Serum protein leakage in Alzheimer's disease revisited.

Leakage of serum proteins into the brain parenchyma has been repeatedly used as evidence of blood-brain barrier (BBB) damage in experimental and human studies. However, there is no consensus in the literature concerning this phenomenon in Alzheimer's disease (AD). We have examined this question by comparing frontal lobe sections in seven groups of patients: Multi-infarct dementia (n = 6), AD with (n = 10) and without (n = 10) infarcts, age-matched controls with (n = 10) and without (n = 10) infarcts, controls with neurodegenerative diseases other than AD, and young controls (n = 10). An additional series compared prospectively followed patients with a diagnosis of either multi-infarct dementia (n = 5) or AD (n = 4). Albumin was detected in white-matter astrocytes in all cases, without significant variation in intensity. In addition, diverse combinations of neurons, astrocytes, and (in AD patients) senile plaques were present in the cerebral cortex in an inconsistent manner. Semiquantitative analysis showed no statistically significant differences among groups. Anti-IgG labeled astrocytes in infarcts only. Complement C3c component was detected in rare amyloid plaques in a minority (15%) of AD cases. Selective labeling of AD-specific lesions in a patchy manner was observed for serum amyloid P. We conclude that there is no immunohistochemical evidence of alteration of the BBB in Alzheimer's disease with or without vascular factors or in old age. Serum amyloid P binds avidly to AD lesions, but our findings are consistent with leakage through the BBB during the agonal or immediate postmortem period. Finally, no specific pattern of abnormality in the BBB was detected in multi-infarct dementia.

Proximal sciatic axotomy does not inhibit the induction of neurofilamentous inclusions following intracisternal aluminum chloride exposure.

We have previously demonstrated an acute, dose-dependent suppression of low molecular weight neurofilaments (NFL) and intermediate molecular weight neurofilaments (NFM) steady state mRNA levels while sparing those of high molecular weight (NFH) mRNA 48 hours (h) following the intracisternal inoculation of AlCl3 in young adult New Zealand white rabbits. To determine whether this alteration in NF steady state mRNA stoichiometry is a necessary prerequisite to the induction of neurofilamentous inclusions, we examined the response of spinal motor neurons to aluminum exposure in vivo following axotomy. Forty-eight h following a complete transection of the proximal sciatic nerve, rabbits were inoculated intracisternally with either 1000 microg AlCl3 in 100 microl 0.9% NaCl or 0.9% NaCl alone. Rabbits were killed at either 48 or 120 h post-inoculation, and the extent of neurofilamentous inclusion formation quantified in both the cervical and the lumbosacral cord. Following the axotomy, rabbits developed an ipsilateral hind-limb paralysis. In spinal motor neurons ipsilateral to the axotomy, chromatolytic changes were observed and both NFH and NFM mRNA levels were significantly reduced (p<0.001). At 48 h post-AlCl3 inoculation, 29% of motor neurons contralateral to the axotomy demonstrated inclusions, whereas 43% of ipsilateral motor neurons demonstrated inclusions (Fisher's test, two tailed, p = 0.0196). At 120 h post-axotomy 75% and 83%, respectively, of neurons were involved (p = 0.0212). Neurofilamentous inclusions did not form in NaCl-inoculated rabbits. These observations indicate that an altered stoichiometry of NF mRNA steady levels, with a relative overexpression of NFH mRNA, is not critical to the induction of neurofilamentous inclusions following AlCl3 exposure.

Spinal motor neuron neuroaxonal spheroids in chronic aluminum neurotoxicity contain phosphatase-resistant high molecular weight neurofilament (NFH).

It has previously been shown that a single intracisternal inoculum of AlCl3 in young adult New Zealand white rabbits will induce a dose-dependent phosphatase resistance of high molecular weight neurofilament protein (NFH) that is proportionate to the extent of neurofilamentous inclusion formation (Strong and Jakowec, 1994). To determine if the potential for dissolution of aluminum-induced neurofilamentous inclusions was dependent on the degree of NFH phosphatase resistance, we have examined NFH phosphatase sensitivity in a reversible chronic model of aluminum neurotoxicity. Rabbits receiving repeated intracisternal inoculums of 100 microgram AlCl3 at 28 day intervals until day 267 develop spinal motor neuron perikaryal and neuroaxonal neurofilamentous aggregates in a stereotypic, dose-dependent fashion. In the rabbits receiving inoculums until day 156 with survival until day 267 without further aluminum exposure, neuroaxonal spheroids remained prominent while perikaryal inclusions largely resolved. Immunoreactivity to a monoclonal antibody recognizing phosphorylated NFH (SMI 31) was abolished in perikaryal aggregates at each time interval by dephosphorylation with bovine alkaline phosphatase. However, neuroaxonal spheroids maintained their immunoreactivity. Using time-course dephosphorylation studies of spinal cord homogenates, we observed a significant reduction in the rate of dephosphorylation of NFH following 267 days of AlCl3 exposure (P < 0.05). These observations suggest that neuroaxonal spheroids contain phosphatase-resistant NFH isoforms and that the potential for resolution of intraneuronal neurofilamentous inclusions correlates with the susceptibility of NF within these inclusions to enzymatic dephosphorylation.

Reversibility of neurofilamentous inclusion formation following repeated sublethal intracisternal inoculums of AlCl3 in New Zealand white rabbits.

In this report, we describe the clinical, topographical and immunohistochemical characteristics of neurofilament (NF) inclusion formation induced by the intracisternal inoculation of young adult New Zealand white rabbits at 28-day intervals with 100 micrograms AlCl3 over the course of 267 days. The ability to recover following cessation of aluminum exposure has also been assessed. The extent of neurofilamentous inclusion formation was proportionate to the cumulative amount of AlCl3 inoculated and initially consisted of fusiform axonal distention in the ventral spinal cord at day 51 following the initial inoculum. Spinal motor neuron perikaryal inclusions and discrete axonal spheroids were observed at day 107 and supraspinal neurofilamentous pathology by day 156. Perikaryal inclusions were immunoreactive to antibodies recognizing both poorly phosphorylated (SMI 32) and more highly phosphorylated high molecular weight NF (NFH). In contrast, axonal spheroids were intensely immunoreactive at all stages with antibodies recognizing highly phosphorylated NFH and an age-dependent NFH phosphorylation state (SMI 34) with only faint SMI 32 immunoreactivity. Immunoreactivity to an antibody recognizing ubiquitin-protein conjugates did not appear until day 156, whereas inclusions were not immunoreactive to antibodies recognizing either phosphatase-dependent or -independent microtubule-associated protein tau at any stage. Upon withdrawal from further AlCl3 exposure after intervals of 51, 107 or 156 days following the initial inoculum, clinical recovery ensued in all rabbits. In all but the most severely affected rabbits, perikaryal neurofilamentous inclusions resolved. However, axonal spheroids continued to be prominent. These studies demonstrate that the repetitive intracisternal inoculation of AlCl3 in New Zealand white rabbits induces a reversible process of neurofilamentous inclusion formation that preferentially affects motor neurons, and in which recovery will occur in those inclusions containing an admixture of both poorly and highly phosphorylated NFH.

Adult onset Hallervorden-Spatz syndrome or Seitelberger's disease with late onset: variants of the same entity? A clinico-pathological study.

The clinical and pathological features, including electron microscopy of a sporadic case of neuroaxonal dystrophy with findings of both Hallervorden-Spatz syndrome (HS) and Seitelberger's disease (SD) are presented. The patient presented with a slowly progressive illness with seizures, extrapyramidal symptoms, cerebellar ataxia, dementia, spasticity, myoclonic movements and a severe demyelinating peripheral neuropathy with secondary muscular atrophy. Neuropathological examination disclosed cerebral and cerebellar atrophy and excessive pigmentation of the globus pallidus and substantia nigra. Spheroids were widely distributed within the central and peripheral nervous system. Numerous neurofibrillary tangles (NFTs) were found within the hippocampal cortex, neocortex and brain stem. Extensive granulovacuolar degeneration (GVD), Hirano bodies and Lewy bodies were also demonstrated. Severe loss of myelin from the peripheral nerves and muscular denervation were striking features. We wish to report this case which shares findings of both entities, HSS and SD.

Optically clear and vacuolated nuclei. Two useful signs for the transoperative diagnosis of papillary carcinoma of the thyroid.

Ground glass nuclei and Orphan Annie Eye nuclei are currently accepted as the most useful signs for the diagnosis of papillary carcinoma of the thyroid. The nuclear appearance, however, is not used in transoperative studies because the general opinion is that they are only found in permanent sections. To compare the nuclear aspect of the permanent with frozen sections and imprints, a prospective double-blind study of 48 transoperative thyroid specimens was performed. The results show that the nuclei are similar when examined by the three techniques.

Jakob-Creutzfeldt disease associated with Wernicke encephalopathy.

Wernicke disease (WD) is a complication of alcoholism and malnutrition and usually presents acutely and is characterized by disturbances of consciousness, paralysis of the external ocular muscles, and ataxia. The disease results from deficiency of vitamin B 1, or thiamine, an essential coenzyme in intermediate carbohydrate metabolism. On the other hand, Jakob-Creutzfeldt disease (J-C) results from infection with an unconventional agent with a long incubation period and is characterized by a rapidly progressive dementia and histologically by a spongiform encephalopathy associated with neuronal destruction and pronounced astrogliosis. Combination of both diseases has not been reported in the literature previously and their relationship is uncertain. We present 3 cases with this interesting association and consider their relationship.

Lesiones pulmonares y renales en pancreatitis aguda. Estudio retrospectivo en material de autopsia. / Pulmonary and renal lesions in acute pancreatitis. Retrospective study in autopsy specimens

Con el objeto de dilucidar si las alteraciones pulmonares y renales que se describen en la literatura como caracteristicas de la pancreatitis aguda (PA) son particularmente frecuentes en este padecimiento, se efectuo un estudio a ciegas de 35 casos de autopsia con PA comparados con un grupo control de 32. Se obervaron en forma significativamente mas frecuente en pancreatitis intensa: edema pulmonar, congestion y membranas hialinas o fibrina intraalveolar (P < 0.05), con analisis semicuantitativo de los signos en conjunto se observo una mayor diferencia (P < 0.01) independientemente de la intensidad de la PA. Las alteraciones renales frecuentes en pancreatitis aguda fueron: edema intersticial y aumento de celularidad y matriz mesangial (P < 0.05), fueron mas significativas en PA intensa (P < 0.01). Si se analizam en forma semicuantitativa estas y otras alteraciones del "rionon de choque" la diferencia es aun mas aparente (P < 0.01).Se concluye que las lesiones de "rinon de choque" y "pulmon de choque" son particularmente frecuentes en PA. En base a la literatura se analiza la fisiopatologia de dichas lesiones