Hui-XinWang, Stockholm Gerontology Research Center Stockholm, SwedenHuixin.wang@phs.ki.se
Submitted June 26, 2001
We thank Rieder and Fricke for their interest in our study. Their
letter underlined three main points: 1. Diagnostic difficulty in
differentiating Alzheimer’s disease (AD) from dementia due to B12
deficiency; 2. Possible inclusion of vascular cases in the AD group, which
may explain the association between vitamin deficiency and
neurodegenerative dementia; 3. Inaccuracy of serum B12 level as clinical
marker of tissue B12 deficiency. While we agree with Rieder and Fricke on
the relevance of the first two points, we are still convinced the low
sensitivity and specificity of serum B12 level does not invalidate our
results, as was extensively discussed in our article.[1]
Regarding the first point, we agree it is difficult to establish a
clinical diagnosis of AD in patients with low vitamin B12 or folate
levels. Indeed, in the absence of other neurologic or non-neurologic
manifestations of vitamin deficiency, only biopsy may help to
differentiate AD cases from dementia due to B12 deficiency. With this
problem in mind, all the clinical diagnoses in our study were made by
physicians that carefully evaluated all causes of dementia and excluded
any systemic conditions. Moreover, to improve the quality of our
diagnosis, we adopted a double diagnostic procedure, in which two senior
clinicians were involved.[1],[6]
In response to the second comment, we acknowledge it is more than
likely that our clinical-based AD diagnoses are contaminated by mixed
cases. However, our findings remained unchanged after taking into account
all vascular diseases. Further, neuroimaging would only have partially
solved the problem of misclassification of mixed cases in the AD group.
Given the observational nature of our study, we cannot identify whether
B12 deficiency is involved in the neurodegenerative mechanisms, or if it
is acting through vascular mechanisms, which may accelerate the clinical
expression of AD. [7]
Our population-based study can only suggest that vitamin B12 and
folate may be related to the development of clinically-diagnosed AD and
dementia. Even when a cut-off of 250 pmol/L was used to define low levels
of B12, an increased risk of clinically-diagnosed AD was found. This
definitely indicates the importance of monitoring vitamin B12 and folate
levels in the elderly. Further observational studies confirming our
findings with clinical and experimental investigations exploring these
possible mechanisms and underlying the reported associations are
warranted.
6 Fratiglioni L, Grut M, Forsell Y, et al. Clinical diagnosis of
Alzheimer's disease and other dementia in a population survey. Agreement
and causes of disagreement in applying DSM-III-R criteria. Arch Neurol
1992;49:927-932.
7 Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA,
Markesbery WR. Brain infarction and the clinical expression of Alzheimer
disease. The Nun Study. JAMA 1997;277:813-817.
We thank Rieder and Fricke for their interest in our study. Their letter underlined three main points: 1. Diagnostic difficulty in differentiating Alzheimer’s disease (AD) from dementia due to B12 deficiency; 2. Possible inclusion of vascular cases in the AD group, which may explain the association between vitamin deficiency and neurodegenerative dementia; 3. Inaccuracy of serum B12 level as clinical marker of tissue B12 deficiency. While we agree with Rieder and Fricke on the relevance of the first two points, we are still convinced the low sensitivity and specificity of serum B12 level does not invalidate our results, as was extensively discussed in our article.[1]
Regarding the first point, we agree it is difficult to establish a clinical diagnosis of AD in patients with low vitamin B12 or folate levels. Indeed, in the absence of other neurologic or non-neurologic manifestations of vitamin deficiency, only biopsy may help to differentiate AD cases from dementia due to B12 deficiency. With this problem in mind, all the clinical diagnoses in our study were made by physicians that carefully evaluated all causes of dementia and excluded any systemic conditions. Moreover, to improve the quality of our diagnosis, we adopted a double diagnostic procedure, in which two senior clinicians were involved.[1],[6]
In response to the second comment, we acknowledge it is more than likely that our clinical-based AD diagnoses are contaminated by mixed cases. However, our findings remained unchanged after taking into account all vascular diseases. Further, neuroimaging would only have partially solved the problem of misclassification of mixed cases in the AD group. Given the observational nature of our study, we cannot identify whether B12 deficiency is involved in the neurodegenerative mechanisms, or if it is acting through vascular mechanisms, which may accelerate the clinical expression of AD. [7]
Our population-based study can only suggest that vitamin B12 and folate may be related to the development of clinically-diagnosed AD and dementia. Even when a cut-off of 250 pmol/L was used to define low levels of B12, an increased risk of clinically-diagnosed AD was found. This definitely indicates the importance of monitoring vitamin B12 and folate levels in the elderly. Further observational studies confirming our findings with clinical and experimental investigations exploring these possible mechanisms and underlying the reported associations are warranted.
6 Fratiglioni L, Grut M, Forsell Y, et al. Clinical diagnosis of Alzheimer's disease and other dementia in a population survey. Agreement and causes of disagreement in applying DSM-III-R criteria. Arch Neurol 1992;49:927-932.
7 Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA 1997;277:813-817.