Cerebrospinal Fluid Metals and the Association with Cerebral Small Vessel Disease.

BACKGROUND: Brain metal homeostasis is essential for brain health, and deregulation can result in oxidative stress on the brain parenchyma. OBJECTIVE: Our objective in this study was to focus on two hemorrhagic MRI manifestations of small vessel disease [cerebral microbleeds (CMBs) and cortical superficial siderosis (cSS)] and associations with cerebrospinal fluid (CSF) iron levels. In addition, we aimed to analyze CSF biomarkers for dementia and associations with CSF metal levels. METHODS: This is a cross-sectional study of 196 patients who underwent memory clinic investigation, including brain MRI. CSF was collected and analyzed for metals, amyloid-ß (Aß) 42, total tau (T-tau), and phosphorylated tau (P-tau), and CSF/serum albumin ratios. Statistical analyses were performed using generalized linear models. RESULTS: No significant difference was found between CSF metal levels across diagnostic groups. Higher iron and copper levels were associated with higher CSF levels of Aß42, T-tau, P-tau, and CSF/serum albumin ratios (p < 0.05). Zinc was associated with higher CSF/serum albumin ratios. There was no significant association between CMBs or cSS and CSF iron levels. An increase in CSF iron with the number of CMBs was seen in APOEɛ4 carriers. CONCLUSION: CSF iron levels are elevated with cerebral microbleeds in APOEɛ4 carriers, with no other association seen with hemorrhagic markers of small vessel disease. The association of elevated CSF iron and copper with tau could represent findings of increased neurodegeneration in these patients.

Comparison of Metal Levels between Postmortem Brain and Ventricular Fluid in Alzheimer's Disease and Nondemented Elderly Controls.

An essential metal hypothesis for neurodegenerative disease suggests an alteration in metal homeostasis contributing to the onset and progression of disease. Similar associations have been proposed for nonessential metals. To examine the relationship between metal levels in brain tissue and ventricular fluid (VF), postmortem samples of frontal cortex (FC) and VF from Alzheimer's disease (AD) cases and nondemented elderly subjects were analyzed for arsenic (As), cadmium (Cd), chromium (Cr), cobalt (Co), copper (Cu), iron (Fe), lead (Pb), manganese (Mn), mercury (Hg), nickel (Ni), tin (Sn), vanadium (V), and zinc (Zn) using inductively coupled plasma sector field mass spectrometry. All metals, with exception of equivalent Pb levels, were lower in the VF, compared to FC. Within-subject comparisons demonstrated that VF levels were not representative of levels within brain tissue. The essential metals Cu, Fe, and Zn were found highest in both compartments. Cd, Hg, and V levels in the VF were below the limit of quantification. In AD cases, FC levels of Fe were higher and As and Cd were lower than levels in controls, while levels of As in the VF were higher. Parameter estimates for FC metal levels indicated an association of Braak stage and higher Fe levels and an association of Braak stage and lower As, Mn, and Zn levels. The data showed no evidence of an accumulation of nonessential metals within the AD brain and, with the exception of As, showed no significant shift in the ratio of FC to VF levels to indicate differential clearance.

Patterns of levels of biological metals in CSF differ among neurodegenerative diseases.

We measured the levels of some biological metals: copper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), and zinc (Zn) in the cerebrospinal fluid (CSF) in patients with neurodegenerative diseases (52 patients with amyotrophic lateral sclerosis (ALS)), 21 patients with Alzheimer's disease (AD), and 20 patients with Parkinson's disease (PD) by inductively coupled plasma mass spectrometry (ICP-MS). The diagnoses were additionally supported by neuroimaging techniques for AD and PD. In ALS, the levels of Mg (p<0.01 significant difference), Fe, Cu (p<0.05), and Zn (p<0.10) in CSF were higher than those in controls. Some patients showed very high levels of Cu and Zn before the critical deterioration of the disease. In AD, the levels of Cu and Zn in CSF were significantly higher in patients with late-onset AD (p<0.01). In PD, we found significantly increased levels of especially Cu and Zn in particular (p<0.01) and Mn (p<0.05) in CSF. A multiple comparison test suggested that the increased level of Mg in ALS and that of Mn in PD were the pathognomonic features. These findings suggest that Cu and Zn in particular play important roles in the onset and/or progression of ALS, AD, and PD. Therefore, Cu-chelating agents and modulators of Cu and Zn such as metallothionein (MT) can be new candidates for the treatment of ALS, AD, and PD.

Metal concentrations in plasma and cerebrospinal fluid in patients with Alzheimer's disease.

BACKGROUND/AIMS: The homeostasis of essential metals such as copper, iron, selenium and zinc may be altered in the brain of subjects with Alzheimer's disease (AD). METHODS: Concentrations of metals (magnesium, calcium, vanadium, manganese, iron, cobalt, nickel, copper, zinc, selenium, rubidium, strontium, molybdenum, cadmium, tin, antimony, cesium, mercury and lead) were determined in plasma and cerebrospinal fluid (CSF) by inductively coupled plasma mass spectrometry in 173 patients with AD and in 87 patients with the combination of AD and minor vascular components (AD + vasc). Comparison was made with 54 healthy controls. RESULTS: The plasma concentrations of manganese and total mercury were significantly higher in subjects with AD (p < 0.001) and AD + vasc (p

Impact of selenium, iron, copper and zinc in on/off Parkinson's patients on L-dopa therapy.

We have quantitated CSF and serum levels of Selenium, iron, copper and zinc by Atomic absorption spectrophotometer in 36 patients with parkinson's disease all on L-dopa therapy. Out of these 19 showed on or positive response to L-dopa where as 21 patients showed on and off response. These data were compared with 21 healthy controls. The results showed that serum levels of iron, copper and zinc remained unchanged where as in CSF, significant decrease in zinc was found in both on and on/off PD patients indicating the deficiency of zinc which continues in the worsening clinical condition of off patients. The level of copper remained unchanged in both on and on/off PD patients. Iron and selenium increase in CSF of both patients which is a clear evidence of relationship between increased iron and selenium level in brain which could be correlated with decrease in dopamine levels and oxidative stress in PD Patients.

Cerebrospinal fluid levels of transition metals in patients with Alzheimer's disease.

We compared CSF and serum levels of iron, copper, manganese, and zinc, measured by atomic absorption spectrophotometry, in 26 patients patients with Alzheimer's disease (AD) without major clinical signs of undernutrition, and 28 matched controls. CSF zinc levels were significantly decreased in AD patients as compared with controls (p < 0.05). The serum levels of zinc, and the CSF and serum levels of iron, copper, and manganese, did not differ significantly between AD-patient and control groups. These values were not correlated with age, age at onset, duration of the disease, and scores of the MiniMental State Examination in the AD group. Weight and body mass index were significantly lower in AD patients than in controls. Because serum zinc levels were normal, the possibility that low CSF zinc levels were due to a deficiency of dietary intake seems unlikely. However, it is possible that they might be related to the interaction of beta-amyloid and/or amyloid precursor protein with zinc, that could result in a depletion of zinc levels.

Cerebrospinal fluid levels of transition metals in patients with Parkinson's disease.

We compared CSF and serum levels of iron, copper, manganese, and zinc, measured by atomic absorption spectrophotometry, in 37 patients with Parkinson's disease (PD) and 37 matched controls. The CSF levels of zinc were significantly decreased in PD patients as compared with controls (p < 0.05). The serum levels of zinc, and the CSF and serum levels of iron, copper, and manganese, did not differ significantly between PD-patient and control groups. There was no influence of antiparkinsonian therapy on CSF levels of none of these transition metals. These values were not correlated with age, age at onset, duration of the disease, scores of the Unified Parkinson Disease Rating Scale of the Hoehn and Yahr staging in the PD group, with the exception of CSF copper levels with the duration of the disease (r = 0.38, p < 0.05). These results suggest that low CSF zinc concentrations might be related with the risk for PD, although they could be related with oxidative stress processes.