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Cognitive dysfunction associated with aluminum hydroxide-induced macrophagic myofasciitis: A reappraisal of neuropsychological profile

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Abstract

Patients with macrophagic myofasciitis (MMF) present with diffuse arthromyalgias, chronic fatigue, and cognitive disorder. Representative features of MMF-associated cognitive dysfunction include attentional dysfunction, dysexecutive syndrome, visual memory deficit and left ear extinction. Our study aims to reevaluate the neuropsychological profile of MMF. 105 unselected consecutive MMF patients were subjected to a neuropsychological battery of screen short term and long-term memory, executive functions, attentional abilities, instrumental functions and dichotic listening. From these results, patients were classified in four different groups: Subsymptomatic patients (n = 41) with performance above pathological threshold (− 1.65 SD) in all tests; Fronto-subcortical patients (n = 31) who showed pathological results at executive functions and selective attention tests; Papezian patients (n = 24) who showed pathological results in storage, recognition and consolidation functions for episodic verbal memory, in addition to fronto-subcortical dysfunction; and Extinction patients (n = 9) who had a left ear extinction at dichotic listening test in association to fronto-subcortical and papezian dysfunction. In addition, inter-test analysis showed that patients with apparently normal cognitive functions (Subsymptomatic group) performed significantly worse to attention tests compared to others. In conclusion, our study shows that (i) most patients have specific cognitive deficits; (ii) all patients with cognitive deficit have impairment of executive functions and selective attention; (iii) patients without measurable cognitive deficits display significant weakness in attention; (iv) episodic memory impairment affects verbal, but not visual, memory; (v) none of the patients show an instrumental dysfunction.

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Macrophagic myofasciitis (MMF), a condition newly recognized in France, is manifested by diffuse myalgias and characterized by highly specific myopathological alterations which have recently been shown to represent an unusually persistent local reaction to intramuscular injections of aluminium-containing vaccines. Among 92 MMF patients recognized so far, eight of them, which included the seven patients reported here, had a symptomatic demyelinating CNS disorder. CNS manifestations included hemisensory or sensorimotor symptoms (four out of seven), bilateral pyramidal signs (six out of seven), cerebellar signs (four out of seven), visual loss (two out of seven), cognitive and behavioural disorders (one out of seven) and bladder dysfunction (one out of seven). Brain T(2)-weighted MRI showed single (two out of seven) or multiple (four out of seven) supratentorial white matter hyperintense signals and corpus callosum atrophy (one out of seven). Evoked potentials were abnormal in four out of six patients and CSF in four out of seven. According to Poser's criteria for multiple sclerosis, the diagnosis was clinically definite (five out of seven) or clinically probable multiple sclerosis (two out of seven). Six out of seven patients had diffuse myalgias. Deltoid muscle biopsy showed stereotypical accumulations of PAS (periodic acid-Schiff)-positive macrophages, sparse CD8+ T cells and minimal myofibre damage. Aluminium-containing vaccines had been administered 3-78 months (median = 33 months) before muscle biopsy (hepatitis B virus: four out of seven, tetanus toxoid: one out of seven, both hepatitis B virus and tetanus toxoid: two out of seven). The association between MMF and multiple sclerosis-like disorders may give new insights into the controversial issues surrounding vaccinations and demyelinating CNS disorders. Deltoid muscle biopsy searching for myopathological alterations of MMF should be performed in multiple sclerosis patients with diffuse myalgias.
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Background: Ideomotor apraxia (IMA) is known to affect individuals with Alzheimer's disease (AD). Combined with impaired cognitive function, IMA can support evidence of probable AD. However, apraxia is a condition that is difficult to diagnose. The Postural Knowledge Test (PKT), developed by Mozaz et al, was designed to easily identify limb apraxia in multiple sclerosis yet demonstrated potential utility for AD. ILIAD is a pilot study to investigate correlation between the PKT and Mini-Mental State Examination (MMSE). Methods: Participants with mild, moderate, and severe AD were administered the MMSE by 1 examiner, followed by the PKT by a second blinded examiner. Results: Seventy-seven participants with mild (25), moderate (26), and severe AD (26) met study criteria. Correlation was demonstrated between the MMSE and PKT at 0.835 among all AD groups. Correlation between MMSE and PKT-1 (transitive) and PKT-2 (intransitive) separately was 0.819 and 0.793. Conclusions: There is significant correlation between the MMSE (memory loss) and PKT (IMA). This suggests the PKT may be used in conjunction with the MMSE to aid in staging AD and to monitor disease severity. Correlation between the MMSE and separate PKT tests suggests that administration of only 1 test may be necessary clinically, saving valuable time.
Article
Exercise has benefit for perimenopause women in many ways, such as affective disorders. Our previous study has demonstrated that inflammation in hippocampus contributes to development of depression-like behavior in ovariectomized (OVX) rats. Recently, oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome has been implicated to be involved in lipopolysaccharide (LPS)- and chronic stress-induced depression-like behavior in rodents. We sought to investigate whether ovariectomy-induced depression-like behavior is associated with NLRP3 inflammasome activation in brain and the effect of exercise on NLRP3 inflammasome activation in this model. The results showed that ovariectomy resulted in depression-like behavior in mice and an increase in levels of IL-1β and IL-18 in hippocampus. Exercise ameliorated the depression-like behavior and decreased levels of IL-1β and IL-18 in hippocampus. The level of IL-1β and IL-18 in hippocampus correlated to depression-like behavior in OVX mice. The levels of NLRP3, cleaved caspase-1 P10 and CD11b in hippocampus were increased in OVX mice compared with control group. Exercise could reduce the levels of NLRP3, cleaved caspase-1 P10 and CD11b in OVX mice. Our study suggests that NLRP3 inflammasome activation contribute to inflammation in hippocampus upon to deprivation of ovary. Exercise amelioration of depression-like behavior is associated with suppression of NLRP3 inflammasome activation in hippocampus of this model.
Aluminum oxyhydroxide (Alhydrogel(®)) is a nano-crystalline compound forming aggregates that has been introduced in vaccine for its immunologic adjuvant effect in 1926. It is the most commonly used adjuvant in human and veterinary vaccines but mechanisms by which it stimulates immune responses remain ill-defined. Although generally well tolerated on the short term, it has been suspected to occasionally cause delayed neurologic problems in susceptible individuals. In particular, the long-term persistence of aluminic granuloma also termed macrophagic myofasciitis is associated with chronic arthromyalgias and fatigue and cognitive dysfunction. Safety concerns largely depend on the long biopersistence time inherent to this adjuvant, which may be related to its quick withdrawal from the interstitial fluid by avid cellular uptake; and the capacity of adjuvant particles to migrate and slowly accumulate in lymphoid organs and the brain, a phenomenon documented in animal models and resulting from MCP1/CCL2-dependant translocation of adjuvant-loaded monocyte-lineage cells (Trojan horse phenomenon). These novel insights strongly suggest that serious re-evaluation of long-term aluminum adjuvant phamacokinetics and safety should be carried out.
Article
Concerns regarding vaccine safety have emerged following reports of potential adverse events in both humans and animals. In the present study, alum, alum-containing vaccine and alum adjuvant tagged with fluorescent nanodiamonds were used to evaluate i) the persistence time at the injection site, ii) the translocation of alum from the injection site to lymphoid organs, and iii) the behavior of adult CD1 mice following intramuscular injection of alum (400 μg Al/kg). Results showed for the first time a strikingly delayed systemic translocation of adju-vant particles. Alum-induced granuloma remained for a very long time in the injected muscle despite progressive shrinkage from day 45 to day 270. Concomitantly, a markedly delayed translocation of alum to the draining lymph nodes, major at day 270 endpoint, was observed. Translocation to the spleen was similarly delayed (highest number of particles at day 270). In contrast to C57BL/6J mice, no brain translocation of alum was observed by day 270 in CD1 mice. Consistently neither increase of Al cerebral content, nor behavioral changes were observed. On the basis of previous reports showing alum neurotoxic effects in CD1 mice, an additional experiment was done, and showed early brain translocation at day 45 of alum injected subcutaneously at 200 μg Al/kg. This study confirms the striking biopersistence of alum. It points out an unexpectedly delayed diffusion of the adjuvant in lymph nodes and spleen of CD1 mice, and suggests the importance of mouse strain, route of administration, and doses, for future studies focusing on the potential toxic effects of aluminum-based adjuvants.
Article
To investigate the relationship between cognitive impairment and global DNA methylation in aluminum (Al) potroom workers. A total of 366 Al-exposed workers were investigated, and their cognitive functions were assessed with the Mini-Mental State Examination (MMSE). Aluminum in serum was quantified using graphite furnace atomic absorption spectrometry. Global DNA methylation was analyzed in whole blood using an enzyme-linked immunosorbent assay-like reaction. Mini-Mental State Examination scores and global DNA methylation decreased with the increase of serum Al concentration. Forty-three mild cognitive impairment (MCI) people were diagnosed. Global DNA methylation of the MCI was lower than the non-MCI. Multiple logistic analysis showed that the Al-exposed workers had lower global DNA methylation and higher serum Al concentration and were at the higher risk of MCI. Long-term exposure to Al may cause MCI. Mild cognitive impairment was significantly associated with global DNA methylation in blood.
Article
Aluminum oxyhydroxide (alum) is a crystalline compound widely used as an immunologic adjuvant of vaccines. Concerns linked to alum particles have emerged following recognition of their causative role in the so-called macrophagic myofasciitis (MMF) lesion in patients with myalgic encephalomyelitis, revealing an unexpectedly long-lasting biopersistence of alum within immune cells and a fundamental misconception of its biodisposition. Evidence that aluminum-coated particles phagocytozed in the injected muscle and its draining lymph nodes can disseminate within phagocytes throughout the body and slowly accumulate in the brain further suggested that alum safety should be evaluated in the long term. However, lack of specific staining makes difficult the assessment of low quantities of bona fide alum adjuvant particles in tissues. We explored the feasibility of using fluorescent functionalized nanodiamonds (mfNDs) as a permanent label of alum (Alhydrogel(®)). mfNDs have a specific and perfectly photostable fluorescence based on the presence within the diamond lattice of nitrogen-vacancy centers (NV centers). As the NV center does not bleach, it allows the microspectrometric detection of mfNDs at very low levels and in the long-term. We thus developed fluorescent nanodiamonds functionalized by hyperbranched polyglycerol (mfNDs) allowing good coupling and stability of alum:mfNDs (AluDia) complexes. Specificities of AluDia complexes were comparable to the whole reference vaccine (anti-hepatitis B vaccine) in terms of particle size and zeta potential. In vivo, AluDia injection was followed by prompt phagocytosis and AluDia particles remained easily detectable by the specific signal of the fND particles in the injected muscle, draining lymph nodes, spleen, liver and brain. In vitro, mfNDs had low toxicity on THP-1 cells and AluDia showed cell toxicity similar to alum alone. Expectedly, AluDia elicited autophagy, and allowed highly specific detection of small amounts of alum in autophagosomes. The fluorescent nanodiamond technology is able to overcome the limitations of previously used organic fluorophores, thus appearing as a choice methodology for studying distribution, persistence and long-term neurotoxicity of alum adjuvants and beyond of other types of nanoparticles.
Article
Language and dementia: some illustrations in Alzheimer's disease and semantic dementia Language disorders are part of the history of neuropsychology. They were described as early as the princeps observations of patients with Alzheimer's disease. Deficits of the written language are one of the characteristics of Alzheimer's disease. Semantic memory disorders are also among the symptoms and can occur very early in the course of the disease. While these deficits are less prevalent than episodic memory impairment in Alzheimer's disease, they predominate the clinical picture of semantic dementia in which episodic memory is relatively spared. Increase knowledge of the brain alterations characterizing these two neurodegenerative conditions allows a better understanding of these cognitive impairment profiles.
Article
Several medical conditions sharing similar signs and symptoms may be related to immune adjuvants. These conditions described as ASIA (Autoimmune/inflammatory Syndrome Induced by Adjuvants), include a condition characterized by macrophagic myofasciitis (MMF) assessing long-term persistence of vaccine derived-alum adjuvants into macrophages at sites of previous immunization. Despite increasing data describing clinical manifestations of ASIA have been reported, biological markers are particularly lacking for their characterization and follow up. We report an extensive cytokine screening performed in serum from 44 MMF patients compared both to sex and age matched healthy controls and to patients with various types of inflammatory neuromuscular diseases. Thirty cytokines were quantified using combination of Luminex® technology and ELISA. There was significant mean increase of serum levels of the monocyte-chemoattractant protein 1 (CCL2/MCP-1) in MMF patients compared to healthy subjects. MMF patients showed no elevation of other cytokines. This contrasted with inflammatory patients in whom CCL2/MCP-1 serum levels were unchanged, whereas several other inflammatory cytokines were elevated (IL1β, IL5 and CCL3/MIP1α). These results suggest that CCL2 may represent a biological marker relevant to the pathophysiology of MMF rather than a non specific inflammatory marker and that it should be checked in the other syndromes constitutive of ASIA.
Article
The work of Cannon,¹ Bard,² Penfield,³ Ranson⁴ and others has greatly advanced knowledge of the functions of the hypothalamus. In the light of these researches the connections of the hypothalamus to the medial wall of the cerebral cortex gain a new significance. The following discussion presents some anatomic, clinical and experimental data dealing with the hypothalamus, the gyrus cinguli, the hippocampus and their interconnections. Taken as a whole, this ensemble of structures is proposed as representing theoretically the anatomic basis of the emotions. It is generally recognized that in the brain of lower vertebrates the medial wall of the cerebral hemisphere is connected anatomically and integrated physiologically with the hypothalamus and that the lateral wall is similarly related to the dorsal thalamus (Herrick⁵). These fundamental relations are not only retained but greatly elaborated in the mammalian brain by the further development of the hippocampal formation
Article
L’encéphalite limbique est une affection le plus souvent d’origine paranéoplasique se manifestant par des troubles électifs de la mémoire antérograde, une épilepsie et des troubles psychiatriques, notamment dépressifs. L’observation que nous présentons, chez un homme de 60 ans, a comme double particularité de s’être manifestée par un état dépressif sévère survenant chez un sujet ayant des antécédents personnels et familiaux de dépression, et de ne comporter aucune pathologie paranéoplasique associée. On discutera les différentes hypothèses de cet état dépressif chez ce patient et les liens qui pourraient exister au niveau physiopathologique entre son état dépressif et sa pathologie neurologique.
Article
New effects and mechanisms of alum on innate immunity have emerged in recent years. A number of cellular and molecular mechanisms induced by aluminum adjuvant have been reported, while the role of NALP3 and inflammasome in the cellular pathway induced by alum is still controversial. The effect of injection of alum alone without vaccine antigen into human has not been reported so far。 Recently, in a phase IIIa double-blinded placebo controlled clinical trial testing the therapeutic HBsAg-anti-HBs vaccine formulated with alum against chronic viral hepatitis B patients, the placebo group receiving alum only showed substantial therapeutic effects. To explore possible underlying therapeutic mechanisms, mice were treated either with multiple injections of alum alone or with alum adsorbed to proteins (HBsAg-anti-HBs). After 4 injections Gr1(+)/CD11b(+) cells in the spleen were increased in both alum alone and alum adsorbed in proteins groups. Increased Gr1(+)/CD11b(+) cells in spleens remained consistently high in the alum alone treated group, while Gr1(+)/CD11b(+)cells decreased in the alum adsorbed to proteins group after 6 injections. Both treatments triggered increased levels of TNF-alpha measured in the plasma, but only the alum alone treated mice showed increased levels of IL-10. Histology of the liver tissues revealed a higher number of spotty necrotic foci in the alum alone immunized group. Taken together, potent inflammatory responses were induced in the alum alone immunized mice, which suggests that the substantial therapeutic effects observed in chronic hepatitis B patients immunized with alum alone might be attributed to inflammatory responses.
Article
The report attempts to delineate certain residual learning capacities of H.M., a young man who became amnesic in 1953 following a bilateral removal in the hippocampal zone. In addition to being able to acquire new motor skills (CORKIN [2]), this patient shows some evidence of perceptual learning. He also achieves some retention of very simple visual and tactual mazes in which the sequence of required turns is short enough to fit into his immediate memory span; even then, the rate of acquisition is extremely slow. These vestigial abilies, which have their occasional parallels in the patient's everyday life, are assessed against the background of his continuing profound amnesia for most on-going events, an amnesia that persists in spite of above-average intelligence and superior performance on many perceptual tasks.
Article
Macrophagic myofasciitis (MMF) is characterized by specific muscle lesions assessing long-term persistence of aluminum hydroxide within macrophages at the site of previous immunization. Affected patients are middle-aged adults, mainly presenting with diffuse arthromyalgias, chronic fatigue, and cognitive dysfunction. Representative features of MMF-associated cognitive dysfunction (MACD) include (i) dysexecutive syndrome; (i) visual memory; (iii) left ear extinction at dichotic listening test. In present study we retrospectively evaluated the progression of MACD in 30 MMF patients. Most patients fulfilled criteria for non-amnestic/dysexecutive mild cognitive impairment, even if some cognitive deficits seemed unusually severe. MACD remained stable over time, although dysexecutive syndrome tended to worsen. Long-term follow-up of a subset of patients with 3 or 4 consecutive neuropsychological evaluations confirmed the stability of MACD with time, despite marked fluctuations.
Article
Vaccines against microbial diseases have improved the health of millions of people. In the next decade and beyond, many conceptual and technological scientific advances offer extraordinary opportunities to expand the portfolio of immunisations against viral and bacterial diseases and to pioneer the first vaccines against human parasitic and fungal diseases. Scientists in the public and private sectors are motivated as never before to bring about these innovations in immunisation. Many societal factors threaten to compromise realisation of the public health gains that immunisation can achieve in the next decade and beyond--understanding these factors is imperative. Vaccines are typically given to healthy individuals and safety issues loom high on the list of public concerns. The public needs to regain confidence in immunisation and trust the organisations responsible for the research, development, and implementation of vaccines. In the past, by use of a judicious amalgam of knowledge and empiricism, successful vaccines were largely developed by microbiologists who identified antigens that induced immune responses to conserved pathogen components. In the future, vaccines need to be developed against deadly diseases for which this strategy is often not feasible because of the extensive antigenic variability of relevant pathogens. High microbial diversity means that immunity after natural infection is often ineffective for prevention of disease on subsequent exposure, for example in HIV infection and malaria. Additionally, vaccines need to be generated to protect the people who are most vulnerable because of age or underlying diseases. Thus, in the future, a much deeper understanding of the immunological challenges--including the diversifying role of host genetics and environmental factors, leading perhaps to more personalised approaches-will be the touchstone for rational design and development of adjuvants that result in novel safe and effective vaccines.
Article
Disorders of executive functions are among the most frequent cognitive deficits, but they remain poorly defined and are subject to heterogeneous assessment. To address this major issue, the Groupe de Réflexion sur l'Evaluation des Fonctions Exécutives (GREFEX) group has proposed criteria for behavioral and cognitive dysexecutive syndromes and has designed a battery including a specific heteroquestionnaire and 7 cognitive tests. We investigated the frequency of behavioral and cognitive dysexecutive disorders in patients suffering from various diseases and the association of these disorders with loss of autonomy. A total of 461 patients aged between 16 and 90 years with severe traumatic brain injury, stroke, mild cognitive impairment, Alzheimer disease, multiple sclerosis, and Parkinson disease were recruited into this prospective cohort study by 21 centers between September 2003 and June 2006. Behavioral and cognitive dysexecutive disorders were examined using the GREFEX battery. A dysexecutive syndrome was observed in 60% of patients, concerning both behavioral and cognitive domains in 26% and dissociated in 34%. All behavioral and cognitive dysexecutive disorders discriminated (p = 0.001, all) patients from controls. The pattern of cognitive syndrome differed (p = 0.0001) according to the disease. Finally, behavioral (odds ratio [OR], 4.6; 95% confidence interval [CI], 2. 3-9.1; p = 0.0001) and cognitive (OR, 3.36; 95% CI, 1.7-6.6; p = 0.001) dysexecutive syndromes and Mini Mental State Examination score (OR, 0.79; 95% CI, 0.68-0.91; p = 0.002) were independent predictors of loss of autonomy. This study provided criteria of dysexecutive syndrome and showed that both behavioral and cognitive syndromes contribute to loss of autonomy. Profiles vary across patients and diseases, and therefore systematic assessment of behavioral and cognitive disorders in reference to diagnostic criteria is needed.
Article
A clear double dissociation between the effects of left and right temporal-lobe excisions was demonstrated for two identically-designed learning tasks that utilized different memoranda. Patients with left temporal-lobe lesions showed a deficit for the verbal task and normal performance for the non-verbal analogue, whereas the converse was evident for patients with right temporal-lobe lesions. Again, on two formally similar tests of short-term recall with interpolated activity, this same pattern of dissociation was observed for the retention of verbal as compared with non-verbal information. For both pairs of experiments, the severity of the material-specific learning and retention deficits was directly related to the extent of surgical encroachment upon the hippocampal zone of the affected hemisphere. These studies implicate the hippocampal region in the crucial transfer of experience from a temporary storage system (primary memory) to more permanent long-term storage (secondary memory).
Article
Evidence for the neurotoxicity of extended exposure to low levels of aluminum salts is described using an animal model treated with aluminum at low levels reflecting those found in some water supplies. Emphasis is given to the potential role of aluminum in acceleration and promotion of some indices characteristic of brain aging. These hallmarks include the appearance of excess levels of inflammation in specific brain areas. Aluminum salts can increase levels of glial activation, inflammatory cytokines and amyloid precursor protein within the brain. Both normal brain aging and to a greater extent, Alzheimer's disease are associated with elevated basal levels of markers for inflammation. These are not attributable to obvious exogenous stimuli and may reflect the lifespan history of the organism's immune responses. It is possible that aluminum salts can act as a subtle promoter of such apparently unprovoked responses.
Article
One literature treats the hippocampus as a purely cognitive structure involved in memory; another treats it as a regulator of emotion whose dysfunction leads to psychopathology. We review behavioral, anatomical, and gene expression studies that together support a functional segmentation into three hippocampal compartments: dorsal, intermediate, and ventral. The dorsal hippocampus, which corresponds to the posterior hippocampus in primates, performs primarily cognitive functions. The ventral (anterior in primates) relates to stress, emotion, and affect. Strikingly, gene expression in the dorsal hippocampus correlates with cortical regions involved in information processing, while genes expressed in the ventral hippocampus correlate with regions involved in emotion and stress (amygdala and hypothalamus).
Article
Vaccines have been used for over 200 years and are the most effective way of preventing the morbidity and mortality associated with infections. Like other drugs, vaccines can cause adverse events, but unlike conventional medicines, which are prescribed to people who are ill, vaccines are administered to healthy individuals, thus increasing the concern over adverse reactions. Most side effects attributed to vaccines are mild, acute and transient; however, rare reactions such as hypersensitivity, induction of infection, and autoimmunity do occur and can be severe and even fatal. The rarity and subacute presentation of post-vaccination autoimmune phenomena means that ascertaining causality between these events can be difficult. Moreover, the latency period between vaccination and autoimmunity ranges from days to years. In this article, on the basis of published evidence and our own experience, we discuss the various aspects of the causal and temporal interactions between vaccines and autoimmune phenomena, as well as the possible mechanisms by which different components of vaccines might induce autoimmunity.
Article
Macrophagic myofasciitis (MMF) is an emerging condition, characterized by specific muscle lesions assessing long-term persistence of aluminum hydroxide within macrophages at the site of previous immunization. Affected patients mainly complain of arthromyalgias, chronic fatigue, and cognitive difficulties. We designed a comprehensive battery of neuropsychological tests to prospectively delineate MMF-associated cognitive dysfunction (MACD). Compared to control patients with arthritis and chronic pain, MMF patients had pronounced and specific cognitive impairment. MACD mainly affected (i) both visual and verbal memory; (ii) executive functions, including attention, working memory, and planning; and (iii) left ear extinction at dichotic listening test. Cognitive deficits did not correlate with pain, fatigue, depression, or disease duration. Pathophysiological mechanisms underlying MACD remain to be determined. In conclusion, long-term persistence of vaccine-derived aluminum hydroxide within the body assessed by MMF is associated with cognitive dysfunction, not solely due to chronic pain, fatigue and depression.
Article
The neurocognitive effects of aluminum (Al) were studied in 35 hemodialysis patients. Higher Al levels were associated with a decline in visual memory. As Al levels increased, patients with lower vocabulary scores (a measure of premorbid intelligence) showed a decline in attention/concentration, frontal lobe functions, and on several neurocognitive measures, while those with higher vocabulary scores revealed no Al-related decline. These results suggest that individuals with lower verbal intelligence may possess less well-developed compensatory strategies to overcome the neurocognitive effects associated with Al. These data also indicate that Al is neurotoxic and, therefore, potential sources of environmental Al should be identified and eliminated.
Article
Aluminium is widely used as an adjuvant in human vaccines, and children can often receive up to 3.75 mg of parenteral aluminium during the first six months of life. We show that intraperitoneal injection of aluminium adsorbed vaccines into mice causes a transient rise in brain tissue aluminium levels peaking around the second and third day after injection. This rise is not seen in the saline control group of animals or with vaccine not containing aluminium. It is likely that aluminium is transported to the brain by the iron-binding protein transferrin and enters the brain via specific transferrin receptors.
Article
Aluminum was observed in the nucleolus, interchromatin granules, rough endoplasmic reticulum, free ribosomes, euchromatin, and the heterochromatin of the neuron. The association of aluminum with the first four r-RNA-containing cellular components and with the last two DNA-containing chromatins suggests the association of aluminum with the nucleic acids. The aluminum may interfere with the normal mechanism of the protein synthesis of r-RNA and of the transcription or gene modulation of DNA. Aluminum was also observed in the astrocytic process and in the nuclei of endothelial cells, pericytes, and the muscle cells of the blood vessels. The detection of aluminum in the pyrimidal cells of the cerebral cortex and hippocampus and in the spinal cord neurons, was observed 1 h after i.v. injection, indicating a rapid entry of aluminum from the injection site through the blood-brain barrier (BBB) to the neurons. Using Morin stain, pyramidal neurons of the cerebral cortex and hippocampus, motoneurons of spinal cord, ganglion cells, and bipolar cells of retina and Purkinje cells of cerebellum, exhibited yellow fluorescence, with peak intensity at 560 nm. Tangles were observed in these six types of neurons. The granule cells of hippocampus and cerebellum and the photoreceptors of the retina exhibited green fluorescence with the peak intensity at 490-500 nm. Tangles were not observed in these three types of neurons.
Article
A review of recent anatomical evidence shows that every neocortical area and many nuclei from the dorsal thalamus project to restricted neostriatal regions. The neurobehavioral literature offers many examples of the same results obtained with lesions, stimulations or recordings in a neocortical area and the associated neostriatal region. This evidence is abundant in the case of the prefrontal cortex and rostra1 neostriatum, but it is available also for other corticoneostriatal pairs. It seems possible to conclude that the function of a neostriatal region is determined by its cortical and possibly by its thalamic input. However, the possibility that the behavioral effects of lesions and stimulation of neostriatum were in fact produced by involving the fibers passing to and from the overlying cortex has not been convincingly excluded. An attempt was made to develop a simple concept about the relation between the prefrontal cortex and the region of neostriatum associated with it. A serial paradigm, suggesting that prefrontal cortex in adult monkeys and cats acts via neostriatum when mediating performance in certain behavioral tasks, seems to account for most of the available data.
Article
In the present study, aluminum (Al) accumulation has been examined after aluminum loading in mice. The kidney, liver, and brain aluminum levels for mice that had been treated orally with aluminum hydroxide for 105 d and for the control group were determined using graphite furnace atomic absorption spectrophotometry (GFAAS) following an acid digestion. Matrix modifier consisted of 2% Triton X-100 and 2% Mg (NO3)2. Al loaded mice showed a significant increase in tissue aluminum levels, relative to the control group.
Article
An unusual inflammatory myopathy characterised by an infiltration of non-epithelioid histiocytic cells has been recorded with increasing frequency in the past 5 years in France. We reassessed some of these cases. We did a retrospective analysis of 18 such cases seen in five myopathology centres between May, 1993, and December, 1997. The myopathological changes were reassessed at a clinopathology seminar. Detailed clinical information was available for 14 patients. The main presumptive diagnoses were polymyositis and polymyalgia rheumatica. Symptoms included myalgias in 12 patients, arthralgias in nine, muscle weakness in six, pronounced asthenia in five, and fever in four. Abnormal laboratory findings were occasionally observed, and included raised creatine kinase concentrations, increased erythrocyte sedimentation rate, and myopathic electromyography. Muscle biopsy showed infiltration of the subcutaneous tissue, epimysium, perimysium, and perifascicular endomysium by sheets of large macrophages, with a finely granular PAS-positive content. Also present were occasional CD8 T cells, and inconspicuous muscle-fibre damage. Epithelioid and giant cells, necrosis, and mitotic figures were not seen. The images were easily distinguishable from sarcoid myopathy and fasciitis-panniculitis syndromes. Whipple's disease, Mycobacterium avium intracellulare infection, and malakoplakia could not be confirmed. Ten patients were treated with various combinations of steroids and antibiotics; symptoms improved in eight patients, and stabilised in two. A new inflammatory muscle disorder of unknown cause, characterised by a distinctive pathological pattern of macrophagic myofasciitis, is emerging in France.
Article
Recent neurobiological studies have begun to reveal the cognitive and neural coding mechanisms that underlie declarative memory--our ability to recollect everyday events and factual knowledge. These studies indicate that the critical circuitry involves bidirectional connections between the neocortex, the parahippocampal region and the hippocampus. Each of these areas makes a unique contribution to memory processing. Widespread high-order neocortical areas provide dedicated processors for perceptual, motor or cognitive information that is influenced by other components of the system. The parahippocampal region mediates convergence of this information and extends the persistence of neocortical memory representations. The hippocampus encodes the sequences of places and events that compose episodic memories, and links them together through their common elements. Here I describe how these mechanisms work together to create and re-create fully networked representations of previous experiences and knowledge about the world.