Isolated, Subtle Neurological Abnormalities in Mild Cognitive Impairment Types.

BACKGROUND: Isolated, subtle neurological abnormalities (ISNA) are commonly seen in aging and have been related to cerebral small vessel disease (SVD) and subcortical atrophy in neurologically and cognitively healthy aging subjects. OBJECTIVE: To investigate the frequency of ISNA in different mild cognitive impairment (MCI) types and to evaluate for each MCI type, the cross-sectional relation between ISNA and white matter hyperintensities (WMH), lacunes, caudate atrophy, and ventricular enlargement. METHODS: One thousand two hundred fifty subjects with different MCI types were included in the analysis and underwent brain magnetic resonance imaging. WMHs were assessed through two visual rating scales. Lacunes were also rated. Atrophy of the caudate nuclei and ventricular enlargement were assessed through the bicaudate ratio (BCr) and the lateral ventricles to brain ratio (LVBr), respectively. Apolipoprotein E (APOE) genotypes were also assessed. The routine neurological examination was used to evaluate ISNAs that were clustered as central-based signs, cerebellar-based signs, and primitive reflexes. The items of Part-III of the Unified Parkinson's Disease Rating Scale were used to evaluate ISNAs that were clustered as mild parkinsonian signs. Associations of ISNAs with imaging findings were determined through logistic regression analysis. RESULTS: The ISNAs increase with the age and are present in all MCI types, particularly in those multiple domains, and carrying the APOE ϵ4 allele, and are associated with WMH, lacunes, BCr, and LVBr. CONCLUSION: This study demonstrates that cortical and subcortical vascular and atrophic processes contribute to ISNAs. Long prospective population-based studies are needed to disentangle the role of ISNAs in the conversion from MCI to dementia.

Des anomalies neurologiques subtiles et isolées associées à différents types de déficience cognitive légère. Contexte: Des anomalies neurologiques à la fois subtiles et isolées sont fréquemment observées chez les personnes vieillissantes. Elles ont été associées à la maladie des petits vaisseaux du cerveau (cerebral small vessel disease) et à une atrophie des structures sous-corticales chez des sujets âgés en santé sur les plans neurologique et cognitif. Objectif: Étudier la fréquence de ces anomalies dans le cas de différents types de déficience cognitive légère ; évaluer, pour chaque type de déficience, la relation transversale entre ces anomalies et des hyper-signaux de la substance blanche, des lacunes cérébrales, l'atrophie du noyau caudé et l'élargissement des ventricules. Méthodes: Au total, 1250 sujets atteints de différents types de déficience cognitive légère ont été inclus dans notre analyse et ont passé un examen d'IRM du cerveau. On a évalué les hyper-signaux de la substance blanche à l'aide de deux échelles d'évaluation visuelle. À noter que les lacunes cérébrales ont également été évaluées. Du côté de l'atrophie du noyau caudé et de l'élargissement des ventricules, ces anomalies ont été mesurées respectivement au moyen de l'index bicaudé (bicaudate ratio) et du ratio volumique ventricule-cerveau (lateral ventricles to brain ratio). Enfin, les génotypes associés à l'apolipoprotéine E (ApoE) ont été examinés. Fait à souligner, des examens neurologiques de routine portant sur les signes du système nerveux central, sur les signes du cervelet et sur les réflexes archaïques ont été utilisés pour tenter de cerner les anomalies évoquées ci-dessus. Des éléments de la partie III de l'échelle UPDRS (Unified Parkinson's Disease Rating Scale) ont été par ailleurs mis à profit pour évaluer les anomalies regroupées au sein de la catégorie des signes bénins de la maladie de Parkinson. Les liens entre ces anomalies et les résultats aux examens d'IRM ont été déterminés à l'aide d'une analyse de régression logistique. Résultats: Ces anomalies neurologiques à la fois subtiles et isolées augmentent en fonction de l'âge et sont présentes parmi tous les types de déficience cognitive légère, en particulier dans ces domaines multiples et chez les sujets porteurs de l'allèle ϵ4 du gène de l'ApoE. On a vu également qu'elles sont associées à des hyper-signaux de la substance blanche, à des lacunes cérébrales, à l'atrophie du noyau caudé et à l'élargissement des ventricules. Conclusion: Cette étude démontre que les processus vasculaires et atrophiques des structures corticales et sous-corticales contribuent à l'apparition d'anomalies neurologiques à la fois subtiles et isolées. Des études prospectives de longue haleine basées sur la population sont toutefois nécessaires pour mieux comprendre le rôle de ces anomalies dans l'évolution des cas de déficience cognitive légère vers la démence.

Nociceptive Primitive Reflexes in Neurologically and Cognitively Healthy Aging Subjects.

BACKGROUND: To assess the prevalence of three nociceptive primitive reflexes (nPR), i.e., glabellar tap, snout reflex, and palmomental reflex, in neurologically and cognitively healthy (NCH) aging subjects. OBJECTIVE: To investigate whether nPR are cross-sectionally associated with white matter hyperintensities (WMH), lacunes, atrophy of the caudate nuclei, and global brain atrophy. METHODS: A total of 1246 NCH subjects aged 45-91 years were included in the study and underwent standard brain MRI. Atrophy of the caudate nuclei and global brain atrophy were assessed through the bicaudate ratio (BCr) and lateral ventricles to brain ratio (LVBr), respectively. WMH were assessed through visual rating scales. Lacunes were also rated. Association of nPR with vascular risk factors/diseases and imaging findings was evaluated using logistic regression analysis. RESULTS: nPR were exhibited by 33.1% of subjects and increased with age. Subjects with nPR performed less than subjects without nPR in tests evaluating global cognition, executive functions, attention, and language. Snout reflex was the most common nPR, followed by glabellar tap and palmomental reflex. Glabellar tap was associated with parieto-temporal WMH, BCr, and LVBr; snout reflex was associated with frontal lacunes, temporal WMH, BCr, and LVBr; palmomental reflex was associated with parieto-occipital WMH, basal ganglia lacunes, BCr, and LVBr. CONCLUSIONS: This study demonstrates that in NCH aging individuals, nPR are associated with WMH, lacunes, BCr, and LVBr and are probably a warning sign of incipient cognitive decline. Therefore, NCH subjects presenting nPR should manage their vascular risk factors/vascular diseases rigorously in order to prevent or delay progression of small vessel disease, and future neurological and cognitive disabilities.

Mild Parkinsonian Signs in a Hospital-based Cohort of Mild Cognitive Impairment Types: A Cross-sectional Study.

BACKGROUND: Mild Parkinsonian Signs (MPS) have been associated with Mild Cognitive Impairment (MCI) types with conflicting results. OBJECTIVE: To investigate the association of individual MPS with different MCI types using logistic ridge regression analysis, and to evaluate for each MCI type, the association of MPS with caudate atrophy, global cerebral atrophy, and the topographical location of White Matter Hyperintensities (WMH), and lacunes. METHODS: A cross-sectional study was performed among 1,168 subjects with different types of MCI aged 45-97 (70,52 ± 9,41) years, who underwent brain MRI. WMH were assessed through two visual rating scales. The number and location of lacunes were also rated. Atrophy of the caudate nuclei and global cerebral atrophy were assessed through the bicaudate ratio, and the lateral ventricles to brain ratio, respectively. Apolipoprotein E (APOE) genotypes were also assessed. Using the items of the motor section of the Unified Parkinson's Disease Rating Scale, tremor, rigidity, bradykinesia, and gait/balance/axial dysfunction were evaluated. RESULTS: Bradykinesia, and gait/balance/axial dysfunction were the MPS more frequently encountered followed by rigidity, and tremor. MPS were present in both amnestic and non-amnestic MCI types, and were associated with WMH, lacunes, bicaudate ratio, and lateral ventricles to brain ratio. CONCLUSION: MPS are present in both amnestic and non-amnestic MCI types, particularly in those multiple domain, and carrying the APOE ε4 allele. Cortical and subcortical vascular and atrophic processes contribute to MPS. Long prospective studies are needed to disentangle the contribution of MPS to the conversion from MCI to dementia.

Vascular Risk Factors, Vascular Diseases, and Imaging Findings in a Hospital-based Cohort of Mild Cognitive Impairment Types.

BACKGROUND: Mild Cognitive Impairment (MCI) is a transitional state between normal cognition and dementia. OBJECTIVE: The aim of this study is to investigate the role of vascular risk factors, vascular diseases, cerebrovascular disease and brain atrophy in a large hospital-based cohort of MCI types including 471 amnestic MCI (a-MCI), 693 amnestic MCI multiple domain (a-MCImd), 322 single non-memory MCI (snm-MCI), and 202 non amnestic MCI multiple domain (na-MCImd). For comparison, 1,005 neurologically and cognitively healthy subjects were also evaluated. METHOD: Several vascular risk factors and vascular diseases were assessed. All participants underwent neurological, neuropsychological and behavioural assessments as well as carotid ultrasonography and standard brain MRI. Multinomial logistic regression models on the MCI cohort with the NCH group and a-MCI type as reference categories were used to assess the effects of the variables evaluated on the estimated probability of one of the four MCI types. RESULTS: This study demonstrates that cerebrovascular disease contributes substantially to the risk of non-memory MCI types and a-MCImd type, and that brain atrophy is present in all MCI types and is greater in multiple domain types particularly in the na-MCI type. CONCLUSION: Improving detection and control of cerebrovascular disease in aging individuals should be mandatory. Since the incidence of MCI and dementia will be expected to rise because of the progressive life expectancy, a better management of cerebrovascular disease could indeed prevent or delay the onset of MCI, or could delay progression of MCI to dementia.

Association Between Atrophy of the Caudate Nuclei, Global Brain Atrophy, Cerebral Small Vessel Disease and Mild Parkinsonian Signs in Neurologically and Cognitively Healthy Subjects Aged 45-84 Years: A Crosssectional Study.

BACKGROUND: Mild Parkinsonian signs (MPS) are commonly seen in aging, and have been related to cerebral Small Vessel Diseases (SVD) with no univocal results. OBJECTIVE: The aim of this study was to investigate the cross-sectional relation between MPS and White Matter Hyperintensities (WMH), lacunes, caudate atrophy, and global cerebral atrophy in a large cohort of Neurologically and Cognitively Healthy (NCH) aging individuals. METHOD: 1,219 NCH individuals were included in the analysis, and underwent standard brain MRI. The items of the motor section of the Unified Parkinson's Disease Rating Scale were used to evaluate tremor, rigidity, bradykinesia, and gait/balance/axial dysfunction. Caudate atrophy and global cerebral atrophy were assessed through the bicaudate ratio and the lateral ventricles to brain ratio, respectively. WMH were assessed through two visual rating scales. Lacunes were also rated. Associations of MPS with vascular risk factors/diseases and imaging findings were determined through the logistic regression analysis. RESULTS: Frontal and basal ganglia lacunes, frontal WMH, caudate atrophy, and global cerebral atrophy were associated with bradykinesia. Basal ganglia lacunes, caudate atrophy, and global cerebral atrophy were associated with gait/balance/axial dysfunction. Rigidity was associated with frontal WMH, and tremor with caudate atrophy and global cerebral atrophy. NCH subjects with MPS, performed less than subjects without MPS in tests evaluating global cognition and language. CONCLUSION: This study demonstrates that in NCH aging individuals, MPS are associated with cortical and subcortical vascular and atrophic changes, and are probably, a warning sign of incipient cognitive decline. Subjects with MPS should manage rigorously cerebral SVD to prevent future physical and cognitive disabilities.

Double negative (IgG+IgD-CD27-) B cells are increased in a cohort of moderate-severe Alzheimer's disease patients and show a pro-inflammatory trafficking receptor phenotype.

Alzheimer's disease (AD) is a progressive, irreversible, and debilitating disease for which no effective preventive or disease modifying therapies or treatments have so far been detected. The crucial step in AD pathogenesis is the production of amyloid-ß42 peptide, which causes chronic inflammation. Activated cells in the central nervous system (CNS) produce pro-inflammatory mediators that lead to the recruitment of myeloid or lymphocytic cells. As a consequence, the communication between the CNS and peripheral blood of AD subjects could influence the lymphocyte distribution and/or the expression of phenotypic markers. In the present paper, we show a significant decrease in total CD19+ B lymphocytes and a remodeling of the B cell subpopulations in moderate-severe AD patients, compared with their coeval healthy controls and mild AD subjects. In particular, we report a significant reduction in naïve B cells (IgD+CD27-) and a simultaneous increase in double negative (DN, IgD-CD27-) memory B lymphocytes. We have also evaluated the expression of the pro-inflammatory chemokine receptors CCR6 and CCR7 in total and naïve/memory B cells from mild and moderate-severe AD patients, with the aim to detect a possible relationship between the trafficking profile and the stage of the disease. Our results demonstrate that both the amount and the trafficking profile of B cells are related to the severity of AD. The results discussed in this paper suggest a well-selected antibody panel should be used as an additional test for the identification of early AD.

Double negative (CD19+IgG+IgD-CD27-) B lymphocytes: a new insight from telomerase in healthy elderly, in centenarian offspring and in Alzheimer's disease patients.

Immunosenescence is characterized by the impairment of humoral immunity with changes in the memory/naive B cell compartment. In particular we have previously reported the percentage increase of a Memory IgD(-)CD27(-) (Double Negative, DN) B cell population in aged people. In this study, we have further characterized DN B cells with the aim to better understand their contribution to immunosenescence. As DN B cells show a poor ability to proliferate in vitro, we have evaluated the expression of the inhibitory receptors CD307d and CD22 on these cells from young and old individuals. In addition we have evaluated the ability to activate DN B cells by the simultaneous use of innate (CpG) and adaptive (α-Ig/CD40) ligands. Our data demonstrate that the refractoriness to proliferate of DN B cells does not depend on the expression of inhibitory receptors, but it is due to the kind of stimulation. Indeed, when DN B cells are stimulated engaging both BCR and TLR9, they become able to proliferate and reactivate the telomerase enzyme. In the present study, we have also compared the telomerase activity in a group of people genetically advantaged for longevity as centenarian offspring (CO) and in a group of moderate-severe Alzheimer's disease (AD) patients, who represent a model of unsuccessful aging. Our study suggests that telomerase reactivation of DN B cells, as well as their number and ability in activating, depend essentially by the biological age of the subjects studied, so the evaluation of DN B cells might allow to gain insight to healthy and unsuccessful aging.