Combined spectroscopic and computational study for optimising catalyst design in hydrocarbon transformations.

Molecular interactions of hydrocarbons within the confined pores of heterogeneous catalysts can influence reaction pathways, which play a crucial role in determining the overall efficacy of catalytic transformations. We probe the interactions of n-butane with a solid-acid zeolite, mordenite, combining inelastic neutron scattering with DFT calculations. This reveals that the solid-acid sites within mordenite induce a conformer change, which could be key in designing optimised catalysts, for hydrocarbon transformations.

Morphometry of the hippocampal microvasculature in post-stroke and age-related dementias.

BACKGROUND: Optimal vascular function is vital for prevention of dementia. We hypothesized that elderly post-stroke survivors who preserve cognitive function show unperturbed cerebral microvasculature compared with those who develop dementia. METHODS: Using stereological spherical probe software, we compared the length density (Lv, cumulative vessel length per unit tissue volume) of hippocampal microvessels in post mortem brain tissue from post-stroke survivors, Alzheimer's disease (AD), vascular dementia (VaD) and normal ageing control subjects. We also assessed microvessel diameters in the same subjects. Microvessels were identified by markers of endothelial cells (glucose transporter 1; GLUT1), basement membrane (collagen IV; COL4) and smooth muscle cell α-actin (SMA). RESULTS: We found increased Lv of both GLUT1 and COL4 immunostained microvessels (P < 0.05) in the hippocampal CA1 region of post-stroke demented (PSD) and AD cases compared with post-stroke nondemented (PSND), control and VaD subjects. However, no changes were apparent in the CA2 region. We also noted significant increase in Lv in the entorhinal cortex of AD compared with PSND and PSD subjects. The mean diameter of microvessels was decreased in PSD, compared with PSND, as well as in AD and VaD compared with controls. Cumulative frequency analysis showed PSND subjects to have significantly greater proportion of microvessels with diameters, ranging from 7 to 12 µm. CONCLUSIONS: An increase in microvascular Lv in AD and PSD suggests either an increase in angiogenesis or the formation of newer microvessel loops in response to cerebral hypoperfusion. The decreased vessel diameters found in AD and VaD suggests increased vasoconstriction in dementia.

Staging and natural history of cerebrovascular pathology in dementia.

OBJECTIVE: Most pathologic studies indicate that significant vascular changes are found in the majority of elderly persons, either alone or in association with neurodegenerative processes such as Alzheimer disease (AD) or dementia with Lewy bodies (DLB). Cumulative burden of cerebrovascular lesions can explain cognitive decline described as vascular cognitive impairment, but because there is a lack of consensus in the best way to quantify vascular pathology, the relationship between cognitive decline and cerebrovascular disease remains uncertain. We developed a rating scheme for cerebrovascular lesions using postmortem brains from patients with dementia from 2 European tertiary care memory clinics. METHODS: A total of 135 brains with a neuropathologic diagnosis of vascular dementia (VaD) (n = 26), AD + VaD (n = 39), DLB + VaD (n = 21), AD + DLB + VaD (n = 9), AD (n = 19), and DLB (n = 21) were investigated in this study. Cerebrovascular lesions were rated on large sections from the hippocampus, the temporal lobe, the frontal lobe, and basal ganglia. RESULTS: In patients with dementia, vessel wall modifications such as arteriolosclerosis or amyloid angiopathy are the most common and presumably the earliest changes. Modifications in perivascular spaces and myelin loss are the next most common. Lacunar or regional infarcts may occur as a consequence of an independent process or in the final phase of small vessel diseases. CONCLUSION: A staging system based on this conceptual model of cerebrovascular pathology could enable the neuropathologic quantification of the cerebrovascular burden in dementia. Further studies are needed to determine whether this system can be used in large-scale studies to understand clinical-cerebrovascular pathologic correlations.

Estradiol enables cortisol to act directly upon the pituitary to suppress pituitary responsiveness to GnRH in sheep.

We have shown that cortisol infusion reduced the luteinizing hormone (LH) response to fixed hourly GnRH injections in ovariectomized ewes treated with estradiol during the non-breeding season (pituitary-clamp model). In contrast, cortisol did not affect the response to 2 hourly invariant GnRH injections in hypothalamo-pituitary disconnected ovariectomized ewes during the breeding season. To understand the differing results in these animal models and to determine if cortisol can act directly at the pituitary to suppress responsiveness to GnRH, we investigated the importance of the frequency of GnRH stimulus, the presence of estradiol and stage of the circannual breeding season. In experiment 1, during the non-breeding season, ovariectomized ewes were treated with estradiol, and pulsatile LH secretion was restored with i.v. GnRH injections either hourly or 2 hourly in the presence or absence of exogenous cortisol. Experiments 2 and 3 were conducted in hypothalamo-pituitary disconnected ovariectomized ewes in which GnRH was injected i.v. every 2 h. Experiment 2 was conducted during the non-breeding season and saline or cortisol was infused for 30 h in a cross-over design. Experiment 3 was conducted during the non-breeding and breeding seasons and saline or cortisol was infused for 30 h in the absence and presence of estradiol using a cross-over design. Samples were taken from all animals to measure plasma LH. LH pulse amplitude was reduced by cortisol in the pituitary clamp model with no difference between the hourly and 2-hourly GnRH pulse mode. In the absence of estradiol, there was no effect of cortisol on LH pulse amplitude in GnRH-replaced ovariectomized hypothalamo-pituitary disconnected ewes in either season. The LH pulse amplitude was reduced in both seasons in experiment 3 when cortisol was infused during estradiol treatment. We conclude that the ability of cortisol to reduce LH secretion does not depend upon the frequency of GnRH stimulus and that estradiol enables cortisol to act directly on the pituitary of ovariectomized hypothalamo-pituitary disconnected ewes to suppress the responsiveness to GnRH; this effect occurs in the breeding and non-breeding seasons.

Medullary autonomic pathology in carotid sinus hypersensitivity.

AIMS: Carotid sinus hypersensitivity (CSH) is an ageing-related autonomic disorder, rarely occurring before the age of 50 years but increasing in incidence thereafter. Clinical symptoms of CSH include falls and dizziness, thought to be precipitated by dysfunctional baroreflex responses. CSH is highly prevalent in Alzheimer's disease (AD), Parkinson's disease (PD) and dementia with Lewy bodies (DLB); diseases that are associated with variable degeneration of medullary autonomic nuclei which regulate baroreflex responses. Currently, there are no descriptions of the integrity of medullary autonomic nuclei in CSH. We hypothesized medullary autonomic degeneration is found in elderly patients with CSH. METHODS: Using in vitro digital imaging, we quantified the burden of tau, amyloid beta and alpha-synuclein in autonomic nuclei of 12 patients prospectively assessed with CSH (age 83 years) compared with 14 (80 years) control subjects. RESULTS: We found increased tau (P < 0.000) accumulation in baroreflex associated nuclei, but not the hypoglossal or raphe in the CSH patients. Medullary tau accumulation was not related to the development of AD in the CSH patients. Tau was colocalized to catecholaminergic neurones and occurred in the absence of neuronal loss. We found no difference in alpha-synuclein, amyloid beta or microglial numbers between the CSH cases and controls. CONCLUSIONS: We suggest that hyperphosphorylated tau accumulation particularly in tyrosine hydroxylase containing neurones may impair central regulation of baroreflex responses in patients with CSH. Future clinic-pathological investigations should reveal whether medullary degeneration is the cause of CSH symptoms.

Individual dopaminergic neurons show raised iron levels in Parkinson disease.

OBJECTIVE: Evidence suggests that abnormal iron metabolism is associated with Parkinson disease (PD), with raised iron levels found in pathologically affected areas in PD. It is unknown if this elevated iron is actually associated with neurons or reactive glia, and we therefore addressed this issue by determining if raised iron was present in single dopaminergic neurons. METHODS: We used unfixed frozen sections from postmortem tissue of PD patients and elderly normal individuals to avoid metal contamination and translocation. Levels of iron and other elements were measured using sensitive and specific wavelength dispersive electron probe x-ray microanalysis coupled with cathodoluminescence spectroscopy in individual substantia nigra dopaminergic neurons. RESULTS: We identified raised intraneuronal iron in single defined substantia nigra neurons in PD (mean neuronal iron 2,838 vs 1,611, p < 0.0001) but not in other movement disorders such as Huntington disease. These findings were unrelated to the density of remaining neurons. CONCLUSIONS: Primary changes in neuronal iron could lead to neurodegeneration in Parkinson disease.

Medullary microvessel degeneration in multiple system atrophy.

Multiple system atrophy (MSA) is a rare and fatal early-onset autonomic disorder which is characterised by Parkinsonism and orthostatic hypotension (OH). The pathophysiology of MSA is not fully understood but key features include the depletion of medullary autonomic neurons and presence of glial cellular inclusions. We hypothesise that the degeneration of medullary autonomic microvessels is an additional finding in MSA. Using digital pathology we quantified basement membrane collagen (Coll IV), smooth muscle actin (alpha-actin) and endothelial glucose transporter (Glut 1) expression in medullary autonomic nuclei of 8 MSA and 8 OH cases, compared with 12 controls with no autonomic dysfunction. We found decreased Coll IV (p=0.000) and Glut 1 (p=0.000) but not alpha-actin expression, in medullary autonomic nuclei of MSA, but not OH cases compared with control subjects. Medullary microvessel degeneration in MSA may be secondary to the primary neuro-glial pathogenesis of the disorder, and could accelerate its ageing-related progression.

Effects of NOS inhibition on the cardiopulmonary system and brain microvascular markers after intermittent hypoxia in rats.

We previously demonstrated that rats subjected to intermittent hypoxia (IH) by exposure to 10% O(2) for 4 h daily for 56 days in a normobaric chamber, developed pulmonary hypertension, right ventricular hypertrophy and wall-thickening in pulmonary arterioles, compared with normoxic (N) controls. These changes were greater in rats subjected to continuous hypoxia (CH breathing 10% O(2) for 56 days). Cerebral angiogenesis was demonstrated by immunostaining with glucose transporter 1 (GLUT1) antibody, in viable vessels, in CH and to a lesser degree in IH. In this study, adult Wistar rats were subjected to the same hypoxic regimes and given the nitric oxide synthase (NOS) inhibitor N(6)-nitro-L-arginine methyl ester (L-NAME) in drinking water (NLN, IHLN and CHLN regimes) to induce hypertension. There was significant systemic hypertension in NLN and IHLN rats, compared with N and IH, but surprisingly not in CHLN compared with CH. Hematocrit rose in all hypoxic groups (up to 79% in CHLN). There was no significant pulmonary hypertension in IHLN versus NLN rats, although there was asymmetric wall thickening in pulmonary arterioles. Cerebral GLUT1 immunoreactivity increased with L-NAME, with or without hypoxia, especially in CHLN rats, but conspicuously there was no evidence of angiogenesis in brains of IHLN compared with NLN rats. NOS blockade may attenuate the cerebral and pulmonary vascular changes of IH while augmenting cerebral angiogenesis in continuous hypoxia. However, whether cerebral effects are due to systemic hypertension or changes in cerebral nitric oxide production needs to be evaluated.

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.

Aggregation of A beta Alzheimer's disease-related peptide studied by dynamic light scattering.

The aggregation behavior of the major component of Alzheimer's disease-related, amyloid peptides, Abeta-(1-40) and Abeta-(1-42), was studied in solution using dynamic light scattering. With most solvents employed, we found fibrils coexisting with oligomeric Abeta species. Pronounced differences were observed in aggregation of Abeta-(1-40) and (1-42) sequences in acetonitrile-water mixtures. Cofactors such as Zn2+ were found to induce deaggregation of Abeta instead of aggregation. The results indicated that the initial state of the peptide immediately after synthesis is rather poorly defined. Using freezing instead of lyophilization after the final peptide synthesis step, may partially relieve these problems.

Nicotinic and muscarinic cholinergic receptor binding in the human hippocampal formation during development and aging.

High-affinity nicotine, alpha-bungarotoxin (alpha BT) and muscarinic receptor binding was measured in the human hippocampal formation in a series of 57 cases aged between 24 weeks gestation and 100 years. Changes in nicotine receptor binding during development and aging were more striking than differences in alpha BT and muscarinic binding. Nicotine binding was higher at the late foetal stage than at any other subsequent time in all areas investigated. In the hippocampus a fall in binding then occurred within the first six months of life, with little or no subsequent fall during aging, whereas in the entorhinal cortex and the presubiculum the major loss of nicotine binding occurred after the fourth decade. alpha BT binding was significantly elevated in the CA 1 region, but in no other region of the hippocampus, in the late foetus, and there was also a fall in alpha BT binding in the entorhinal cortex during aging from the second decade. The modest changes in total muscarinic binding, which appeared to reflect those in M1 and M3 + 4 rather than M2 binding, were a rise in the entorhinal cortex between the foetal stage and childhood and a tendency for receptors to fall with age in the hippocampus and subicular complex. These findings implicate mechanisms controlling the expression of nicotinic receptors to a greater extent than muscarinic receptors in postnatal development and aging in the human hippocampus.

A comparison of the techniques of secondary ion mass spectrometry and resonance ionization mass spectrometry for the analysis of potentially toxic element accumulation in neural tissue.

A comparison is made of the techniques of secondary ion mass spectrometry (SIMS) and resonance ionization mass spectrometry (RIMS) for the detection of the neuro-toxic element aluminium in cortical tissue. Experiments were performed using a reflectron-type time-of-flight mass spectrometer (TOFMS) in conjunction with an Ar+ source for target sputtering and a pulsed tuneable dye laser system for resonance ionization. It is shown how isobaric interference of species such as CNH and C2H3 in the case of aluminium greatly affect the quantitative accuracy and the detection limit of aluminium in biological samples when analysed using SIMS. In contrast the use of RIMS virtually eliminates this problem, so allowing easier quantification and much lower detection limits to be achieved. Detection limits of approximately 3 ppm for aluminium in brain tissue homogenates were achieved using RIMS, with a spatial resolution of less than 100 microns.

An immunocytochemical study of the distribution of AMPA selective glutamate receptor subunits in the normal human motor system.

Glutamate is the major mediator of fast excitatory neurotransmission in the mammalian central nervous system. Disturbances of this neurotransmitter system have been implicated in chronic degenerative neurological disease. Recently, major advances in our knowledge and understanding of the molecular biology of the glutamatergic receptor system have been made. It is now known that functional glutamate receptors consist of various combinations of some 20 identified subunits. A growing body of circumstantial evidence suggests that the non-N-methyl-D-aspartate subtype of glutamate receptors may mediate, at least in part, the selective motor neuron death seen in the human neurodegenerative disease amyotrophic lateral sclerosis. We have used subunit specific immunocytochemistry to study the distribution and potential subunit composition of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) selective glutamate receptors, (a subgroup of non-N-methyl-D-aspartate selective glutamate receptors formed by combinations of GluR1-4 subunits), in the human motor system. Motor neurons in the spinal cord, brainstem, and motor cortex were relatively strongly immunoreactive with the GluR2/3 subunit antibody, moderately so with the GluR4 subunit antibody, and showed relatively low levels of immunoreactivity with the GluR1 subunit antibody. This is the first detailed study of AMPA receptor subunit expression in the human motor system. Motor neurons express a distinct subunit profile when compared with other groups of neurons in the human nervous system. There were no significant differences in the pattern of relative AMPA subunit expression (GluR2/3 > or = GluR4 > GluR1) between groups of motor neurons typically affected (in the spinal cord and hypoglossal nucleus), or spared (oculomotor and Onufs nucleus) by the amyotrophic lateral sclerosis disease process. However, oculomotor motor neurons had higher levels of expression of all AMPA subunit proteins which may indicate greater AMPA mediated glutamatergic input in the normal function of this neuronal population. This study does not support a role for differential subunit composition of AMPA receptors in determining the selective vulnerability of motor neurons in amyotrophic lateral sclerosis. However, the overall density of receptors may be of importance.

The role of the cholinergic system in the development of the human cerebellum.

High affinity (-)nicotine ([3H]nicotine), alpha-bungarotoxin ([125I]alpha-bungarotoxin) and muscarinic binding ([3H]N-methyl scopolamine) in the human cerebellum were compared between the foetal period (23-39 weeks gestation) and young adulthood (14-34 years) in an autoradiographic study. To estimate proportions of muscarinic receptor subtypes variable wash times and displacement with pirenzepine were employed. [3H]Nicotine binding and total muscarinic binding in foetuses exceeded that in young adults by a factor of 6 and 2 respectively in the dentate nucleus, and by a factor of 3 in white matter. [3H]Nicotine and muscarinic binding was also higher in the foetal external granule cell layer than in the internal granule cell layer of adult, [125I]alpha-Bungarotoxin binding was raised in the dentate nucleus of the foetus compared with the adult. The M2 subtype appeared to be the predominant muscarinic receptor in the cerebellum, however it tended to represent a lower proportion of the muscarinic binding in the foetus than the adult. All 3 receptor types were highest in the foetal brainstem where the M3 + M4 muscarinic subtypes appeared to predominate. The p75 nerve growth factor receptor, measured by immunocytochemistry, in common with cholinergic receptors, paralleled choline acetyltransferase activity which has previously been reported to be high in the cerebellum during late foetal development and to fall in adulthood.

Brain iron homeostasis.

The anatomical and cellular distribution of non-haem iron, ferritin, transferrin, and the transferrin receptor have been studied in postmortem human brain and these studies, together with data on the uptake and transport of labeled iron, by the rat brain, have been used to elucidate the role of iron and other metal ions in certain neurological disorders. High levels of non-haem iron, mainly in the form of ferritin, are found in the extrapyramidal system, associated predominantly with glial cells. In contrast to non-haem iron, the density of transferrin receptors is highest in cortical and brainstem structures and appears to relate to the iron requirement of neurones for mitochondrial respiratory activity. Transferrin is synthesized within the brain by oligodendrocytes and the choroid plexus, and is present in neurones, consistent with receptor mediated uptake. The uptake of iron into the brain appears to be by a two-stage process involving initial deposition of iron in the brain capillary endothelium by serum transferrin, and subsequent transfer of iron to brain-derived transferrin and transport within the brain to sites with a high transferrin receptor density. A second, as yet unidentified mechanism, may be involved in the transfer of iron from neurones possessing transferrin receptors to sites of storage in glial cells in the extrapyramidal system. The distribution of iron and the transferrin receptor may be of relevance to iron-induced free radical formation and selective neuronal vulnerability in neurodegenerative disorders.

Aluminium accumulation in relation to senile plaque and neurofibrillary tangle formation in the brains of patients with renal failure.

The effects of long-term exposure to aluminium on the development of Alzheimer-type neuropathological changes have been studied post-mortem in patients with chronic renal failure who did not have dialysis encephalopathy. Administration of aluminium-containing phosphate binding compounds appears to be a major factor in the accumulation of aluminium in the brain of dialysis patients. The mean serum aluminium concentrations determined during life and brain aluminium concentrations determined post-mortem correlated with both the duration and total amount of aluminium hydroxide administered to these patients. No correlation was found between the presence of bone aluminium and either the mean serum or brain aluminium concentration. Longitudinal monitoring of serum aluminium concentrations may provide a more reliable index than bone biopsy of brain aluminium concentrations in dialysis patients. Dynamic secondary ion mass spectrometry revealed focal accumulations of aluminium associated with cortical pyramidal neurones. The majority of patients also showed immunostaining in pyramidal neurones with an antibody to the N-terminal region of the beta/A4 amyloid precursor protein, while staining was absent in age-matched control cases. One-third of the patients exhibited beta/A4-positive amorphous senile plaques in the cerebral cortex. However, there was no clear correlation between either the presence and intensity of beta/A4 amyloid precursor immunostaining or the presence of senile plaques and the concentration of aluminium in the cerebral cortex. Cortical neurofibrillary tangles were not observed in any of the dialysis patients. These data suggest that it is unlikely that aluminium plays any major role in neurofibrillary tangle formation and that its putative role in senile plaque formation is likely to be only part of a complex cascade of changes.

Aluminium accumulation, beta-amyloid deposition and neurofibrillary changes in the central nervous system.

Deposition of beta-amyloid and the formation of neurofibrillary tangles (NFTs) are central to the aetiopathogenesis of Alzheimer's disease (AD). The possible effects of aluminium on these processes have been investigated in patients with renal failure who are exposed chronically to high blood levels of aluminium. Focal accumulation of aluminium was observed in neurons with high densities of transferrin receptors, indicating transferrin-mediated uptake, in regions such as cortex and hippocampus which are selectively vulnerable in AD. Increased staining for the beta-amyloid precursor protein (APP) in cortical pyramidal neurons was evident in the majority of renal patients and immature senile plaques were present in 30% of cases, suggesting that aluminium may induce or accelerate beta-amyloid deposition. The absence of neurofibrillary changes in this group of renal patients indicates that aluminium does not directly cause the formation of NFTs. The brain aluminium content was not raised in neuropathologically assessed cases of AD and we have been unable to confirm claims of defective transferrin binding in this disorder. If aluminium contributes to the development of sporadic AD, it must do so indirectly, perhaps via effects on the synthesis or metabolism of APP, or by contributing generally to the age-related attrition of neurons and thus reducing the threshold for deficits produced by more specific disease-related processes.

Histochemical distribution of non-haem iron in the human brain.

The detailed anatomical distribution of iron in the post-mortem human brain has been studied using Perl's and Turnbull's methods with the diaminobenzidine intensification procedure for the demonstration of non-haem Fe3+ and Fe2+, respectively. Attention to methodological procedures has revealed that even brief immersion of tissue in routinely used fixatives causes a reduction of staining intensity in areas of high iron content and, often, loss of staining in areas of low iron content. Optimal staining is obtained using frozen section briefly fixed for 5 min in 4% formalin and Perl's stain (Fe3+) with diaminobenzidine intensification. Highest levels of stainable iron were found in the extrapyramidal system with the globus pallidus, substantia nigra zona reticulata, red nucleus and myelinated fibres of the putamen showing highest staining reactivity. Moderate staining intensity with Perl's technique was found in the majority of forebrain, midbrain and cerebellar structures with the striatum, thalamus, cortex and deep white matter, substantia nigra zona compacta, and cerebellar cortex showing consistent staining patterns with intensification of Perl's stain. The brain-stem and spinal cord generally only showed staining with the intensification procedure and even this was of low intensity. Microscopically the non-heam iron appears to be found predominantly in glial cells as fine cytoplasmic granules which in heavily stained areas coalesce to fill the entire cell. Iron-positive granules appear to be free in the neuropil and also around blood vessels in the globus pallidus, striatum and substantia nigra. The neuropil shows a fibrous impregnation when stained for iron which is, in part, derived from glial processes, myelinated fibres and fibre bundles. Neurones, in general, show only very low reactivity for iron, and this is difficult to discern due, often, to the higher reactivity of the surrounding neuropil. In the globus pallidus and substantia nigra zona reticulata, neurones with highly stainable iron content are found with granular cytoplasmic iron reactivity similar to that seen in the local glial cells. Our results are comparable with those of early workers, but with the use of intensification extend the distribution of non-haem iron to areas previously reported as negative. No apparent correlation of iron staining with known neurotransmitter systems is seen and the predilection for the extrapyramidal system is not easily explained, though the non-haem iron in the brain appears to be as a storage form in the iron storage protein ferritin. The localization of iron in the brain provides a foundation for the study of iron in certain neurodegenerative diseases such as Parkinson's disease, where iron has been implicated in the pathogenesis.

The imaging and quantification of aluminium in the human brain using dynamic secondary ion mass spectrometry (SIMS).

Dynamic secondary ion mass spectrometry (SIMS) has been utilised to study the post-mortem distribution of aluminium in air-dried frozen sections from unfixed, unstained human brain in order to minimise contamination of the tissue and avoid redistribution and extraction of endogenous tissue aluminium. Substrates, sputter-coated with silver, were found to be free of focal aluminum surface contamination and thus minimised substrate induced artefacts in the tissue aluminium ion image. SIMS imaging of aluminium secondary ions at a mass resolution that eliminated the major molecular interferences, combined with a photomontage technique provided a unique strategy for studying aluminium distribution in tissue unrivalled by other spatially resolved microanalytical techniques such as laser microprobe mass spectrometry or X-ray microanalysis. Using this strategy, high densities of focal aluminium accumulations have been demonstrated in the cerebral cortex of the majority of chronic renal dialysis patients studied. In contrast, such aluminium accumulations were absent in control patients. SIMS imaging of aluminium appeared to provide much better discrimination between the dialysis patient group and the control group than one of the most widely used techniques for measuring aluminium in bulk samples, graphite furnace atomic absorption spectrometry. Preliminary studies have shown the feasibility of quantifying focal aluminium SIMS images obtained from brain tissue using aluminium-loaded brain homogenates as reference standards.