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Increased levels of protein in cerebrospinal fluid of patients with alzheimer's diseaseЧcorrelation with degree of cognitive impairment.

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requirements may be the significant variable that triggered
corrective saccades without a visual stimulus. T o investigate
this possibility, we performed a saccadic task, with this same
patient, in which he was asked to look to a flashed (50 msec)
target that always appeared at a 30-degree lateral location
either to the right or to the left of the central target in a
48-trial set. In this situation our patient did not make corrective saccades in the dark, indicating that the effort on the
part of the patient to perform accurately in a “complex,”
unpredictable task may be the critical factor triggering corrective saccades without a visual stimulus. Such dependence on
test conditions indicates that the failure of elicitation of corrective saccades in the dark is not specific to cerebellar lesions.
MRC Human Movement and Balance Unit
National Hospital for Neurology and Neurosurgery
Queen Square
London W C l N j B G , UK
proprioception o r the efference copy correctly to trigger accurate corrective saccades after a dysmetric saccade. Furthermore, these results extend such a hypothesis by suggesting
that cerebellar patients are able to use not only visual signals,
but also vestibular or cervical proprioceptive signals to compare eye and target positions.
However, it would be simplistic to expect the percentage
of such saccades (dysmetric saccades without corrective saccades) to follow an all-or-nothing law, i.e., be 1007o in
cerebellar patients and 0% in other patients. We suggest that,
besides the factors mentioned above (existence of visual, vestibular, or cervical proprioceptive information), other factors
such as task complexity or the characteristics of the lesion
(location in the cerebellum and the degree of cerebellar dysfunction) are able to induce variations in this percentage. It
should be noted that, in the case reported by Bronstein and
colleagues, smooth pursuit was normal, suggesting that the
fastigio-vermal region, which controls both smooth pursuit
and saccades [3], was only partially damaged by the angioma
of this patient.
1. Gaymard B, Rivaud S, Amarenco P, Pierrot-Deseilligny C. Influence of visual information on cerebellar saccadic dysmetria.
Ann Neurol 1994;35:108-111
2. Kanayama R, Bronstein AM, Shallo-Hoffmann J, et al. Visually
and memory guided saccades in a case of cerebellar saccadic dysmetria. J Neurol Neurosurg Psychiatry 1994;57:1081-1084
Bertrand M. Gaymard, MD, Sophie Rivaud, Pierre
Amarenco, MD, and Charles Pierrot-Deseilligny, M D
We thank Dr Bronstein and his colleagues for their interest
in our study on cerebellar patients { 11. Their comments concern the existence or absence of corrective saccades following
dysmetric saccades performed by cerebellar patients 121. According to their hypothesis, the existence of corrective saccades would depend on the complexity of the oculomotor
task, and not, as we suggested, on the presence or absence
of a visual target when the saccade is triggered. Their hypothesis could be partially correct, even though it is based on the
result of a single case. Nevertheless, Bronstein and colleagues seem to have missed an essential point in their study
{2): If the number of dysmetric saccades that were not followed by a corrective saccade is calculated in each of the four
paradigms performed by their patient, it appears clearly that
the frequency of these saccades was markedly higher in the
second paradigm, i.e., in the memory-guided saccade paradigm (20 of 5 2 ) , than in any of the other three paradigms (2
of 58, 0 of 49, and 0 of 43 in the first, third, and fourth
paradigms, respectively), with statistical significance (x’:p <
0.001). In their memory-guided saccade paradigm (second
paradigm), as in our memory-guided saccade paradigm, no
sensory information about target location was present when
the saccade was triggered; whereas, in the other paradigms,
present visual (first paradigm) and cervical proprioceptive information (fourth paradigm), or memorized vestibular information (third paradigm), could be used to localize the target.
Thus, it appears that these results are not conflicting with
ours, and even confirm our hypothesis, since they show that,
in the second paradigm, their patient was unable to use ocular
414 Annals of Neurology Vol 37 N o 3 March 1995
Hijpital de la Sa@triire
INSERM 289 et Service de Neurologie
47 Bd de I‘H6pital
7565 1 Parii ce‘dex, France
1. Gaymard B, Rivaud S, Amarenco P, Pierrot-Deseilligny C. Influence of visual information on cerebellar saccadic dysmetria.
Ann Neuroi 1994;35:108-112
2. Kanayama R, Bronstein AM, Shallo-Hoffmann J, et al. Visually
and memory guided saccades in a case of cerebellar saccadic dysmetria. J Neurol Neurosurg Psychiatry 1994;57:1081-1084
3. Leigh RJ, Zee DS. The neurology of eye movement. 2nd ed.
Philadelphia: Davis Company, 1991:424-425
Increased Levels of T
Protein in Cerebrospinal
Fluid of Patients
with Alzheimer’s
Disease-Correlation with
Degree of Cognitive
Christoph Hock, MD, Sidonie Golombowski, PhD,
Werner Naser, PhD, and Franz Muller-Spahn, M D
Alzheimer’s disease (AD) is characterized by progressive dementia ultimately leading t o death. As with other ageassociated disorders, the prevalance of A D is dramatically
increasing due to the current increase in the elderly population. Since a 15- to 30-year preclinical period of continuous
deposition of senile plaques and neurofibrillary tangles (and
their constituent: paired helical filaments, PHFs) 111 might
precede the clinical phase of approximately 7 years 121, it is
assumed that only preventive therapies will be effective. But
a major prerequisite for evaluating preventive therapeutic
strategies is still lacking, i.e., the availability of valid biological
markers either to identify preclinical subjects at high risk for
developing AD, o r to have reliable time course parameters
to control for therapeutic efficacy.
We have quantitated levels of the microtubule-associated
protein T , the main protein component of PHF, in the cerebrospinal fluid (CSF) of patients with a diagnosis of probable
A D according to the National Institute of Neurological and
Communicative Disorders and Stroke-Alzheimer’s Disease
and Related Disorders Association (NINCDS-ADRDA) criteria [3] (n = 19, 7 men, 12 women; age, 70 k 8 yr) compared with age-matched control subjects (elderly patients
with major depression, according to ICDlO (F32.0x/ lx,
lx) and the Diagnostic and Statistical Manual of Mental Disorders, third edition revised (DSM-IIIR) (296.20-22,
296.30-32), n = 18, 3 men, 15 women; age, 62 & 12 yr).
A D patients were free of psychotropic medication. Control
subjects were treated with antidepressants (amitriptyline, n
= 8; doxepin, n = 4;trimipramine, n = 2; moclobemide,
n = 2; paroxetine, n = 2). It is currently unknown whether
these treatments can influence CSF levels of T . Informed
consent was taken from each patient o r their caregivers before the investigation. To avoid the possible influence of a
ventriculo-lumbar gradient we have performed the lumbar
puncture between 0730 and 0800 h, before breakfast and
before the patient was getting up. CSF samples were frozen
( - 30°C) at the bedside in 0.5-ml aliquots. CSF was thawed
immediately before the enzyme-linked immunosorbent assay
(ELISA) procedure and 50-p.1 CSF volumes were assayed in
duplicate determinations. The monoclonal antibody AT120
that reacts with both normal and PHF T was used in a sensitive sandwich ELISA (Innogenetics, Belgium) performed according to Vandermeeren and colleagues [4].The detection
limit was 10 pg/ml, the mean recovery 92%, the assay was
linear in the range of 10 to 160 pglml, and the intraassay
variance was below 11%. AT120-coated microtiter plates
(Nunc, MaxiSorp) were incubated with 25-wI unconcentrated
CSF samples supplemented with 5% Tween 20. After washing with phosphate-buffered saline/O.O5% Tween 20, the
biotinylated monoclonal antibodies HT7 and BT2 IS] that
recognize different epitopes of r were used as capturing
reagents. After incubation with peroxidase-conjugated streptavidin and a final washing, 3,5,3‘,5’-tetramethylbenzidine
(TMB) was added as chromogen. Absorbance was read at
450 nm in a Labsystems (Helsinki, Finland) Multiscan microplate reader.
T protein concentrations in CSF of the A D group were 70
t 8 pg/ml (mean SEM) compared with 27 ? 4 in controls
(independent samples t test: p < 0.001; Fig, left panel). Linear regression analysis of T protein levels in CSF of the A D
patients and the Mini-Mental State test scores, an indicator
of the cognitive status, revealed an inverse correlation of
these measures ( Y = -0.663, p < 0.002, Pearson type of
correlation; Fig, right panel).
Our results indicate that T levels are increased in CSF of
A D patients and that T levels correlate with clinical measures
of dementia severity. Together these findings suggest that
CSF levels of T increase during the course of dementia in
AD. T in CSF may thus be a biological marker that parallels
r = -0.663
Mini Mental State fmax. 301
(Left)Cerebrospinal j u i d (CSF) r protein concentrations in the
Alzheimer’s disease (AD) group (given in mean pglml -+ SEM,
70 ? 81 compared with controls (27 4; independent samples
t test: p < 0.0011. (Right) CSF rprotein concentrations of
the A D patients plotted against the performance in the MiniMental State test, an indicator of the cognitive status. Significant correlation was demonstrated (r = -0.663, p < 0.002,
Pearson type of correlation).
severity of dementia in AD. Our results, however, also point
to the limitations of such measurements as an early diagnostic
test, because T levels appear to be increased during the more
advanced stages of dementia. It remains to be shown whether
CSF T is also increased in preclinical stages in a subpopulation
of subjects at high risk for AD, such as familial A D cases. The
use of more specific antibodies that can distinguish between
normally and abnormally phosphorylated T may further enhance the discriminative properties of such assays.
S. G. did this work as part of her biological doctoral thesis at the
Department of Psychiatry
University of Munich
Munich, Germany
Boehringer Mannheim
Reseavcb Laboratory
Tutzing, Germany
1. Rumble B, Retallack R, Hilbich M, et al. Amyloid A4 protein
and its precursor in Down’s syndrome and Alzheimer’s disease.
N Engl J Med 1989;320:1446-1452
2. Growdon JH. Clinical profiles of Alzheimer’s disease. In: Gottfries CG, ed. Normal aging, Alzheimer’s disease and senile dementia-aspects on etiology, pathogenesis, diagnosis and treatment. Editions de I’Universite de Bruxelles, Bruxelles, Belgium:
19851213-2 18
3. McKhann G, Drachman D, Folstein M, er al. Clinical diagnosis
of Alzheimer’s disease: report of the NINCDS-ADRDA work
group under the auspices of Department of Health and Human
Services task force o n Alzheimer’s disease. Neurology 1984;34:
4. Vandermeeren M, Mercken M, Vanmechelen E, er al. Detection
of T proteins in normal and Alzheimer’s disease cerebrospinal
fluid with a sensitive sandwich enzyme-linked immunosorbent
assay. J Neurochem 1993;61:1828-1834
5. Mercken M, Vandermeeren M, Liibke U, et al. Affinity purification of human T proteins and the construction of a sensitive sandwich enzyme-linked immunosorbent assay for human T detection.
J Neurochem 1992;58:548-553
Annals of Neurology
Vol 37 N o 3 March 1995 415
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diseaseчcorrelation, level, increase, patients, protein, degree, impairments, cognitive, alzheimers, fluid, cerebrospinal
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