L. Frölich

Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease

Summary. The search for the causes of neurodegenerative disorders is a major theme in brain research. Acquired disturbances of several aspects of cellular metabolism appear pathologically important in sporadic Alzheimers disease (SDAT). Among these brain glucose utilisation is reduced in the early stages of the disease and the regulatory enzymes important for glucose metabolism are reduced. In the brain, insulin, insulin-like growth factors and their receptors regulate glucose metabolism and promote neuronal growth. To detect changes in the functional activity of the brain insulin neuromodulatory system of SDAT patients, we determined the concentrations of insulin and c-peptide as well as insulin receptor binding and IGF-I receptor binding in several regions of postmortem brain cortex during aging and Alzheimers disease. Additionally, we performed immunohistochemical staining with antibodies against insulin in neocortical brain areas in SDAT and controls. We show for the first time that insulin and c-peptide concentration in the brain are correlated and decrease with aging, as do brain insulin receptor densities. Weak insulin-immunoreactivity could be demonstrated histochemically in pyramidal neurons of controls, whereas in SDAT a stronger insulin-immunoreactivity was found. On a biochemical level, insulin and c-peptide levels were reduced compared to middle-aged controls, but were unchanged compared to age-matched controls. Brain insulin receptor densities in SDAT were decreased compared to middle-aged controls, but increased in comparison to age-matched controls. IGF-I receptor densities were unchanged in aging and in SDAT. Tyrosine kinase activity, a signal transduction mechanism common to both receptor systems, was reduced in SDAT in comparison to middle-aged and age-matched control groups. These data are consistent with a neurotrophic role of insulin in the human brain and a disturbance of insulin signal transduction in SDAT brain and favor the hypothesis that insulin dependent functions may be of pathogenetic relevance in sporadic SDAT.

Clinical efficacy of Ginkgo biloba special extract EGb 761 in dementia of the Alzheimer type

Among the psychiatric illnesses associated with old age primary degenerative dementia of the Alzheimer type (DAT) has gained increasing importance in recent years. Even though a curative treatment of the disease is currently impossible, various drugs can be used to slow down its progression. In the present study the influence of oral treatment with 240 mg/day of Ginkgo bilabo special extract EGb 761 (Tebonin forte, manufactured by Dr Willmar Schwabe, Karlsruhe) on the clinical course of DAT was investigated in a double-blind, randomized, placebo-controlled parallel-group design in 20 outpatients. The duration of treatment was 3 months. The primary outcome variable was the sum score in the SKT-test for the determination of attention and memory. Other psychometric tests (trailmaking test, ADAS, CGI) and electrophysiological investigations (EEG topography) were evaluated descriptively. Although the active-treatment group, with a mean sum score of 19.67 points in the, S.K.T., had a poorer baseline level than the placebo group (18.11 points), it experienced an improvement to 16.78 points under treatment with EGb 761 whereas the placebo group deteriorated to 18.89 points. The differences between the baseline and final values formed the basis for a statistical group comparison, which gave a result favourable to EGb 761, at a significance level of p < .013. In addition to this psychometric confirmation of efficacy, certain descriptive trends were found at the psychopathological (Clinical Global Impression) and dynamic functional (EEG findings) levels, which can be interpreted as evidence of effectiveness of Ginkgo biloba special extract EGb 761 in mild to moderate dementia and of local effects in the central nervous system. Inter-group differences in the ADAS cognitive and non-cognitive subscales did not reach statistical significance, probably because of the small sample size.

Functional imaging of visuospatial processing in Alzheimer's disease

Alzheimers disease (AD) is known to cause a variety of disturbances of higher visual functions that are closely related to the neuropathological changes. Visual association areas are more affected than primary visual cortex. Additionally, there is evidence from neuropsychological and imaging studies during rest or passive visual stimulation that the occipitotemporal pathway is less affected than the parietal pathway. Our goal was to investigate functional activation patterns during active visuospatial processing in AD patients and the impact of local cerebral atrophy on the strength of functional activation. Fourteen AD patients and fourteen age-matched controls were measured with functional magnetic resonance imaging (fMRI) while they performed an angle discrimination task. Both groups revealed overlapping networks engaged in angle discrimination including the superior parietal lobule (SPL), frontal and occipitotemporal (OTC) cortical regions, primary visual cortex, basal ganglia, and thalamus. The most pronounced differences between the two groups were found in the SPL (more activity in controls) and OTC (more activity in patients). The differences in functional activation between the AD patients and controls were partly explained by the differences in individual SPL atrophy. These results indicate that parietal dysfunction in mild to moderate AD is compensated by recruitment of the ventral visual pathway. We furthermore suggest that local cerebral atrophy should be considered as a covariate in functional imaging studies of neurodegenerative disorders.

A Disturbance in the Neuronal Insulin Receptor Signal Transduction in Sporadic Alzheimer's Disease

Disturbances of glucose and energy metabolism are hypothesized as pathogenetic factors in sporadic dementia of Alzheimer type (SDAT). Insulin and is receptors play an important role in the regulation of brain glucose metabolism and neuronal growth. In postmortem brain cortex in SDAT, the densities of brain insulin receptors were decreased compared to adult controls, but were increased in relation to aged controls. Tyrosine kinase activity, a signal transduction mechanism common to insulin and IGF-1 receptors, was reduced in SDAT in comparison to middle-aged and age-matched control groups. The data are consistent with a neurotrophic role of insulin in the human brain and an upregulation of insulin receptors is SDAT brain as a compensatory mechanism, possibly due to impaired signal transduction mechanism.

Insulin-degrading enzyme in the Alzheimer's disease brain: prominent localization in neurons and senile plaques

The anatomical distribution of insulin-degrading enzyme (IDE) was studied in normal and Alzheimers disease (AD) human brains. By use of a monospecific, polyclonal antiserum against the enzyme we identified IDE antigen in multiple cortical and subcortical neurons. Glia did not show IDE immunoreactivity. In AD brains immunostaining appeared stronger than in controls and appeared not only in neurons but also in senile plaques. In a probable case of Lewy body variant of AD Lewy bodies in neurons of the Nuc. basalis of Meynert were immunopositive for IDE. Our anatomical data suggest that the enzyme is associated with typical neuropathologic hallmarks of AD and its expression appears up-regulated in some brain areas.

The cholinergic pathology in Alzheimer's disease--discrepancies between clinical experience and pathophysiological findings.

Summary. The cholinergic hypothesis of Alzheimers disease (AD) states 1. that cholinergic neurons in the basal forebrain are severely affected in the course of disease, detectable both histopathologically by a loss of neurons and neurochemically, by a loss of marker enzymes for acetylcholine synthesis and degradation, and 2. that the resulting cerebral cholinergic deficit leads to memory loss and other cognitive and non-cognitive symptoms, which are characteristic for the illness. This hypothesis was mainly based on studies, which had been conducted on brains of patients with advanced dementia. Nevertheless, it has served as the rationale for the development of drugs, i.e. acetylcholine-esterase inhibitors (AChE-I), which have shown consistent, but modest clinical efficacy against cognitive decline and behavioural symptoms of dementia for a limited period of time. These drugs are presently regarded the standard treatment of dementia in Alzheimers disease. Now, due to a more sensitive and reliable clinical diagnosis, neurobiological investigations can be performed on early stages of disease, when the changes detected presumably are more relevant for the pathogenesis. New studies on the pathophysiology of the cholinergic system in AD suggest 1. that the cholinergic deficit occurs only late in the disease, 2. that at the earliest stages there even is an upregulation of cholinergic activity in the brain, and 3. that an increased activity of AChE may develop under therapy with AChE-Is. These data show that there is a plasticity of the central cholinergic system in AD and that the positive clinical effects of AChE-I are to be weighted against possible detrimental effects on a pathophysiological level. These data challenge the cholinergic hypothesis in its present form, e.g. should stimulate studies on the underlying process, which leads the cholinergic system to increase its activity in patients in the early stage of AD and may have clinical consequences regarding cholinergic drug therapy.

Concordance of DSM-IV Axis I and II diagnoses by personal and informant's interview.

The validity and reliability of using psychological autopsies to diagnose a psychiatric disorder is a critical issue. Therefore, interrater and test-retest reliability of the Structured Clinical Interview for DSM-IV Axis I and Personality Disorders and the usefulness of these instruments for the psychological autopsy method were investigated. Diagnoses by informants interview were compared with diagnoses generated by a personal interview of 35 persons. Interrater reliability and test-retest reliability were assessed in 33 and 29 persons, respectively. Chi-square analysis, kappa and intraclass correlation coefficients, and Kendalls tau were used to determine agreement of diagnoses. Kappa coefficients were above 0.84 for substance-related disorders, mood disorders, and anxiety and adjustment disorders, and above 0.65 for Axis II disorders for interrater and test-retest reliability. Agreement by personal and relatives interview generated kappa coefficients above 0.79 for most Axis I and above 0.65 for most personality disorder diagnoses; Kendalls tau for dimensional individual personality disorder scores ranged from 0.22 to 0.72. Despite of a small number of psychiatric disorders in the selected population, the present results provide support for the validity of most diagnoses obtained through the best-estimate method using the Structured Clinical Interview for DSM-IV Axis I and Personality Disorders. This instrument can be recommended as a tool for the psychological autopsy procedure in post-mortem research.

Mnestic Block Syndrome

The case of a patient with largely preserved intelligence, but severe and persistent memory impairments is reported. FA, a 46-year-old patient with the diagnosis of prolonged depression was investigated repeatedly over a two year period with neuroradiological, neuropsychological, neuromonitoring and other methods. While no brain damage was detectable in FA, he manifested continued and severe anterograde and retrograde memory disorders together with an inhibition in his thinking processes. Otherwise, his intellectual capabilities were in the normal range, that is he was not pseudo-demented. Various approaches with drug treatment and psychotherapy failed to improve his condition. The condition is interpreted as mnestic block syndrome and is considered to be related to an altered brain metabolism which may include changes in various transmitter and hormonal systems (GABA-agonists, glucocorticoids, acetylcholine). Whether depression contributes to this syndrome is uncertain from FAs cognitive performance, but may be a possibility.

Brain metabolism in Alzheimer disease and vascular dementia assessed by in vivo proton magnetic resonance spectroscopy

Proton magnetic resonance spectroscopy (MRS) allows the assessment of various cerebral metabolites non-invasively in vivo. Among 1H MRS-detectable metabolites, N-acetyl-aspartate and N-acetyl-aspartyl-glutamate (tNAA), trimethylamines (TMA), creatine and creatine phosphate (tCr), inositol (Ins) and glutamate (Gla) are of particular interest, since these moieties can be assigned to specific neuronal and glial metabolic pathways, membrane constituents, and energy metabolism. In this study on 94 subjects from a memory clinic population, 1H MRS results (single voxel STEAM: TE 20 ms, TR 1500 ms) on the above metabolites were assessed for five different brain regions in probable vascular dementia (VD), probable Alzheimers disease (AD), and age-matched healthy controls. In both VD and AD, ratios of tNAA/tCr were decreased, which may be attributed to neuronal atrophy and loss, and Ins/tCr-ratios were increased indicating either enhanced gliosis or alteration of the cerebral inositol metabolism. However, the topographical distribution of the metabolic alterations in both diseases differed, revealing a temporoparietal pattern for AD and a global, subcortically pronounced pattern for VD. Furthermore, patients suffering from vascular dementia (VD) had remarkably enhanced TMA/tCr ratios, potentially due to ongoing degradation of myelin. Thus, the metabolic alterations obtained by 1H MRS in vivo allow insights into the pathophysiology of the different dementias and may be useful for diagnostic classification.

Multimodal imaging of residual function and compensatory resource allocation in cortical atrophy: a case study of parietal lobe function in a patient with Huntington's disease

In a case of Huntingtons disease (HD) with dementia and pronounced parieto-frontal atrophy, the functional state of the affected regions was investigated using functional magnetic resonance imaging (fMRI) and fluorodeoxyglucose-positron emission tomography (FDG-PET). It was observed that although parietal areas showed extensive atrophy and reduced resting glucose metabolism, the patient performed with similar accuracy but with longer response time in a visuospatial task compared with healthy control subjects. At the same time, the blood oxygen level-dependent (BOLD) fMRI signal in these areas, which are involved in visuospatial processing, showed a similar task-dependent modulation as in control subjects. The signal amplitude (signal percent change) of the task-dependent activation was even higher for the HD patient than in the control group. This residual functionality of parietal areas involved in visuospatial processing could account for the patients performance in the task concerned, which contrasted with his poor performance in other cognitive tasks. The increased percent-signal change suggests that a higher neuronal effort was necessary to reach a similar degree of accuracy as in control subjects, fitting well with the longer reaction time. We propose that fMRI should be considered as a tool for the assessment of functionality of morphologically abnormal cortex and for the investigation of compensatory resource allocation in neurodegenerative disorders.