Serena Mosti

Predictors of progression of cognitive decline in Alzheimer’s disease: the role of vascular and sociodemographic factors

Rates of disease progression differ among patients with Alzheimer’s disease, but little is known about prognostic predictors. The aim of the study was to assess whether sociodemographic factors, disease severity and duration, and vascular factors are prognostic predictors of cognitive decline in Alzheimer’s disease progression. We conducted a longitudinal clinical study in a specialized clinical unit for the diagnosis and treatment of dementia in Rome, Italy. A total of 154 persons with mild to moderate Alzheimer’s disease consecutively admitted to the dementia unit were included. All patients underwent extensive clinical examination by a physician at admittance and all follow-ups. We evaluated the time-dependent probability of a worsening in cognitive performance corresponding to a 5-point decrease in Mini-Mental State Examination (MMSE) score. Survival analysis was used to analyze risk of faster disease progression in relation to age, education, severity and duration of the disease, family history of dementia, hypertension, hypercholesterolemia, and type 2 diabetes. Younger and more educated persons were more likely to have faster Alzheimer’s disease progression. Vascular factors such as hypertension and hypercholesterolemia were not found to be significantly associated with disease progression. However, patients with diabetes had a 65% reduced risk of fast cognitive decline compared to Alzheimer patients without diabetes. Sociodemographic factors and diabetes predict disease progression in Alzheimer’s disease. Our findings suggest a slower disease progression in Alzheimer’s patients with diabetes. If confirmed, this result will contribute new insights into Alzheimer’s disease pathogenesis and lead to relevant suggestions for disease treatment.

Neuropsychological Predictors of Rapidly Progressing Patients with Alzheimer’s Disease

Background: Alzheimer disease (AD) has heterogeneous clinical manifestations. Different neuropsychological profiles in AD patients might be indicative of the diffusion of the pathological process and might be associated with differences in rates of disease progression. Methods: We studied 154 newly diagnosed AD patients (65.6% women; mean age: 73 years). Performance in memory, executive functions, praxis and language domains was categorized into mild, moderate and severe impairment. The time-dependent probability of losing 5 points on the Mini-Mental State Examination (MMSE) over 2 years was considered as disease progression and evaluated by survival analysis. Results: One fourth of the patients decreased by ≧5 MMSE points over the 2-year follow-up. Rapid disease progression was more frequent in more educated patients and in those with moderate severity of global cognitive impairment. In univariate analysis, more severe memory and executive functioning impairment were associated with higher probabilities of progression. The association with memory was explained by differences in executive function impairment that remained statistically significant in multivariate analyses. Conclusions: Patients with more severe executive functioning impairment have a worse prognosis over 2 years. This might be due to involvement of the prefrontal cortex by the pathological process of AD in patients with severe executive deficits.

Dysregulated NF-κB pathway in peripheral mononuclear cells of Alzheimer's disease patients.

Diagnosis and therapeutic strategies in Alzheimers disease (AD) might greatly benefit of the present multidisciplinary approach for studying the molecular pathogenesis of the disorder. Gene expression profile at peripheral level could be a promising tool for pathogenic studies as well as for early diagnosis of AD. A dysregulated inflammatory response, as well as other systemic disorders, have been described in AD. Therefore, we investigated the expression, at peripheral level, of a number of genes involved in the inflammatory, oxidative stress and proliferative response of a well defined, small cohort of sporadic AD patients. Firstly, the mRNA expression of inflammatory, stress and proliferation/ differentiation genes were evaluated, using SuperArray, in mitogen-stimulated peripheral blood mononuclear cells (PBMC) from a group of 12 well-characterized, sporadic AD patients with various levels of dementia, by comparison with aged-matched controls. Real-time RT-PCR confirmed the trend of alteration in 16 genes out of the 36 supposed to be dysregulated in AD patients, by the preliminary screening. The expression level of the NFKB1(p105/50Kd) gene was significantly higher in AD with respect to adult age-matched controls (AA) and was related to the Mini-Mental State Examination (MMSE) score of the same patients. In addition, the expression of various NF-κB target genes and of both NF-κBp50 and NF-κBp65 DNA-binding activity were increased in PBMC from AD patients in comparison with those from AA. Our results suggest that NF-κB activation at peripheral blood cell level could be a potential new hallmark of AD progression and sustain a rationale to more deeply investigate the therapeutic potential of specific NF-κB inhibitors in AD.

Color discrimination performance in patients with Alzheimer's disease.

Background/Aims: Visual deficits are frequent in Alzheimer’s disease (AD), yet little is known about the nature of these disturbances. The aim of the present study was to investigate color discrimination in patients with AD to determine whether impairment of this visual function is a cognitive or perceptive/sensory disturbance. Methods: A cross-sectional clinical study was conducted in a specialized dementia unit on 20 patients with mild/moderate AD and 21 age-matched normal controls. Color discrimination was measured by the Farnsworth-Munsell 100 hue test. Cognitive functioning was measured with the Mini-Mental State Examination (MMSE) and a comprehensive battery of neuropsychological tests. The scores obtained on the color discrimination test were compared between AD patients and controls adjusting for global and domain-specific cognitive performance. Results: Color discrimination performance was inversely related to MMSE score. AD patients had a higher number of errors in color discrimination than controls (mean ± SD total error score: 442.4 ± 84.5 vs. 304.1 ± 45.9). This trend persisted even after adjustment for MMSE score and cognitive performance on specific cognitive domains. Conclusions: A specific reduction of color discrimination capacity is present in AD patients. This deficit does not solely depend upon cognitive impairment, and involvement of the primary visual cortex and/or retinal ganglionar cells may be contributory.

Discordant effect of IFN-β1a therapy on anti-IFN antibodies and thyroid disease development in patients with multiple sclerosis

Interferon-beta1b (IFN-beta1b) therapy is associated with a relatively high risk of developing thyroid disease. IFN-beta1a is regarded as less immunogenic than IFN-beta1b because of its structural homology to natural IFN-beta. We assessed the effect of 1 year of IFN-beta1a treatment on thyroid function and autoimmunity in 14 multiple sclerosis (MS) patients. The results were compared with those obtained in a series of 31 MS patients treated with IFN-beta1b. The prevalence of positive binding antibody (BAb) titer and neutralizing (NAb) anti-IFN antibody titer in the two groups was also assessed. The BAb and NAb positivity rate in IFN-beta1a-treated patients was significantly lower than in the group submitted to IFN-beta1b therapy (7% vs. 84% and 0% vs. 30%, respectively). Although the incidence of thyroid dysfunction was slightly higher in IFN-beta1b-treated patients than in those undergoing IFN-beta1a treatment (33% vs. 23%, respectively), it did not reach statistical significance. Thyroid disease was unrelated to the presence of positive serum BAb or NAb titer in both the group undergoing IFN-beta1a therapy and in that treated with IFN-beta1b. In both groups, thyroid disease developed mostly in women (71%) against a background of preexisting thyroiditis and a diffuse hypoechoic ultrasound thyroid pattern (80%). IFN-beta1a treatment was associated with a significantly lower prevalence of both BAb and NAb-positive titers than was IFN-beta1b. Conversely, thyroid disease was similar and unrelated to the presence of positive anti-IFN-beta antibody titer. Therefore, routine thyroid assessment may be advised during IFN-beta1a treatment, especially in patients with preexisting thyroiditis.

Increased T-lymphocyte interleukin-6 binding in patients with multiple sclerosis.

Multiple sclerosis (MS) represents a T‐cell‐mediated autoimmune demyelinating disease of the central nervous system associated with altered immunoregulation. Interleukin (IL)‐6 is a cytokine that has several effects on the neuroimmune system. Specific IL‐6 receptors have been found in human lymphocytes and neuroglial cells. The aim of the present study was to assay IL‐6 binding on peripheral blood T lymphocytes in MS patients. We found that T cells from MS patients had significantly more IL‐6 receptors [Bmax: 279 ± 7 vs. 246 ± 8 (mean ± SEM) receptors/cell, in patients and controls, respectively], whereas Kd values were similar to those of healthy subjects [26.8 ± 0.7 vs. 25.4 ± 0.6 (mean ± SEM) pM, in patients and controls, respectively]. Significant (P < 0.05) differences in IL‐6 binding values were observed between stable patients and those relapsing (272 ± 9 vs. 300 ± 12 (mean ± SEM) receptors/cell, respectively). We found significantly (P < 0.001) higher amounts of IL‐6 receptors on CD4+ T cells from MS patients than on CD4+ lymphocytes from controls (434 ± 11 vs. 363 ± 9 (mean ± SEM) receptors/cell, respectively); CD8+ T cells showed very few IL‐6 receptors in both patients and controls. These data are discussed in terms of MS immune pathogenesis and pathophysiology, because T‐cell activation seems to be linked to increased IL‐6 binding. The upregulated IL‐6 system might be involved in antibody‐mediated demyelinating pathways, because IL‐6 is well known to enhance humoral immune response.

T‐cell interleukin‐6 receptor binding in interferon‐β‐1b‐treated multiple sclerosis patients

Multiple sclerosis (MS) is a T‐cell‐mediated autoimmune demyelinating disease of the central nervous system, associated with an altered cytokine network. We previously assayed peripheral blood T‐lymphocyte binding for two prototypic cytokines, tumour necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6), and found that T cells from MS patients had significantly more TNF‐α and IL‐6 receptors than those from healthy controls. In the present work, paralleling a previous one on T‐cell TNF‐α binding, we studied the effect of interferon (IFN)‐β‐1b treatment on T‐lymphocyte IL‐6 binding in patients with relapsing–remitting MS. T cells from MS patients had significantly (P < 0.001) higher amounts of IL‐6 receptors than those from controls [292 ± 6 vs. 228 ± 8 (mean ± SEM) receptors per cell, respectively], whereas the ligand‐receptor affinity values were similar in the two groups [26.2 ± 0.7 and 25.7 ± 0.4 (mean ± SEM) pmoles/l, respectively]. After a 3‐month IFN‐β‐1b treatment, they showed a significant decrease in IL‐6 binding [266 ± 7 (mean ± SEM) receptors per cell]. After 6 and 9 months, T‐cell IL‐6 Bmax values were even lower [258 ± 8 and 251 ± 8 (mean ± SEM) receptors per cell]. Since an increased IL‐6 binding might be linked to a lymphocyte activation, our data give further support for an enhanced immune response in patients with MS. Our data seem to demonstrate that the major effects of IFN‐β‐1b treatment result in a decrease of T‐cell activation.