substantia nigra may cause detrusor hyperactivity due to a loss in the D1 receptor-mediated tonic inhibition of the micturition reflex, although other causes including anti-parkinsonian medication cortical effects have been considered.1 We present the clinical and pathological findings of a patient with parkinsonism who presented with prominent dysautonomia and a poor response to dopaminergic medications and was considered to have possible multiple system atrophy parkinsonism (MSA-P). Pathological examination revealed that the patient had PD with α-synuclein pathology in the Onuf’s nucleus (ON).
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 α-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 body-type 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.
Parkinson's disease; GBA; Gaucher's disease; neuropathology
In cerebral amyloid angiopathy (CAA), amyloid fibrils deposit in walls of arteries, arterioles and less frequently in veins and capillaries of the central nervous system, often resulting in secondary degenerative vascular changes. Although the amyloid-β peptide is by far the commonest amyloid subunit implicated in sporadic and rarely in hereditary forms of CAA, a number of other proteins may also be involved in rare familial diseases in which CAA is also a characteristic morphological feature. These latter proteins include the ABri and ADan subunits in familial British dementia and familial Danish dementia, respectively, which are also known under the umbrella term BRI2 gene-related dementias, variant cystatin C in hereditary cerebral haemorrhage with amyloidosis of Icelandic-type, variant transthyretins in meningo-vascular amyloidosis, disease-associated prion protein (PrPSc) in hereditary prion disease with premature stop codon mutations and mutated gelsolin (AGel) in familial amyloidosis of Finnish type. In this review, the characteristic morphological features of the different CAAs is described and the implication of the biochemical, genetic and transgenic animal data for the pathogenesis of CAA is discussed.
Central nervous system; Cerebral amyloid angiopathy; Amyloid proteins; Amyloid-β; ABri; ADan; Cystatin C; Transthyretin; Prion protein; Gelsolin; Genetics; Biochemistry; Pathogenesis
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.
β-Amyloid (Aβ) related pathology shows a range of lesions which differ both qualitatively and quantitatively. Pathologists, to date, mainly focused on the assessment of both of these aspects but attempts to correlate the findings with clinical phenotypes are not convincing. It has been recently proposed in the same way as ι and α synuclein related lesions, also Aβ related pathology may follow a temporal evolution, i.e. distinct phases, characterized by a step-wise involvement of different brain-regions. Twenty-six independent observers reached an 81% absolute agreement while assessing the phase of Aβ, i.e. phase 1 = deposition of Aβ exclusively in neocortex, phase 2 = additionally in allocortex, phase 3 = additionally in diencephalon, phase 4 = additionally in brainstem, and phase 5 = additionally in cerebellum. These high agreement rates were reached when at least six brain regions were evaluated. Likewise, a high agreement (93%) was reached while assessing the absence/presence of cerebral amyloid angiopathy (CAA) and the type of CAA (74%) while examining the six brain regions. Of note, most of observers failed to detect capillary CAA when it was only mild and focal and thus instead of type 1, type 2 CAA was diagnosed. In conclusion, a reliable assessment of Aβ phase and presence/absence of CAA was achieved by a total of 26 observers who examined a standardized set of blocks taken from only six anatomical regions, applying commercially available reagents and by assessing them as instructed. Thus, one may consider rating of Aβ-phases as a diagnostic tool while analyzing subjects with suspected Alzheimer’s disease (AD). Because most of these blocks are currently routinely sampled by the majority of laboratories, assessment of the Aβ phase in AD is feasible even in large scale retrospective studies.
Mutations in the progranulin gene (GRN) are a major cause of frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U) but the distinguishing clinical and anatomical features of this subgroup remain unclear. In a large UK cohort we found five different frameshift and premature termination mutations likely to be causative of FTLD in 25 affected family members. A previously described 4-bp insertion mutation in GRN exon 2 comprised the majority of cases in our cohort (20/25), with four novel mutations being identified in the other five affected members. Additional novel missense changes were discovered, of uncertain pathogenicity, but deletion of the entire gene was not detected. The patient collection was investigated by a single tertiary referral centre and is enriched for familial early onset FTLD with a high proportion of patients undergoing neuropsychological testing, MRI and eventual neuropathological diagnosis. Age at onset was variable, but four mutation carriers presented in their 40s and when analysed as a group, the mean age at onset of disease in GRN mutation carriers was later than tau gene (MAPT) mutation carriers and duration of disease was shorter when compared with both MAPTand FTLD-U without mutation. The most common clinical presentation seen in GRN mutation carriers was behavioural variant FTLD with apathy as the dominant feature. However, many patients had language output impairment that was either a progressive non-fluent aphasia or decreased speech output consistent with a dynamic aphasia. Neurological and neuropsychological examination also suggests that parietal lobe dysfunction is a characteristic feature of GRN mutation and differentiates this group from other patients with FTLD. MR imaging showed evidence of strikingly asymmetrical atrophy with the frontal, temporal and parietal lobes all affected. Both right- and left-sided predominant atrophy was seen even within the same family. As a group, the GRN carriers showed more asymmetry than in other FTLD groups. All pathologically investigated cases showed extensive type 3 TDP-43-positive pathology, including frequent neuronal cytoplasmic inclusions, dystrophic neurites in both grey and white matter and also neuronal intranuclear inclusions. Finally, we confirmed a modifying effect of APOE-E4 genotype on clinical phenotype with a later onset in the GRN carriers suggesting that this gene has distinct phenotypic effects in different neurodegenerative diseases.
frontotemporal lobar degeneration; frontotemporal dementia; progranulin; progressive aphasia
To describe the clinical, neuropsychological and radiological features of a family with a C31LfsX35 mutation in the progranulin gene (PGRN).
A large British kindred (DRC255) with a PGRN mutation was assessed. Affected individuals presented with a mean age of 57.8 (54 to 67) and mean duration of disease of 6.1 years (2 to 11).
All cases exhibited a clinical and radiological phenotype compatible with FTLD based on current consensus criteria. However, unlike sporadic FTLD, parietal deficits consisting of limb apraxia, dyscalculia, visuoperceptual and/or visuospatial impairment were a common feature, and brain imaging showed posterior extension of frontotemporal atrophy to involve the parietal lobes. Other common clinical features included language output impairment with either dynamic aphasia or non-fluent aphasia, and a behavioural syndrome dominated by apathy.
We propose that parietal features may be a prominent feature of PGRN mutations and that this may be due to disruption of fronto-parietal functional pathways.
Drugs used for remission induction therapy for childhood precursor-B acute lymphoblastic leukemia (ALL) are nonselective for malignant cells. Several garlic compounds have been shown to induce apoptosis of cancer cells and to alter lymphocyte function. To investigate the effect of garlic on the apoptosis of ALL cells and lymphocyte immune function, cells from newly diagnosed childhood ALL patients were cultured with several commonly used chemotherapeutic agents and several garlic compounds. Apoptosis, lymphocyte proliferation and T-cell cytokine production were determined using multiparameter flow cytometry. At concentrations of garlic compounds that did not result in significant increases in Annexin V and 7-AAD staining of normal lymphocytes, there was a significant increase in apoptosis of ALL cells with no alteration of T-cell proliferation as determined by CD25/CD69 upregulation or interferonγ, interleukin-2 or tumor necrosis factor-α intracellular cytokine production. In contrast, the presence of chemotherapeutic agents resulted in nonselective increases in both lymphocyte and ALL apoptosis and a decrease in T-cell proliferation and cytokine production. In conclusion, we show selective apoptosis of malignant cells by garlic compounds that do not alter T-cell immune function and indicate the potential therapeutic benefit of garlic compounds in the treatment of childhood ALL.
childhood precursor-B acute lymphoblastic leukemia; garlic; apoptosis; immune function; intracellular cytokines
Ependymomas are glial cell–derived tumors characterized by varying degrees of chromosomal abnormalities and variability in clinical behavior. Cytogenetic analysis of pediatric ependymoma has failed to identify consistent patterns of abnormalities, with the exception of monosomy of 22 or structural abnormalities of 22q. In this study, a total of 19 pediatric ependymoma samples were used in a series of expression profiling, quantitative real-time PCR (Q-PCR), and loss of heterozygosity experiments to identify candidate genes involved in the development of this type of pediatric malignancy. Of the 12,627 genes analyzed, a subset of 112 genes emerged as being abnormally expressed when compared to three normal brain controls. Genes with increased expression included the oncogene WNT5A; the p53 homologue p63 and several cell cycle, cell adhesion, and proliferation genes. Underexpressed genes comprised the NF2 interacting gene SCHIP-1 and the adenomatous polyposis coli (APC)-associated gene EB1 among others. We validated the abnormal expression of six of these genes by Q-PCR. The subset of differentially expressed genes also included four underexpressed transcripts mapping to 22q12.3-13.3. By Q-PCR we show that one of these genes, CBX7 (22q13.1), was deleted in 55% of cases. Other genes mapping to cytogenetic hot spots included two overexpressed and three underexpressed genes mapping to 1q31-41 and 6q21-q24.3, respectively. These genes represent candidate genes involved in ependymoma tumorigenesis. To the authors’ knowledge, this is the first time microarray analysis and Q-PCR have been linked to identify heterozygous/homozygous deletions.