Richard E. Powers

Medial and superior temporal gyral volumes and cerebral asymmetry in schizophrenia versus bipolar disorder

Prior magnetic resonance imaging (MRI) studies report both medial and lateral cortical temporal changes and disturbed temporal lobe asymmetries in schizophrenic patients compared with healthy controls. The specificity of temporal lobe (TL) changes in schizophrenia is unknown. We determined the occurrence and specificity of these TL changes. Forty-six schizophrenic patients were compared to 60 normal controls and 27 bipolar subjects on MRI measures of bilateral volumes of anterior and posterior superior temporal gyrus (STG), amygdala, entorhinal cortex, and multiple medial temporal structures, as well as global brain measures. Several regional comparisons distinguished schizophrenia from bipolar disorder. Entorhinal cortex, not previously assessed using MRI in schizophrenia, was bilaterally smaller than normal in schizophrenia but not in bipolar disorder. Schizophrenic but not bipolar patients had an alteration of normal posterior STG asymmetry. Additionally, left anterior STG and right amygdala were smaller than predicted in schizophrenia but not bipolar disorder. Left amygdala was smaller and right anterior STG larger in bipolar disorder but not schizophrenia.

Distal spinal and bulbar muscular atrophy caused by dynactin mutation.

Impaired axonal transport has been postulated to play a role in the pathophysiology of multiple neurodegenerative disorders. In this report, we describe the results of clinical and neuropathological studies in a family with an inherited form of motor neuron disease caused by mutation in the p150Glued subunit of dynactin, a microtubule motor protein essential for retrograde axonal transport. Affected family members had a distinct clinical phenotype characterized by early bilateral vocal fold paralysis affecting the adductor and abductor laryngeal muscles. They later experienced weakness and atrophy in the face, hands, and distal legs. The extremity involvement was greater in the hands than in the legs, and it had a particular predilection for the thenar muscles. No clinical or electrophysiological sensory abnormality existed; however, skin biopsy results showed morphological abnormalities of epidermal nerve fibers. An autopsy study of one patient showed motor neuron degeneration and axonal loss in the ventral horn of the spinal cord and hypoglossal nucleus of the medulla. Immunohistochemistry showed abnormal inclusions of dynactin and dynein in motor neurons. This mutation of dynactin, a ubiquitously expressed protein, causes a unique pattern of motor neuron degeneration that is associated with the accumulation of dynein and dynactin in neuronal inclusions. Ann Neurol 2005;57:687–694

Magnetic resonance imaging in childhood intractable partial epilepsies: Pathologic correlations

We conducted a retrospective single-blind study assessing the value of MRI in 44 children surgically treated for partial epilepsy, and correlated the MRI findings with the pathology in all cases. MRI revealed abnormalities in concordance with the clinical and electroencephalographic data in 84% of patients. Developmental neuronal migration pathology was present in 25% of patients and was relatively more common in the sensorimotor cortex. There was hippocampal sclerosis in 50% of patients with temporal lobe resection; however, only two of the 10 children with hippocampal sclerosis were below the age of 12 years. Similarly, ganglioglial tumors were more common than astrocytomas in children below age 12. These results indicate that MRI is sensitive in the detection of pathologic abnormalities in most pediatric candidates for epilepsy surgery, and that the distribution and type of pathology appear to be age related in this population.

Transglutaminase activity is increased in Alzheimer's disease brain

Transglutaminase is a calcium-activated enzyme that crosslinks substrate proteins into insoluble, often filamentous aggregates resistant to proteases. Because the neurofibrillary tangles in Alzheimers disease have similar characteristics, and because tau protein, the major component of these tangles is an excellent substrate of transglutaminase in vitro, transglutaminase activity and levels were measured in control and Alzheimers disease brain. Frozen prefrontal cortex and cerebellum samples from Alzheimers disease and control cases matched for age and postmortem interval were used in the analyses. Total transglutaminase activity was significantly higher in the Alzheimers disease prefrontal cortex compared to control. In addition the levels of tissue transglutaminase, as determined by quantitative immunoblotting, were elevated approximately 3-fold in Alzheimers disease prefrontal cortex compared to control. To our knowledge, this is the first demonstration that transglutaminase is increased in Alzheimers disease brain. There were no significant differences in transglutaminase activity or levels in the cerebellum between control and Alzheimers disease cases. Because the elevation of transglutaminase in the Alzheimers disease samples occurred in the prefrontal cortex, where neurofibrillary pathology is usually abundant, and not in the cerebellum, which is usually spared in Alzheimers disease, it can be suggested that transglutaminase could be a contributing factor in neurofibrillary tangle formation.

Neurofibrillary Tangles and Senile Plaques in Aged Bears

In aged human beings and in individuals with age-associated degenerative disorders, particularly Alzheimers disease (AD), neurons develop cytoskeletal abnormalities, including neurofibrillary tangles (NFT) and senile plaques (SP). Senile plaques occur in several nonhuman species; however, NFT, with ultrastructural or immunocytochemical similarities to those occurring in humans, have not been identified in other mammals. In this study of five aged bears (Ursus, 20-30 years of age), we identified cytoskeletal abnormalities similar to those occurring in humans. An aged Asiatic brown bear had NFT, composed of straight 10-16-nm filaments, that were immunoreactive with antibodies directed against: phosphorylated epitopes of neurofilaments (NF); tau; A68 (a protein enriched in AD); and an antigen associated with paired helical filaments (PHF). An aged polar bear had numerous SP; neurites of these plaques were immunoreactive with antibodies against phosphorylated epitopes of NF, but NFT were not identified. These results indicate that nonprimate species develop age-related cytoskeletal abnormalities similar to those occurring in humans. Investigations of the comparative pathology of aged mammals may be useful in elucidating the pathogeneses of these abnormalities.

Knowledge about Alzheimer disease among primary care physicians, psychologists, nurses, and social workers.

Although much of the care of Alzheimer disease (AD) patients and their families is carried out by health professionals who are not specialists in AD or geriatrics, little is known about how knowledgeable these health professionals are about AD. An AD knowledge test was constructed through careful instrument development procedures and then administered through a mail survey. Subjects were 693 individuals, including experts in AD care, generalist health care professionals (primary care physicians, psychologists, social workers, and nurses), nursing students, hospital staff nurses, and assorted health professionals. A 12-item scale with excellent psychometric properties was developed. Experts in AD care performed significantly better than generalist health care professionals on all items. All four groups of generalist health care professionals showed important deficits in fundamental knowledge about AD; for example, only 40% of generalists (vs. 97% of experts) knew that AD is the most common cause of severe memory loss in people over age 65. Results suggest that, although knowledge about assessment and management of AD has increased and has been widely disseminated, many health care professionals remain uninformed about AD. Suggestions for professional education and for use of the UAB AD Knowledge Test for Health Professionals are discussed.

Neurocognitive predictors of financial capacity across the dementia spectrum: Normal aging, mild cognitive impairment, and Alzheimer’s disease

Financial capacity is a complex instrumental activity of daily living critical to independent functioning of older adults and sensitive to impairment in patients with amnestic mild cognitive impairment (MCI) and Alzheimers disease (AD). However, little is known about the neurocognitive basis of financial impairment in dementia. We developed cognitive models of financial capacity in cognitively healthy older adults (n = 85) and patients with MCI (n = 113) and mild AD (n = 43). All participants were administered the Financial Capacity Instrument (FCI) and a neuropsychological test battery. Univariate correlation and multiple regression procedures were used to develop cognitive models of overall FCI performance across groups. The control model (R2 = .38) comprised (in order of entry) written arithmetic skills, delayed story recall, and simple visuomotor sequencing. The MCI model (R2 = .69) comprised written arithmetic skills, visuomotor sequencing and set alternation, and race. The AD model (R2 = .65) comprised written arithmetic skills, simple visuomotor sequencing, and immediate story recall. Written arithmetic skills (WRAT-3 Arithmetic) was the primary predictor across models, accounting for 27% (control model), 46% (AD model), and 55% (MCI model) of variance. Executive function and verbal memory were secondary model predictors. The results offer insight into the cognitive basis of financial capacity across the dementia spectrum of cognitive aging, MCI, and AD.

Cholinergic activation of phosphoinositide signaling is impaired in Alzheimer's disease brain

The function of the phosphoinositide signal transduction system was compared in membranes from Alzheimers disease (AD) and control postmortem brain. [3H]Phosphatidylinositol hydrolysis was concentration-dependently stimulated by GTP[S] and this was 40% lower than controls in AD prefrontal cortical membranes. Carbachol induced a response greater than that of GTP[S] alone, and this response was impaired in AD by 45%. Differential analysis of the receptor-coupled and G-protein contributions to the responses indicated that the G-protein deficit in AD had a predominant influence on the lowered responses to cholinergic agonists. Similar deficits were observed in AD in the responses to five additional cholinergic agonists, including acetylcholine with three different acetylcholinesterase inhibitors. Deficits in stimulated phosphoinositide hydrolysis were regionally selective and these deficits did not correlate directly with reductions in choline acetyltransferase activity in AD tissues. These data demonstrate that in AD there is a brain region-selective, large impairment of cholinergic agonist-induced signal transduction mediated by the phosphoinositide system, which we speculate may impact on amyloid precursor protein processing.

Neuropeptidergic systems in plaques of alzheimer’s disease

Polyclonal antibodies directed against substance P, somatostatin, neurotensin, cholecystokinin (CCK), leucine enkephalin, and vasoactive intestinal polypeptide (VIP) were employed to determine the immunoreactivities of neurites of senile plaques (SP) in Alzheimers disease (AD). All of the antibodies labeled some neurites in some SP. The transmitter specificities of immunoreactive neurites tended to reflect the distribution of transmitter-associated fibers in normal tissue. This investigation also documented the presence of abnormal axons (as distinct from neurites within plaques) in the neuropil in brains of individuals with AD and in some aged controls. These findings suggest that a variety of transmitter systems are involved in the formation of neuropil abnormalities of SP. They also indicate that a greater number of neuronal systems are affected in AD than have been documented by neurochemical studies.

Phosphoinositide hydrolysis, Gαq, phospholipase C, and protein kinase C in post mortem human brain : effects of post mortem interval, subject age, and Alzheimer's disease

Influences of post mortem time interval, subject age and Alzheimers disease were investigated on several components of the phosphoinositide second messenger system, including stimulation of [3H]phosphatidylinositol hydrolysis by GTP[S] and several receptor agonists and the levels of Galphaq, beta, delta and gamma subtypes of phospholipase C, and five protein kinase C isoforms, in membranes prepared from post mortem human prefrontal cortex. Most of these components were stable with post mortem delays in the range of 5-21 h, but decreases of Galphaq and the alpha and xi protein kinase C subtypes were detected. Within the subject age range of 19-100 years, G-protein- and agonist-induced [3H]phosphatidylinositol hydrolysis decreased, as did levels of Galphaq, but the levels of phospholipase C and protein kinase C subtypes were generally unchanged. In Alzheimers disease, compared with age- and post mortem interval-matched controls, there was a decrease in [3H]phosphatidylinositol hydrolysis stimulated by G-proteins and by several receptor agonists, but the levels of Galphaq and most of the phospholipase C and protein kinase C isoforms were unaffected. The greatest deficits, which were >50%, occurred with GTP[S]- and carbachol-induced [3H]phosphatidylinositol hydrolysis, indicating that this G-protein function and the response to cholinergic stimulation are significantly impaired in Alzheimers disease. In summary a comprehensive assessment of several components of the phosphoinositide second messenger system was made in post mortem human brain. Most elements were stable within the post mortem interval range of 5-21 h, lending validity to measurements using these tissues. Significant age-related reductions in several components were identified, indicating loss of responses with increasing age. Most importantly, severe reductions in responses to several stimuli were found in Alzheimers disease brain, deficits in signal transduction which may contribute to impaired cognition and to the limited therapeutic responses to drugs, such as those used to activate cholinergic receptors coupled with the phosphoinositide system.