Serum Tau-A and Tau-C Levels and Their Association with Cognitive Impairment and Dementia Progression in a Memory Clinic Derived Cohort.

BACKGROUND: Serum-measured fragments of Tau cleaved by ADAM-10 (Tau-A) and Caspase-3 (Tau-C) have been found linked to change in cognitive function and risk of dementia. OBJECTIVES: 1) To determine the discriminatory abilities of Tau-A, and Tau-C in subjects with either mild cognitive impairment (MCI) due to Alzheimer's disease (AD) or AD dementia compared to a control group. 2) To determine if there is a relation between Tau-A, and Tau-C and established cerebrospinal fluid (CSF) markers of AD- ß-Amyloid1-42 (AB42), Phosphorylated-tau-181 (p-tau), and total-tau. 3) To determine if Tau-A and Tau-C are associated with progression rate from MCI due to AD to AD dementia. DESIGN: Cross-sectional and a substudy using a retrospective cohort design. SETTING: Memory clinic derived subjects contributing to the Danish Dementia Biobank. PARTICIPANTS: Cognitively unimpaired subjects (n=49), patients with mild cognitive impairment (MCI) due to AD (n=45), and Alzheimer's dementia (n=52). MEASUREMENTS: Competitive enzyme-linked immunosorbent assay (ELISA)-measured serum levels of Tau-A, and Tau-C. RESULTS: The ratio between Tau-A and Tau-C differed between the three groups (p=0.015). Age- and sex-adjusted Tau-A differed between groups with lower ratios being associated with more severe disease (p=0.023). Tau-C was trending towards significant correlation to CSF-levels of AB42 (Pearson correlation coefficient 0.164, p=0.051). Those with Tau-C-levels in the 2nd quartile had a hazard ratio (HR) of 2.91 (95% CI 1.01 - 8.44, p=0.04) of progression compared to those in the 1st quartile. Those in the 3rd quartile was found to have a borderline significant (p=0.055) HR of 2.63 (95% CI 0.98 - 7.05) when compared to those in the lowest quartile. CONCLUSIONS: Tau-A and the ratio between Tau-A and Tau-C showed significant differences between groups and were correlated to CSF-AB42. Tau-C values in the middle range were associated with faster progression from MCI to dementia. This pilot study adds to the mounting data suggesting serum-measured Tau-A and Tau-C as biomarkers useful in relation to diagnosis and progression rate in AD but need further validation.

Does Alzheimer's disease with early onset progress faster than with late onset? A case-control study of clinical progression and cerebrospinal fluid biomarkers.

BACKGROUND: Early-onset Alzheimer's disease (EOAD) is generally thought to have a more rapid course compared to late-onset Alzheimer's disease (LOAD). The faster progression of EOAD observed in some studies has also been thought to correlate with cerebrospinal fluid (CSF) biomarkers. Our clinical experience has not been suggestive of any difference in disease progression; therefore, we decided to investigate whether differences in clinical progression and CSF biomarkers between EOAD and LOAD could be demonstrated. METHODS: Case-control study with 42 patients, 21 EOAD and 21 matched LOAD patients. Rates of progression were calculated and these, as well as CSF biomarker levels, were statistically compared. RESULTS: There were no statistically significant differences in clinical progression between the EOAD group and the LOAD group. There was no significant difference in the absolute values of CSF biomarkers, but a tendency towards lower levels of ß-amyloid in patients with EOAD was observed. CONCLUSIONS: Our findings did not converge with results from the majority of previous studies, which have been suggestive of a faster clinical progression in EOAD. Possibly, the very strict algorithm by which our patients were matched explains our findings. However, the findings should be repeated in a larger study population.

Idiopathic normal-pressure hydrocephalus: clinical comorbidity correlated with cerebral biopsy findings and outcome of cerebrospinal fluid shunting.

OBJECTIVES: To elucidate the importance of clinically diagnosed cerebral comorbidity in idiopathic normal-pressure hydrocephalus (INPH) and its effect on improvement after shunt surgery as well as concordance with parenchymal pathological changes described in frontal cerebral biopsy specimens. METHODS: In 28 consecutive patients diagnosed with INPH and shunted according to clinical, radiological and cerebrospinal fluid dynamic criteria, concomitant disorders were carefully registered, with special emphasis on cerebrovascular disease (CVD) and possible Alzheimer's disease. During shunt surgery, a frontal cerebral biopsy specimen was obtained and subsequently analysed for pathological changes. RESULTS: One or several concurrent disorders were present in 89% of the patients, most often CVD (n = 17) and possible Alzheimer's disease (n = 12), of which eight patients presented both, diagnosed according to the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association. The shunt success rate was 33%. A clear tendency towards increasing prevalence of CVD or Alzheimer's disease was found in the subgroups with no improvement or clinical deterioration compared with the patients improving after shunt surgery. The presence of CVD tended towards an unfavourable shunt outcome. The pathological parenchymal changes reflected the clinical diagnoses of comorbidity, and were described in about half of the biopsy specimens, with Alzheimer's disease (n = 7) and vascular changes (n = 7) being the most common findings. However, no significant correlation was found with the clinical diagnoses of Alzheimer's disease and CVD. The presence of cerebral comorbidity, whether diagnosed clinically or by brain biopsy, did not preclude clinical improvement after shunt operation. CONCLUSIONS: A high prevalence of CVD and Alzheimer's disease was found in patients shunted for INPH, which was reflected, although less commonly, by similar neuropathological biopsy findings. No significant correlation was found between the presence of comorbidity and shunt outcome. The findings support the perception of INPH as a multiaetiological clinical entity, possibly overlapping pathophysiologically with CVD and Alzheimer's disease.

A gender difference in the association between APOE genotype and age-related cognitive decline.

OBJECTIVE: To determine whether the APOE epsilon4 allele is associated with age-related intellectual decline in a community-dwelling sample of Danes. METHODS: A sample of 189 subjects who did not have dementia was tested with the Wechsler Adult Intelligence Scale (WAIS) at the ages of 50 and 80 years. Of these subjects, 163 (84 women and 79 men) completed all WAIS subtests at both assessments and 139 completed the digit symbol and block design subtests at the ages of 50, 60, 70, and 80 years. RESULTS: Cognitive decline from the age of 50 to the age of 80 years was substantial and larger for the performance subtests than for the verbal subtests (the declines were 18.40 for the performance IQ and 8.39 for the verbal IQ). APOE genotype was unrelated to the observed WAIS results of the 80-year assessment, but there was a significant interaction between APOE genotype and sex for decline scores in the performance IQ and three performance subtests (digit symbol, block design, and object assembly). In women, 26 epsilon4 carriers showed larger decline than 58 noncarriers, whereas there was no significant relation between APOE genotype and cognitive decline in men. The association in women between APOE genotype and cognitive decline was significant only for decline in the decade from age 70 to age 80 years. The interaction between sex and APOE genotype remained significant when education was included as a covariate. CONCLUSION: The APOE epsilon4 allele is associated with normal age-related decline in cognitive functions in women only. This finding may be supportive of recent evidence suggesting sex differences in APOE-associated risk for AD. Thus, the sex difference in the risk of sporadic AD may partly be explained by a sex-specific impact of the APOE epsilon4 allele on age-related cognitive decline.

Epilepsy presenting as AD: neuroimaging, electroclinical features, and response to treatment.

Three patients with progressive memory impairment initially attributed to AD underwent serial neuropsychometry, MRI, and EEG. Registered serial MRI volumetric analysis showed no loss of whole or regional brain volume. EEG revealed temporal lobe spike activity and antiepileptic treatment was optimized. Memory functions improved with antiepileptic medication in all three patients. The demonstration of temporal lobe spike activity in patients with progressive memory impairment is an indication for a trial of antiepileptic medication.

Characterization of the dermal lesions induced by a purified protein from toxigenic Pasteurella multocida.

The dermonecrotic effect of purified Pasteurella multocida toxin (PMT) was studied sequentially in guinea pigs and rats. The skin reaction was initially an acute inflammatory reaction, with edema and emigration of neutrophils and a few eosinophils and diapedesis of some erythrocytes. Four hours after intracutaneous injection the vessels were congested and thrombocytes were focally attached to the endothelial wall. Twenty-four h after the injection the inflammatory reaction appeared more severe and venules and arterioles were thrombosed. Necrotic changes were seen in hair follicles and in striated muscle fibers. Crude extracts from P. multocida and Clostridium perfringens injected intracutaneously into guinea pigs induced skin lesions qualitatively similar to the lesions induced by the purified PMT, indicating that dermonecrotic bacterial toxins may share similar biochemical properties.

Single photon emission computed tomography and apolipoprotein E in Alzheimer's disease: impact of the epsilon4 allele on regional cerebral blood flow.

The aim of this study was to examine the impact of the apolipoprotein E (APOE) epsilon4 allele on semiquantitative regional cerebral blood flow (rCBF) in Alzheimer's disease. Single photon emission computed tomography technetium (SPECT) with (99m)Tc d,l-hexamethyl propylenamine oxine was used to determine rCBF in 41 consecutive patients (18 males/23 females) with probable Alzheimer's disease according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria (mean age 71.0 years; range 54-85). The mean Mini-Mental State Examination (MMSE) score was 20.4 (range 10-30). After normalization of CBF to mean blood flow in the cerebellum, values for rCBF in several cortical regions of interest, side-to-side asymmetry indices, and anterior-posterior ratios were calculated. Determination of the APOE genotype from blood samples was performed using restriction enzyme polymerase chain reaction technique. Multivariate regression analyses and the Wilcoxon rank-sum test for unpaired data (Mann-Whitney) were used for statistical analysis. The patients comprised 27APOE epsilon4-positive and 14APOE epsilon4-negative individuals. Five patients were APOE epsilon4 homozygotes. APOE epsilon4-positive patients had significantly reduced rCBF in the right frontal and left occipital lobes. On nonparametric analysis, the most prominent differences between epsilon4-negative and epsilon4-positive patients were demonstrated in subregions representing the frontal association cortex (Mann-Whitney, P < .01). Age-stratified analysis suggested that these findings could be demonstrated predominantly in the elderly patients. The results of this study suggest that the APOE genotype in itself may have an impact on the pattern of rCBF deficits in Alzheimer's disease. The more pronounced reduction of rCBF in frontal association cortex observed in elderly APOE epsilon4-positive patients might predict clinical progression.

The apolipoprotein E epsilon4-allele and antihypertensive treatment are associated with increased risk of cerebral MRI white matter hyperintensities.

OBJECTIVE: Apolipoprotein E-epsilon4 (APOE-epsilon4) is a potential risk factor for cerebral vascular disease. The aim of the present study was to examine the relative importance of APOE-epsilon4 and other relevant risk factors for the extent of cerebral white matter hyperintensity (WMH) in a community-based sample of elderly subjects. MATERIALS AND METHODS: From a cohort of 976 subjects born in 1914, APOE genotype was determined and MRI examinations were carried out in 75 subjects. WMH were rated using a standard semi-quantitative method. ANOVA and regression analyses were conducted to explore the relative importance of the potential risk factors. RESULTS: APOE genotype and antihypertensive treatment were significantly associated with severity of total WMH load (P < 0.05). CONCLUSIONS: The study confirmed the association between APOE-epsilon4 and WMH. Pharmaceutical treatment for arterial hypertension was also associated with the total burden of WMH in this study.

APOE epsilon variation in multiple sclerosis susceptibility and disease severity: some answers.

BACKGROUND: Previous studies have examined the role of APOE variation in multiple sclerosis (MS), but have lacked the statistical power to detect modest genetic influences on risk and disease severity. The meta- and pooled analyses presented here utilize the largest collection, to date, of MS cases, controls, and families genotyped for the APOE epsilon polymorphism. METHODS: Studies of MS and APOE were identified by searches of PubMed, Biosis, Web of Science, Cochrane Review, and Embase. When possible, authors were contacted for individual genotype data. Meta-analyses of MS case-control data and family-based analyses were performed to assess the association of APOE epsilon genotype with disease risk. Pooled analyses of MS cases were also performed to assess the influence of APOE epsilon genotype on disease severity. RESULTS: A total of 22 studies (3,299 MS cases and 2,532 controls) were available for meta-analysis. No effect of epsilon2 or epsilon4 status on MS risk was observed (summary OR 1.14, 95% CI 0.96-1.34 and OR 0.89, 95% CI 0.78-1.01). Results obtained from analyses of APOE genotypes in 1,279 MS families were also negative (p = 0.61). Finally, results from pooled analyses of 4,048 MS cases also argue strongly that APOE epsilon status does not distinguish a relapsing-remitting from primary progressive disease course, or influence disease severity, as measured by the Expanded Disability Status Scale and disease duration. CONCLUSION: Overall, these findings do not support a role for APOE in multiple sclerosis, and underscore the importance of using large sample sizes to detect modest genetic effects, particularly in studies of genotype-phenotype relationships.

Experimental studies on serum treatment and vaccination against Cl. perfringens type C infection in piglets.

Subcutaneous administration of serum to piglets just after birth resulted in serum titres of 9-18 I.U. beta-antitoxin per ml in the first three days of life. At the ages of 7, 14, and 28 days the titres had dropped to about 5-9, 2 and 1 I.U. per ml, respectively. Oral administration of the same dose of serum resulted in serum titres of about half of those found after s.c. administration. In infected herds a significant protective effect after both s.c. and oral administration of serum was found to be dependent on the time of treatment but independent of the route of administration. After vaccination a correlation was noted between the levels of beta-antitoxin in colostral whey and specific mortality in the litters. An initial beta-antitoxin concentration of about 10 I.U. per ml whey seems to be sufficient to secure effective prevention. By vaccination once during gestation the beta-antitoxin levels in colostral whey were all less than 10 I.U. per ml. Two vaccinations during gestation resulted in whey titres greater than 10 I.U. per ml in 12 of 20 dams. By revaccinating once only during the following gestation effective beta-antitoxin levels in colostral whey were secured regardless of whether the vaccination had been performed once or twice during the previous gestation : the mean was 87.4 I.U. beta-antitoxin per ml; three of 20 dams had titres less than 10 I.U. per ml whey. From mortality studies including 63 liters in three infected herds specific mortalities of 17.3% and 4.6% were found after one and two vaccinations respectively, as compared with 36.6% in the control group. After revaccination during the ensuing gestation the figures were 1.4%, 0.0% and 32.2% named in the same order. 2 ml serum given as soon as possible after birth or 5 ml vaccine injected twice during gestation followed by one revaccination during subsequent gestations effectively protect piglets against infection with Cl. perfringens type C.

Potentially reversible conditions in 1000 consecutive memory clinic patients.

OBJECTIVES: To investigate the prevalence and classification of potentially reversible conditions in a prospective memory clinic cohort of younger and elderly patients with cognitive symptoms. PATIENTS: 1000 consecutive patients referred during a period of 54 months to a university hospital multidisciplinary memory clinic based in neurology. METHODS: All patients were referred for diagnostic evaluation and treatment of cognitive symptoms. The multidisciplinary staff prospectively established a standardised consensus report for each patient based on the results of clinical and ancillary investigations with classification of cognitive profile, primary underlying cause, and concomitant conditions. RESULTS: The mean age of the patients was 66.1 years (range 17-98) and 43% met diagnostic criteria for dementia. A potentially reversible primary aetiology for cognitive symptoms was identified in 19% and a potentially reversible concomitant condition in 23% of all patients. In the subgroup of patients with dementia, 4% had a potentially reversible primary aetiology. Careful clinical examination, routine laboratory tests, and cranial computed tomography identified most of these conditions. CONCLUSIONS: Reversible conditions are most often encountered in patients with mild cognitive disturbances. Although treatment may not always result in full reversal of cognitive symptoms, potentially reversible conditions should be identified in the diagnostic evaluation of the patient.

Functional brain imaging with single-photon emission computed tomography in the diagnosis of Alzheimer's disease.

High-resolution single-photon emission computed tomography (SPECT) with brain-retained technetium-99m (99mTc)-labeled tracers may be used for 3-dimensional measurements of regional cerebral blood flow (rCBF). This article summarizes important findings in SPECT studies of Alzheimer's disease (AD). There are three distinct potential applications of SPECT in diagnosing AD: (a) as a diagnostic adjunct in patients with mild cognitive or behavioral symptoms, suggesting a possible dementia disorder; (b) as a diagnostic adjunct for demented patients in whom the history, physical examination, and laboratory studies are in agreement with a diagnosis of probable AD; and (c) for determining the relative contributions of degenerative and vascular pathology to the clinical picture in demented patients with mixed disease. A clinical diagnosis of probable AD is associated with focal perfusion deficits as measured by SPECT. Characteristically, hypoperfusion is observed in the frontal and temporoparietal association areas, whereas other brain regions are relatively spared. The changes are present in the early phases of AD. The topography of rCBF deficits displays a marked heterogeneity among patients and correlates with cognitive profiles. In patients with mild cognitive complaints, the presence of focal hypoperfusion on SPECT may increase the accuracy of the diagnosis by confirming the presence of brain disease. In patients with probable AD, the presence of temporoparietal rCBF deficits on SPECT increases the accuracy of the clinical diagnosis, in particular when associated with medial temporal lobe atrophy on cranial X-ray computed tomography (CT). The role of SPECT in diagnosing patients with mixed disease remains to be clarified.

Morphological heterogeneity among spirochetes isolated from cases of swine dysentery.

Pathogenic and non-pathogenic spirochetes isolated from the intestines of pigs were examined by electron microscopy using the negative staining and ultrathin sectioning techniques. Morphological differences were observed among cells of different strains. The cells differed in length as well as in width and in the number of flagella inserted at each end. In addition, the cells from different strains also varied in their resistance to the action of the detergents, Teepol and sodium deoxycholate. Three of the strains studied contained weakly haemolytic spirochetes, two of which differed markedly in their morphology from the cells of the other strains. These spirochetes had fewer flagella inserted at each end than those from other isolates and showed a distinct lattice-like substructure covering the ends of the cells. The spirochetes examined were found to be morphologically more similar to those of the genus Borrelia than to those of the genus Treponema but were clearly different from the cells of both of these genera. The taxonomic implications of the observations are discussed in brief.

White matter magnetic resonance hyperintensities in dementia of the Alzheimer type: morphological and regional cerebral blood flow correlates.

In a prospective MRI study the presence, appearance, volume, and regional cerebral blood flow (rCBF) correlates of periventricular hyperintensities (PVHs) and deep white matter hyperintensities (DWMHs) were examined in 18 patients with probable Alzheimer's disease and in 10 age matched healthy control subjects, all without major cerbrovascular risk factors. The 133Xe inhalation method and the [99mTc]-d,l-hexamethyl-propylene-amine-oxime (HMPAO) technique with single photon emission computed tomography (SPECT) were used to measure rCBF. Rating scores for PVHs were significantly higher in the Alzheimer's disease group (p < 0.01) and correlated significantly with the volume of ventricles (p < 0.05) and with systolic arterial blood pressure (p < 0.01), but not with rCBF. By contrast, there was no significant difference in the rating scores or volumes of DWMHs between the two groups, although three patients had extensive DWMH lesions in the central white matter. In the group of patients with Alzheimer's disease as a whole, the volume of DWMHs correlated well with rCBF in the hippocampal region ( r = -0.72; p < 0.001), but not with frontal, temporal, parietal, or occipital rCBF. Postmortem histopathology of extensive DWMH lesions in one patient with definite Alzheimer's disease showed a partial loss of myelin and astrocytic gliosis, but no ischaemic changes. It is concluded that DWMH lesions may be associated with reduced rCBF in the hippocampal region. The heterogenous topography of neocortical rCBF deficits in Alzheimer's disease could not be explained by deafferentation from underlying white matter hyperintensities and therefore may reflect variations in the topography of cortical abnormalities.