Cortical synapse loss in progressive supranuclear palsy

Cortical synapse loss, the probable substrate of cognitive impairment in Alzheimer disease (AD), has not previously been evaluated in progressive supranuclear palsy (PSP). Hypothesizing that synapse loss would be greater in demented than non-demented PSP patients, we examined synaptophysin concentrations in 8 cases of PSP (5 demented and 3 nondemented cases). We found a decrease in mean synaptophysin concentration in these 8 cases in frontal, temporal, and parietal lobes, and in cerebellum, compared to the means in corresponding lobes of 16 controls. The decreases were similar to those in 28 cases of AD, but not as great. We determined synaptophysin concentration from motor cortex in only 4 of our PSP cases, 2 demented and 2 non-demented. The average concentrations in these 4 cases were lower than in AD motor cortex; both were lower than controls. When demented and non-demented PSP cases were compared, neocortical synaptophysin concentrations in non-demented PSP cases were lower than in demented cases. There appears to be a link between AD and PSP, in that synapse loss is found in both. However, the basis and significance of the prominent neocortical synapse loss in PSP, especially in non-demented subjects, remain to be explored.     

Neuronal intranuclear inclusions are ultrastructurally and immunologically distinct from cytoplasmic inclusions of neuronal intermediate filament inclusion disease

Abnormal neuronal cytoplasmic inclusions (NCIs) containing aggregates of -internexin and the neurofilament (NF) subunits, NF-H, NF-M, and NF-L, are the signature lesions of neuronal intermediate filament (IF) inclusion disease (NIFID). The disease has a clinically heterogeneous phenotype, including frontotemporal dementia, pyramidal and extrapyramidal signs presenting at a young age. NCIs are variably ubiquitinated and about half of cases also have neuronal intranuclear inclusions (NIIs), which are also ubiquitinated. NIIs have been described in polyglutamine-repeat expansion diseases, where they are strongly ubiquitin immunoreactive. The fine structure of NIIs of NIFID has not previously been described. Therefore, to determine the ultrastructure of NIIs, immunoelectron microscopy was undertaken on NIFID cases and normal aged control brains. Our results indicate that the NIIs of NIFID are strongly ubiquitin immunoreactive. However, unlike NCIs which contain ubiquitin, -internexin and NF epitopes, NIIs contain neither epitopes of -internexin nor NF subunits. Neither NIIs nor NCIs were recognised by antibodies to expanded polyglutamine repeats. The NII of NIFID lacks a limiting membrane and contains straight filaments of 20 nm mean width (range 11–35 nm), while NCIs contain filaments with a mean width of 10 nm (range 5–18 nm; t-test, P<0.001). Biochemistry revealed no differences in neuronal IF protein mobilities between NIFID and normal brain tissue. Therefore, NIIs of NIFID contain filaments morphologically and immunologically distinct from those of NCIs, and both types of inclusion lack expanded polyglutamine tracts of the triplet-repeat expansion diseases. These observations indicate that abnormal protein aggregation follows separate pathways in different neuronal compartments of NIFID.     

Cellular damage and prevention in childhood hydrocephalus

The literature concerning brain damage due to hydrocephalus, especially in children and animal models, is reviewed. The following conclusions are reached:

• 1. 

  Hydrocephalus has a deleterious effect on brain that is dependent on magnitude and duration of ventriculomegaly and modified by the age of onset.

       

Frontotemporal lobar degeneration with motor neuron disease-type inclusions predominates in 76 cases of frontotemporal degeneration

This report presents the largest series of consecutive, neuropathologically confirmed cases of frontotemporal degeneration (FTD). Prior studies have found dementia lacking distinctive histology (DLDH) to be the most common pathology underlying the clinical diagnosis of FTD. In this series of 76 cases, 29 (38%) were found to have frontotemporal lobar degeneration with motor neuron disease-type inclusions (FTLD-MND-type) or FTLD-MND (with ALS), the most common neuropathological classification in our series. Only eight (11%) were classified as Picks disease. Several cases originally designated as DLDH could be reclassified as FTLD-MND-type based on current recommendations for classification of FTD.     

Spectroscopic sensing of cancer and cancer therapy: current status of translational research

Various types of optical spectroscopy have been investigated as methods to effect a non-invasive, real-time in-situ assessment of tissue pathology. All of these methods have one basic principle in common: the optical spectrum of a tissue contains information about the biochemical composition and/or the structure of the tissue, and that information conveys diagnostic information. The biochemical information can be obtained by measuring absorption, fluorescence, or Raman scattering signals. Structural and morphological information may be obtained by techniques that assess the elastic-scattering properties of tissue. These basic approaches are useful for the detection of cancer as well as for other diagnostic applications such as hemoglobin saturation, intra-luminal detection of atherosclerosis, and simply the identification of different tissue types during procedures. Optical spectroscopic measurements can also be employed in the management of disease treatment. The site-specific pharmacokinetics of chemotherapy and photodynamic therapy agents can be used to customize dosage to the patient, and diagnostic spectroscopy can be used to monitor response to treatment. In recent years clinical studies have provided indications of potential efficacy, and some of these modalities are now entering a translational research stage, with an eye to approval and commercialization. A benefit of these methods is their inherent low cost and ease of implementation, generally mediated with small portable instruments, not requiring any specialized facilities, and eventually not requiring expert interpretation. This paper reviews briefly the most common methods of diagnostic optical spectroscopy, and reviews in greater depth recent clinical translational research invoking scattering spectroscopy as the enabling technology, which has been the experience of the authors.     

Can alzheimer's disease and dementias with Lewy bodies be distinguished clinically?

To determine if Alzheimer's disease (AD), its Lewy body (LB) variant (LBV), and diffuse LB disease (DLBD) are distinguishable at initial clinical evaluation, data from autopsy-confirmed AD, LBV, and DLBD were examined. No significant differences were found in age at onset, age at death, total duration of illness, duration of illness before initial visit, duration of illness from initial visit to death, or severity of illness at initial evaluation. Hallucinations and delusions were significantly more frequent for LBV and DLBD, respectively, than for AD, and falls were more frequent for DLBD than for AD. Extrapyramidal symptoms (EPS) were less frequent in neuroleptic-free AD subjects than in LB subjects; the percentage of AD patients with EPS after neuroleptic exposure was less than that among LB patients. Seizures were significantly more common for DLBD than for AD or LBV. LB dementias differed from AD at initial evaluation, with more frequent hallucinations and delusions, EPSs, and seizures, and longitudinally in neuroleptic sensitivity, but the data did not distinguish LBV from DLBD.     

Intracerebral hemorrhage induces macrophage activation and matrix metalloproteinases

Intracerebral hemorrhage (ICH) is characterized by parenchymal hematoma formation with surrounding inflammation. Matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of neurological diseases defined by inflammation and cell death. To investigate the expression profile and pathogenic aspects of MMPs in ICH, we examined MMP expression in vivo using a collagenase-induced rat model of ICH. ICH increased brain MMP-2, -3, -7, and -9 mRNA levels relative to sham-injected (control) animals in the vicinity of the hematoma, but MMP-12 (macrophage metalloelastase) was the most highly induced MMP (>80-fold). Immunohistochemistry showed MMP-12 to be localized in activated monocytoid cells surrounding the hematoma. In vitro studies showed that thrombin, released during ICH, induced MMP-12 expression in monocytoid cells, which was reduced by minocycline application. Similarly, in vivo minocycline treatment significantly reduced MMP-12 levels in brain. Neuropathological studies disclosed marked glial activation and apoptosis after ICH that was reduced by minocycline treatment. Neurobehavioral outcomes also were improved with minocycline treatment compared with untreated ICH controls. Thus, select MMPs exhibit increased expression after ICH, whereas minocycline is neuroprotective after ICH by suppressing monocytoid cell activation and downregulating MMP-12 expression.     

Pathophysiologic consequences of hydrocephalus

Hydrocephalus-induced damage is dependent on the rate and magnitude of ventricular dilatation, the proximity to the ventricle, and the developmental stage at which the disturbance occurs. It is mediated through a combination of mechanical, ischemic, and metabolic-toxic disturbances. Developmental processes, including myelin production, can be impaired. Periventricular axons are the primary target, however. The potential for reversal of damage by shunting diminishes as the duration and severity of hydrocephalus increases. Ancillary pharmacologic means for preventing hydrocephalus-induced brain damage are worth pursuing.     

Influence of caloric restriction on the development of atherosclerosis in nonhuman primates: progress to date

Caloric restriction (CR) has been observed to retard aging processes and extend the maximum life span in rodents. In an effort to evaluate the effect of this nutritional intervention on physiologic variables in higher species, several nonhuman primate trials are ongoing. In particular, a study evaluating the independent effect of CR on the extent of atherosclerosis was initiated in 1993 in 32 adult cynomolgus monkeys. Therefore, the trial was designed to achieve identical cholesterol intake after animals were randomized to a control group or a calorie-restricted group (30% reduction from baseline caloric intake). The animals were routinely evaluated for glycated proteins, plasma insulin and glucose levels, insulin sensitivity, and specific measures for abdominal fat distribution by CT scans over a 4-year interval. The results from 4 years of intervention demonstrate that CR improves cardiovascular risk factors (such as visceral fat accumulation) and improves insulin sensitivity. In contrast to other primate studies with normolipidemic animals, CR had no independent effects on plasma lipid levels and composition in the presence of equivalent amounts of dietary cholesterol intake. Preliminary analysis of atherosclerotic lesion extent in the abdominal aorta has failed to demonstrate differences between control animals and CR animals. Follow- up studies are being conducted to determine the effect of CR on atherosclerosis extent in coronary and carotid arteries.