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Biomedical subjects

P G Ince

Publications and source records attributed to P G Ince.

At least 19 recordsLinked to original sources
PubMed2006

ALS phenotypes with mutations in CHMP2B (charged multivesicular body protein 2B).

Mutation in the CHMP2B gene has been implicated in frontotemporal dementia. The authors screened CHMP2B in patients with ALS and several cohorts of control samples. They identified mutations (Q206H; I29V) in two patients with non-SOD1 ALS. Neuropathology of the Q206H case showed lower motor neuron predominant disease with ubiquitylated inclusions in motor neurons. Antibodies to p62 (sequestosome 1) showed novel oligodendroglial inclusions in the motor cortex.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Return of the cycad hypothesis - does the amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) of Guam have new implications for global health?

Recently published work provides evidence in support of the cycad hypothesis for Lytico--Bodig, the Guamanian amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC), based on a new understanding of Chamorro food practices, a cyanobacterial origin of beta-methylaminoalanine (BMAA) in cycad tissue, and a possible mechanism of biomagnification of this neurotoxic amino acid in the food chain. BMAA is one of two cycad chemicals with known neurotoxic properties (the other is cycasin, a proven developmental neurotoxin) among the many substances that exist in these highly poisonous plants, the seeds of which are used by Chamorros for food and medicine. The traditional diet includes the fruit bat, a species that feeds on cycad seed components and reportedly bioaccumulates BMAA. Plant and animal proteins provide a previously unrecognized reservoir for the slow release of this toxin. BMAA is reported in the brain tissue of Guam patients and early data suggest that some Northern American patients dying of Alzheimer's disease (AD) have detectable brain levels of BMAA. The possible role of cyanobacterial toxicity in sporadic neurodegenerative disease is therefore worthy of consideration. Recent neuropathology studies of ALS/PDC confirm understanding of this disorder as a 'tangle' disease, based on variable anatomical burden, and showing biochemical characteristics of 'AD-like' combined 3R and 4R tau species. This model mirrors the emerging view that other neurodegenerative disease spectra comprise clusters of related syndromes, owing to common molecular pathology, with variable anatomical distribution in the nervous system giving rise to different clinical phenotypes. Evidence for 'ubiquitin-only' inclusions in ALS/PDC is weak. Similarly, although there is evidence for alpha-synucleinopathy in ALS/PDC, the parkinsonian component of the disease is not caused by Lewy body disease. The spectrum of sporadic AD includes involvement of the substantia nigra and a high prevalence of 'incidental'alpha-synucleinopathy in sporadic AD is reported. Therefore the pathogenesis of Lytico-Bodig appears still to have most pertinence to the ongoing investigation of the pathogenesis of AD and other tauopathies.

Amyotrophic Lateral Sclerosis↗
PubMed2004

Comparison of the pathology of cerebral white matter with post-mortem magnetic resonance imaging (MRI) in the elderly brain.

White matter lesions (WML) on magnetic resonance imaging (MRI) brain scans are associated with ageing. They are unrelated to specific disorders, and their impact on cognitive and other brain functions is poorly characterized. Pathological studies often omit systematic survey of WML because of the need to study multiple full coronal tissue blocks, and uncertainty over the significance of lesions identified in periventricular and deep subcortical regions. Post-mortem MRI provides a means of mapping WML but the sensitivity and specificity of the method are unresolved. In this study post-mortem MRI of WML in fixed brain slices was compared with pathology in 33 brains donated to the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). This study shows that MRI detection of WML was less sensitive than pathology: periventricaular lesions (PVL) sensitivity = 95% (87-99%), specificity = 71% (44-90%); deep subcortical lesions (DSCL) sensitivity = 86% (79-93%), specificity = 80% (72-88%). False negative MRI was associated with milder pathology, but lesions detected by myelin attenuation alone showed both microglial and endothelial activation. Therefore post-mortem MRI of formalin-fixed brain slices is a reliable method to obtain systematic data on the severity and distribution of cerebral white matter disease, and appears to detect those WML most likely to have clinical impact.

Aged↗
PubMed2003

Corticospinal tract degeneration in the progressive muscular atrophy variant of ALS.

OBJECTIVE: Examining the unresolved relationship between the lower motor neuron disorder progressive muscular atrophy (PMA) and ALS is important in clinical practice because of emerging therapies. METHODS: Spinal and brainstem tissues donated from patients with ALS/motor neuron disorder (n = 81) were examined. Using retrospective case note review, the authors assigned patients into three categories: PMA (12), PMA progressing to ALS (6), and ALS ab initio (63). Conventional stains for long tract degeneration and immunocytochemistry for ubiquitin and the macrophage marker CD68 were examined. RESULTS: Rapid progression and typical ubiquitinated inclusions in lower motor neurons were present in 77 (95%) of the cases. Immunocytochemistry for CD68 was a more sensitive marker of long tract pathology in comparison with conventional stains. Half of the cases with PMA showed corticospinal tract degeneration by CD68. CONCLUSION: Patients with PMA frequently have undetected long tract pathology and most have ubiquitinated inclusions typical of ALS. A patient presenting with PMA with rapid clinical evolution likely has the pathology and pathophysiology of ALS whether or not upper motor neuron signs evolve.

Aged↗
PubMed2002

Quantitative assessment of AMPA receptor mRNA in human spinal motor neurons isolated by laser capture microdissection.

Disturbance of glutamate neurotransmission may contribute to the motor neuron injury seen in amyotrophic lateral sclerosis. Previous studies have suggested that human spinal motor neurons express a specific profile of the AMPA subtype of glutamate receptor with low mRNA expression for the GluR2 AMPA receptor subunit but other studies have contested this finding. The present study uses laser capture microdissection to isolate specifically identified neurons coupled with quantitative RT-PCR to demonstrate that the level of expression of the GluR2 subunit is lower in spinal motor neurons than in dorsal horn neurons from the same spinal cord region. Thus, it is likely that human spinal motor neurons express a proportion of Ca2+-permeable AMPA receptors which may contribute to the selective vulnerability of these cells in amyotrophic lateral sclerosis.

Aged↗
PubMed2002

CADASIL and genetics of cerebral ischaemia.

Recent advances suggest the existence of several autosomal dominantly inherited forms of cerebrovascular disorders. Mutations in diverse genes may induce direct pathological changes in intracranial vessels to cause cerebral ischaemic or haemorrhagic strokes leading to cognitive impairment and dementia. Similar pathology may also be caused by systemic vascular disease resulting from mutations and polymorphisms in genes that regulate cardiovascular physiology, blood coagulation and metabolic functions. The most common form of familial stroke appears to be CADASIL or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. CADASIL is an arterial disease that has been linked to nucleotide substitutions and deletions in the Notch 3 gene. The pathogenesis of the disorder or how the mutations lead to cerebral infarcts and dementia is not known. However, elucidation of the microvascular pathology associated with such genetic disorders not associated with physiological risk factors for cardiovascular disease or stroke can bear much light on primary vascular mechanisms that lead to ischaemic blood flow and neuronal vulnerability.

Animals↗
PubMed2002

The expression of the glutamate re-uptake transporter excitatory amino acid transporter 1 (EAAT1) in the normal human CNS and in motor neurone disease: an immunohistochemical study.

A monoclonal antibody to excitatory amino acid transporter 1 (EAAT1) has been generated which robustly stains paraffin-embedded, formaldehyde-fixed as well as snap-frozen human post-mortem brain tissue. We have used this antibody to map the distribution of EAAT1 throughout normal human CNS tissue. In addition this antibody has been used to perform a semi-quantitative immunohistochemical analysis of the expression of EAAT1 in motor cortex and cervical cord tissue taken from motor neurone disease cases (n=17) and neurologically normal controls (n=12). By comparing the relative optical density measurements of identical regions of motor cortex and cervical spinal cord an increase in the expression levels of EAAT1 was observed in motor neurone disease tissue compared to the control tissue and in both motor cortex and cervical spinal cord (9-17% and 13-33% increases respectively). EAAT1 was observed to be the most abundant transporter in more "caudal" brain regions such as the diencephalon and brainstem and its expression in other regions was frequently more uniform than that of EAAT2. In the motor cortex, EAAT1 immunoreactivity was present in all grey matter laminae, with some staining of individual astrocytes in the white matter. In spinal cord, EAAT1 immunoreactivity was strongest in the substantia gelatinosa. In the ventral horn, motor neurones were surrounded with a dense rim of perisomatic EAAT1 immunoreactivity, and the neuropil showed diffuse staining. Additional studies using double-labelling immunocytochemistry demonstrated that astrocytic co-localisation of EAAT1 and EAAT2 may occasionally be seen, but was not widespread in the human CNS and that in general astrocytes were positive for either EAAT1 or EAAT2. These results demonstrate that the EAAT1 has a widespread abundance throughout all regions of the human CNS examined and that there exist discrete populations of astrocytes that are positive solely for either EAAT1 or EAAT2. Furthermore, there is evidence to suggest that altered EAAT1 expression in motor neurone disease follows a different pattern to the reported changes of EAAT2 expression in this condition, indicating that the role of glutamate transporters in the pathogenesis of motor neurone disease appears more complex than previously appreciated.

Aged↗
PubMed2002

The role of cytochrome c oxidase deficient hippocampal neurones in Alzheimer's disease.

Defects of mitochondrial function have been proposed as a potential mechanism in the development and pathogenesis of Alzheimer's disease (AD) and neuronal apoptosis. Mitochondrial enzyme-deficient pyramidal neurones are found in greater quantities in the hippocampus of AD patients than in age-matched controls. The presence of these neurones indicates that high levels of mutant mtDNA (mitochondrial DNA), sufficient to cause a biochemical deficiency within individual neurones, occur more frequently in AD than in normal ageing. This study analyses the relationship of cytochrome c oxidase (COX)-deficient neurones with the neuropathological markers of AD, neurofibrillary tangles (NFTs) and amyloid plaques, as well as markers of neuronal apoptosis known to occur in AD brains. Frozen sections of hippocampi from three AD patients were used to directly colocalize in situ the presence of histochemically COX-deficient neurones with immunohistology for the classical neuropathological markers of AD, tau and beta-amyloid. In addition, we also directly colocalized these mitochondrial-enzyme deficient neurones using terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling and cleaved caspase-3. The distribution of amyloid plaques is anatomically distinct from the COX-deficient hippocampal pyramidal neurones and the neurones that contained NFTs or apoptotic labelling were always COX-positive. COX-deficient, succinate dehydrogenase-positive hippocampal neurones indicative of high mtDNA mutation load do not appear to be prone to apoptosis or to directly participate in the over production of tau or beta-amyloid. Biochemically significant mitochondrial defects do occur in AD and are likely to contribute to the overall central nervous system dysfunction in impairing neuronal function and possibly causing neurodegeneration via mechanisms other than apoptosis.

Aged↗
PubMed2001

Mitochondrial enzyme-deficient hippocampal neurons and choroidal cells in AD.

OBJECTIVE: To determine whether hippocampal neurons and choroidal epithelial cells demonstrate a mitochondrial enzyme deficiency in AD more frequently than in normal aging. BACKGROUND: High levels of mutant mitochondrial DNA (mtDNA) cause a deficiency in cytochrome c oxidase (COX) (complex IV activity) because three of its 13 subunits are encoded for by mtDNA. In contrast, succinate dehydrogenase (SDH) (complex II activity) remains intact because all of its subunits are nuclear encoded. The histologic hallmark of cells containing high levels of mtDNA mutation in both primary mtDNA disorders and normal aging muscle is the presence of COX-deficient SDH-positive cells. METHODS: The authors applied a sequential histochemical method for COX and SDH to hippocampal sections in 17 AD and 17 age-matched control brains. This confers the advantages of both looking at individual cells in situ and measuring the actual mitochondrial complex activity rather than simply the complex quantity. RESULTS: COX-deficient SDH-positive hippocampal neurons and choroidal epithelial cells are more prevalent in patients with AD than in controls. In addition the COX-deficient SDH-positive choroidal cells are associated with an enlargement in size. CONCLUSION: This increase in number of COX-deficient SDH-positive hippocampal pyramidal neurons and choroid epithelial cells provides strong evidence that a substantial mitochondrial enzyme activity defect occurs in individual cells more frequently in AD than in normal aging and that mitochondria may play a significant role in the pathogenesis of AD.

Aged↗
PubMed2001

Multiple substrates of late-onset dementia: implications for brain protection.

Age is the single most important risk factor for progressive dementia in populations worldwide. In developed countries the prevalence of dementia is estimated to be 3-5% at age 65 years and expected to double every decade thereafter. Although there is ageing-related attrition of neural tissue accompanied by profound changes in brain glia, marked neuronal loss and severe cognitive impairment are associated with pathological changes. Accelerated somatic ageing of the vasculature comprising endothelial and smooth muscle cells and slowed glial replacement are also likely to pre-dispose to degenerative processes. Approximately 90% of patients with late-onset dementia have neuropathological features of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), or vascular dementia (VaD), alone or in combination. Both AD and DLB reveal extensive amyloid beta deposition within senile plaques. Neurofibrillary tangles evident as tau pathology are much reduced in DLB where symptoms may be more related to cholinergic transmitter abnormalities than structural pathology. Depletion of brain acetylcholine is also encountered in VaD, which like AD and DLB may respond to cholinergic therapy. Cerebrovascular pathology, ischaemic brain damage and neurovascular instability resulting in cerebral hypoperfusion appears fundamental in the pathogenesis of late-onset dementia. The apolipoprotein E epsilon 4 allele, a major genetic susceptibility factor for AD also associated with cardiovascular pathology, may contribute to neurodegenerative changes through vascular mechanisms. The interrelationships of these multiple substrates of late-onset dementia have major implications for neuroprotective and disease slowing therapies. Measures that improve cardiovascular function and increase brain perfusion would be useful to attenuate cognitive decline.

Age of Onset↗
PubMed2001

Glial cells of the spinal cord and subcortical white matter up-regulate neuronal nitric oxide synthase in sporadic amyotrophic lateral sclerosis.

Several studies have suggested that excessive generation of nitric oxide (NO) may contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS). Recently, a selective induction of the neuronal isoform of nitric oxide synthase (nNOS) in glial cells has been reported in an animal model of familial ALS. We therefore examined in postmortem tissue the expression of nNOS in patients with sporadic ALS and patients without any history of neurological disease. Using immunohistochemistry, we found an up-regulation of nNOS in glial cells of the spinal cord and subcortical white matter in ALS patients compared to controls. The enhanced glial nNOS expression seen in ALS patients could conceivably contribute to motoneuronal degeneration through NO-mediated cytotoxic effects.

Aged↗
PubMed2001

Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease.

We describe here a previously unknown, dominantly inherited, late-onset basal ganglia disease, variably presenting with extrapyramidal features similar to those of Huntington's disease (HD) or parkinsonism. We mapped the disorder, by linkage analysis, to 19q13.3, which contains the gene for ferritin light polypeptide (FTL). We found an adenine insertion at position 460-461 that is predicted to alter carboxy-terminal residues of the gene product. Brain histochemistry disclosed abnormal aggregates of ferritin and iron. Low serum ferritin levels also characterized patients. Ferritin, the main iron storage protein, is composed of 24 subunits of two types (heavy, H and light, L) which form a soluble, hollow sphere. Brain iron deposition increases normally with age, especially in the basal ganglia, and is a suspected causative factor in several neurodegenerative diseases in which it correlates with visible pathology, possibly by its involvement in toxic free-radical reactions. We found the same mutation in five apparently unrelated subjects with similar extrapyramidal symptoms. An abnormality in ferritin strongly indicates a primary function for iron in the pathogenesis of this new disease, for which we propose the name 'neuroferritinopathy'.

Adult↗
PubMed2001

Apoptosis in amyotrophic lateral sclerosis: a review of the evidence.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily affecting the upper and lower motor neurones of the central nervous system. Recently, a lot of interest has been generated by the possibility that a mechanism of programmed cell death, termed apoptosis, is responsible for the motor neurone degeneration in this condition. Apoptosis is regulated through a variety of different pathways which interact and eventually lead to controlled cell death. Apart from genetic regulation, factors involved in the control of apoptosis include death receptors, caspases, Bcl-2 family of oncoproteins, inhibitor of apoptosis proteins (IAPs), inhibitors of IAPs, the p53 tumour suppressor protein and apoptosis-related molecules. The first part of this article will give an overview of the current knowledge of apoptosis. In the second part of this review, we will examine in detail the evidence for and against the contribution of apoptosis in motor neurone cell death in ALS, looking at cellular-, animal- and human post-mortem tissue-based models. In a chronic neurodegenerative disease such as ALS, conclusive evidence of apoptosis is likely to be difficult to detect, given the rapidity of the apoptotic cell death process in relation to the relatively slow time course of the disease. Although a complete picture of motor neurone death in ALS has not been fully elucidated, there is good and compelling evidence that a programmed cell death pathway operates in this disorder. The strongest body of evidence supporting this comes from the findings that, in ALS, changes in the levels of members of the Bcl-2 family of oncoproteins results in a predisposition towards apoptosis, there is increased expression or activation of caspases-1 and -3, and the dying motor neurones in human cases exhibit morphological features reminiscent of apoptosis. Further supporting evidence comes from the detection of apoptosis-related molecules and anti-Fas receptor antibodies in human cases of ALS. However, the role of the p53 protein in cell death in ALS is at present unclear. An understanding of the mechanism of programmed cell death in ALS may provide important clues for areas of potential therapeutic intervention for neuroprotection in this devastating condition.

Amyotrophic Lateral Sclerosis↗
PubMed2001

Accelerated ageing changes in the choroid plexus of a case with multiple mitochondrial DNA deletions.

Mitochondrial abnormalities, in particular the accumulation of mitochondrial DNA mutations, have been proposed as a potential cause of normal ageing. One group of patients with mtDNA disorders have a nuclear DNA defect which accelerates the chronological accumulation of mitochondrial DNA mutations. These patients provide an ideal means of investigating whether accelerated mitochondrial DNA defects can cause accelerated ageing pathology. The choroid plexus demonstrates a robust accumulation of pathological changes, in the form of Biondi bodies, with normal ageing. We have therefore examined the choroid plexus of a case with multiple mitochondrial DNA deletions for evidence of accelerated ageing and compared it with two cases with point mutation mitochondrial DNA disorders and several age-matched and elderly controls with and without clinical and neuropathological evidence of neurodegenerative disease. We also demonstrate that the choroid plexus of the mitochondrial DNA cases contain cells with levels of mitochondrial DNA mutation sufficient to cause a biochemical deficiency in the oxidative phosphorylation pathway. As previously reported, both cases with point mutation mitochondrial DNA disorders exhibit a characteristic oncocytic type transformation of the choroidal epithelial cells. However, in the case with multiple mitochondrial DNA deletions we demonstrate pathological changes in choroid plexus that are strongly suggestive of accelerated ageing. We believe that this finding supports the theory that the accumulation of mitochondrial DNA mutations can lead to pathological changes typical of ageing cells.

Adult↗
PubMed2000

Relapsing ischemic encephaloenteropathy and cryoglobulinemia.

Cryoglobulinemia is a rare cause of encephalopathy. The authors report three patients with strikingly similar clinical features of recurrent encephalopathy accompanied by symptoms of gastrointestinal ischemia. In only one patient was cryoglobulinemia ascertained in life during the final illness. The autopsy examinations all showed diffuse cerebral, enteral, and systemic small vessel lesions immunoreactive for immunoglobulins and typical of mixed essential cryoglobulinemia. This unusual relapsing clinical syndrome is readily misinterpreted as of nonorganic origin despite its potentially fatal prognosis.

Aged↗
PubMed2000

Clinical and pathologic findings in hereditary spastic paraparesis with spastin mutation.

OBJECTIVE: To describe a family with chromosome 2p-linked hereditary spastic paraparesis (HSP) associated with dementia and illustrate the cerebral pathology associated with this disorder. BACKGROUND: HSP comprises a heterogeneous group of inherited disorders in which the main clinical feature is severe, progressive lower limb spasticity. Nongenetic classification relies on characteristics such as mode of inheritance, age at onset, and the presence or absence of additional neurologic features. Several loci have been identified for autosomal dominant pure HSP. The most common form, which links to chromosome 2p (SPG4), has recently been shown to be due to mutations in spastin, the gene encoding a novel AAA-containing protein. RESULTS: The authors report four generations of a British family with autosomal dominant HSP in whom haplotype analysis indicates linkage to chromosome 2p. In addition, a missense mutation has been identified in exon 10 of the spastin gene (A1395G). Dementia was documented clinically in one member of the family, two other affected family members were reported to have had late onset memory loss, and a younger affected individual showed evidence of memory disturbance and learning difficulties. Autopsy of the demented patient confirmed changes in the spinal cord typical of HSP and also demonstrated specific cortical pathology. There was neuronal depletion and tau-immunoreactive neurofibrillary tangles in the hippocampus and tau-immunoreactive balloon cells were seen in the limbic and neocortex. The substantia nigra showed Lewy body formation. The pathologic findings are not typical of known tauopathies. CONCLUSIONS: The authors confirm that chromosome 2p-linked HSP can be associated with dementia and that this phenotype may be associated with a specific and unusual cortical pathology.

Adenosine Triphosphatases↗
PubMed2000

Prospective validation of consensus criteria for the diagnosis of dementia with Lewy bodies.

OBJECTIVE: To determine the validity of a clinical diagnosis of probable or possible dementia with Lewy bodies (DLB) made using International Consensus criteria. BACKGROUND: Validation studies based on retrospective chart reviews of autopsy-confirmed cases have suggested that diagnostic specificity for DLB is acceptable but case detection rates as low as 0.22 have been suggested. METHODS: We evaluated the first 50 cases reaching neuropathologic autopsy in a cohort to which Consensus clinical diagnostic criteria for DLB, National Institute for Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for AD, and National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences criteria for vascular dementia (VaD) had been prospectively applied. RESULTS: Twenty-six clinical diagnoses of DLB, 19 of AD, and 5 of VaD were made. At autopsy, 29 DLB cases, 15 AD, 5 VaD, and 1 progressive supranuclear palsy were identified. The sensitivity and specificity of a clinical diagnosis of probable DLB in this sample were 0.83 and 0.95. Of the five cases receiving a false-negative diagnosis of DLB, significant fluctuation was present in four but visual hallucinations and spontaneous motor features of parkinsonism were generally absent. Thirty-one percent of the DLB cases had additional vascular pathology and in two cases this contributed to a misdiagnosis of VaD. No correlations were found between the distribution of Lewy bodies and clinical features. CONCLUSION: The Consensus criteria for DLB performed as well in this prospective study as those for AD and VaD, with a diagnostic sensitivity substantially higher than that reported by previous retrospective studies. DLB occurs in the absence of extrapyramidal features and in the presence of comorbid cerebrovascular disease. Fluctuation is an important diagnostic indicator, reliable measures of which need to be developed further.

Aged↗