pattismith
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Thyroid hormone levels in the cerebrospinal fluid correlate with disease severity in euthyroid patients with Alzheimer’s disease
Introduction
Several reports suggest that subclinical abnormalities in thyroid function may play a role in Alzheimer’s disease (AD) [ 1 – 3 ]. Because of the complexity of thyroid hormone (TH) transport and metabolism in the brain, this hypothesis should be tested by assaying TH in cerebrospinal fluid (CSF). Reduced T 3 and increased 3,3 0 ,5 0 -triiodothyronine (rT3 )[ 4 ], or decreased T4 with unchanged T3 [ 5 ], were reported in CSF of AD patients.
A limitation of these studies is the use of immunological methods, which were only validated for plasmatic TH. In the present investiga- tion, we used mass spectrometry (MS) coupled to high- performance liquid chromatography (HPLC), a highly specific and sensitive analytical technique [ 6 ], to assay CSF T4 ,T3 and rT3 in a retrospective series of 35 patients (9 males, 26 females, age 66 ± 2 years), observed at the Neurological Unit of Pisa University.
CSF TH concentra- tions were related to serum TH concentration, and to other laboratory and clinical variables.
(FTP = Fronto-Temporal dementia)
Result:
In the whole series, CSF T4 ,T3 and rT3 averaged 1.54 ± 0.08 nM, 14.0 ± 0.6 and 155.0 ± 12.1 pM, respectively.
No significant difference was observed for any of these variables between the three subgroups, namely CON, FTD and AD.
CSF T4 was about 60-fold lower than serum T4 (95.6 ± 2.91 nM) and over 100-fold higher than serum-free-T4 (11.7 ± 0.41 pM).
CSF T3 was about 90-fold lower than serum T3 (1.35 ± 0.04 nM) and about fourfold higher that serum-free-T3 (3.61 ± 0.11 pM), while CSF rT3 was on the same order as serum rT3 (222.8 ± 20.1 pM).
Discussion
We assayed for the first time TH in human CSF by HPLC–MS/MS. With regard to T3 and T4, we obtained results that were comparable to previous investigations, where immunological methods were applied.
...
The absence of any correlation between serum and CSF T4 and rT3 and the relatively weak correlation observed for T3 , reflect the complex brain TH distribution and meta- bolism.
Indeed, TH can reach the CSF either through blood–brain barrier or choroid plexus filtration, and dif- ferent transporters are expressed at both levels. Moreover, most of brain T 3 is produced locally [ 14 ], as a consequence of a fine balance between D2 and D3 deiodinases which, in addition, are expressed in different cell types [ 15 , 16 ].
No significant difference was identifiable in CSF T4 ,T3 or rT3 between patients and controls. This may result from the fact that it is very difficult to find proper controls available to undergo an invasive assessment as LP.
Therefore, our control group included patients who underwent LP because of the suspect (not confirmed by subsequent evaluations) of several conditions, which may have affected blood–brain barrier permeability and/or CSF dynamics.
A significant negative correlation between rT3 ,or rT3 /T3 ratio, and MMSE (= an index of cognitive decline severity), was observed only in AD patients.
Notably, no other bio- chemical variable derived from serum or CSF analysis was significantly related to MMSE
Due to the small population size, our results are not conclusive. However, the observed correlations deserve further evaluations since they might suggest the existence of a link between AD severity and local alterations of TH metabolism.
The mechanisms that mediate this association have not been completely elucidated yet.
However, there is evidence that TH regulates two of the main pathogenetic processes in AD, namely, tau protein phosphorylation [ 17 ] and the altered metabolism of amyloid precursor protein [ 18 ].
In addition, TH and TSH levels correlate with reduced brain perfusion in temporal lobes, brain areas primarily involved in AD pathology
Introduction
Several reports suggest that subclinical abnormalities in thyroid function may play a role in Alzheimer’s disease (AD) [ 1 – 3 ]. Because of the complexity of thyroid hormone (TH) transport and metabolism in the brain, this hypothesis should be tested by assaying TH in cerebrospinal fluid (CSF). Reduced T 3 and increased 3,3 0 ,5 0 -triiodothyronine (rT3 )[ 4 ], or decreased T4 with unchanged T3 [ 5 ], were reported in CSF of AD patients.
A limitation of these studies is the use of immunological methods, which were only validated for plasmatic TH. In the present investiga- tion, we used mass spectrometry (MS) coupled to high- performance liquid chromatography (HPLC), a highly specific and sensitive analytical technique [ 6 ], to assay CSF T4 ,T3 and rT3 in a retrospective series of 35 patients (9 males, 26 females, age 66 ± 2 years), observed at the Neurological Unit of Pisa University.
CSF TH concentra- tions were related to serum TH concentration, and to other laboratory and clinical variables.
(FTP = Fronto-Temporal dementia)
Result:
In the whole series, CSF T4 ,T3 and rT3 averaged 1.54 ± 0.08 nM, 14.0 ± 0.6 and 155.0 ± 12.1 pM, respectively.
No significant difference was observed for any of these variables between the three subgroups, namely CON, FTD and AD.
CSF T4 was about 60-fold lower than serum T4 (95.6 ± 2.91 nM) and over 100-fold higher than serum-free-T4 (11.7 ± 0.41 pM).
CSF T3 was about 90-fold lower than serum T3 (1.35 ± 0.04 nM) and about fourfold higher that serum-free-T3 (3.61 ± 0.11 pM), while CSF rT3 was on the same order as serum rT3 (222.8 ± 20.1 pM).
Discussion
We assayed for the first time TH in human CSF by HPLC–MS/MS. With regard to T3 and T4, we obtained results that were comparable to previous investigations, where immunological methods were applied.
...
The absence of any correlation between serum and CSF T4 and rT3 and the relatively weak correlation observed for T3 , reflect the complex brain TH distribution and meta- bolism.
Indeed, TH can reach the CSF either through blood–brain barrier or choroid plexus filtration, and dif- ferent transporters are expressed at both levels. Moreover, most of brain T 3 is produced locally [ 14 ], as a consequence of a fine balance between D2 and D3 deiodinases which, in addition, are expressed in different cell types [ 15 , 16 ].
No significant difference was identifiable in CSF T4 ,T3 or rT3 between patients and controls. This may result from the fact that it is very difficult to find proper controls available to undergo an invasive assessment as LP.
Therefore, our control group included patients who underwent LP because of the suspect (not confirmed by subsequent evaluations) of several conditions, which may have affected blood–brain barrier permeability and/or CSF dynamics.
A significant negative correlation between rT3 ,or rT3 /T3 ratio, and MMSE (= an index of cognitive decline severity), was observed only in AD patients.
Notably, no other bio- chemical variable derived from serum or CSF analysis was significantly related to MMSE
Due to the small population size, our results are not conclusive. However, the observed correlations deserve further evaluations since they might suggest the existence of a link between AD severity and local alterations of TH metabolism.
The mechanisms that mediate this association have not been completely elucidated yet.
However, there is evidence that TH regulates two of the main pathogenetic processes in AD, namely, tau protein phosphorylation [ 17 ] and the altered metabolism of amyloid precursor protein [ 18 ].
In addition, TH and TSH levels correlate with reduced brain perfusion in temporal lobes, brain areas primarily involved in AD pathology