Blast-related disinhibition and risk seeking in mice and combat Veterans: Potential role for dysfunctional phasic dopamine release.

Mild traumatic brain injury (mTBI) caused by exposure to high explosives has been called the "signature injury" of the wars in Iraq and Afghanistan. There is a wide array of chronic neurological and behavioral symptoms associated with blast-induced mTBI. However, the underlying mechanisms are not well understood. Here we used a battlefield-relevant mouse model of blast-induced mTBI and in vivo fast-scan cyclic voltammetry (FSCV) to investigate whether the mesolimbic dopamine system contributes to the mechanisms underlying blast-induced behavioral dysfunction. In mice, blast exposure increased novelty seeking, a behavior closely associated with disinhibition and risk for subsequent maladaptive behaviors. In keeping with this, we found that veterans with blast-related mTBI reported greater disinhibition and risk taking on the Frontal Systems Behavior Scale (FrSBe). In addition, in mice we report that blast exposure causes potentiation of evoked phasic dopamine release in the nucleus accumbens. Taken together these findings suggest that blast-induced changes in the dopaminergic system may mediate aspects of the complex array of behavioral dysfunctions reported in blast-exposed veterans.

Acid sphingomyelinase deficient mice: a model of types A and B Niemann-Pick disease.

Types A and B Niemann-Pick disease (NPD) result from the deficient activity of acid sphingomyelinase (ASM). An animal model of NPD has been created by gene targeting. In affected animals, the disease followed a severe, neurodegenerative course and death occurred by eight months of age. Analysis of these animals showed their tissues had no detectable ASM activity, the blood cholesterol levels and sphingomyelin in the liver and brain were elevated, and atrophy of the cerebellum and marked deficiency of Purkinje cells was evident. Microscopic analysis revealed 'NPD cells' in reticuloendothelial organs and characteristic NPD lesions in the brain. Thus, the ASM deficient mice should be of great value for studying the pathogenesis and treatment of NPD, and for investigations into the role of ASM in signal transduction and apoptosis.

Alzheimer's disease: X-ray spectrometric evidence of aluminum accumulation in neurofibrillary tangle-bearing neurons.

The elemental content of neurons of the hippocampus was studied by a combination of scanning electron microscopy and x-ray spectrometry in autopsy-derived brain tissue from three cases of senile dementia (Alzheimer type) and three nondemented elderly controls. Foci of aluminum were detected within the nuclear region of a high percentage of neurons containing neurofibrillary tangles from the cases of senile dementia as well as the elderly controls. The adjacent normal-appearing neurons from both groups of patients were virtually free of detectable aluminum. These findings suggest that the association of aluminum to Alzheimer's disease extends to the neuronal level.

Intraneuronal aluminum accumulation in amyotrophic lateral sclerosis and Parkinsonism-dementia of Guam.

Scanning electron microscopy with energy-dispersive x-ray spectrometry was used to analyze the elemental content of neurofibrillary tangle (NFT)-bearing and NFT-free neurons within the Sommer's sector (H1 region) of the hippocampus in Guamanian Chamorros with amyotrophic lateral sclerosis and parkinsonism-dementia and in neurologically normal controls. Preliminary data indicate prominent accumulation of aluminum within the nuclear region and perikaryal cytoplasm of NFT-bearing hippocampal neurons, regardless of the underlying neurological diagnosis. These findings further extend the association between intraneuronal aluminum and NFT formation and support the hypothesis that environmental factors are related to the neurodegenerative changes seen in the Chamorro population.

Alzheimer disease and related neurodegenerative diseases in elderly patients with schizophrenia: a postmortem neuropathologic study of 100 cases.

BACKGROUND: Clinical studies suggest that severe cognitive impairment is common among elderly patients with schizophrenia who reside in long-stay psychiatric institutions; however, previous autopsy-based neuropathologic investigations have provided conflicting results about the occurrence of Alzheimer disease (AD) in elderly patients with schizophrenia. We report the results of a comprehensive neuropathologic study performed to identify AD and other dementing neurodegenerative diseases in elderly patients with schizophrenia. METHODS: A neuropathologic examination was performed on 100 consecutive autopsy brain specimens of patients aged 52 to 101 years (mean, 76.5 years). A cognitive assessment of these cases was also done by employing the Clinical Dementia Rating Scale. For comparison, we included 47 patients with nonschizophrenic psychiatric disorders from the same psychiatric hospital and 50 age-matched control subjects. RESULTS: Although 72% of the patients with schizophrenia showed cognitive impairment, AD was diagnosed in only 9% of the patients and other dementing diseases were diagnosed in only 4% of the patients. The degree of senile plaques or neurofibrillary tangles was not different in the group with schizophrenia compared with the age-matched controls or the group with nonschizophrenic psychiatric disorders. The higher Clinical Dementia Rating Scale scores lacked correlation with neuropathologic evidence of dementing disorders. In the 87 cases lacking a neuropathologic diagnosis of AD or other dementing disorders, the mean (+/-SD) Clinical Dementia Rating Scale score was 2.21 (+/-1.14), with 43 of the cases scoring 3 or higher (indicating severe, profound, or terminal cognitive impairment). CONCLUSIONS: This study provides evidence that elderly patients with schizophrenia are not inordinately prone to the development of AD or to increased senile plaques or neurofibrillary tangle formation in the brain. Other dementing neurodegenerative disorders are also uncommon. The cognitive impairment in elderly patients with schizophrenia must, therefore, be related to some alternative mechanisms.

Neuropeptide abnormalities in patients with early Alzheimer disease.

BACKGROUND: Deficits in somatostatin-like immunoreactivity (SLI) and corticotropin-releasing factor immunoreactivity (CRF-IR) are well recognized as prominent neurochemical deficits in Alzheimer disease (AD). The question of whether these profound neuropeptidergic deficits found in patients with end-stage disease extend into those with much earlier disease is relatively unanswered. To determine the relation between level of SLI and CRF-IR in different cerebrocortical regions to the earliest signs of cognitive deterioration in AD. METHODS: We examined SLI and CRF-IR levels in 9 neocortical brain regions of 66 elderly patients in a postmortem study of nursing home residents who had either no significant neuropathologic lesions or lesions associated only with AD. Patients were assessed by the Clinical Dementia Rating scale (CDR) to have no dementia or questionable, mild, or moderate dementia, and were compared with 15 patients with severe dementia. RESULTS: Both CRF-IR and SLI were significantly reduced in the cortices of patients with the most severe dementia, but only the levels of CRF-IR were reduced in those with mild (CDR = 1.0) and moderate dementia (CDR = 2.0). Levels of CRF-IR and SLI correlated significantly with CDR, but this correlation was more robust for CRF-IR and persisted even when severely cognitively impaired patients were eliminated from analysis. CONCLUSIONS: Although SLI and CRF-IR levels are significantly reduced in patients with severe dementia, only CRF-IR is reduced significantly in the cortices of those with mild dementia. Thus, CRF-IR can serve as a potential neurochemical marker of early dementia and possibly early AD.

The sweet thing about Type 1 diabetes: a cryoprotective evolutionary adaptation.

The reasons for the uneven worldwide distribution of Type 1 diabetes mellitus have yet to be fully explained. Epidemiological studies have shown a higher prevalence of Type 1 diabetes in northern Europe, particularly in Scandinavian countries, and Sardinia. Recent animal research has uncovered the importance of the generation of elevated levels of glucose, glycerol and other sugar derivatives as a physiological means for cold adaptation. High concentrations of these substances depress the freezing point of body fluids and prevent the formation of ice crystals in cells through supercooling, thus acting as a cryoprotectant or antifreeze for vital organs as well as in their muscle tissue. In this paper, we hypothesize that factors predisposing to elevated levels of glucose, glycerol and other sugar derivatives may have been selected for, in part, as adaptive measures in exceedingly cold climates. This cryoprotective adaptation would have protected ancestral northern Europeans from the effects of suddenly increasingly colder climates, such as those believed to have arisen around 14,000 years ago and culminating in the Younger Dryas. When life expectancy was short, factors predisposing to Type 1 diabetes provided a survival advantage. However, deleterious consequences of this condition have become significant only in more modern times, as life expectancy has increased, thus outweighing their protective value. Examples of evolutionary adaptations conferring selection advantages against human pathogens that result in deleterious effects have been previously reported as epidemic pathogenic selection (EPS). Such proposed examples include the cystic fibrosis mutations in the CFTR gene bestowing resistance to Salmonella typhi and hemochromatosis mutations conferring protection against iron-seeking intracellular pathogens. This paper is one of the first accounts of a metabolic disorder providing a selection advantage not against a pathogenic stressor alone, but rather against a climatic change. We thus believe that the concept of EPS should now include environmental factors that may be nonorganismal in nature. In so doing we propose that factors resulting in Type 1 diabetes be considered a result of environmental pathogenic selection (EnPS).

Accumulation of phosphorylated neurofilaments in anterior horn motoneurons of amyotrophic lateral sclerosis patients.

Perikaryal collections of intermediate filaments have been described in the anterior horn motoneurons of patients with amyotrophic lateral sclerosis (ALS), but these inclusions have generally been considered rare and mainly associated with the familial form of ALS. Using the monoclonal antibody NF2F11, which recognizes phosphorylated neurofilament epitopes, we showed that focal collections of neurofilaments in anterior horn motoneurons were a characteristic finding in sporadic as well as in familial ALS; they were present in seven of nine ALS patients, but in none of nine control spinal cords. These neurofilamentous collections are not cross-reactive with antibodies directed against paired helical filaments and the microtubule associated protein tau. In addition, diffuse staining for phosphorylated neurofilament epitopes in chromatolytic anterior horn perikarya was significantly more frequent in ALS patients than in controls.

Multiple microabscesses in the central nervous system: a clinicopathologic study.

We reviewed 2,107 consecutive autopsies with neuropathologic examination at the Medical Center Hospital of Vermont, and identified 92 cases with significant pathologic evidence for infection involving the central nervous system (CNS). Of these, 35 took the form of multiple microabscesses. There were 19 men and 16 women, mean age 56. All patients were chronically ill, usually with an associated impaired immunity. The lung was the most frequent site of primary infection, and sepsis was often present. The most commonly identified causative organisms were Staphylococcus aureus and Candida albicans. Patients with CNS microabscesses developed a progressive encephalopathy associated with waxing and waning signs and symptoms. Laboratory and neuroradiologic studies were not helpful in elucidating the problem. We conclude that multiple microabscesses are a frequent, usually unrecognized, manifestation of CNS infection, and should be considered in the differential diagnosis of encephalopathy in hospitalized patients with chronic disease, immunosuppression and sepsis.

Protein nitration in Parkinson's disease.

Oxidative stress has been proposed as a pathogenetic mechanism in Parkinson's disease (PD). One mechanism of oxidative cellular injury is the nitration of protein tyrosine residues, mediated by peroxynitrite, a reaction product of nitric oxide and superoxide radicals. We demonstrate here the presence of nitrotyrosine immunoreactivity in Lewy bodies within melanized neurons and in amorphous deposits associated with intact and degenerating neurons. The core of the Lewy body was frequently intensely immunolabeled, while the rim was lightly labeled or unlabeled. This likely reflects the fact that tyrosine residues of neurofilament proteins are primarily localized to Lewy body cores, and suggests that nitrotyrosine is present in neurofilament protein itself. Although these observations are as yet unable to provide a definitive link between oxidative stress and neuronal dysfunction, they demonstrate that oxidative stress has occurred within the vulnerable neurons of PD, leaving a permanent marker of oxidative modification of neuronal proteins within the target cells of neurodegeneration. In addition, these observations provide a potential link between excitotoxicity and oxidative stress within the vulnerable neurons of PD and represent a pathogenetic mechanism in common with the 2 other major age-related neurodegenerative diseases, Alzheimer disease and amyotrophic lateral sclerosis.

Identification of phosphorylation sites in PHF-TAU from patients with Guam amyotrophic lateral sclerosis/parkinsonism-dementia complex.

Guam Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (Guam ALS/PDC) is a progressive neurodegenerative disorder characterized by abundant neurofibrillary tangles (NFTs) composed of aggregated paired helical filaments (PHFs). These abnormal filaments resemble the PHFs in neurofibrillary lesions of classic Alzheimer's disease (AD), and recent studies demonstrated that tau in Guam ALS/PDC is aberrantly phosphorylated and biochemically similar to the abnormal tau proteins (PHFtau) in classic AD. However, unlike PHFtau in AD, there is little information on the specific sites of phosphorylation in PHFtau from Guam ALS/PDC. Thus, to address this important issue, we examined tangle-rich Guam ALS/PDC and AD brains by Western blot, immunoelectron microscopy and immunohistochemistry using 13 antibodies to defined phosphate-dependent or -independent epitopes distributed throughout AD PHFtau. These studies identified 7 previously unknown sites of phosphorylation in PHFtau from Guam ALS/PDC (i.e. Thr181, Thr231, Ser262, Ser396, Ser404, Ser422, and the site defined by monoclonal antibody AT10), all of which also are found in AD PHFtau. Indeed, the Western blot, light and immunoelectron microscopic data suggest that NFTs, PHFs and PHFtau in Guam ALS/PDC are very similar to their counterparts in classic AD. Thus, insights into mechanisms leading to the accumulation of neurofibrillary lesions in Guam ALS/PDC may advance understanding of the pathogenesis and biological consequences of these lesions in classic AD.

Spinal cord neurofibrillary pathology in Alzheimer disease and Guam Parkinsonism-dementia complex.

We examined spinal cords of neurodegenerative disease patients and controls living on the Island of Guam and in the continental United States. These patients had pathologically confirmed parkinsonism dementia-complex (PDC) with or without amyotrophic lateral sclerosis (ALS), or Alzheimer disease (AD), respectively. Nearly all of the spinal cords examined from both groups of patients contained neurofibrillary tangles (NFT). The immunohistochemical profile of these NFTs indicates that they are composed of hyperphosphorylated tau protein like their counterparts in the brains of these patients. Western blot analysis confirmed this by revealing that sarcosyl insoluble tau in spinal cord extracts from patients with NFTs exhibited the presence of all 6 tau isoforms similar to that from AD and ALS/PDC cortical gray matter.

Neuropeptide deficits in schizophrenia vs. Alzheimer's disease cerebral cortex.

Neuropeptide concentrations were determined in the postmortem cerebral cortex from 19 cognitive-impaired schizophrenics, 4 normal elderly subjects, 4 multi-infarct dementia (MID) cases, and 13 Alzheimer's disease (AD) patients. Only AD patients met criteria for AD. The normal elderly and MID cases were combined into one control group. Somatostatin concentrations were reduced in both schizophrenia and AD. Neuropeptide Y concentrations were reduced only in schizophrenia, and corticotropin-releasing hormone concentrations were primarily reduced in AD. Concentrations of vasoactive intestinal polypeptide and cholecystokinin also were reduced in schizophrenia, although not as profoundly as somatostatin or neuropeptide Y. In AD, cholecystokinin and vasoactive intestinal peptide were unchanged. Neuropeptide deficits in schizophrenics were more pronounced in the temporal and frontal lobes than in the occipital lobe. The mechanisms underlying these deficits in schizophrenia and AD are likely distinct. In schizophrenia, a common neural element, perhaps the cerebral cortical gaba-aminobutyric acid (GABA)-containing neuron, may underlie these deficits.

Severe cognitive impairment in elderly schizophrenic patients: a clinicopathological study.

The severe cognitive impairment that affects many of the elderly schizophrenic patients could represent the outcome of schizophrenia in old age for the very severe and chronically ill patients or may be the result of lengthy institutionalization and somatic treatment. Alternatively, it could be due to the presence of concurrent dementing disorders, such as Alzheimer's disease (AD) or multi-infarct dementia. Using an identical neuropathological protocol, brain specimens from schizophrenic patients who showed evidence of severe cognitive impairment were compared with 12 age-matched control cases and the same number of age-matched cases of neuropathologically confirmed patients with AD. Despite their relatively advanced age (mean age 77.1 years +/- 2.8), none of the schizophrenia cases showed sufficient degree of senile plaques and neurofibrillary tangle formations to confirm a diagnosis of AD. Other neurodegenerative disorders associated with dementia were also not identified. These studies suggest that alternative explanations need to be sought for the severe cognitive impairment commonly encountered in elderly schizophrenic patients.

Genetics and Alzheimer's disease: notes of an environment watcher (with apologies to L. Thomas).

Support has recently been voiced for the genetic hypothesis of Alzheimer's disease; frequently at the expense of considerations of environmental factors. In the adult, genetic diseases rarely exist without modification by environment forces. Atherosclerosis leading to myocardial infarction may provide a useful model to consider genetic and environmental factors in Alzheimer's disease. Familial hypercholesterolemia produces a premature inherited form of myocardial infarction, whereas, atherosclerosis with myocardial infarction, seen in advanced age, relates more closely to environmental factors such as smoking, diet, etc.

Proposal to revise the morphologic criteria for the diagnosis of Alzheimer's disease.

Ten years have passed since the drafting of the original National Institute on Aging/American Association of Retired Persons or Khatchaturian criteria for the neuropathologic diagnosis of Alzheimer's disease. In that time, much progress has been made in the study of this disorder. It is clear that although the Khatchaturian criteria have been useful, advances in our understanding of the morphologic substrate of the disease needs to be incorporated in any newly proposed diagnostic criteria. We propose diagnostic criteria to be employed in establishing the diagnosis of Alzheimer's disease in a research setting. Here, we require that a level of density and distribution of senile plaques and neurofibrillary tangles be identified and that other superimposed conditions, such as major cerebral infarcts and/or Parkinson's disease changes, are absent. We also propose separate criteria for diagnosing individuals who die in the early stages of the disease. These latter cases are of extreme research interest and are characterized by a distribution of neurofibrillary tangles that remains primarily restricted to the entorhinal cortex and hippocampus.

Cytology of human caudomedial cingulate, retrosplenial, and caudal parahippocampal cortices.

Brodmann showed areas 26, 29, 30, 23, and 31 on the human posterior cingulate gyrus without marking sulcal areas. Histologic studies of retrosplenial areas 29 and 30 identify them on the ventral bank of the cingulate gyrus (CGv), whereas standardized atlases show area 30 on the surface of the caudomedial region. This study evaluates all areas on the CGv and caudomedial region with rigorous cytologic criteria in coronal and oblique sections Nissl stained or immunoreacted for neuron-specific nuclear binding protein and nonphosphorylated neurofilament proteins (NFP-ir). Ectosplenial area 26 has a granular layer with few large pyramidal neurons below. Lateral area 29 (29l) has a dense granular layer II-IV and undifferentiated layers V and VI. Medial area 29 (29m) has a layer III of medium and NFP-ir pyramids and a layer IV with some large, NFP-ir pyramidal neurons that distinguish it from areas 29l, 30, and 27. Although area 29m is primarily on the CGv, a terminal branch can extend onto the caudomedial lobule. Area 30 is dysgranular with a variable thickness layer IV that is interrupted by large NFP-ir neurons in layers IIIc and Va. Although area 30 does not appear on the surface of the caudomedial lobule, a terminal branch can form less that 1% of this gyrus. Area 23a is isocortex with a clear layer IV and large, NFP-ir neurons in layers IIIc and Va. Area 23b is similar to area 23a but with a thicker layer IV, more large neurons in layer Va, and a higher density of NFP-ir neurons in layer III. The caudomedial gyral surface is composed of areas 23a and 23b and a caudal extension of area 31. Although posterior area 27 and the parasubiculum are similar to rostral levels, posterior area 36' differs from rostral area 36. Subregional flat maps show that retrosplenial cortex is on the CGv, most of the surface of caudomedial cortex is areas 23a, 23b, and 31, and the retrosplenial/parahippocampal border is at the ventral edge of the splenium. Thus, Brodmann's map understates the rostral extent of retrosplenial cortex, overstates its caudoventral extent, and abridges the caudomedial extent of area 23.

Acridine orange-nucleic acid fluorescence. Its use in routine diagnostic muscle biopsies.

Acridine orange-RNA fluorescence in diagnostic muscle biopsies is a sensitive, specific method to identify single fibers undergoing neurogenic atrophy. Fibers thus identified may be clearly distinguished from nonfluorescent type-specific atrophic fibers, as well as from atrophic fibers encountered in other myopathic conditions. Regenerating fibers, inflammatory cells, and mast cells stain prominently with acridine orange but area easily identified by their morphologic features. Acridine orange-RNA fluorescence is extremely useful in the evaluation of early neurogenic atrophy without fiber-type grouping and may be performed on paraffin-embedded sections, thus allowing retrospective studies. In addition, this technique may provide clues to the pathogenesis of neuromuscular disease that involves altered nucleic acid metabolism.

The evolution of diagnosis in early Parkinson disease. Parkinson Study Group.

CONTEXT: Since there is no diagnostic biological marker for Parkinson disease (PD), the diagnosis is based on the results of clinical assessment. The accuracy of diagnosis improves with time and repeated assessments. Studies that require only inclusion of early cases of PD present a diagnostic challenge. Previous studies concluded that initial diagnoses of PD made by general neurologists were incorrect in 24% to 35% of the cases when patients were examined at autopsy. Experts in movement disorders are expected to have greater accuracy of initial diagnosis of PD. OBJECTIVE: To determine the evolution of clinical diagnosis in patients with early PD made initially by experts in PD. DESIGN: Eight hundred patients with mild parkinsonian symptoms (Hoehn and Yahr stage 1 or 2) who received a diagnosis of PD less than 5 years before the beginning of the study were included in the original Deprenyl and Tocopherol Antioxidative Therapy for Parkinson's Disease study. These patients were followed up prospectively with repeated clinical assessments. The following clinical criteria were used to reassess the initial diagnosis: investigator's confidence in the diagnosis of PD, presence of atypical clinical features, findings of imaging studies, response to levodopa, and results of autopsy examinations. RESULTS: The mean +/- SD duration of illness in the 800 cases at enrollment was 2.2+/-1.3 years, and the mean +/- SD Hoehn and Yahr stage was 1.6+/-0.5. The mean +/- SD follow-up was 6.0+/-1.4 years (range, 0.2-7.6 years). In 5 cases, PD was not confirmed at autopsy, and in 15 patients, the results of imaging studies indicated the presence of other pathological conditions. Of the 550 cases treated with levodopa, 49 (8.9%) had little or no improvement; 6 of these cases overlap with either autopsy or imaging study exclusion criteria. Two other cases had at least 4 of the 6 atypical clinical features arguing against the diagnosis of PD. Thus, of the 800 patients, 65 (8.1%) did not have PD according to the study criteria. Compared with those patients with the final diagnosis of PD, in the diagnoses of 60 patients without autopsy, the duration of symptoms (mean +/- SD, 7.2+/-2.0 years vs. 8.3+/-1.9 years; P<.001) and the duration of follow-up (5.3+/-1.6 years vs. 6.1+/-1.3 years; P<.001) were shorter. CONCLUSIONS: We found that 65 (8.1%) of patients initially diagnosed as having PD were later found to have an alternate diagnosis based on multifactorial clinical diagnostic criteria. This alternate diagnosis indicated that experts in PD changed their diagnoses infrequently during the 7.6-year follow-up.

Age-related distribution of neuropathologic changes in the cerebral cortex of patients with Down's syndrome. Quantitative regional analysis and comparison with Alzheimer's disease.

OBJECTIVE: To investigate whether changes in the cerebral cortex exhibit similar distribution patterns in both disorders of Down's syndrome and Alzheimer's disease, we performed a comparative neuropathologic study of patients with these disorders to further clarify the possible relationships between these dementing conditions. DESIGN: The regional and laminar distribution and density of neurofibrillary tangles and senile plaques were analyzed in the cerebral cortex of a series of 16 patients (aged 6 to 74 years) with Down's syndrome and in 10 elderly individuals with Alzheimer's disease. RESULTS: Quantitative analyses revealed that the time course of neurofibrillary tangle formation in Down's syndrome displays regional patterns comparable with those observed in aging and Alzheimer's disease with layer II of the entorhinal cortex being affected first in Down's syndrome, followed by the hippocampus proper and neocortex. The oldest patients with Down's syndrome had neurofibrillary tangle densities sometimes higher than in patients with Alzheimer's disease. At variance with Alzheimer's disease, amyloid deposition was widespread in all of the cortical areas investigated and was observed much earlier than neurofibrillary tangle formation. Patients with Down's syndrome also frequently had higher senile plaque densities than patients with Alzheimer's disease. CONCLUSIONS: These results indicate that the development of pathologic changes in patients with Down's syndrome does not parallel that observed in elderly individuals and patients with Alzheimer's disease in all respects. However, the comparable development patterns of neurofibrillary tangle formation suggest that detailed analysis of patients with Down's syndrome may be useful to further our knowledge of the mechanisms underlying the installation of the neuropathologic alterations leading to the demonstrated loss of select neuronal populations in Alzheimer's disease.