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Cerebrospinal fluid tau levels in frontotemporal dementia.

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versely, induced a significant reduction of AIMs in all patients, as measured by comparing pre- and postconditions.
The effect was still observable 30 minutes from the baseline
evaluation, but not after 45 minutes and 60 minutes. Only
one patient presented a transient bradykinesia worsening immediately after 1Hz rTMS (Fig).
Based on the assumption that 1Hz rTMS causes a transient depression of excitability at the cortical level,4 we propose that overactivity of the SMA plays an essential role in
choreic symptoms in HD. Studies with repeated rTMS sessions could evaluate possible long-lasting beneficial effects of
1Hz rTMS in HD patients.
From the 1Clinica Neurologica, Dipartimento di
Neuroscienze, Università Tor Vergata; 2Unita Operative
Complessa Neurologia, Ospedale S Eugenio; and 3Fondazione
Santa Lucia Istituto di Ricovero e Cura a Carattera
Scientifico, Rome, Italy
References
1. Brambilla P, Perez J, Monchieri S, et al. Transient improvement
of tardive dyskinesia induced with rTMS. Neurology 2003;61:
1155.
2. Koch G, Brusa L, Caltagirone C, et al. rTMS of the supplementary motor area modulates therapy-induced dyskinesias in Parkinson’s disease. Neurology (in press).
3. Shoulson I, Fahn S. Huntington’s disease: clinical care and evaluation. Neurology 1979;29:1–3.
4. Wasserman EM, Lisanby DH. Therapeutic application of repetitive transcranial magnetic stimulation: a review. Clin Neurophysiol 2001;112:1367–1377.
5. Huntington Study Group. Unified Huntington’s Disease Rating
Scale: reliability and consistency. Mov Disorders 1996;11:
136 –142.
Cerebrospinal Fluid Tau Levels in Frontotemporal
Dementia
Marcel M. Verbeek,1,2 Yolande A. Pijnenburg,3
Niki S. Schoonenboom,3 Berry P. H. Kremer,1 and
Philip Scheltens3
Fig. Differential effects of 1Hz and sham repetitive transcranial
magnetic stimulation (rTMS) in Huntington’s disease (HD)
patients with chorea. The chorea and bradykinesia items of the
motor section of the Unified HD rating scale (UHDRS)5 were
used. (A) Chorea score was calculated in seven body parts (face,
mouth, trunk, and extremities) with a five-point (0 – 4) scale.
(B) Bradykinesia score was obtained by using finger taps and
pronate/spinate-hands (right and left) with a five-point scale
(0 – 4). A first videotape recording was performed at baseline
(T0). Further videos were repeated 15 minutes (T15), 30 minutes (T30), 45 minutes (T45), and 60 minutes (T60) after the
baseline evaluation. rTMS was performed immediately after T0.
Videotapes were rated independently by two blinded raters and
randomized in order before being viewed. Data were analyzed
by using Friedman analysis of variance with times as mean
effect. Wilcoxon test was used as a post hoc when allowed.
656
Annals of Neurology
Vol 58
No 4
October 2005
In a recent issue of the Annals, Grossman and colleagues1
investigated the potential of the cerebrospinal fluid (CSF)
markers tau, amyloid ␤42 protein (A␤42), phosphorylated
tau181 (p-tau181) to differentiate frontotemporal dementia
(FTD) from Alzheimer’s disease (AD). Mean tau levels were
lower in FTD than in AD, whereas CSF Ptau-181 levels
were comparable between the two groups. The authors concluded that CSF tau may help to discriminate AD from
FTD. This conclusion was based on the, unexpected, finding
of a significantly reduced tau concentration in 34% of the
FTD patients, of which 19 patients were below the assay
detection limit (16pg/ml). The authors suggested that either
specific retention of tau within the brain, for example, in the
form of Pick bodies or balloon cells, or depletion of soluble
tau is one of the mechanisms leading to decreased CSF tau
levels.
The experience of two Dutch centers over the past 4 years
with CSF analysis in dementia disorders, by using the same
immunoassays for tau and p-tau181 as used by Grossman, is
summarized in the Table. A clinical diagnosis of dementia
patients was verified according to accepted criteria
(NINCDS-ARDRA for AD; Lund–Manchester criteria for
FTD). In both centers, the mean CSF tau concentration in
FTD patients was elevated compared with controls. Tau levels in FTD were neither below the detection limit of the
assay (60pg/ml) nor lower than the control population. Our
data, and data from literature2,3 (see also references 3– 8 in
Grossman and colleagues1), are in sharp contrast with those
reported by Grossman and colleagues. This raises serious
methodological questions regarding appropriate sample han-
Table. Cerebrospinal Fluid Concentrations, Mean ⫾ SD (n); [minimum ⫺ maximum] of tau, p-tau181, and A␤42 in Patients
with AD, FTD, and Controls by Center
Controls
Group
Tau
p-tau181
A␤42
N
FTD
A
N
AD
A
N
A
202 ⫾ 110 (88) 294 ⫾ 213 (33) 383 ⫾ 215 (25)a,b 489 ⫾ 417 (59)a 643 ⫾ 333 (99) 804 ⫾ 513 (166)
[115–828]
[65–2400]
[154–1747]
[75–2,615]
[62–713]
[75–1200]
52 ⫾ 15 (44)
47 ⫾ 28 (32)
66 ⫾ 30 (23)a
56 ⫾ 39 (59)a
105 ⫾ 43 (85) 91 ⫾ 42 (169)
[22–93]
[15–156]
[30–122]
[18–268]
[31–250]
[18–279]
849 ⫾ 277 (89) 740 ⫾ 269 (33) 666 ⫾ 247 (25)a,b 653 ⫾ 301 (60)a 413 ⫾ 137 (99) 414 ⫾ 173 (169)
[195–2,172]
[348–1,427]
[279–1202]
[202–1408]
[119–873]
[124–1,320]
CSF was obtained via lumbar puncture, directly centrifuged, aliquoted and stored in polypropylene tubes at ⫺80 C until analysis.
a
p ⬍ 0.001 vs AD; bp ⬍ 0.01 vs controls (within-center comparison: analysis of variance with Tukey’s post hoc test).
SD ⫽ standard deviation; FTD ⫽ frontotemporal dementia; AD ⫽ Alzheimer’s disease; N ⫽ Nijmegen; A ⫽ Amsterdam.
dling, including use of appropriate tubes, possible blood contamination, centrifugation, and use of the number of freezethaw cycles, as possible confounders of the findings in their
study. In the Methods section, there is no mention of the
exact type of tubes used, other than that they had a red cap.
Collection of CSF in tubes other than polypropylene or storage of samples at elevated temperatures4 might have been a
cause for the finding of unexpected low tau in the FTD
group that was never reported by others despite adequate
studies.
1
Radboud University Nijmegen Medical Centre, Department
of Neurology and Alzheimer Centre; 2Laboratory of Pediatrics
and Neurology; 3VU University Medical Centre Amsterdam,
Department of Neurology and Alzheimer Center, Amsterdam,
the Netherlands
References
1. Grossman M, Farmer J, Leight S, et al. Cerebrospinal fluid profile in frontotemporal dementia and Alzheimer’s disease. Ann
Neurol 2005;57:721–729.
2. Riemenschneider M, Wagenpfeil S, Diehl J, et al. Tau and
Abeta42 protein in CSF of patients with frontotemporal degeneration. Neurology 2002;58:1622–1628.
3. Rosso SM, van Herpen E, Pijnenburg YA, et al. Total tau and
phosphorylated tau 181 levels in the cerebrospinal fluid of patients with frontotemporal dementia due to P301L and G272V
tau mutations. Arch Neurol 2003;60:1209 –1213.
4. Schoonenboom NS, Mulder C, Vanderstichele H, et al. Effects
of processing and storage conditions on amyloid beta (1-42) and
tau concentrations in cerebrospinal fluid: implications for use in
clinical practice. Clin Chem 2005;51:189 –195.
10.1002/ana.20642
Reply
Murray Grossman, MD, EdD,
Virginia M. Y. Lee, PhD, MBA, Jennifer Farmer, MS,
Susan Leight, BS, and John Q. Trojanowski, MD, PhD
We thank Verbeek and colleagues for their comments regarding our experience with the usefulness of tau and other cerebrospinal fluid (CSF) biomarkers in differentiating frontotemporal dementia (FTD) from Alzheimer’s disease (AD).1 As in
our report, Verbeek and colleagues demonstrated significantly
lower average levels of CSF tau in FTD relative to AD. Averaged data should be interpreted cautiously when there is a very
broad standard deviation, and our study focused on the basis
for the very broad standard deviation in the CSF tau levels of
FTD patients seen in Grossman and colleagues2 and in the
literature. This broad standard deviation was evident in the
data provided by Verbeek and colleagues as well. Verbeek and
colleagues expressed concern that this could have been caused
in part by our handling of the samples. All samples were collected for the reported enzyme-linked immunosorbent assay
(ELISA) after approximately 10ml had been obtained for clinical purposes, so the CSF was generally clear, although we cannot exclude the presence of rare red blood cells in an occasional sample. Upon receiving the CSF samples, the laboratory
promptly aliquoted them (with no centrifugation) into 1ml
aliquots in sterile 2ml polypropylene tubes, and the samples
were always stored at ⫺80°C. Samples were frozen and
thawed usually twice but no more than three times because
1ml aliquots could be used for two and no more than three
ELISAs. The ELISA data reported in Grossman and colleagues
were generated in a single assay; that is, all of the samples from
control, AD patients, and FTD patients were performed at the
same time. There were 19 samples that had a total tau value
below the cutoff of our assay, but our assay was functioning
normally because the remaining 84 samples behaved as expected, including samples from AD patients that were quite
elevated in the same assay. Our view is that CSF biomarkers
represent an important source of in vivo information about
the large spectrum of histopathological entities contributing to
FTD and reflected in the broad standard deviation of CSF tau
levels in these patients. We encourage our colleagues to pursue
additional analyses studying the basis for the broad range of
CSF tau levels in their large and well-characterized cohort.
University of Pennsylvania School of Medicine, Philadelphia,
PA
Reference
1. Grossman M, Farmer J, Leight S, et al. Cerebrospinal fluid profile in frontotemporal dementia and Alzheimer’s disease. Ann
Neurol 2005;57:721–729.
DOI: 10.1002/ana.20618
Annals of Neurology
Vol 58
No 4
October 2005
657
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