Pathologic evaluation of the human suprachiasmatic nucleus in severe dementia

Sleep disruption and other circadian rhythm disturbances are frequently seen in dementia patients. In this study, we examined the suprachiasmatic nucleus (SCN), the putative site of the hypothalamic circadian pacemaker, to determine the nature and degree of pathologic changes caused by severe dementia. Neuropathologic examination indicated that among 30 patients with a clinical history of severe dementia, 22 had Braak and Braak stage V-VI Alzheimer disease, 3 had combined Alzheimer and Parkinson disease, 3 had Pick disease and 2 had severe hippocampal sclerosis. Comparisons were made with a control group composed of 13 age-matched patients with no clinical or pathological evidence of dementia or other CNS disorders. To determine the pathologic involvement within the SCN, human hypothalami were stained with: Nissl, Bielchowsky silver, thioflavin S and specific antibodies directed against vasopressin (VP), neurotensin (NT), neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), beta-amyloid (B/A4) and glial fibrillary acidic protein (GFAP). Pathologic damage was primarily limited to neuronal loss and neurofibrillary tangle formation. Only rare diffuse plaques were noted. The pathologic changes within the SCN were less severe than in the other brain regions. Morphometric analysis was accomplished using a stereological approach to sample the average total number of positively stained neurons and astrocytes in 10 different 0.1mm2 microscopic fields in the dorsal subdivision of the SCN. Patients with Alzheimer disease exhibited a significant decrease in vasopressin (9.75 vs 16.7, p < 0.001) and neurotensin (6.82 vs 9.63, p < 0.002) neurons, as well as a corresponding increase in the GFAP-stained astrocyte/Nissl-stained neuron ratio (0.54 vs 0.10, p < 0.009). These studies provide evidence that both vasopressin and neurotensin neurons are lost in Alzheimer disease, and that the astrocyte/neuron ratio is a reliable indicator of disease-related pathology within the SCN. Taken collectively, our data support the hypothesis that damage to the SCN may be an underlying anatomical substrate for the clinically observed changes in circadian rhythmicity that have been observed in Alzheimer patients.     

Cells containing immunoreactive estrogen receptor-alpha in the human basal forebrain

The distribution of estrogen receptor protein-alpha (ER-alpha)-containing cells in the human hypothalamus and adjacent regions was studied using a monoclonal antibody (H222) raised against ER-alpha derived from MCF-7 human breast cancer cells. Reaction product was found in restricted populations of neurons and astrocyte-like cells. Neurons immunoreactive for ER-alpha were diffusely distributed within the basal forebrain and preoptic area, infundibular region, central hypothalamus, basal ganglia and amygdala. Immunoreactive astrocyte-like cells were noted within specific brain regions, including the lamina terminalis and subependymal peri-third-ventricular region. These data are consistent with the location of estrogen receptors in the basal forebrain of other species and the known effects of estrogens on the cellular functions of both neurons and supporting elements within the human hypothalamus and basal forebrain.     

Advanced glycation end products contribute to amyloidosis in Alzheimer disease.

Alzheimer disease (AD) is characterized by deposits of an aggregated 42-amino-acid beta-amyloid peptide (beta AP) in the brain and cerebrovasculature. After a concentration-dependent lag period during in vitro incubations, soluble preparations of synthetic beta AP slowly form fibrillar aggregates that resemble natural amyloid and are measurable by sedimentation and thioflavin T-based fluorescence. Aggregation of soluble beta AP in these in vitro assays is enhanced by addition of small amounts of pre-aggregated beta-amyloid "seed" material. We also have prepared these seeds by using a naturally occurring reaction between glucose and protein amino groups resulting in the formation of advanced "glycosylation" end products (AGEs) which chemically crosslink proteins. AGE-modified beta AP-nucleation seeds further accelerated aggregation of soluble beta AP compared to non-modified "seed" material. Over time, nonenzymatic advanced glycation also results in the gradual accumulation of a set of posttranslational covalent adducts on long-lived proteins in vivo. In a standardized competitive ELISA, plaque fractions of AD brains were found to contain about 3-fold more AGE adducts per mg of protein than preparations from healthy, age-matched controls. These results suggest that the in vivo half-life of beta-amyloid is prolonged in AD, resulting in greater accumulation of AGE modifications which in turn may act to promote accumulation of additional amyloid.     

Randomized Controlled Trial of Visualization versus Neuromonitoring of the External Branch of the Superior Laryngeal Nerve during Thyroidectomy

Background  

Injury to the external branch of the superior laryngeal nerve (EBSLN) during thyroidectomy results in a lowered fundamental frequency of the voice and deteriorated voice performance in producing high-frequency sounds. It remains unclear if the use of intraoperative nerve monitoring (IONM) can improve the clinical outcome of thyroidectomy in terms of preserved individual voice performance. This study was designed to test that hypothesis.     

Thyrotropin releasing hormone (TRH) in the hippocampus of Alzheimer patients

Thyrotropin-releasing hormone (TRH) is best known for its hypothalamic neuroendocrine role in regulating thyroid function. In extra-hypothalamic regions in vitro, we have shown TRH to have a protective effect against synaptic loss and neuronal apoptosis. A role for TRH in Alzheimer's disease (AD) has not been established previously. In this study, we examined the content of the TRH peptide in the hippocampus of elderly controls (n=5) and AD patients (n=7) by radioimmunoassay (RIA). The TRH concentration was decreased in the AD hippocampus compared to normal elderly controls (p < 0.01). In a separate series of experiments utilizing primary cell cultures made from rat hippocampus, TRH peptide concentration was depleted by the addition of TRH antiserum. TRH withdrawal was found to enhance the activity of glycogen synthetase kinase-3 (GSK-3beta), a critical enzyme necessary for the phosphorylation of tau, as well as the phosphorylation of the tau protein itself. This TRH depletion induced upregulation in phosphorylation that was observed to initiate axonal retraction in cultured neurons. These data suggest that TRH within the hippocampus can regulate the activity of various proteins by phosphorylation/dephosphorylation that may be involved in the pathogenesis of AD.     

Familial frontotemporal dementia: a report of three cases of severe cerebral atrophy with rare inclusions that are negative for tau and synuclein,but positive for ubiquitin

We describe the brain autopsy findings from three of five siblings who suffered dementia with clinical diagnoses including Alzheimers, Parkinsons, and Picks disease. Five other living siblings appear unaffected. All of the autopsied brains showed severe atrophy (brain weights 613, 641, and 750 g) of the frontal and temporal lobes, and to a slightly lesser extent of the parietal lobes, while the occipital lobes were relatively preserved. The substantia nigra showed marked neuronal loss with gliosis. No ballooned neurons, neurofibrillary tangles, neuritic plaques, Pick bodies, or Lewy bodies were found in these brains. Immunohistochemistry for tau protein failed to reveal neuronal or glial inclusions, and normal tau protein was found in a separate Western blot study [Adamec et al. (2001) Neurosci Lett 315:21–24]. Rare neurons with ubiquitinated cytoplasmic inclusions were scattered in the neocortex and hippocampus. The overall pathological features were consistent with a severe form of frontotemporal dementia (FTD) with involvement of the substantia nigra. Whether the rare ubiquitinated inclusions are sufficient to classify these cases as FTD with motor neuron disease type inclusions but without motor neuron disease, or FTD dementia lacking distinctive histological features remains unclear. The features of lobar circumscribed atrophy without Pick bodies and without ballooned neurons, however, are consistent with Pick disease group C in the Constantinidis classification [Constantinidis et al. (1974) Eur Neurol 11:208–217].     

Towards a cognitive model and measure of dissociation

Dissociation comprises a range of psychological processes, which have largely been the subject of psychodynamic discussion. Dissociative phenomena are for the most part unaddressed by cognitive theorists. Current measures are atheoretical and our understanding of dissociation has been hampered by the absence of clear psychological models. This paper describes a new cognitive model of dissociation and the development and validation of a theoretically based measure-the Wessex Dissociation Scale (WDS). The WDS has adequate internal consistency, shows convergent validity with the Dissociative Experiences Scale (DES-II), and is equivalent to the DES-II in its associations with severe psychopathology. However, the WDS has some advantages over the DES-II, in that it is sensitive to milder manifestations of dissociation, demonstrating links to less severe pathologies. The findings described here provide preliminary support for the usefulness of the cognitive model, and the varied consequences of dissociative processes. The clinical and research utility of the model and the scale are discussed.     

Treatment results of treatment for congenital, unilateral microcoria and pupil displacement--case report

The purpose of this report was to present rarely occurring developmental anomaly of congenital unilateral microcoria and pupil displacement. We present a case of a boy, who underwent a plastic surgery of pupil at age of 3 year. Despite of relatively tardy onset of treatment and existing profound amblyopia (light perception with projection), a full vision recovery was achieved after 4 years of occlusion therapy.