Ruth Dukoff

Longitudinal stability of CSF tau levels in Alzheimer patients

BACKGROUND Antemortem levels of tau in the cerebrospinal fluid (CSF) of Alzheimers disease (AD) patients have repeatedly been demonstrated to be elevated when compared to controls. Although CSF tau has been reported to be elevated even in very mild AD, it is unknown how tau levels change during the course of the disease. METHODS We have followed 29 mild-to-moderately affected AD subjects over 2 years with repeated CSF taps. Clinical measures of dementia severity (Clinical Dementia Rating Scale, Global Deterioration Scale and Mini-Mental Status Examination) were obtained at the start and conclusion of the observation period, and CSF tau was measured with a standard enzyme-linked immunoabsorbent assay (ELISA) using two monoclonal antibodies. RESULTS Despite significant changes in the clinical measures consistent with progression of the disease, no significant overall change in CSF tau levels (548 +/- 355 vs. 557 +/- 275 pg/mL, NS) was observed. None of the clinical variables was significantly correlated with either baseline measures of CSF tau or delta CSF tau (last-first). Similarly, CSF tau at baseline and changes over time were not significantly related to Apolipoprotein E (APO E) phenotype. CONCLUSIONS These data suggest that CSF tau levels are stable over extended periods of time in a group of mild-to-moderately demented AD subjects and that CSF tau levels do not predict the severity or rate of progression of AD, at least not during the middle stages of the illness.

Discriminant power of combined cerebrospinal fluid τ protein and of the soluble interleukin-6 receptor complex in the diagnosis of Alzheimer's disease

Alzheimers disease (AD) still can only be definitively diagnosed with certainty by examination of brain tissue. There is a great need for a noninvasive, sensitive and specific in vivo test for AD. We combined cerebrospinal fluid analyses of tau protein (levels were significantly increased in AD patients [p=0.0001]), a putative marker of neuronal degeneration, with components of the soluble interleukin-6 receptor complex (sIL-6RC: IL-6, soluble IL-6 receptor and soluble gp130), putative markers of neuroregulatory and inflammatory processes in the brain. A stepwise multivariate discriminant analysis revealed that tau protein and soluble gp130 (levels were significantly reduced in AD subjects [p=0.007]), the affinity converting and signal-transducing receptor of neuropoietic cytokines, maximized separation between the investigated groups. The discriminant function predicted 23 of 25 clinically diagnosed AD patients (sensitivity 92%) with mild to moderate dementia correctly as having AD. Furthermore, 17 of 19 physically and cognitively healthy age-matched control subjects (specificity 90%) were accurately distinguished by this test. Later predicting with the jackknife procedure each case in turn through the remaining patient group, the discriminant function remained stable. Our data suggest that multivariate discriminant analysis of combined CSF tau protein and sIL-6RC components may add more certainty to the diagnosis of AD, however, the method will need to be extended to an independent group of patients, comparisons and control subjects to assess the true applicability.

Interleukin-6 is not altered in cerebrospinal fluid of first-degree relatives and patients with Alzheimer's disease

We investigated interleukin-6 (IL-6) levels in cerebrospinal fluid (CSF) of 25 patients with clinically diagnosed sporadic Alzheimers disease (AD) and 19 healthy control subjects (HC). For comparison 19 clinically healthy subjects with at least one first-degree relative with clinical or autopsy confirmed AD (CF/AD) were examined. CSF levels of IL-6 did not show statistically significant differences between AD patients, CF/AD and HC subjects. There was no correlation between age, gender, age of onset, degree of cognitive impairment, blood-brain barrier dysfunction and IL-6 values. We could not demonstrate altered CSF concentrations of IL-6 that may indicate an inflammatory response or capability to support neuronal survival in the central nervous system (CNS) of first-degree relatives and patients with AD. We suggest that combined measurement of all parameters of the IL-6-receptor complex could yield more insight in a probably altered IL-6 function.

Interleukin-6 and the soluble IL-6 receptor are decreased in cerebrospinal fluid of geriatric patients with major depression: no alteration of soluble gp130.

Interleukin-6 (IL-6) is hypothesized to play an important role in the interaction between immune mechanisms and the central nervous system. We investigated whether cerebrospinal fluid (CSF) concentrations of interleukin-6 (IL-6), the soluble IL-6 receptor (sIL-6R) and the soluble form of the signal transducing and affinity converting receptor gp130 (sgp130) are altered in geriatric patients with major depression (MD). In 20 geriatric patients with MD and 20 age-matched healthy control subjects CSF concentrations of the three components of the sIL-6R complex were analyzed by enzyme-linked immunosorbent assays (ELISA). All patients except one were treated with psychotropic drugs. We found statistically significant decreased CSF concentrations of IL-6 (P<0.001) and of the sIL-6R (P<0.001) of patients with MD. Levels of sgp130 showed no statistically significant difference between patients and controls.

Decreased soluble interleukin-6 receptor in cerebrospinal fluid of patients with Alzheimer's disease.

The function of the cytokine interleukin-6 (IL-6) is augmented by soluble IL-6 receptors (sIL-6R). We investigated cerebrospinal fluid sIL-6R concentrations in patients with Alzheimers disease (AD) compared to age-matched healthy subjects and individuals with at least one first degree relative with AD. We found a statistically significant decrease in sIL-6R levels in the AD group compared to controls. Complete analysis of the IL-6R complex seems crucial to better understand the impact of IL-6 in AD pathophysiology.

Acetylcholine affects the spatial scale of attention: evidence from Alzheimer's disease.

Location precues were used to manipulate the spatial scale of attention in visual search for a target in an array of letters in patients with dementia of the Alzheimer type (DAT) and in age-matched older controls. Cue size varied in the amount of spatial precision conferred. Scopolamine, a muscarinic antagonist, decreased overall arousal and broadened spatial attention after a precise precue (small and valid) to target location for DAT patients but not for controls, suggesting a selective effect for attentional impairment induced by cholinergic blockade. In contrast, physostigmine, a cholinesterase inhibitor, did not alter the distribution of spatial attention relative to no-drug baseline testing for patients. Results support a differential role for cholinergic mechanisms in the modulation of the spatial scale of visual attention.

Diagnosis and Treatment of Geriatric Depression

SummaryGeriatric depression is a common psychiatric illness affecting as many as one-third of the older population. With the growing number of elderly in many countries of the world, the morbidity and mortality associated with untreated and partially treated depression is of great concern from both a medical and economic perspective.Depression in the elderly often presents with more somatic or anxious features and less of the subjective sadness expressed by younger groups. In addition, in the elderly, depressive-spectrum disorders (which include minor depression, dysthymia, mixed anxiety/depression, bereavement-related depression and even suicidal ideation) are generally under-recognised and undertreated by health professionals.The clinical mismatch between high prevalence but undertreatment stems from patient and physician attitudes toward depression as a ‘normal’ response to aging and loss, diagnostically confusing medical illness-related symptomatology, and noncompliance with prescribed treatment. Furthermore, late-onset depression may hold special prognostic value in the elderly, with the relationship between late-onset depression and cerebrovascular events and progressive dementing illness being particularly strong.Therapeutically, there has been a recent expansion in the pharmacological tools that can be used to treat depression. A variety of new agents are now available that have adverse effect, pharmacodynamic and target-receptor profiles that differ from the older agents. For example, newer drugs that block the serotonin (5-hydroxytryptamine; 5-HT) transporter have supplanted older agents that cause more frequent and toxic adverse effects. These newer agents have also focused attention on the impact of polypharmacy on the hepatic cytochrome P450 system, which is responsible for drug metabolism and elimination. Electroconvulsive therapy and psychotherapy remain effective nonpharmacological treatments for geriatric depression.Generally, the opportunities for therapeutic intervention in geriatric depression suggest that greater diagnostic attention and more widespread application of treatments for this increasingly prevalent disorder continue to be needed.

Apolipoprotein E ?4 allele in association with global cognitive performance and CSF markers in Alzheimer's disease

To better define the influence of apolipoprotein E (ApoE) ϵ4 genotype on the cognitive and biochemical features of Alzheimers disease (AD), cross‐sectional analysis of global cognitive measures and cerebrospinal fluid studies gathered on AD subjects at a tertiary care facility between 1986 and 1997 was carried out. The 112 AD patients examined included 62 women and 50 men with a mean (SD) age of 64·2 (9·2) years. Patient demographics, illness onset age and duration, education level and global cognitive measures were recorded systematically. Genetic analysis for ApoE allele type and biochemical characterization of CSF, including total tau concentration, was performed. Descriptive statistics of demographics, cognitive and CSF measures were performed by chi‐square, ANOVA and Tukeys tests. Overrepresentation of the ϵ4 allele was found, with 45·5% of AD patients heterozygous and 20·5% homozygous for ApoE ϵ4. Overall, ApoE ϵ4 status had no effect on mean onset age of AD (F=1·56; p=0·214), but an earlier mean onset age of AD (F=4·10; p=0·02) was seen in the late‐onset subjects. No differences were found with regard to ApoE ϵ4 status and measures of disease, duration of illness or global cognitive performance. Although CSF tau was elevated in our sample (575·4±290·3 pg/ml), ApoE ϵ4 status did not influence total CSF tau or neurotransmitter metabolite levels. ApoE ϵ4 genotype had no impact on a variety of illness severity, cognitive and CSF examinations in the largest cross‐sectional analysis of AD subjects yet reported. Copyright

Quantitative assessment of apolipoprotein E genotypes by image analysis of PCR-RFLP fragments.

Apolipoprotein E (APOE) genotyping usually involves polymerase chain reaction (PCR) and assessment of restriction fragment length polymorphism (RFLP) by gel electrophoresis. We made determination of HhaI restriction endonuclease digestive patterns more objective and improved diagnostic accuracy with a quantitative approach using sensitive DNA stain (SYBR Green) and image analysis of gel patterns. For distinguishing true and partially-digested restriction fragments, band ratios were calculated for the staining intensity of gel patterns from 116 sample runs of 63 human blood specimens. Each of these specimens was independently genotyped for APOE by at least two (and most of them by three) different PCR-RFLP methods. Based on the distribution of band ratios, decision levels were established and used for developing a program for computer-aided interpretation of APOE genotypes (Microsoft Excel software). Appropriateness of the decision levels for band ratios was validated by APOE genotyping of additional 61 specimens. The approach described here is applicable to a variety of other molecular diagnostic techniques that are based on PCR-RFLP or sequence-specific signal amplifications.

Penetration of tacrine into cerebrospinal fluid in patients with Alzheimer's disease.

Tacrine is widely used for the treatment of Alzheimers disease, but data are limited regarding cerebrospinal fluid (CSF) concentrations at steady state. To evaluate CSF penetration, seven patients with Alzheimers disease who were receiving tacrine at doses of 40 to 140 mg/day as a part of a double-blind trial were studied. After 6 weeks of tacrine therapy, concomitant plasma and CSF samples were collected 30 minutes after the morning dose of tacrine. Although this time point is before the peak oral absorption in most patients, the critical issue for this study is that the plasma and CSF samples were collected concomitantly so that a percentage of tacrine penetration could be derived. The morning dose of tacrine ranged from 10 to 40 mg, which was given in the fasting state. Mean (+/-SD) plasma levels of tacrine were 8.01+/-7.07 ng/mL, whereas mean (+/-SD) CSF levels of tacrine were 5.21+/-6.00 ng/mL. The mean (+/-SD) ratio of CSF to plasma tacrine concentration was 0.50+/-0.45, with wide interindividual variability. No relationship between dose and percentage of penetration was observed. Plasma concentrations ranged from 0.99 to 22.6 ng/mL and were unrelated to dose, suggesting erratic oral absorption and/or rapid metabolism. CSF concentrations ranged from not detectable to 15.92 ng/mL. The authors support that penetration of tacrine into CSF is highly variable in patients with Alzheimers disease and that disparity in tacrine concentrations at the site of action may be one reason for conflicting results from studies of the efficacy of tacrine in Alzheimers disease.