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Alzheimer´s disease (AD) stands out as the most common chronic neurodegenerative disorder. AD is characterized by progressive cognitive decline and memory loss, with neurodegeneration as its primary pathological feature. The role of neuroinflammation in the disease course has become a focus of intense research. While microglia, the brain's resident macrophages, have been pivotal to study central immune inflammation, recent evidence underscores the contributions of other cellular entities to the neuroinflammatory process. In this article, we review the inflammatory role of microglia and astrocytes, focusing on their interactions with AD's core pathologies, amyloid beta deposition, and tau tangle formation. Additionally, we also discuss how different modes of regulated cell death in AD may impact the chronic neuroinflammatory environment. This review aims to highlight the evolving landscape of neuroinflammatory research in AD and underscores the importance of considering multiple cellular contributors when developing new therapeutic strategies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Dysfunctional RNA-binding proteins (RBPs) have been implicated in several neurodegenerative disorders. Recently, this paradigm of RBPs has been extended to pathophysiology of Alzheimer's disease (AD). Here, we identified disease subtype specific variations in the RNA-binding proteome (RBPome) of sporadic AD (spAD), rapidly progressive AD (rpAD), and sporadic Creutzfeldt Jakob disease (sCJD), as well as control cases using RNA pull-down assay in combination with proteomics. We show that one of these identified proteins, splicing factor proline and glutamine rich (SFPQ), is downregulated in the post-mortem brains of rapidly progressive AD patients, sCJD patients and 3xTg mice brain at terminal stage of the disease. In contrast, the expression of SFPQ was elevated at early stage of the disease in the 3xTg mice, and in vitro after oxidative stress stimuli. Strikingly, in rpAD patients' brains SFPQ showed a significant dislocation from the nucleus and cytoplasmic colocalization with TIA-1. Furthermore, in rpAD brain lesions, SFPQ and p-tau showed extranuclear colocalization. Of note, association between SFPQ and tau-oligomers in rpAD brains suggests a possible role of SFPQ in oligomerization and subsequent misfolding of tau protein. In line with the findings from the human brain, our in vitro study showed that SFPQ is recruited into TIA-1-positive stress granules (SGs) after oxidative stress induction, and colocalizes with tau/p-tau in these granules, providing a possible mechanism of SFPQ dislocation through pathological SGs. Furthermore, the expression of human tau in vitro induced significant downregulation of SFPQ, suggesting a causal role of tau in the downregulation of SFPQ. The findings from the current study indicate that the dysregulation and dislocation of SFPQ, the subsequent DNA-related anomalies and aberrant dynamics of SGs in association with pathological tau represents a critical pathway which contributes to rapid progression of AD.

Extracellular vesicles (EVs), including exosomes, microvesicles, and oncosomes, are nano-sized particles enclosed by a lipid bilayer. EVs are released by virtually all eukaryotic cells and have been shown to contribute to intercellular communication by transporting proteins, lipids, and nucleic acids. In the context of neurodegenerative diseases, EVs may carry toxic, misfolded forms of amyloidogenic proteins and facilitate their spread to recipient cells in the central nervous system (CNS). CNS-originating EVs can cross the blood-brain barrier into the bloodstream and may be found in other body fluids, including saliva, tears, and urine. EVs originating in the CNS represent an attractive source of biomarkers for neurodegenerative diseases, because they contain cell- and cell state-specific biological materials. In recent years, multiple papers have reported the use of this strategy for identification and quantitation of biomarkers for neurodegenerative diseases, including Parkinson's disease and atypical parkinsonian disorders. However, certain technical issues have yet to be standardized, such as the best surface markers for isolation of cell type-specific EVs and validating the cellular origin of the EVs. Here, we review recent research using CNS-originating EVs for biomarker studies, primarily in parkinsonian disorders, highlight technical challenges, and propose strategies for overcoming them., (© 2023. The Author(s).)

In 2012, an international consensus paper reported that medulloblastoma comprises four molecular subgroups (WNT, SHH, Group 3, and Group 4), each associated with distinct genomic features and clinical behavior. Independently, multiple recent reports have defined further intra-subgroup heterogeneity in the form of biologically and clinically relevant subtypes. However, owing to differences in patient cohorts and analytical methods, estimates of subtype number and definition have been inconsistent, especially within Group 3 and Group 4. Herein, we aimed to reconcile the definition of Group 3/Group 4 MB subtypes through the analysis of a series of 1501 medulloblastomas with DNA-methylation profiling data, including 852 with matched transcriptome data. Using multiple complementary bioinformatic approaches, we compared the concordance of subtype calls between published cohorts and analytical methods, including assessments of class-definition confidence and reproducibility. While the lowest complexity solutions continued to support the original consensus subgroups of Group 3 and Group 4, our analysis most strongly supported a definition comprising eight robust Group 3/Group 4 subtypes (types I-VIII). Subtype II was consistently identified across all component studies, while all others were supported by multiple class-definition methods. Regardless of analytical technique, increasing cohort size did not further increase the number of identified Group 3/Group 4 subtypes. Summarizing the molecular and clinico-pathological features of these eight subtypes indicated enrichment of specific driver gene alterations and cytogenetic events amongst subtypes, and identified highly disparate survival outcomes, further supporting their biological and clinical relevance. Collectively, this study provides continued support for consensus Groups 3 and 4 while enabling robust derivation of, and categorical accounting for, the extensive intertumoral heterogeneity within Groups 3 and 4, revealed by recent high-resolution subclassification approaches. Furthermore, these findings provide a basis for application of emerging methods (e.g., proteomics/single-cell approaches) which may additionally inform medulloblastoma subclassification. Outputs from this study will help shape definition of the next generation of medulloblastoma clinical protocols and facilitate the application of enhanced molecularly guided risk stratification to improve outcomes and quality of life for patients and their families.

At the time of their clinical manifestation, the heterogeneous group of adult and pediatric gliomas carries a wide range of diverse somatic genomic alterations, ranging from somatic single-nucleotide variants to structural chromosomal rearrangements. Somatic abnormalities may have functional consequences, such as a decrease, increase or change in mRNA transcripts, and cells pay a penalty for maintaining them. These abnormalities, therefore, must provide cells with a competitive advantage to become engrained into the glioma genome. Here, we propose a model of gliomagenesis consisting of the following five consecutive phases that glioma cells have traversed prior to clinical manifestation: (I) initial growth; (II) oncogene-induced senescence; (III) stressed growth; (IV) replicative senescence/crisis; (V) immortal growth. We have integrated the findings from a large number of studies in biology and (neuro)oncology and relate somatic alterations and other results discussed in these papers to each of these five phases. Understanding the story that each glioma tells at presentation may ultimately facilitate the design of novel, more effective therapeutic approaches.

In multiple sclerosis (MS), iron accumulates inside activated microglia/macrophages at edges of some chronic demyelinated lesions, forming rims. In susceptibility-based magnetic resonance imaging at 7 T, iron-laden microglia/macrophages induce a rim of decreased signal at lesion edges and have been associated with slowly expanding lesions. We aimed to determine (1) what lesion types and stages are associated with iron accumulation at their edges, (2) what cells at the lesion edges accumulate iron and what is their activation status, (3) how reliably can iron accumulation at the lesion edge be detected by 7 T magnetic resonance imaging (MRI), and (4) if lesions with rims enlarge over time in vivo, when compared to lesions without rims. Double-hemispheric brain sections of 28 MS cases were stained for iron, myelin, and microglia/macrophages. Prior to histology, 4 of these 28 cases were imaged at 7 T using post-mortem susceptibility-weighted imaging. In vivo, seven MS patients underwent annual neurological examinations and 7 T MRI for 3.5 years, using a fluid attenuated inversion recovery/susceptibility-weighted imaging fusion sequence. Pathologically, we found iron rims around slowly expanding and some inactive lesions but hardly around remyelinated shadow plaques. Iron in rims was mainly present in microglia/macrophages with a pro-inflammatory activation status, but only very rarely in astrocytes. Histological validation of post-mortem susceptibility-weighted imaging revealed a quantitative threshold of iron-laden microglia when a rim was visible. Slowly expanding lesions significantly exceeded this threshold, when compared with inactive lesions (p = 0.003). We show for the first time that rim lesions significantly expanded in vivo after 3.5 years, compared to lesions without rims (p = 0.003). Thus, slow expansion of MS lesions with rims, which reflects chronic lesion activity, may, in the future, become an MRI marker for disease activity in MS., Competing Interests: Compliance with ethical standards The institutional review board of the Medical University in Vienna approved the post-mortem study (EK number 535/2004). No institutional review board was necessary at Vanderbilt University for the post-mortem study. The in vivo study was conducted in Vienna upon local institutional review board approval (EK number: 154/2009). Written informed consent in accordance with the 1964 declaration of Helsinki and its later amendments was obtained from all individual participants included in the study. Conflict of interest The authors declare no conflict of interest with respect to the study and data presented in this paper. Funding This work was supported by funds of the Oesterreichische Nationalbank (Anniversary Fund, project number 16153 to GG and SH and 15680 to ST) and the Austrian Science Fund (FWF project P27744-B27).

Multiple sclerosis is a complex and heterogeneous, most likely autoimmune, demyelinating disease of the central nervous system (CNS). Although a number of histological classification systems for CNS lesions have been used by different groups in recent years, no uniform classification exists. In this paper, we propose a simple and unifying classification of MS lesions incorporating many elements of earlier histological systems that aims to provide guidelines for neuropathologists and researchers studying MS lesions to allow for better comparison of different studies performed with MS tissue, and to aid in understanding the pathogenesis of the disease. Based on the presence/absence and distribution of macrophages/microglia (inflammatory activity) and the presence/absence of ongoing demyelination (demyelinating activity), we suggest differentiating between active, mixed active/inactive, and inactive lesions with or without ongoing demyelination. Active lesions are characterized by macrophages/microglia throughout the lesion area, whereas mixed active/inactive lesions have a hypocellular lesion center with macrophages/microglia limited to the lesion border. Inactive lesions are almost completely lacking macrophages/microglia. Active and mixed active/inactive lesions can be further subdivided into lesions with ongoing myelin destruction (demyelinating lesions) and lesions in which the destruction of myelin has ceased, but macrophages are still present (post-demyelinating lesions). This distinction is based on the presence or absence of myelin degradation products within the cytoplasm of macrophages/microglia. For this classification of MS lesions, identification of myelin with histological stains [such as luxol fast blue-PAS] or by immunohistochemistry using antibodies against myelin basic-protein (MBP) or proteolipid-protein (PLP), as well as, detection of macrophages/microglia by, e.g., anti-CD68 is sufficient. Active and demyelinating lesions may be further subdivided into the early and late demyelinating lesions. The former is defined by the presence in macrophages of major and small molecular weight myelin proteins, such as cyclic nucleotide diphosphoesterase (CNP), myelin oligodendrocyte glycoprotein (MOG), or myelin-associated protein (MAG), whereas macrophages in the latter demonstrate merely the presence of the major myelin proteins MBP or PLP. We discuss the histological features and staining techniques required to classify MS lesions, and, in addition, describe the histological hallmarks of cortical pathology and diffuse white matter changes, as well as of remyelination.

Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of astroglial tau pathology in the aged brain, facilitating communication among neuropathologists and researchers, and informing interpretation of clinical biomarkers and imaging studies that focus on tau-related indicators.

Frontotemporal lobar degeneration (FTLD) is clinically, pathologically and genetically heterogeneous. Three major proteins are implicated in its pathogenesis. About half of cases are characterized by depositions of the microtubule associated protein, tau (FTLD-tau). In most of the remaining cases, deposits of the transactive response (TAR) DNA-binding protein with Mw of 43 kDa, known as TDP-43 (FTLD-TDP), are seen. Lastly, about 5-10 % of cases are characterized by abnormal accumulations of a third protein, fused in sarcoma (FTLD-FUS). Depending on the protein concerned, the signature accumulations can take the form of inclusion bodies (neuronal cytoplasmic inclusions and neuronal intranuclear inclusions) or dystrophic neurites, in the cerebral cortex, hippocampus and subcortex. In some instances, glial cells are also affected by inclusion body formation. In motor neurone disease (MND), TDP-43 or FUS inclusions can present within motor neurons of the brain stem and spinal cord. This present paper attempts to critically examine the role of such proteins in the pathogenesis of FTLD and MND as to whether they might exert a direct pathogenetic effect (gain of function), or simply act as relatively innocent witnesses to a more fundamental loss of function effect. We conclude that although there is strong evidence for both gain and loss of function effects in respect of each of the proteins concerned, in reality, it is likely that each is a single face of either side of the coin, and that both will play separate, though complementary, roles in driving the damage which ultimately leads to the downfall of neurons and clinical expression of disease.

Array comparative genomic hybridization (aCGH) is a powerful tool for detecting DNA copy number alterations (CNA). Because diffuse malignant gliomas are often sampled by small biopsies, formalin-fixed paraffin-embedded (FFPE) blocks are often the only tissue available for genetic analysis; FFPE tissues are also needed to study the intratumoral heterogeneity that characterizes these neoplasms. In this paper, we present a combination of evaluations and technical advances that provide strong support for the ready use of oligonucleotide aCGH on FFPE diffuse gliomas. We first compared aCGH using bacterial artificial chromosome (BAC) arrays in 45 paired frozen and FFPE gliomas, and demonstrate a high concordance rate between FFPE and frozen DNA in an individual clone-level analysis of sensitivity and specificity, assuring that under certain array conditions, frozen and FFPE DNA can perform nearly identically. However, because oligonucleotide arrays offer advantages to BAC arrays in genomic coverage and practical availability, we next developed a method of labeling DNA from FFPE tissue that allows efficient hybridization to oligonucleotide arrays. To demonstrate utility in FFPE tissues, we applied this approach to biphasic anaplastic oligoastrocytomas and demonstrate CNA differences between DNA obtained from the two components. Therefore, BAC and oligonucleotide aCGH can be sensitive and specific tools for detecting CNAs in FFPE DNA, and novel labeling techniques enable the routine use of oligonucleotide arrays for FFPE DNA. In combination, these advances should facilitate genome-wide analysis of rare, small and/or histologically heterogeneous gliomas from FFPE tissues.

In many instances, nerve biopsy is not necessary in the diagnostic work-up of a peripheral neuropathy. However, histological examination of a tissue sample is still mandatory to show specific lesions in various conditions involving peripheral nerves. As there are fewer laboratories that examine human nerve samples, practitioners including neurologists and general pathologists may not be completely aware of the technical issues and data that are provided by nerve biopsy. Nerve biopsy is considered an invasive diagnostic method, although, its complications are by far less disabling than most of the disorders that lead to its indications. Nevertheless, the decision to perform a nerve biopsy has to be made on a case-by-case basis, and its results must be discussed between the pathologist and the clinician who is in charge of the patient's care. In this paper, we review the minimal technical requirements for proper peripheral nerve tissue analysis. Moreover, we provide data on the usefulness of nerve biopsy in various situations including abnormal deposits, cell infiltrates, link between peripheral neuropathy and monoclonal gammopathy, and numerous hereditary disorders.

The clinical syndrome of primary progressive aphasia (PPA) can be associated with a variety of neuropathologic diagnoses at autopsy. Thirty percent of cases have Alzheimer disease (AD) pathology, most often in the usual distribution, which defies principles of brain-behavior organization, in that aphasia is not symptomatic of limbic disease. The present study investigated whether concomitant TDP-43 pathology could resolve the lack of clinico-anatomic concordance. In this paper, 16 cases of clinical PPA and 10 cases of primarily non-aphasic frontotemporal dementia (FTD), all with AD pathology, were investigated to determine whether their atypical clinical phenotypes reflected the presence of additional TDP-43 pathology. A comparison group consisted of 27 cases of pathologic AD with the typical amnestic clinical phenotype of probable AD. Concomitant TDP-43 pathology was discovered in only three of the FTD and PPA but in more than half of the typical amnestic clinical phenotypes. Hippocampal sclerosis (HS) was closely associated with TDP-43 pathology when all groups were combined for analysis. Therefore, the clinical phenotypes of PPA and FTD in cases with pathologic AD are only rarely associated with TDP-43 proteinopathy. Furthermore, medial temporal TDP-43 pathology is more tightly linked to HS than to clinical phenotype. These findings challenge the current notions about clinicopathologic correlation, especially about the role of multiple pathologies.

The ubiquitin proteasome system (UPS) orchestrates the turnover of innumerable cellular proteins. In the process of ubiquitination the small protein ubiquitin is attached to a target protein by a peptide bond. The ubiquitinated target protein is subsequently shuttled to a protease complex known as the 26S proteasome and subjected to degradative proteolysis. The UPS facilitates the turnover of proteins in several settings. It targets oxidized, mutant or misfolded proteins for general proteolytic destruction, and allows for the tightly controlled and specific destruction of proteins involved in development and differentiation, cell cycle progression, circadian rhythms, apoptosis, and other biological processes. In neuropathology, alteration of the UPS, or mutations in UPS target proteins may result in signaling abnormalities leading to the initiation or progression of tumors such as astrocytomas, hemangioblastomas, craniopharyngiomas, pituitary adenomas, and medulloblastomas. Dysregulation of the UPS may also contribute to tumor progression by perturbation of DNA replication and mitotic control mechanisms, leading to genomic instability. In neurodegenerative diseases caused by the expression of mutant proteins, the cellular accumulation of these proteins may overload the UPS, indirectly contributing to the disease process, e.g., sporadic Parkinsonism and prion diseases. In other cases, mutation of UPS components may directly cause pathological accumulation of proteins, e.g., autosomal recessive Parkinsonism and spinocerebellar ataxias. Defects or dysfunction of the UPS may also underlie cognitive disorders such as Angelman syndrome, Rett syndrome and autism, and muscle and nerve diseases, e.g., inclusion body myopathy and giant axon neuropathy. This paper describes the basic biochemical mechanisms comprising the UPS and reviews both its theoretical and proven involvement in neuropathological diseases. The potential for the UPS as a target of pharmacological therapy is also discussed.

Glucocorticoids are used in the treatment of gliomas to decrease tumour-associated oedema and to reduce the risk of acute encephalopathy associated with radiotherapy. However, the mechanisms by which glucocorticoids work are still largely unknown. In this paper, we survey the experimental and clinical evidence for the effects of glucocorticoids on tumour cell proliferation, apoptosis and sensitivity to chemotherapy, angiogenesis and vascular permeability. We then review current guidelines on the choice of molecule, dose and duration of glucocorticoid treatment for gliomas.

The purpose of this study was to develop a spinal cord injury model in the mouse. Various degrees of extradural compression were used to induce mild, moderate or severe compression injuries. Furthermore, a locomotor rating scale was developed by which the functional outcome of the spinal cord injury could be assessed. The introduction of such a model will be useful for further studies on the pathogenesis and treatment strategies of spinal cord injury. To assess hindlimb motor function, a 10-point scale was used. Initially, the animals were allowed to move freely in an open field and were rated 0-5, 0 being no movement and 5 being almost normal. Animals scoring a 5 were then assessed using steel bars with decreasing widths from 2 cm to 5 mm. For each bar successfully crossed over, they gained additional points. Before injury the hindlimb motor function score (MFS) in all the animals was 10. In mice with mild compression, MFS was decreased slightly on day 1 and recovered to 9 +/- 0.6 on day 14. For mice with moderate compression, the MFS decreased to 4.6 +/- 0.4 on day 1 after injury and gradually improved to 8.1 +/- 0.6 on day 14. Severe injury resulted in paraplegia of the hindlimbs day 1 after injury with a score of 0.6 +/- 0.2. By day 14 after injury, these animals gradually recovered to 3.9 +/- 0.1, could bear the weight on the hindlimbs and walk with a severe deficit. There was a 3%, 9% and 19% decrease in the total cross-sectional area of the spinal cord 14 days after mild, moderate and severe injury, respectively. Microtubule-associated protein immunostaining revealed that the gray matter decreased to 61 +/- 7% in moderately injured animals, while severe compression resulted in a complete loss of gray matter. White matter decreased to 86 +/- 6% in moderately injured animals and 29 +/- 11% in severely injured animals. This study shows that the mouse can be used to achieve reproducible spinal cord compression injuries of various degrees of severity. The force of the impact correlates well with the neurological and light microscopic outcome. The motor function test presented in this paper and the computerized quantification of tissue damage can be used to evaluate the efficacy of different treatment strategies.

Aluminum has been presumed to be involved in the pathogenesis or etiology of Alzheimer's disease. Histochemical demonstration of aluminum in autopsy brains from Alzheimer's disease victims by means of the solochrome azurine method in combination with the methenamine silver technique revealed aluminum-related staining in some neocortical and hippocampal senile plaques and tangles, as well as in the cytoplasm and/or the nuclei of some neurons, and in the cytoplasm of endothelial cells of blood capillaries and pericytes around larger blood vessels. In double-stained samples (first with methenamine silver and then with solochrome azurine) only some plaques displayed the presence of aluminum, while others did not show any sign of the presence of the trace metal. The specificity and sensitivity of solochrome azurine staining was checked in paper spot-test and test-tube experiments combined with flameless atomic absorption spectrophotometry. The results suggest that aluminum is present in brain samples from Alzheimer's disease victims, but the structural localization indicates that it is not primarily involved in the etiology of the disease.

The presence of connective tissue elements in gliomas necessitates in every case a thorough analysis of the character and derivation of such elements to allow the formulation of an appropriate diagnosis. Four cases are presented in this paper. In cases 1 and 2 (anaplastic astrocytomas in two children, 9 and 4 years old, respectively) all the neoplastic elements were astrocytes and their ability to produce or indirectly promote the production of reticulin and collagen fibers accounted for the presence of such elements in close association with the tumor cells. The term "gliofibroma" has been coined for such tumors, but "desmoplastic astrocytoma", (low grade or anaplastic) or in highly malignant cases "desmoplastic glioblastoma", as the case may be, also seem to be appropriate terms for such neoplasms. In contrast, cases 3 and 4 represented composite tumors in adults (66 and 58 years old, respectively) and the neoplasms of these patients consisted of glioblastoma and sarcoma, the latter component demonstrably being of vascular origin. This is the type of tumor usually referred to as gliosarcoma or "Feigin tumor". Although some apparent similarities between the two groups may exist at times, the histogenesis of the latter group's sarcomatous or sarcoma-like portions is different from that of the first group and, therefore, warrants separate diagnostic terms and placement in brain tumor classification.

Thirty-four rats were killed by transcardial perfusion fixation 1 min after a contusing concussive head injury, and 17 rats 1 day later. From the results obtained with a new silver method demonstrating traumatically damaged neuronal somata, dendrites and axons the following conclusions were drawn: (1) outside the contused territories all features of traumatically induced neuronal argyrophilia are similar to those found in non-contusing concussive head injury, as reported in an accompanying paper; (2) within contused territories the neuronal argyrophilia is abolished by some substance released either from damaged blood vessels or damage parenchymal cells, while the neuronal damage otherwise underlying the induction of argyrophilia is present; (3) different phenotypes of neurons are vulnerable to different values of the parameters of the intracranial pressure wave generated by the trauma; (4) some of the neurons may recover from the traumatically induced argyrophilic damage; (5) traumatically induced inundation of neurons with extracellular tracers, as reported by other authors, and somato-dendritic argyrophilia may be different manifestations of one and the same phenomenon; and (6) diffuse primary traumatic axonal injury in human neuropathology may be closely correlated to axonal argyrophilia.

Forty anesthetized rats were cooled below 3 degrees C by 30-min transcardial perfusion of chilled physiological saline before a concussive head injury. The animals were then perfusion-fixed with a buffered formaldehyde-glutaraldehyde solution. Another forty rats were fixed by 30-min transcardial perfusion of the same fixative before a similar concussive head injury. In brain sections of both groups of animals a new silver method stained, in a Golgi-like fashion, a number of neurons and long axonal segments scattered among unstained ones. The similarity between these findings and those obtained following in vivo concussive head injuries described in accompanying papers suggests that the formation of traumatically induced argyrophilic neuronal damage is independent of metabolic processes, i.e., it may be a primary morphopathological process.

In this paper enzyme activities in cylindric structures from striated muscle fibers of the beige mutant mouse are described. While most of the sarcoplasm possesses a reaction for myosin and sarcoplasmic reticular ATPase, succinic dehydrogenase, and lactic dehydrogenase similar to that described for normal non-mutant mice, the cylinders are totally free from activity of these enzymes. The staining pattern thus resembles earlier reports of the central core disease in humans and suggests that the beige mouse is a suitable animal model for this myopathy.

This paper reports on the study of a symptomless fusiform enlargement of the superficial peroneal nerve. The swelling was located in the part of the nerve passing through the aponevrosis. On incision of the epineurium small swellings were seen in the nerve fascicles. A fascicular biopsy was done and the fascicles studied by teasing and by optic and electron microscopy. Isolated nerve fiber study gave evidence of segmental demyelinisation with subsequent remyelinisation in almost all the myelinated fibers. These abnormalities were only encountered in the swollen part of the fascicle. A striking proliferation of cells was demonstrated in isolated fibers by counterstaining with hematoxylin. Electron microscopy showed primary demyelinsation and cellular proliferation affecting Schwann-cells (without onion bulb formations), fibroblasts and giant-vacuolated histiocytes. There was also a massive increase of endoneurial fluid. A few Bünger bands were seen. These rare abnormalities appear to be caused by chronic irritation of the nerve in its passage through the aponebrosis.

This paper reports the case of a 16-year-old girl with acute lymphoblastic leukemia who received chemotherapy including intrathecal injections of methotrexate and preventive irradiation of the brain, but not of the spinal cord. Several months later, she died from an acute ascending poliomyelitic syndrome evolving during 10 days. Clinical, bacteriological, and viral investigations failed to demonstrate any pathological agent. Autopsy revealed an acute ischemic lesion involving both anterior horns of the whole spinal cord and extending from the lower segment up to the mesencephalic region, without significant alteration of the white matter. Neither tumoral invasion, nor vascular obstruction was found. The pathogenesis of this yet undescribed lesion remained unclear but a metabolic disorder seemed the most plausible pathological factor.

Most studies on lead toxicity in the suckling rat have been performed with doses leading to growth retardation. In a previous paper ( Sundstr öm et al. 1983), the effects of different lead doses on normal suckling rats were described. The dose of 10 mg/kg body weight daily given on days 1-15 pp produced minute hemorrhagic lesions on day 15 in the cerebellum, whereas rats given 5 mg/kg body weight daily lacked microscopically discernible pathologic changes in the brain. None of these groups exhibited growth retardation. To further elucidate the association between lead encephalopathy and malnutrition, lead was administered to protein-deprived suckling rats. Protein deprivation was achieved by a diet with 50% reduction of protein content. The mothers of the pups were fed this diet from 2 weeks before conception throughout the experiment. Experimental animals were injected i.p. with 5 mg or 10 mg lead nitrate/kg b.wt. daily. Littermates, injected with vehicle without lead nitrate served as controls. Protein-deprived rats without either treatment were "external" controls. Animals were killed at 10, 15, and 20 days age for determination of lead content in blood and brain and for light-microscopic examination. The protein-deprived rats given 10 mg/kg b.wt. daily were growth-retarded as compared to unexposed protein-deprived rats. The mortality was almost 100% at 15-20 days pp. At 15 days, the cerebellum of these rats showed abundant hemorrhages, and the cerebrum was also hemorrhagically discolored. Protein-deprived rats given 5 mg/kg b.wt. daily did not differ significantly from unexposed protein-deprived rats with regard to body weight gain.(ABSTRACT TRUNCATED AT 250 WORDS)

A case is presented in which the fourfold increase of the HI titer during the progression of the disease, and an increase in IgM content found at the beginning of the second week of the disease confirmed the diagnosis of tick-borne encephalitis. The light microscopic changes correspond to the findings accepted as characteristic to tick-borne encephalitis. Viruses, morphologically belonging to the Flavivirus genus were found by electron microscopy in the thalamus, substantia nigra, and cerebellum of the dissected brain. This paper presents the first demonstration of the virus in a case of a human tick-borne encephalitis.

In an earlier study, it was reported that clusters of ectopic neurons developed postnatally in the hippocampus of rats which were exposed to Methylazoxymethanol acetate (MAMac) during fetal development (Singh, 1977b). This paper describes the perforant tract and commissural connections of hippocampal eutopic and ectopic neurons. These connections were traced with a reduced-silver method (Eager, 1970). Two observations of significance were made: (i) Ectopic neurons misplaced in stratum radiatum received terminals from axons in the perforant tract. The upper boundary for these redirected fibers was stratum pyramidale--approximately 350 mu outside the normal boundary which is situated near the hippocampal fissure. (ii) Ectopic neurons received a dramatically reduced commissural projection, compared with eutopic pyramidal neurons in Ammon's horn. Eutopic neurons in the hippocampus were found to receive afferent perforant tract and commissural fibers in the same way--i.e., density and distribution, as in control rats.

In spite of several cases reported in the literature, the exact pathogenetic mechanism of neuropathic changes in porphyric neuropathy remains uncertain. Various authors have ascribed the neuropathologic findings to either a dying-back axonal degeneration or segmental demyelination. In recent years, the hypothesis of an axonal and myelinic disorder has received support by the demonstration of a combined and simultaneous involvement of both these structures. Such different opinions are also a consequence of the reduced number of detailed bioptic observations in the different forms of acute porphyria not only during acute phases but also between attacks. In this paper we report the results of light- and electron-microscopic examination of two sural nerve biopsies from subjects with hereditary coproporphyria. The first was performed 6 months after an acute attack, the second specimen was obtained from a patient without acute attacks, who had clinical and electrophysiologic signs of a chronic progressive neuropathy. In both cases a dying-back axonal degeneration is considered the primary change. The pathogenetic mechanism of peripheral nerve lesions in porphyric neuropathy will be discussed finally.

Five patients died of a severe neuromyopathy months after the ingestion of adulterated rapeseed oil. These patients were selected for this study due to the presence of striking chromatolytic lesions in symmetric and scattered nuclei of the brain stem, including the locus coeruleus, midline raphe, lateral reticular nuclei of the medulla and cuneate nuclei. Two of the five cases, in addition to these topographic levels of involvement, had remarkable chromatolysis, vacuolar degeneration and heavy silver impregnation of the swollen perykarya and proximal dendrites in the nuclei of the basis pontis. In this paper we analyze the features of the chromatolytic lesion and suggest that the neuronal pathology observed in these cases is an example of irreversible chromatolysis involving vacuolization and filamentous proliferation as final events of the chromatolytic process. The cause of the cell degeneration in the toxic oil syndrome (TOS) is yet undetermined. Chromatolysis in this disease may be the result of a neurotoxic action of the toxic factor in the adulterated oil.

This paper describes three cases of what is probably a new form of storage disorder. The affected animals were English Springer Spaniels and they had developed progressive neurological signs when 2-3 years old. They had gross enlargement of the vagi and of the spinal nerves supplying the brachial plexus. By light microscopy in these nerves these were massive amounts of endoneurial loose fibrous tissue with dispersion of nerve fibres and many foamy phagocyte-like cells. In the central nervous system there was very severe cytoplasmic vacuolation of most neurones and neuroglia, perivascular phagocyte-like cells, loss of myelin, loss of Purkinje cells, numerous spheroids, hypertrophic astrocytes and fibrous astrocytosis. There was also foamy cytoplasmic vacuolation of renal convoluted tubules and pancreatic exocrine parenchyma and numerous foamy phagocyte-like cells in lymph node and lung. On ultrastructural examination membrane bound vacuoles were present in the cytoplasm of affected neurones and phagocyte-like cells. Most of the vacuoles were empty, some contained amorphous materials and some, in neurones, contained stacks of curved or straight lamellae. It is suggested that the stored material could be an oligosaccharide.

Severe spongy degeneration of the central nervous system (CNS) was seen in 11 cattle, 19 sheep, 4 pigs and 1 goat, associated with a variety of hepatic diseases, particularly those caused by hepatotoxic pyrrolizidine alkaloids. It was also seen in a milder form in 2 of 8 horses examined, 1 dog of 5 dogs examined, and in 1 rabbit only of a large number of laboratory animals examined. This paper reports results of experiments which confirmed initially that the CNS disease cold be caused by pyrrolizidine alkaloid intoxication. This was done by poisoning lambs with lasiocarpine. As the disease was seen in hepatoses not caused by pyrrolizidine alkaloids, the hypothesis that CNS spongy degeneration in lambs could follow any hepatic disease irrespective of its cause, was tested by poisoning lambs with allyl formate, an hepatotoxin chemically unrelated to pyrrolizidine alkaloids. Three of 4 lambs poisoned by the allyl formate showed spongy degeneration in their brains. As the CNS spongy degeneration was an apparent form of hepatocerebral disease, an experiment was conducted to show that the neural disease in sheep was caused by hyperammonaemia. CNS spongy degeneration developed in the brains of all sheep infused intravenously with ammonium acetate, and advanced spongy changes developed in the sheep infused for more than 3 days. The cerebral changes were probably temporary, since sheep infused for 5 days and retained for 3 weeks showed marked regression of vacuolation. Hyperammonaemia caused by intravenous ammonium acetate infusion is a simple, rapid model of CNS spongy degeneration. The syndrome, CNS spongy degeneration caused by hepatic failure and hyperammonaemia, is probably one of the morphologic expressions of hepatocerebral disease in domestic animals and could be an analogue of similar congenital and hepatocerebral diseases in man.

This field is meagerly represented in the literature. The aim of this paper is to check in man the descriptions which for the most part were made in animals. Specimens were taken during the course of neurosurgical operations. Arachnoidea of the vault of the skull is situated beneath the subdural neurothelium previously described in man by the same authors. Its cells have epithelial features. Its extracellular spaces are more or less dilated and contain connective tissue fibers. Subarachnoid spaces appear as dilated perivascular spaces. Under the conditions in which human specimens were obtained, we cannot determine whether the cellular coverings of the deep surface of the arachnoidea are continuous. The adventitiae of the subarachnoid vessels contain an apparently continuous cellular sheath, which does not usually occur in other vessels. Arachnoid trabeculae are of uncommon occurrence. Their connective tissue fibers are isolated from the surrounding cerebrospinal fluid by an apparently continuous cellular covering.

As reported previously, the perivascular cells laden with fluorescent granules (FGP cell) are situated in Virchow-Robin space and show marked uptake capacity for intraventricularly administered substances. The phagocytic FGP cells are derived developmentally form leptomeningeal cells and are recognizable in various kinds of animals, including humans. In the present paper, the FGP cells of rodents are studied by immunological techniques. It is clearly demonstrated that rat FGP cells express the antigenic determinant for Ia antibody at about 7 days after birth, and also that mouse FGP cells show a positive reaction against mouse Fc and splenic macrophage antibodies at about the same developmental stage. The specific determinants of FGP cells appear concurrently with the initiation of horseradish peroxidase uptake. On the other hand, Ia antigen is also shown in subarachnoid macrophages, but not in immature FGP cells, endothelium and pericyte. Based on these findings, it seems reasonable to consider that the FGP cells are indigenous cerebral macrophages and significant for the local immune response in a cerebral tissue. Further, in this paper, to prevent confusion of the FGP cell with the other perivascular cells, the authors propose designating the FGP cell as Mato cell.

In rat striatum severe hypoglycemia causes an irreversible nerve cell injury, which does not become manifest until during the post-insult recovery period. This injury can be ameliorated by lesions of the glutamatergic cortico-striatal pathway, which suggests that an "excitotoxic" effect mediated by the glutamatergic input is the likely cause of the post-hypoglycemic nerve cell destruction. In this paper we further characterize the protective effect of abolishing the glutamatergic innervation to striatum at the ultrastructural level. Two weeks after a unilateral cortical ablation rats were subjected to 30 min of severe hypoglycemia with isoelectric EEG and killed either immediately after the insult or following 60 min of recovery induced by restoring the blood glucose levels. Immediately after the hypoglycemic insult the structure of striatum was similar on both sides (except for the changes attributable to the ablation); i.e., the neurons and their dendrites had pale cytoplasm with condensed mitochondria, sparse RER and pinpoint ribosomes. After 60 min restitution numerous striatal neurons on the non-protected, non-ablated side had turned variably dark and condensed, whereas underneath the ablation they remained similar as immediately after hypoglycemia. This sequence indicates that the most likely cause of nerve cell destruction on the non-protected side is the "excitotoxic" effect mediated by the glutamatergic innervation, which is superimposed on the action of the hypoglycemic insult per se. Furthermore, the primary condensation of neurons and their dendrites indicate existence of another type of acute "excitotoxic" nerve cell injury which differs from the previously described injury characterized by neuronal swelling.

Progressive systemic sclerosis (PSS) is a chronic inflammatory disease of the connective tissue with involvement of the skin and other organs. The disease is characterized by an abnormal accumulation of collagen in all tissues and by microangiopathy. The involvement of the peripheral nervous system during PSS is very unusual and few cases are reported in the literature. A morphological study on the neuropathy associated with sclerodermia has been performed in rare cases. In this paper we demonstrate the role that the vascular lesions have in the pathogenesis of neuropathy during scleroderma. In particular, the primary role of the peripheral microangiopathy during PSS (observed in different clinical cases) is verified.

Two siblings born from consanguineous tunisian parents are reported. They showed a severe form of Farber's disease with prominent involvement of the central and peripheral nervous system: low conduction velocity was noticed in both children. Macular cherry red spots were observed in one of them. The diagnosis for the girl investigated was confirmed by evidence of ceramidase deficiency in cultured fibroblasts. Here we report the pathological findings in the subcutaneous nodules using light and electron microscopy (one case), and in sural nerves using morphometric studies (both cases). Varying morphological aspects of intracellular inclusions, depending on the tissues involved, are described and discussed. A review of all cases reported since Farber's first paper in 1952 is given.

This paper examines the neuropathology of oxygen-glucose deprivation uncomplicated by stagnant conditions. Rabbit vagus nerves were pulled into a multi-compartment perfusion chamber, stimulated five times per second and deprived of energy by substituting nitrogen and deoxyglucose for oxygen and glucose in the Locke's perfusate. After incubation the compartments were perfused with gluteraldehyde solution, and the nerves were prepared for electron microscopy. Fixation in the compartments ensured precise cross and longitudinal sections which permitted quantitative comparisons. Although the action potentials ceased in 45 min, 1 h of energy deprivation did not significantly affect the ultrastructure. After 2 h of deprivation the axons were smaller and flattened and microtubules appeared packed together. In the smallest axons the microtubules were gone, the neurofilaments were compacted and the few mitochondria had a dense, homogenous appearance. By 4 h the shrinking was extreme, yet 8% were swollen much larger than any of the controls. Longitudinal views showed these ballooned areas were greatly expanded regions of the smallest axons. Both tiny and huge regions were devoid of microtubules and the swollen axons contained expanded mitochondria. Calcium is indirectly implicated in the pathogenesis by the concurrence of mitochondrial alteration as the microtubules disappear coupled with the known role of mitochondria in calcium regulation and the reported effect of high calcium on microtubual dissociation. It is suggested that axons first shrink as osmotically active molecules are used or washed out. After a time without energy the mitochondria can no longer regulate the intracellular calcium, microtubules dissociate, and calcium-activated phospholipases create osmotically active molecules. Finally, high-amplitude, disruptive swelling occurs.

The lesions of scrapie are confined to the CNS, and the most characteristic histopathological change in mice terminally infected with scrapie is vacuolation. With most laboratory strains of scrapie, one of the regions affected by this lesion is the cerebral cortex, including the hippocampus. Under some circumstances, however, a more destructive degeneration occurs in the hippocampus, with pyramidal cell necrosis accompanied by glial reactions, which can extend to a severe hippocampal sclerosis especially when an intracerebral route of infection has been used. The purpose of this paper is to identify some of the factors involved in these differences in the pathology of the hippocampus and their interdependence; this has necessitated the development and use of a scoring system for sclerosis in the hippocampus, in conjunction with an already established scoring system for vacuolation. Comparison of average hippocampal sclerosis scores and the vacuolation index (an estimate of the severity of grey matter vacuolation throughout the brain) reveals that hippocampal sclerosis is generally associated with scrapie models which produce intense vacuolation in the hippocampus, and also in the brain as a whole. Scrapie-induced hippocampal sclerosis provides an experimental system for investigating the basis for similar lesions, which occur in a variety of conditions, such as Alzheimer's disease and epilepsy.

Ultrastructural study of the biopsied sural nerve in a case of infantile neuroaxonal dystrophy was made. The characteristic change in the ballooned axons is an accumulation of membranous profiles associated with mitochondria, glycogen like granules, dense bodies, vesicles and electron lucent material. The membranous profile is classified into three morphological types and discussed on each of them. Probably tubulomembranous profile of the first type is most common and may be cardinal deposit in this condition. These membranous structures of various types might be, however, only different manifestations occurring on the same morbid process. Enormous amount of glycogen like granules and mitochondria might be related to the metabolic derangement of carbohydrate in the ballooned axons. Electron lucent material we observed was not described in the previous papers on this condition. We added one more example showing that nerve biopsy is helpful to confirm the diagnosis in infantile neuroaxonal dystrophy.

Antisera to isolated Alzheimer neurofibrillary tangles (ANT) of paired helical filaments ( PHF ) were raised in rabbits. These anti- PHF sera immunolabeled both ANT in sections of Alzheimer hippocampus and ANT which were isolated and extracted with sodium dodecyl sulfate (SDS). The immunostaining of ANT in tissue sections was removed by absorption of the anti- PHF serum with small amounts of PHF and also with 40-fold the amount of a fraction prepared identically from normal brain; neurofilament and brain microtubule preparations used at the same concentration as the normal brain control fraction did not eliminate the tangle staining. Furthermore, the tangle staining was also not removed with glial filaments or actin and myosin filaments. No labeling of the neurofilaments of axons and cerebellar basket fibers by anti- PHF sera was observed in tissue sections from non-neurologic brain. On paper blots of SDS-polyacrylamide gels anti- PHF serum reacted with neither polypeptides of the normal brain control fraction nor major microtubule and neurofilament polypeptides. However, the immunoblots of PHF preparations with the anti- PHF serum revealed staining of several polypeptide bands in the 45,000-70,000 molecular weight (MW) region, material on top of the gel and diffuse staining of the high MW region. The tangles staining in tissue sections by the anti- PHF serum was abolished by its absorption with PHF polypeptides extracted from high and low molecular weight areas of SDS polyacrylamide gels but not with identically prepared neurofilament polypeptides.(ABSTRACT TRUNCATED AT 250 WORDS)

In this paper, the characterization of four human malignant glioma cell lines is described. The four lines are positive for glial fibrillary acidic protein (GFAP) in variable amounts. One of them, LN 992, is positive for S-100 protein. Myelin basic protein could not be detected in any of the four lines. The four lines had high levels of CNPase activity. The karyotype shows polyploidy for all lines, with modal numbers ranging from 80 to 120 and various numbers of marker chromosomes. Particular attention has been paid to the surface phenotype and a panel of three antiglioma monoclonal antibodies (Mabs), five antimelanoma Mabs, one anti-CALLA Mab, and two anti-HLA-DR Mabs has been used in an antibody-binding radioimmunoassay for the four cell lines. Lines LN 215 and LN 235 are positive with two antiglioma Mabs, LN 992 is negative. The four lines are positive with all five antimelanoma Mabs, except for LN 992 which ist negative with Mab D5. LN 992 and LN 215 are positive with the anti-CALLA Mab N2A12. LN 308 and LN 992 are positive with anti-HLA-DR Mab D4-22. There was no correlation between the in vitro morphology of the lines and the expression of the various biochemical or surface markers. These results stress the heterogeneity of the phenotype of human malignant glioma lines. These lines will be useful tools for further immunologic studies.

Part I of this paper has documented the evolution of dark neurons into acidophilic neurons in the superficial laminae as well as the reversion of dark neurons to normal neurons in the deep laminae of the cerebral cortex in hypoglycemic brain damage. The present study describes the temporal evolution of hypoglycemic brain damage in the hippocampus. The evolution of dark neurons to acidophilic neurons was confirmed in this brain region. Four additional problems were addressed: Firstly, delayed neuronal death was looked for, and was found to occur in areas of CA1 undergoing mild damage. However, it was not preceded by a morphological free interval, had ultrastructural characteristics distinct from delayed neuronal death in ischemia, and hence should be considered a distinct phenomenon. Secondly, the gradient in the density of neuronal necrosis in the rat hippocampal pyramidal cell band was exploited to test the hypothesis that a more severe insult causes a more rapid evolution of neuronal changes. This was found to be the case, with a temporal spectrum in the timing of neuronal death: Necrosis occurred already after 2 h medially in the subiculum, and was delayed by up to several weeks laterally in CA1. Thirdly, the almost universal sparing of CA3 pyramidal neurons after 30 min hypoglycemic isoelectricity was exploited to address the question of whether reactive changes, which could with certainty be deemed reversible, occur in CA3. Mitochondrial injury was seen in these cells, and was found to be recoverable. No reactive changes of the type previously described following ischemic insults were observed. Fourthly, the astrocytic and vascular response of the tissue was studied. A sequence of astrocytic changes representing structural and probably metabolic activation of astrocytes was seen, consisting of morphological indices of increased turnover of cellular components. Capillaries demonstrated endothelial pits, vesicles, and prominent microvilli hours to days after recovery. The results demonstrate that, in the hippocampal gyrus as in other brain regions, hypoglycemic brain damage is distinct from ischemic brain damage and likely has a different pathogenesis.

The brain lesions in spontaneously hypertensive stroke-prone rats (SHRSP) are characterised by multifocal microvascular damage, breakdown of the blood-brain barrier, massive extravasation of plasma constituents and severe brain oedema, with consequent spongy and cystic tissue destruction in the cerebral cortex and basal ganglia as well as loosening of the white matter. In this paper we analyse in greater detail the pathogenetic mechanisms by which the spongy and cystic lesions are formed and the response of astrocytic cells. For this purpose, tracer (Evans blue)-stained brain lesions were examined in 8-month-old SHRSP immunohistochemically and electron microscopically. Sponginess of the neuropil in small lesions and at the periphery of larger lesions was due to swollen neuronal and astrocytic cell processes, i.e. at this stage the oedema was mainly intracellular. Cystic lesions were formed in the grey matter both by expansion of the extracellular space (ECS) containing protein-rich oedema fluid, and by rupture and subsequent loss of massively swollen cellular elements. In the white matter small slit-formed cysts along the fibre tracts were also formed by the expansion of ECS. In apparently recent lesions astrocytes displayed cyto-plasmic oedema but otherwise were still fairly normal. In more chronic lesions increased numbers of enlarged astrocytes with prominent staining for glial fibrillary acidic protein were present. Their distribution corresponded well to the spread of oedema, i.e. they were prominent around the leaky vessels in the grey matter, in the subpial zone and in the white matter. In the reparative phase the grey matter cysts became lined by astrocytic processes, a new glia limitans. Profuse sheets of glial processes in the neuropil around the cysts reestablished the compactness of the brain parenchyma.

The paper describes the clinical and morphological features of a congenital neurological disease affecting two in-bred litter-mate kittens. The principal neurological features were ataxia and dysmetria. In one of the kittens light microscopy revealed widespread vacuolation of white and grey matter of the brain and spinal cord. Electron microscopy revealved intra-myelinic vacuolation and some expansion of the extracellular space. Neuronal, axonal and glial changes were not seen, nor was there evidence of myelin breakdown. The entity is compared with congenital brain oedema of calves and spongy degeneration of the CNS in man.

This review paper deals with the transport of the protein tracer horseradish peroxidase across cerebral vessels under normal and various experimental conditions. Electronmicroscopical investigations have revealed that, under normal conditions, a minor vesicular transfer of intravenously injected peroxidase occurs across the endothelium in segments of arterioles, capillaries and venules, especially in arterioles with a diameter about 15-30 mu. This normally occurring vesicular transport is susceptible to various experimental conditions. Thus the transfer of tracer increases when a hypertonic solution is injected into the internal carotid artery presumably due to vesicular transport. Extensive acute hypertension of short duration also increases the vesicular transfer of peroxidase from blood to brain. Identical observations are obtained when the hypertension is evoked by intravenous injection of phentolamine and by electrically induced seizures. During the postischemic period, one hour after release of the occlusion of an internal carotid artery in the Mongolian gerbil the vesicular transport of peroxidase is increased across the endothelium of cerebral vessels. The explanation may be release of serotonin from blood platelets during the occlusion. The serotonin could then increase the blood pressure locally in the brain resulting in an enhanced permeability. Serotonin, after perfusion through the cerebral ventricular system, is also able to increase the normally occurring vesicular transfer. The most likely mechanism behind this phenomenon seems at the moment to be local hypertension evoked by serotonin-induced vasoconstriction of arterioles. Finally, the enhanced vesicular transport across cerebral endothelium caused by porto-caval anastomosis is mentioned and the possible role of disturbances in the metabolism of amines as responsible for the extravasation is discussed.

Axonal dystrophy in normal ageing can be studied in experimental animals. Primary sensory neurones show two different kinds of change with ageing, i.e. axonal dystrophy and axonal atrophy (degeneration). This paper reports the chronology and topography of these two processes in relation to growth and involution of these neurones throughout the lifespan of the rats used in this study. Axonal spheroids preferentially form at presynaptic terminal regions in many of the collaterals of central branches of the axons, i.e. in the posterior funiculus nuclei, posterior column and posterior funiculus. Axonal dystrophy in normal ageing is essentially a morbid process restricted to the terminal parts of the axon. It shows little tendency to expand retrogradely along the axon. Evidence is presented that spheroids in posterior funiculus also derive from terminal axons. Preference is also noted in the lumbosacral rather than cervical neurons, and in longer (posterior funiculus nuclei) rather than shorter (posterior column) collaterals. Quantitative study of myelinated fibres in posterior funiculus shows that they increase in number until middle age (400 days) of the animals, before beginning to decline. On the other hand, axonal atrophy begins to appear early in small numbers, and increases in numbers with age. Atrophy involves the whole length of the axon within the posterior funiculus from the start, suggesting, therefore, that it does not belong to a dying-back process. It is noteworthy that the main development of axonal dystrophy lies in the earlier half of the animals' life, while that of axonal atrophy lies in the latter half. This fact adds to the evidence that axonal dystrophy, as far as in normal ageing is concerned, is more related to the positive side of neuronal activity, e.g. one form of growth abnormality of axon.