Pathogenetic mechanisms in vascular dementia

Vascular dementia accounts for approximately 20% of all cases of dementia and for about 50% in subjects over 80 years. Thromboembolism with multiple cerebral infarcts was considered to be almost the only pathogenetic pathway of vascular dementia, with multi-infarct dementia as its clinical manifestation. However, there is a great heterogeneity of vascular dementia syndromes and pathological subtypes, as documented by the number of pathogenetic mechanisms now known to underlie the clinical picture. They include thromboembolism and extracerebral and cerebral factors. Among the extracerebral factors are ischemic hypoxic dementia (i.e., dementia due to hypoperfusion), vasculitis, hyperviscosity and abnormalities of hemostasis. Among the cerebral factors are lipohyalinosis, cerebral amyloid angiopathy, disruption of the blood-brain barrier and altered regulation of cerebral blood flow. Therefore, the approach to vascular dementia should take the heterogeneity into account. In this context, the importance of non-infarct type should be considered; subcortical white matter disorder seems to be a noteworthy common pathway of vascular dementia produced by various vascular mechanisms. Finally, the heterogeneity of the vascular mechanisms involved in vascular dementia-namely hypoperfusion-might be a factor that can be positively influenced by targeted therapeutic intervention

Endo-lysosomal proteins and ubiquitin CSF concentrations in Alzheimer's and Parkinson's disease

BACKGROUND: Increasing evidence implicates dysfunctional proteostasis and the involvement of the autophagic and endo-lysosomal system and the ubiquitin-proteasome system in neurodegenerative diseases. In Alzheimer's disease (AD), there is an accumulation of autophagic vacuoles within the neurons. In Parkinson's disease (PD), susceptibility has been linked to genes encoding proteins involved in autophagy and lysosomal function, as well as mutations causing lysosomal disorders. Furthermore, both diseases are characterized by the accumulation of protein aggregates. METHODS: Proteins associated with endocytosis, lysosomal function, and the ubiquitin-proteasome system were identified in the cerebrospinal fluid (CSF) and targeted by combining solid-phase extraction and parallel reaction monitoring mass spectrometry. In total, 50 peptides from 18 proteins were quantified in three cross-sectional cohorts including AD (N = 61), PD (N = 21), prodromal AD (N = 10), stable mild cognitive impairment (N = 15), and controls (N = 68). RESULTS: A pilot study, including subjects selected based on their AD CSF core biomarker concentrations, showed increased concentrations of several targeted proteins in subjects with core biomarker levels indicating AD pathology compared to controls. Next, in a clinically characterized cohort, lower concentrations in CSF of proteins in PD were found compared to subjects with prodromal AD. Further investigation in an additional clinical study again revealed lower concentrations in CSF of proteins in PD compared to controls and AD. CONCLUSION: In summary, significantly different peptide CSF concentrations were identified from proteins AP2B1, C9, CTSB, CTSF, GM2A, LAMP1, LAMP2, TCN2, and ubiquitin. Proteins found to have altered concentrations in more than one study were AP2B1, CTSB, CTSF, GM2A, LAMP2, and ubiquitin. Interestingly, given the genetic implication of lysosomal function in PD, we did identify the CSF concentrations of CTSB, CTSF, GM2A, and LAMP2 to be altered. However, we also found differences in proteins associated with endocytosis (AP2B1) and the ubiquitin-proteasome system (ubiquitin). No difference in any peptide CSF concentration was found in clinically characterized subjects with AD compared to controls. In conclusion, CSF analyses of subjects with PD suggest a general lysosomal dysfunction, which resonates well with recent genetic findings, while such changes are minor or absent in AD

A magnetization transfer study of mild and advanced Parkinson's disease

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Neurofilament light chain as a biomarker in neurological disorders

In the management of neurological diseases, the identification and quantification of axonal damage could allow for the improvement of diagnostic accuracy and prognostic assessment. Neurofilament light chain (NfL) is a neuronal cytoplasmic protein highly expressed in large calibre myelinated axons. Its levels increase in cerebrospinal fluid (CSF) and blood proportionally to the degree of axonal damage in a variety of neurological disorders, including inflammatory, neurodegenerative, traumatic and cerebrovascular diseases. New immunoassays able to detect biomarkers at ultralow levels have allowed for the measurement of NfL in blood, thus making it possible to easily and repeatedly measure NfL for monitoring diseases’ courses. Evidence that both CSF and blood NfL may serve as diagnostic, prognostic and monitoring biomarkers in neurological diseases is progressively increasing, and NfL is one of the most promising biomarkers to be used in clinical and research setting in the next future. Here we review the most important results on CSF and blood NfL and we discuss its potential applications and future directions

Tau protein, A beta 42 and S-100B protein in cerebrospinal fluid of patients with dementia with Lewy bodies

The intra vitam diagnosis of dementia with Lewy bodies (DLB) is still based on clinical grounds. So far no technical investigations have been available to support this diagnosis. As for tau protein and beta-amyloid((1-42)) (Abeta42), promising results for the diagnosis of Alzheimer's disease ( AD) have been reported; we evaluated these markers and S-100B protein in cerebrospinal fluid (CSF), using a set of commercially available assays, of 71 patients with DLB, 67 patients with AD and 41 nondemented controls (NDC) for their differential diagnostic relevance. Patients with DLB showed significantly lower tau protein values compared to AD but with a high overlap of values. More prominent differences were observed in the comparison of DLB patients with all three clinical core features and AD patients. Abeta42 levels were decreased in the DLB and AD groups versus NDC, without significant subgroup differences. S-100B levels were not significantly different between the groups. Tau protein levels in CSF may contribute to the clinical distinction between DLB and AD, but the value of the markers is still limited especially due to mixed pathology. We conclude that more specific markers have to be established for the differentiation of these diseases. Copyright (C) 2005 S. Karger AG, Basel

Cumulative Lead Dose and Cognitive Function in Adults: A Review of Studies That Measured Both Blood Lead and Bone Lead

OBJECTIVE: We review empirical evidence for the relations of recent and cumulative lead dose with cognitive function in adults. DATA SOURCES: A systematic search of electronic databases resulted in 21 environmental and occupational studies from 1996 to 2006 that examined and compared associations of recent (in blood) and cumulative (in bone) lead doses with neurobehavioral outcomes. DATA EXTRACTION: Data were abstracted after consideration of exclusion criteria and quality assessment, and then compiled into summary tables. CONCLUSIONS: At exposure levels encountered after environmental exposure, associations with bio-markers of cumulative dose (mainly lead in tibia) were stronger and more consistent than associations with blood lead levels. Similarly, in studies of former workers with past occupational lead exposure, associations were also stronger and more consistent with cumulative dose than with recent dose (in blood). In contrast, studies of currently exposed workers generally found associations that were more apparent with blood lead levels; we speculate that the acute effects of high, recent dose may mask the chronic effects of cumulative dose. There is moderate evidence for an association between psychiatric symptoms and lead dose but only at high levels of current occupational lead exposure or with cumulative dose in environmentally exposed adults

DMSO and Temperature Contributions to Synthesis of Silver Nano-Particles by the Bacterium Shewanella oneidensis

Nanomaterial are widely used in different areas such as optical device, drug delivery, chemicals, mechanics, magnetics, catalysis, energy science, Nano therapeutics and space industries depend on the special physical properties. However, most methods to produce nanoparticles are expensive or environmental unfriendly which can involve in toxic chemical. Another reason is that the nanoparticles from bio-based protocols are hydrophilic which is compatible with biological materials. In this project, we chose Shewanella oneidensis which is Gram-negative bacterium as the organism to produce sliver nanoparticles from sliver nitrate solution. The mechanism of bacterial of ion metal ion reduction to stable metal nanoparticles is unclear, but the NADH-dependent reeducates, quinines, and soluble electron-shuttles are thought to play an important role in metal reduction. This research focused on the temperature and DMSO affects the synthesis of silver nanoparticles by Shewanella Oneidensis. At various temperatures, the bio-activity of bacterium is different which can affect the silver nanoparticles reducing rate and the spherical size and nanoparticle geometry. DMSO is an aprotic, polar solvent which can penetrate skin and other membranes without damaging the cells. Due to this property of DMSO, DMSO was utilized as a co-solvent, which may change biosynthesis of silver nanoparticles. The synthesis processes were carried out at different temperatures and DMSO concentration and the nanoparticle formation monitored by using UV-vis spectrometer scans of the aqueous layer of reaction at 0 hr, 24 hr and 48 hr.https://ecommons.udayton.edu/stander_posters/1429/thumbnail.jp

Vascular Dementia Italian Sulodexide Study (VA.D.I.S.S.) Clinical and biological results

In order to evaluate the biological effects on some haemostasis factors of antithrombotic-hemorheological treatments on patients with vascular dementia, a multicenter, randomized, double-blind, double-dummy, study comparing sulodexide (Sdx, 50 mg bid orally for 6 months) and pentoxifylline (Ptx, 400 mg tid orally for six months) was carried out. Eighty-six patients, 46 in Sdx group, 40 in Ptx group, fulfilling the NINDS-AIREN criteria for probable vascular dementia were evaluated. Plasma fibrinogen levels showed a significant reduction in both groups, in patients with high basal levels (≤350 mg/dl), the reduction being earlier in Sdx group (2nd month of therapy) than in Ptx group (4th month of therapy). In Sdx group a significant reduction in factor VII-Ag (baseline 102.8 U/dl; 6th month 90.1 U/dl) was also observed. Both drags induced a slight reduction in activated factor VII levels as well. A parallel improvement of G.B.S. Rating Scale for dementia scores was observed in Sdx group. These results seem to indicate that sulodexide treatment can have positive effects in vascular dementia

Vascular Dementia Italian Sulodexide Study (VA.D.I.S.S.) Clinical and biological results

In order to evaluate the biological effects on some haemostasis factors of antithrombotic-hemorheological treatments on patients with vascular dementia, a multicenter, randomized, double-blind, double-dummy, study comparing sulodexide (Sdx, 50 mg bid orally for 6 months) and pentoxifylline (Ptx, 400 mg tid orally for six months) was carried out. Eighty-six patients, 46 in Sdx group, 40 in Ptx group, fulfilling the NINDS-AIREN criteria for probable vascular dementia were evaluated. Plasma fibrinogen levels showed a significant reduction in both groups, in patients with high basal levels ( 64350 mg/dl), the reduction being earlier in Sdx group (2nd month of therapy) than in Ptx group (4th month of therapy). In Sdx group a significant reduction in factor VII-Ag (baseline 102.8 U/dl; 6th month 90.1 U/dl) was also observed. Both drags induced a slight reduction in activated factor VII levels as well. A parallel improvement of G.B.S. Rating Scale for dementia scores was observed in Sdx group. These results seem to indicate that sulodexide treatment can have positive effects in vascular dementia

Roadmap and standard operating procedures for biobanking and discovery of neurochemical markers in ALS

Despite major advances in deciphering the neuropathological hallmarks of amyotrophic lateral sclerosis (ALS), validated neurochemical biomarkers for monitoring disease activity, earlier diagnosis, defining prognosis and unlocking key pathophysiological pathways are lacking. Although several candidate biomarkers exist, translation into clinical application is hindered by small sample numbers, especially longitudinal, for independent verification. This review considers the potential routes to the discovery of neurochemical markers in ALS, and provides a consensus statement on standard operating procedures that will facilitate multicenter collaboration, validation and ultimately clinical translation