Progression of neurofibrillary changes and PHF-tau in end-stage Alzheimer's disease is different from plaque and cortical microglial pathology.

In terminal Alzheimer's disease (AD) the frequency of plaques was found to be reduced in single cases. To test this finding in a larger sample, and in order to determine whether the number of plaques labeled with different markers and the distribution of neurofibrillary tangles are correlated positively to each other and to the degree of dementia, a sample of 134 autopsy brains with and 15 without AD-related pathology has been examined. All of the cases were staged according to Braak and Braak. Both the frequency of plaques immunopositive for beta-amyloid, amyloid precursor protein, and apolipoprotein E and that of microglial cells in the cortex and in the white matter were determined semiquantitatively. The content and distribution of PHF-tau was ascertained by ELISA and immunohistochemistry. Both the clinical dementia rating and the global deterioration scale were used as clinical parameters retrospectively. Correlation coefficients were calculated for all parameters and differences were evaluated statistically. With progressive distribution of neurofibrillary tangles and increasing content of PHF-tau the plaque stages and the degree of cortical microglia reaction increased up to the Braak-stages IV and V, thereafter showing a slightly decreasing tendency in the investigated regions. In end-stage AD resorption of beta-amyloid seems to surpass its deposition. The microglial reaction in the white matter correlated neither with the Braak-stage nor with the accumulation of amyloid. With regard to the degree of dementia, both scales correlated well with the pathological changes. Our data show that neuronal cytoskeletal alterations progressively increase with progressive dementia until the end stage of AD in contrast to the frequencies of plaques and cortical microglial cells, and are therefore preferable for staging purposes.

Increased expression and subcellular translocation of the mitogen activated protein kinase kinase and mitogen-activated protein kinase in Alzheimer's disease.

The sequential activation of the mitogen-activated protein kinase kinase and its substrate, the mitogen-activated protein kinase is involved in a cascade of protein kinases which link a number of cell surface signals to intracellular changes in enzyme activity and gene expression. In vitro, mitogen-activated protein kinase is able to phosphorylate the microtubule-associated protein tau at Ser-Pro and Thr-Pro sites, thereby generating abnormally hyperphosphorylated tau species that are similar to paired helical filament-tau found in Alzheimer's disease. In the present study, we analysed the levels of immunoreactive mitogen-activated protein kinase kinase and mitogen-activated protein kinase in the temporal cortex (area 22) of patients with Alzheimer's disease by means of enzyme-linked immuno-sorbent assays and compared these changes with the content of abnormally phosphorylated paired helical filament-tau. The levels of immunochemically detected mitogen-activated protein kinase kinase and mitogen-activated protein kinase were both increased in Alzheimer's disease by between 35 and 40% compared with age-matched controls. Elevation of mitogen-activated protein kinase kinase was most pronounced during early stages of Alzheimer's disease and was inversely related to the tissue content of abnormally phosphorylated paired helical filament-tau. Pronounced immunoreactivity of mitogen-activated protein kinase kinase and mitogen-activated protein kinase was present in both tangle bearing neurons and unaffected neurons of the temporal cortex. Immunoreactive neurons were most often localized in the direct vicinity of neuritic plaques. In Alzheimer's disease, the subcellular distribution of mitogen-activated protein kinase kinase and mitogen-activated protein kinase showed a striking translocation from the cytoplasmic to the nuclear compartment. It is suggested that the activation of the mitogen-activated protein kinase cascade which appears to be an early feature of Alzheimer's disease might be critically involved in self-stimulating processes of neurodegeneration and aberrant repair under these conditions.

Abnormally phosphorylated tau protein in Alzheimer's disease: heterogeneity of individual regional distribution and relationship to clinical severity.

The distribution of abnormally phosphorylated tau proteins was investigated in a number of cortical areas and in the basal nucleus of Meynert of 12 patients with Alzheimer's disease. Quantification was performed with a sensitive sandwich enzyme-linked immunosorbent assay employing the monoclonal antibody B5-2, which immunoreacts with neurofibrillary tangles, dystrophic neurites surrounding amyloid cores of plaques and neuropil threads. On western blots, the monoclonal antibody B5-2 specifically labels the abnormally phosphorylated paired helical filament-tau species in a phosphorylation-dependent manner but is not cross-reactive to normal tau proteins. The preferential involvement of cytoarchitecturally defined cortical areas showed marked individual differences in Alzheimer's disease, and no unique distribution pattern of abnormally phosphorylated tau proteins could be established. While regional heterogeneities along the rostrocaudal extension of the brain declined with the progression of the disease, lateral differences which were largely non-directional appeared to be more stable over time. The mean content of abnormally phosphorylated tau proteins of individual cases was significantly related to the severity of the disease. On a regional scale, this correlation was highest for the basal nucleus. The formation of abnormally phosphorylated tau was associated with a loss of normal soluble tau proteins. Those cortical areas which in normal brain showed the highest amount of normal soluble tau proteins appeared to be particularly prone to deposition of abnormally phosphorylated tau proteins. The present results indicate that the formation of abnormally phosphorylated tau proteins can be initiated in the neuropil at more than one brain area. The spreading of the pathology appears to involve both intracortical and subcortical pathways but largely spares interhemispheric pathways. It is hypothesized that regional differences in the compartmentation and metabolism of tau proteins might reflect the molecular basis for the regionally different vulnerability in Alzheimer's disease.

The prognosis of mild cognitive impairment in the elderly.

PURPOSE: To determine whether or not subtypes of intellectual functioning are suitable to predict further cognitive decline in individuals with mild cognitive impairment. DESIGN: Naturalistic longitudinal study (mean interval 2.7 years). PATIENTS: 41 subjects with mild cognitive impairment who attended a memory clinic. METHODS: SIDAM, CT, SPECT, and ApoE genotype. RESULTS: At follow-up, 8 out of 41 patients (19.5%) with MCI had progressed to dementia, 8 patients (19.5%) had improved to normal levels of cognitive functioning, 25 patients (61%) had remained stable within the MCI group. At baseline the two prognostic groups differed significantly with regard to age, memory functions, orientation, and the degree of atrophy of the left medial temporal lobe on CT scan. CONCLUSION: The majority of MCI patients in this study remained cognitively stable within the observation period. Patients with older age, poorer test performance on memory tasks and orientation deficits are at higher risk of progressive decline to dementia. CT measures of medial temporal lobe atrophy may be a sensitive parameter of group discrimination.

[Depressive mood and cognitive impairment in results of old age nursing homes]. / Depressivität und kognitive Beeinträchtigungen bei Altenpflegeheim-Bewohnern.

Depression and cognitive impairment associated with dementia are among the most common psychiatric disorders faced by the elderly population. Compared to the elderly population in general, the prevalence of both depressive and cognitive disorders is usually higher in nursing homes. However, a valid assessment and differentiation of depression and dementia in old people is rather difficult. In our study, we examined the extent and co-occurrence of depression and cognitive impairment in a sample of 380 nursing home residents using psychometric tests and clinical rating scales (Geriatric Depression Scale, Mini-Mental-State-Examination, Global Deterioration Scale). At least 50% of the nursing home residents showed a significant degree of cognitive impairment and depression was found in about 48% of those residents, who could be diagnosed (n = 263). The results indicated that the extent of depression was independent of subjects' age, and gender, and nursing home residence duration, whereas the degree of cognitive impairment was correlated with subject's age. Depressive and cognitive disorders coexisted in 15%-24% of nursing home residents. The frequency of co-occurrence of depressive and cognitive disorders was influenced by assessment methods of cognitive impairment.

Changes of activity and isozyme pattern of phosphofructokinase in the brains of patients with Alzheimer's disease.

A severe reduction of the in vivo cerebral glucose consumption rate is generally found in patients with Alzheimer's disease. In postmortem studies changes in the activities of key regulatory glycolytic enzymes, including 6-phosphofructokinase (PFK), have been reported in Alzheimer's disease brains, but the results obtained so far are inconsistent and controversial. We reevaluated the activity of PFK in brain tissue from clinically and neuropathologically confirmed cases of Alzheimer's disease using optimized tissue disintegration and assay methods and determined the PFK isozyme pattern. PFK activity in brains from patients with Alzheimer's disease was significantly increased in frontal and temporal cortex and unchanged in the other brain areas studied when compared with control brains. All three PFK isozymes were detected in each of the brain areas studied. In brains of Alzheimer's disease patients the level of the C-type PFK was slightly reduced at the expense of the M- and L-type subunits. The data presented do not support the results of other groups, which reported up to a 90% reduction of PFK activity in Alzheimer's disease. In contrast, the data presented clearly rule out the suggestion that changes of PFK activity might be one of the causes for the reduced glucose consumption in Alzheimer's disease brains.

Plastic neuronal remodeling is impaired in patients with Alzheimer's disease carrying apolipoprotein epsilon 4 allele.

A relationship between the apolipoprotein E (apoE) genotype and the risk to develop Alzheimer's disease has been established recently. Apolipoprotein synthesis is implicated in developmental processes and in neuronal repair of the adult nervous system. In the present study, we investigated the influence of the apolipoprotein polymorphism on the severity of neuronal degeneration and the extent of plastic dendritic remodeling in Alzheimer's disease. Changes in length and arborization of dendrites of Golgi-impregnated neurons in the basal nucleus of Meynert, locus coeruleus, raphe magnus nucleus, medial amygdaloid nucleus, pedunculopontine tegmental nucleus, and substantia nigra were analyzed after three-dimensional reconstruction. Patients with either one or two apoE epsilon 4 alleles not only showed a more severe degeneration in all areas investigated than in patients lacking the apoE 4 allele but also revealed significantly less plastic dendritic changes. ApoE epsilon 4 allele copy number, furthermore, had a significant effect on the pattern of dendritic arborization. Moreover, the relationship between the intensity of dendritic growth and both the extent of neuronal degeneration and the stage of the disease seen in patients lacking the apoE epsilon 4 allele was very weak in the presence of one epsilon 4 allele and completely lost in patients homozygous for the epsilon 4 allele. The results provide direct evidence that neuronal reorganization is affected severely in patients with Alzheimer's disease carrying the apoE epsilon 4 allele. This impairment of neuronal repair might lead to a more rapid functional decompensation, thereby contributing to an earlier onset and more rapid progression of the disease.

Alzheimer-related tau-pathology in the perforant path target zone and in the hippocampal stratum oriens and radiatum correlates with onset and degree of dementia.

Abnormal phosphorylation of the tau-protein is regarded as a crucial step in the formation of neurofibrillary tangles in the neuronal cell body and neuropil threads in dendrites. We studied the effects of tau-pathology on the clinical expression of dementia in 106 autopsy cases in the entorhinal region, the hippocampal stratum oriens, the stratum radiatum, and the perforant path target zone. The first cytoskeletal lesions were located in the perikarya and dendrites of the pre-alpha cells of the transentorhinal and entorhinal region. Next, abnormally phosphorylated tau-protein (PHF-tau) was found in the neuropil of the CA1-subiculum region. Thereafter, the stratum radiatum and stratum oriens began to be involved in PHF-tau pathology in Braak stage II. In the Braak stages IV and V, the stratum radiatum was completely involved, the stratum oriens increasingly so. Beginning in Braak stage III, we noted cases having PHF-tau pathology in the perforant path target zone of the outer molecular layer of the dentate gyrus. The increase of this pathology with ever greater involvement on the part of the entorhinohippocampal circuit correlated significantly not only with the Braak stages and with the neurochemically determined hippocampal content of PHF-tau but also with the degree of dementia as defined by the clinical dementia rating (CDR) scale. The affection of the stratum oriens in combination with PHF-tau pathology in the stratum radiatum and in the outer molecular layer of the dentate gyrus was encountered almost exclusively in demented individuals (CDR 1-3). These results indicate that axonal PHF-tau pathology in hippocampal pathways presumably is critical for the clinical expression of dementia and may constitute an anatomical substrate of clinically verifiable memory dysfunction in Alzheimer's disease.

Changes in local cerebral blood flow by neuroactivation and vasoactivation in patients with impaired cognitive function.

Imaging of local cerebral blood flow (lCBF) may serve as an important supplementary tool in the aetiological assessment of dementias. In early or preclinical disease, however, there are less characteristic changes in lCBF. In the present study it was investigated whether vasoactivation or neuroactivation may produce more pronounced local lCBF deficits. Local CBF was investigated by using technetium-99m hexamethylpropylene amine oxime and single-photon emission tomography (SPET) in 80 patients (50 with mild cognitive impairment and 30 with dementia of Alzheimer type (DAT), all without evidence of cerebrovascular disease) at rest (baseline) and during activation. In 31 studies patients underwent vasomotor activation with acetazolamide, while 62 studies were performed under cognitive challenge (neuroactivation by labyrinth task). Cortical activity relative to that of cerebellum increased significantly in a right temporal region and tended to increase in other cortical regions upon vasoactivation. In contrast, neuroactivation reduced cortical activity relative to that of cerebellum in several left and right temporal and in left parietal regions. Visual classification of SPET images of patients with probable DAT by three observers resulted in a reduction of the number of definitely abnormal patterns from 9/12 to 4/12 by vasoactivation and an increase from 10/18 to 15/18 by neuroactivation. Correspondingly, abnormal ratings in patients with mild cognitive dysfunction were reduced from 7/19 to 5/19 by vasoactivation and were increased from 12/21 to 18/21 by neuroactivation. In conclusion, vasoactivation does not enhance local relative perfusion deficits in patients with cognitive impairment of non-vascular aetiology, whereas neuroactivation by labyrinth task produces more pronounced local flow differences and enhances abnormal patterns in lCBF imaging.

[Early diagnosis and treatment of Alzheimer's disease. Implementation in the doctor's office]. / Frühdiagnostik und Therapie der Alzheimer-Krankheit. Zum Vorgehen in der Praxis.

The efficacy of antidemential agents proven in comprehensive studies and by clinical experience, now justifies an active and positive approach by the general physician to the diagnosis and treatment of patients with dementia. The proposals on how to implement diagnostic and therapeutic measures in the doctor's office comply both with medical quality criteria and the requirements for appropriateness of treatment and considerations of economy stipulated by German law. They therefore provide the basis for a modern diagnostic work-up and treatment strategy, which will also meet economical demands.