The spatial arrangement patterns of senile plaques in senile dementia of the Alzheimer type (SDAT)

The spatial arrangement patterns of senile plaques have been studied in 10 micron cresyl violet stained sections cut from embedded portions of 20 brain regions from SDAT brains. Two studies are reported: an initial study using the Poisson distribution and a subsequent study using pattern analysis. The initial study indicated that plaques are arranged in discrete clumps in all brain regions when examined at x100 and x400 – suggesting that both small and larger scale clumping may be present. The pattern analysis study was applied to 8 cortical regions. This technique allows a more detailed study of pattern to be made. In all regions the technique revealed that the basic pattern of plaque arrangement is the regularly spaced discrete clump – which may be present on both large and small scales.

Are there two distinct populations of cored senile plaques in senile dementia of the Alzheimer type?

The relationship between plaque diameter (PD) and core diameter (CD) was studied in four brains from each of four SDAT brains. The regions studied were parahippocampal gyrus (PHG), hippocampus, frontal and inferior temporal lobes. The largest diameters of 100 cored classical plaques and their cores were measured. CD was positively correlated with PD (Pearson's 'r' 0.4 - 0.95) in all region studied. Significant linear regressions of CD on PD with positive slopes (0.10 - 0.65) were found. Two distinct types of regression were found. Type A had a steep slope and a negative intercept on the ordinate whereas Type B had a shallow slope and a positive intercept. Both types can be found within the same brain but Type A or B predominate in a particular tissue. The data suggest that core development may occur either early or late in the development of the plaque. The two types of plaque may thus have different aetiologies. Such an interpretation is consistent with current ideas of plaque formation.

The 'hard problem' and the quantum physicists. Part 2: modern times

This is the second part of a review of the work of quantum physicists on the ‘hard part’ of the problem of mind. After an introduction which sets the scene and a brief review of contemporary work on the neural correlates of consciousness (NCC) the work of four prominent modern investigators is examined: J.C. Eccles/Friedrich Beck; Henry Stapp; Stuart Hameroff/Roger Penrose; David Bohm. With the exception of David Bohm, all attempt to show where in the brain’s microstructure quantum affects could make themselves felt. It is reluctantly concluded that none have neurobiological plausibility. They are all instances, to paraphrase T.H. Huxley, of a beautiful hypothesis destroyed by ugly facts. David Bohm does not attempt to fit his new quantum physics to contemporary neurobiology but instead asks for a radical rethink of our conventional scientific paradigm. He suggests that we should look towards developing a ‘pan-experientialism’ or ‘dual-aspect monism’ where consciousness goes ‘all the way down’ and that the ‘hard problem’ is not soluble within the framework of ideas provided by ‘classical’ natural science.

Tetrahydrobiopterin metabolism in mental disorders

Changes in DHPR activity in those aged 12 and under with a variety of mental disorders were investigated using dried blood spots on Guthrie cards. DHPR activity was found to be lowered in autism and Rett's syndrome. DHPR activity was unaffected in non specific mental retardation suggesting that the deficit seen in autism and Rett's syndrome does not arise secondary to the mental dysfunction. In Down's syndrome blood biopterin levels correlated with blood spot DHPR activity. Human brain BH4 synthetic activity was investigated in aging and senile dementia of the Alzheimer type (SDAT). BH4 synthetic activity and DHPR activity decline with age in non-demented controls. In SDAT, decreases in BH4 synthetic activity were seen in temporal and visual cortices and locus coeruleus. The site of the defect is probably at 6-pyruvoyl-tetrahydropterin synthase. Aluminium inhibits human brain BH4 synthesis in vitro and produces an `Alzheimeresque' pattern of abnormalities in rats chronically exposed to the acetate salt in drinking water. Aluminium appears to chiefly affect enzymes requiring a metal ion cofactor. Aluminium induced inhibition of BH4 synthesis can be reversed by treatment with transferrin, an aluminium chelator. Transferrin treatment improves BH4 synthetic activity in SDAT brains whilst having no effect on controls, further implicating aluminium as the key neurotoxin in SDAT. Lithium inhibits human brain BH4 synthesis in vitro and lowers rat brain total biopterins and inhibits rat brain BH4 synthesis on chronic exposure to the carbonate salt in drinking water. A possible mechanism for the anti-manic actions of lithium is suggested. Monoamine oxidase inhibitors decrease human brain BH4 synthetic activity in vitro. 5-methyl-tetrahydrofolate had no effect on human brain BH4 synthesis in vitro but methionine increased BH4 synthesis in vitro. Oxotremorine is a potent inhibitor of BH4 synthesis in man and the rat. This may prove useful as a tool for modelling BH4 deficiency.

Folate metabolism in the female weanling rat

The metabolism of a mixture of [2-14C] and [3',5',7,9-3H] folic acid was studied in female weanling rats. Intact folates and folate catabolites were excreted in the urine. Folate polyglutamates were found in the tissues. Rats treated with the oestrogen diethylstilbestrol and 17 -ethynyloestradiol exhibited marked changes in the metabolic handling of folic acid and folate catabolism was greatly increased compared to controls. Allopurinol treatment gave greater label retention in the gut, with a substantial increase in catabolism compared to normals. A dose response relationship was illustrated between allopurinol dose and folate catabolism. After lead acetate dosing there was little radioactivity in the urine and tissues over 72h and more radioactivity was retained in the faeces compared to normals. Excretion of intact folates was depressed, especially 5MeTHF and 10CHOTHF. A tenfold increase in both lead and folic acid dosage resulted in an even further decrease of radioactivity in the tissues and urine over 72h. Excretion in the faeces was further elevated. Ferrous sulphate administration resulted in increased catabolism. The retention of radioactivity in the liver, kidney and gut was greatly reduced. A new method of folate analysis; Sephadex LH-20 was introduced. In vitro superoxide anion formation was illustrated using an allopurinol/xanthine oxidase system. Histological studies were employed to qualitatively and quantitatively illustrate the oxidative status in livers and brains of allopurinol and ferrous sulphate dosed rats. Increased dose related formazan deposition was observed when livers of pretreated animals were incubated with nitroblue tetrazolium. Formazan deposition was reduced in pretreated animals also treated with the anti-oxidants vitamin E, mannitol or 4-hydroxy-methyl-4,6-ditertiary-butylphenol. A possible route of folate catabolism is scission by a non-enzymic oxidation involving active oxygen species.

Further studies on the patterns of senile plaques in senile dementia of the Alzheimer type (SDAT) with a hypothesis on the colonization of the cortex

The pattern of senile plaques was investigated in various brain regions of six SDAT brains. In 91 pattern analyses, the regularly spaced clump was the most common pattern found in 64.8% of analyses. Clumping due to large aggregations of uncored plaques in sulci was also common. Regularly spaced clumps were equally common in the hippocampus and neocortex. The pattern of plaques varied in different tissue sections from the same brain region. Cored and uncored plaques presented a similar range of patterns but their pattern varied when they were both present in the same tissue section. Both clump diameter and the intensity of clumping were positively correlated with cored but unrelated to uncored plaque density. Plaques may develop in regular clumps on subcortical afferents and during development of the disease the clumps may spread laterally and ultimately coalesce.

A quantitative study of abnormally enlarged neurons in cognitively normal brain and neurodegenerative disease

Abnormally enlarged neurons (AEN) occur in many neurodegenerative diseases. To define AEN more objectively, the frequency distribution of the ratio of greatest cell diameter(CD) to greatest nuclear diameter (ND) was studied in populations of cortical neurons in tissue sections of seven cognitively normal brains. The frequency distribution of CD/ND deviated from a normal distribution in 15 out of 18 populations of neurons studied and hence, the 95th percentile (95P) was used to define a limit of the CD/ND ratio excluding the5% most extreme observations. The 95P of the CD/ ND ratio varied from 2.0 to 3.0 in different cases and regions and a value of 95P = 3.0 was chosen to define the limit for normalneurons under non-pathological conditions. Based on the 95P = 3.0 criterion, the proportion of AEN with a CD/ND ≥ 3 varied from 2.6% in Alzheimer's disease (AD) to 20.3% in Pick's disease (PiD). The data suggest: (1) that a CL/ND ≥ 3.0 may be a useful morphological criterion for defining AEN, and (2) AEN were most numerous in PiD and corticobasal degeneration (CBD) and least abundant in AD and in dementia with Lewy bodies (DLB). © 2013 Dustri-Verlag Dr. K. Feistle.

Biologising parenting:neuroscience discourse, English social and public health policy and understandings of the child

In recent years, claims about children's developing brains have become central to the formation of child health and welfare policies in England. While these policies assert that they are based on neuro-scientific discoveries, their relationship to neuroscience itself has been debated. However, what is clear is that they portray a particular understanding of children and childhood, one that is marked by a lack of acknowledgment of child personhood. Using an analysis of key government-commissioned reports and additional advocacy documents, this article illustrates the ways that the mind of the child is reduced to the brain, and this brain comes to represent the child. It is argued that a highly reductionist and limiting construction of the child is produced, alongside the idea that parenting is the main factor in child development. It is concluded that this focus on children's brains, with its accompanying deterministic perspective on parenting, overlooks children's embodied lives and this has implications for the design of children's health and welfare services.

Biologising parenting:neuroscience discourse, English social and public health policy and understandings of the child

In recent years, claims about children's developing brains have become central to the formation of child health and welfare policies in England. While these policies assert that they are based on neuro-scientific discoveries, their relationship to neuroscience itself has been debated. However what is clear is that they portray a particular understanding of children and childhood, one that is marked by a lack of acknowledgment of child personhood. Using an analysis of key government-commissioned reports and additional advocacy documents, this chapter illustrates the ways that the mind of the child is reduced to the brain, and this brain comes to represent the child. It is argued that a highly reductionist and limiting construction of the child is produced, alongside the idea that parenting is the main factor in child development. It is concluded that this focus on children's brains, with its accompanying deterministic perspective on parenting, overlooks children's embodied lives and this has implications for the design of children's health and welfare services.

The role of amyloid precursor protein in neuronal and non-neuronal cell lines

Models of Alzheimer’s disease (AD) have provided useful insights into the pathogenesis and mechanistic pathways that lead to its development. One emerging idea about AD is that it may be described as a hypometabolic disorder due to the reduction of glucose uptake in AD brains. Inappropriate processing of Amyloid Precursor Protein (APP) is considered central to the initiation and progression of the disease. Although the exact role of APP misprocessing is unclear, it may play a role in neuronal metabolism before the onset of neurodegeneration. To investigate the potential role of APP in neuronal metabolism, the SHSY5Y neuroblastoma cell line was used to generate cell lines that stably overexpress wild type APP695 or express Swedish mutated-APP observed in familial AD (FAD), both under the control of the neuronal promoter, Synapsin I. The effects of APP on glucose uptake, cellular stress and energy homeostasis were studied extensively. It was found that APP-overexpressing cells exhibited decreased glucose uptake with changes in basal oxygen consumption in comparison to control cell lines. Similar studies were also performed in fibroblasts taken from FAD patients compared with control fibroblasts. Previous studies found FAD-derived fibroblasts displayed altered metabolic profiles, calcium homeostasis and oxidative stress when compared to controls. As such, in this study fibroblasts were studied in terms of their ability to metabolise glucose and their mitochondrial function. Results show that FAD-derived fibroblasts demonstrate no differences in mitochondrial function, or response to oxidative stress compared to control fibroblasts. However, control fibroblasts treated with Aβ1-42 demonstrated changes in glucose uptake. This study highlights the importance of APP expression within non-neuronal cell lines, suggesting that whilst AD is considered a brain-associated disorder, peripheral effects in non-neuronal cell types should also be considered when studying the effects of Aβ on metabolism.

Greetings, Earthlings

This blow to the myth of distinct male and female brains is welcome, says Gina Rippon

Brain oscillations and connectivity in autism spectrum disorders (ASD):new approaches to methodology, measurement and modelling

Although atypical social behaviour remains a key characterisation of ASD, the presence ofsensory and perceptual abnormalities has been given a more central role in recentclassification changes. An understanding of the origins of such aberrations could thus prove afruitful focus for ASD research. Early neurocognitive models of ASD suggested that thestudy of high frequency activity in the brain as a measure of cortical connectivity mightprovide the key to understanding the neural correlates of sensory and perceptual deviations inASD. As our review shows, the findings from subsequent research have been inconsistent,with a lack of agreement about the nature of any high frequency disturbances in ASD brains.Based on the application of new techniques using more sophisticated measures of brainsynchronisation, direction of information flow, and invoking the coupling between high andlow frequency bands, we propose a framework which could reconcile apparently conflictingfindings in this area and would be consistent both with emerging neurocognitive models ofautism and with the heterogeneity of the condition.