Sergio Cammarata

Balance features in Alzheimer's disease and amnestic mild cognitive impairment.

We evaluated alterations of balance by stabilometry in patients with amnestic mild cognitive impairment (aMCI) and with mild-moderate Alzheimers disease (AD). Fifteen patients with aMCI and 15 with mild AD were recruited according to the current diagnostic criteria. Fifteen healthy subjects of the same age range were recruited as controls. Stabilometry was carried out using a commercial 4 load cell platform. Statistical analysis of between group differences was performed using one-way analysis of variance for parametric data and Kruskal-Wallis tests for non-parametric data. Spearman correlation coefficients were used to investigate the association between cognitive test scores and stabilometric data. All stabilometry measures were significantly altered in mild AD patients compared to normal controls. Antero-posterior sway was found to be the most sensitive parameter, since it correlated with the ADAS-cog orientation subscale in AD patients, and also discriminated between aMCI and normal controls. Our study shows that impairment in balance is a feature not only of AD, but also of aMCI. The alterations found suggest that a progressive failure of the vestibular system, possibly linked to reduced hippocampal performance, may be responsible for such a feature. Further research must be focused on studying the predictive value of stabilometry in the conversion of aMCI.

Ubiquitin-reactive neurites in cerebral cortex of subjects with Huntington's chorea: a pathological correlate of dementia?

We studied the prevalence of ubiquitin-reactive dystrophic neurites in neocortex of cases with Huntingtons disease (HD), with a history of dementia lasting from 5 to 8 years before death, and in four age-matched controls. The ubiquitin-reactive neurites, identified as round structures localized outside neuronal and glial cells, were quantified in six microscopic fields of cingulate, 2nd temporal and 2nd parietal cortical gyri. The number of ubiquitin-reactive neurites in HD was 12 to 16 times that of controls in the three cortical areas examined. The finding indicates that in HD neocortex there is a severe degeneration of neuronal processes and suggests that it may represent a pathological correlate of dementia.

Formic acid treatment exposes hidden neurofilament and tau epitopes in abnormal cytoskeletal filaments from patients with progressive supranuclear palsy and Alzheimer's disease.

In cases of progressive supranuclear palsy (PSP) and Alzheimers disease (AD) the treatment of tissue sections with formic acid (FA) disclosed a neurofilament epitope in subcortical straight (SF) and paired helical (PHF) filaments. The same treatment produced a two-fold increase of tau-reactive neuropil threads and plaque-related neurites in AD cortical tissue. These findings indicate that epitopes of cytoskeletal proteins are hidden by the beta-pleated conformation of SF and PHF components. FA treatment should be used in immunohistochemical detection of intraneuronal abnormal cytoskeletal filaments.

Elevation of β-Amyloid 1-42 Autoantibodies in the Blood of Amnestic Patients With Mild Cognitive Impairment

OBJECTIVE To develop a blood-based test for screening populations at risk for Alzheimer disease. DESIGN Case-control study. Subjects A total of 180 patients with mild cognitive impairment (MCI) and 105 age-matched, cognitively normal controls. INTERVENTIONS The titer of beta-amyloid 1-42 autoantibodies in the plasma was obtained at the time of diagnosis and evaluated by enzyme-linked immunosorbent assay before and after dissociation of the antigen-antibody complexes. A total of 107 patients with MCI were followed up for 36 months; 70 of the 107 cases progressed to Alzheimer disease. RESULTS The average level of beta-amyloid 1-42 plasma autoantibodies in patients with MCI that progressed to Alzheimer disease, but not that of the stable cases, was significantly higher than in cognitively normal controls (P < .001). CONCLUSIONS The results suggest that the plasma beta-amyloid 1-42 autoantibodies parallel beta-amyloid 42 deposition in the brain, which is known to precede by several years the clinical onset of Alzheimer disease. The evaluation of beta-amyloid 1-42 autoantibodies after dissociation of the complexes is a simple and inexpensive method that can be used to predict the occurrence of Alzheimer disease.

Amyloid-β42 plasma levels are elevated in amnestic mild cognitive impairment

Amnestic mild cognitive impairment (aMCI) is considered a prodromal stage of Alzheimers disease (AD). We measured plasma levels of amyloid-beta40 (Abeta40) and Abeta42 in 191 subjects with aMCI. Seventy-nine of them were clinically followed for two years. In the total cohort of aMCI cases, the average level of Abeta42, as well as the Abeta42/Abeta40 ratio, was significantly higher than those of the 102 cognitively normal age-matched subjects. The aMCI cases that converted to probable AD within 2 years had higher levels of Abeta42 and, to a lesser extent, Abeta40 than the stable cases. However the large variability of measured values indicates that plasma Abeta is not a suitable marker of incipient AD.

β-Amyloid 1-42 induces physiological transcriptional regulation of BACE1

J. Neurochem. (2012) 122, 1023–1031.

The H1 haplotype of the tau gene (MAPT) is associated with mild cognitive impairment.

Mild cognitive impairment is often considered a transitional condition prodromal to Alzheimers disease. The dissection of genetic risk factors predisposing to mild cognitive impairment is paramount to assess the individual predisposition and reliably evaluate the effectiveness of early therapeutic interventions. We designed a cross-sectional analysis to test whether the occurrence of mild cognitive impairment is influenced by variations of the tau protein gene. The genotypes of seven polymorphisms tagging the major tau haplotypes were assayed on 186 patients with amnestic mild cognitive impairment and 191 unrelated controls. Association study was conducted by logistic regression including APOE genotype and age as covariates. Case-control analysis showed that the common H1 haplotype is significantly overrepresented in patients (OR, 95% CI: 2.31, 1.52-3.51; p<0.001), whereas did not provide positive signals for any of the H1 sub-haplotypes that had been described as associated with Alzheimer inverted exclamation mark s disease. This finding was confirmed when the epsilon4 allele of the APOE gene was taken into account (OR, 95% CI: 2.319, 1.492-3.603; p<0.001). These results firstly suggest that the risk of mild cognitive impairment is influenced by tau protein gene variations and that mild cognitive impairment shares a common genetic background with Alzheimers disease. They may help elucidating the genetic risk to cognitive decline and designing effective clinical trials.

Artificial Neural Networks Identify the Predictive Values of Risk Factors on the Conversion of Amnestic Mild Cognitive Impairment

The search for markers that are able to predict the conversion of amnestic mild cognitive impairment (aMCI) to Alzheimers disease (AD) is crucial for early mechanistic therapies. Using artificial neural networks (ANNs), 22 variables that are known risk factors of AD were analyzed in 80 patients with aMCI, for a period spanning at least 2 years. The cases were chosen from 195 aMCI subjects recruited by four Italian Alzheimers disease units. The parameters of glucose metabolism disorder, female gender, and apolipoprotein E epsilon3/epsilon4 genotype were found to be the biological variables with high relevance for predicting the conversion of aMCI. The scores of attention and short term memory tests also were predictors. Surprisingly, the plasma concentration of amyloid-beta (42) had a low predictive value. The results support the utility of ANN analysis as a new tool in the interpretation of data from heterogeneous and distinct sources.

Plasma levels of insulin and amyloid β42 are correlated in patients with amnestic Mild Cognitive Impairment

Epidemiological and experimental data suggest that type 2 diabetes (DM2) and sporadic late-onset Alzheimers disease (AD) share a common mechanism, that is able to produce accumulation of insulin and amyloid beta 42 (Abeta42), the major pathogenic events respectively of the two conditions. In 71 non diabetic patients with amnestic mild cognitive impairment we found a significant linear correlation between fasting plasma levels of insulin and Abeta42 (R = +0.25, P < 0.05). The levels of both peptides were elevated in comparison to 48 age-matched cognitively normal controls. The correlation of insulin and Abeta42 plasma levels suggests a pathogenic link between DM2 and sporadic AD.

Ubiquitin-reactive axons have a widespread distribution and are unrelated to prion protein plaques in Creutzfeldt-Jakob disease

The amyloid plaques of Alzheimer disease (AD) are surrounded by dystrophic axons that contain ubiquitinated dense bodies. To investigate whether deposits of other types of amyloid cause axonal degeneration we studied 5 cases of Creutzfeldt-Jakob disease (CJD) with immunocytochemical methods using ubiquitin and prion protein (PrP) antisera. One of these cases contained PrP plaques in the cerebellum. In all cases dystrophic axons, which contain ubiquitinated dense bodies, were observed in neocortical and cerebellar grey matter, in absence of PrP-reactive amyloid deposits. Only a minority of PrP plaques present in the cerebellum was associated with ubiquitin positive neurites. The results indicate that, unlike in AD, the occurrence of ubiquitinated dystrophic axons is independent from amyloid deposition in CJD and is likely to be a primary phenomenon.