I have some comments concerning the report by S. Jesse, D.R. Thal and
A.C. Ludolph, recently published in JNNP September 15 2015, pag. 1166-1168
"Thiamine deficiency in Amyotrophic Lateral Sclerosis".
In a research dated 1981 Rindi et al. showed that in 12 CSF samples
obtained from different healthy subjects, without any clinical disorder
involving thiamin status, the only thiamin compounds detected after
electrophoretic...
I have some comments concerning the report by S. Jesse, D.R. Thal and
A.C. Ludolph, recently published in JNNP September 15 2015, pag. 1166-1168
"Thiamine deficiency in Amyotrophic Lateral Sclerosis".
In a research dated 1981 Rindi et al. showed that in 12 CSF samples
obtained from different healthy subjects, without any clinical disorder
involving thiamin status, the only thiamin compounds detected after
electrophoretic separation were constantly free thiamine (T) and thiamine-
monophosphate (TMP), their mean percentage being 40.7% and 59.3% of total
thiamin content respectively. EXPERIENTIA 37, 975-976 (1981).
In a successive study Poloni et al. (Arch. Neurol., 1982,39, 507-509)
measured free thiamin and thiamin monophosphate levels in plasma and
cerebral spinal fluid of patients with ALS, alcoholics, and controls. In
plasma of patients with ALS, as well as in plasma and cerebrospinal fluid
(CSF) of alcoholics, both thiamin and thiamin monophosphate concentrations
were decreased. In CSF of patients with ALS, however, thiamin
monophosphate values decreased much more than thiamin levels. This same
finding has been observed, interestingly, only in pigs who showed together
with rabbits, the highest levels of thiamine in the CSF. In our opinion
the selective impairment of thiamin monophosphate production by nerve
cells is likely to result from the reduction of the activity of thiamin
pyrophosphatase, an enzyme synthesized and highly concentrated in the
Golgi complex, a component of the cell where complex molecules such as
proteins are synthesized and packaged for use in the body. Thiamin
pyrophosphatase diminish in ALS, as well as in experimental motor neuronal
degeneration or axotomy. Thus, the thiamin to thiamin monophosphate ratio
could be taken as an index of the impairment of neuronal protein synthesis
in ALS (Poloni et al.., Arch. Neurol., 1982, 39, 507-509).
In an other study, thiamine and thiamine monophosphate levels were
measured in the CSF of patients with typical sporadic ALS (50 cases), in
other motor neuron diseases (MND) (14 cases), and in patients with upper
and/or lower motor neuron lesions of varying origin (disseminated
sclerosis, polyneuropathy, spondylotic myelopathy). The thiamine to
thiamine monophosphate ratio was greater than or equal to 1 in a high
percentage of patients with typical sporadic ALS (94%), in 35.7% of cases
with other MND, while it was below one in all the other patients. The
decrease of thiamin monophosphate with the inversion of the thiamin to
thiamin monophosphate ratio is a finding highly specific to typical
sporadic ALS (Poloni et al. It.J.Neurol: Sci.,1986).
Other researchers measured the enzymes involved in thiamin synthesis:
thiamin pyrophosphatase (TPPase) and thiamin monophosphatase (TMPase) in
brain tissue obtained at autopsy from ALS and Parkinsonism-dementia
patients from Guam and from Guamanian patients who died from other
diseases (controls). TPPase content, chemically determined at pH 9.0, was
found to be significantly reduced in the frontal cortex of ALS and
Parkinsonism-dementia patients compared to controls. TMPase content, on
the contrary, was unchanged (Laforenza et al., J. Neurol. Sci., 1992).
Thiamin deficiency causes dry beriberi, a neurologic al disease
characterized by "burning" feet, peripheral neuropathy, and Wernicke-
Korsakoff syndrome; on this background, in my opinion the method used in
this paper to determinate the level of thiamine is indirect and easily
subject to drawbacks; Wernicke encephalopathy, istologically observed in
two ALS cases, may be due to undernutrition that may be frequently
associated in a disease where severe dysphagia may be present in the
terminal stage.
The reason of the low TMP CSF levels with inversion of the ratio T/TMP,
peculiar of ALS patients and ineterestingly found only in pigs, remains
unexplained.
OLD IS STILL GOOD IF NOT GOLD
The review article on use of aspirin for acute migraine headaches in
adults and an editorial on the same is worth appreciation and is an
excellent documentations, specially for poor patients of third world
countries. Of course the authors have revised and given the message
through an esteemed journal to the neurologists in particular...
OLD IS STILL GOOD IF NOT GOLD
The review article on use of aspirin for acute migraine headaches in
adults and an editorial on the same is worth appreciation and is an
excellent documentations, specially for poor patients of third world
countries. Of course the authors have revised and given the message
through an esteemed journal to the neurologists in particulars and
physicians and general practitioners in general. The standard texts are
already full of such information i.e. aspirin and acetaminophen is
considered superior to simple analgesics1. Aspirin is useful in mild form
of head pain, alone or in combination with acetaminophen or caffeine, and
may prevent migraine if taken in effervescent or soluble form early in the
attack after a drug to promote gastric absorption, such as
metoclopramide2. There are combinations of paracetamol in Indian market
like domcet and grenil but there is also need of the combination of
aspirin along with domperidone and proton pump inhibitoer or ranitidine,
for prompt absorption and avoid gastric irritation respectively, which at
times can be lethal, and also to promote empty stomach ingestion if
required as patient may be in agony to avoid food intake. Regarding the
mechanism of aspirin it helps in prevention of neurogenic
extravasation2.Aspirin can be an effective agent in migraine, providing it
can be adequately absorbed, which can be done with metoclopramide.
Intravenous aspirin has been used in Japan and Europe for headaches and
facial pains3. Aspirin has also been used as prophylaxis, where it was
found to be 20% superior to placebo, which effect is of course modest but
significant4. Episodic tension headaches also often respond promptly to
aspirin or acetaminophen2. Since approximately half of migraine sufferers
are undiagnosed, it is reasonable to conclude that majority of migraine
attacks are treated solely with analgesics such as acetaminophen, aspirin
(dose being 650-1000mg) or non-steroidal anti-inflammatory drugs5. So
aspirin or acetaminophen have been used in migraine for over 50 years and
probably remain the drugs used most frequently in acute therapy5,6.
REFERENCES-
1. Stephen D. Silberstein, Fredrerich G., Freitag, Marcelo E. Bigal.
Migraine treatment in "Wolff's Headache and other Head Pains". Indian
Edition (Editors Stephen D Silberstein, Richard B Lipton, David W Dodick)
Oxford University Press 2008;203-204.
2. James W. Lange, Peter J. Goadsby. Mechanism and Management of Headache.
7th Edition. Publisher Butterworth- Heinemann. First Indian Reprint 2005
; page 31, 136, 100, 175.
3. Fukuda Y and Izumikawa. Intravenous aspirin for intractable headache
and facial pain. Headache, 1988; 28: 47-50.
4. Buring J. E. ,Peto R.,Hennekens and C. H. Low dose aspirin for migraine
prophylaxis JAMA 1996; 264: 1711-1713.
5.-Stephen J. Peroutka, Migraine in; Principles of drug therapy in
neurology. 2nd Edition(Indian edition); editors- Michael J. Johnston and
Robert A. Gross. Oxford university press 2008, Reprinted 2010; 161-164.
6. Limmroth Katsarava Z., Diener H.C. Acetyle salicylic acid in treatment
of headache. Cephalgia 1999; 19: 545-551.
We wish to thank Dr. Morrish for his comments to our review. He argues in his letter that for diagnostic purposes a technique needs to be sensitive to the disease and reproducible and that DAT-SPECT unfortunately falls down on each. Sensitivity is poor, he says, since DAT-SPECT imaging has been found to be normal in about 5 to 15% of individuals with parkinsonism. Such individuals ( SWEDDs ("scans without evidence of dopaminergic...
We wish to thank Dr. Morrish for his comments to our review. He argues in his letter that for diagnostic purposes a technique needs to be sensitive to the disease and reproducible and that DAT-SPECT unfortunately falls down on each. Sensitivity is poor, he says, since DAT-SPECT imaging has been found to be normal in about 5 to 15% of individuals with parkinsonism. Such individuals ( SWEDDs ("scans without evidence of dopaminergic dysfunction") or false negatives scans), he believes, exist not because of failure of diagnosis but because of failure in the technique. These false negative cases may well have Parkinson`s disease (PD) , probably tremor dominant forms that have less abnormality in DAT-SPECT imaging. However, we maintain that available information strongly suggests that most if not all SWEDDs in fact do not have involvement of the nigrostriatal pathway and do not suffer from PD. Poor response to levodopa and lack of progression on sequential dopaminergic imaging (1), indicate that PD is an unlikely diagnosis in most cases of SWEDDs . Furthermore, withdrawal of anti-parkinsonian drug therapy in patients with parkinsonism with normal FP-CIT SPECT without any deleterious effects would not be possible in individuals with true PD, tremor dominant or not.(2) Support for this interpretation also comes from a recent study by Schwingenschuh et al. who has shown that SWEDDs share electrophysiological characteristics similar to patients with segmental dystonia and can clearly be separated from patients with PD and from patients with essential tremor.(3) We believe that the bulk of evidence suggests that the issue with the "false negative" cases (SWEDDs) is not a problem of sensitivity of the DAT-SPECT but rather an issue of an alternative diagnosis. We agree with Morrish that neuropathological studies of SWEDDs cases are needed to clarify this issue.
Morrish also feels DAT-SPECT falls down on reproducibility since in his opinion the result of a scan can vary by 40% from day to day (4), an issue he has previously highlighted in a letter to the JNNP in 2003.(5) The study by Booij et al (6) analyzing variability of [123I] FP-CIT SPECT showed an absolute variability of 7.25 ± 3.22% (ROI method) and 7.47 ± 6.35% (VOI method) in normal volunteers and 7.90 ± 6.89% (ROI method) and 7.36 ± 6.16% (VOI method) in PD patients . The use by Morrish of absolute means may not be appropriate way to calculate the range of variability . In contrast the above mentioned study by Booij et al reported a high test-retest reliability with FP-CIT (intraclass correlation coefficient close to 1) which indicates that with some tracers reproducibility is adequate for diagnostic use and potentially for disease progression studies, where the major issue is the demonstration of sensitivity to clinical change.
Morrish also refers to an earlier study in patients with clinically uncertain parkinsonism in which 6 scans changed over a period of 2 years.(7) As discussed in the paper, the changes in visual assessment were the result of over-interpretation of the images in a small subgroup of patients in whom a mismatch occurred between visual evaluation of the DAT-SPECT and the clinical diagnosis. When independent investigators were asked to read those images there was total consensus about that the images were normal and the same reading was obtained at 2 years follow up. The problem was not reproducibility but over-interpretation in a study done in an unusual subset of individuals with uncertain parkinsonism. We agree with Dr. Morrish that all efforts should be made to reduce variability of DAT SPECT imaging if this technique has to be used successfully in longitudinal studies of disease progression or neuroprotection and that these studies have to take into account variations due to the technique when decisions are taken about endpoints and sample size calculation (8)
Morrish indicates that DAT-SPECT has been validated as a screen for persons at risk of developing PD. While recent evidence shows that DAT-SPECT abnormalities can antedate the development of parkinsonism we do not know the predictive value of positive results in a normal population or even in a population at high risk for PD such as non manifesting carriers of genetic mutation causing autosomal dominant PD and therefore we reaffirm our opinion that DAT-SPECT has indeed not been validated yet as a useful premotor marker of PD.(9)
Morrish mentions in his letter that we write that "its (DAT-SPECT) use in longitudinal monitoring has not been considered; in 2002 a large US review group did just that". We wrote that "DAT-SPECT has also been used as a potential biomarker for disease progression in PD and has shown a progressive decline of striatal DAT binding with increasing disease duration of PD and with increasing disease severity also in agreement with [18F]dopa PET studies." Our statement is in line with the comments of the review of Ravina et al (10) quoted by Morrish in which the authors indicate, referring to studies using F-dopa PET and beta CIT SPECT, that "Natural history studies for each radiotracer have had small sample sizes, but the results are consistent. This suggests that these tracers measure biologic processes that are related to the duration and severity of PD as measured by motor rating scales in the practically defined "off" state". Whether the extra information obtained from these studies may not have justified the radiation exposure of so many patients on two or more occasions, as he states in his letter, is a difficult statement to support. These studies, like the ones he and others have conducted in the past which involve radiation exposure have been performed with the hopes that the information would indeed outweigh the possible risks of this technique.
We obviously agree with Morrish that a good clinician may prefer, instead of ordering a DAT-SPECT, to rely on their own judgment and the fullness of time. However, as it often happens, in the appropriate cases good clinicians may decide that ordering a DAT-SPECT may be a better course to follow than waiting that time may provide clarification of a diagnosis.
Finally Dr Morrish indicates that one of us (ET) did not declare as a conflict of interest in our Review being the principal investigator of a large study on DAT SPECT in parkinsonism 7 funded by GE Healthcare. I want to thank him for bringing this to my and the readership attention and for giving me the opportunity of declaring this now (see below Disclosure).
Reference List
1 Marek K, Jennings DL, Seibyl JP. Long-Term Follow-Up of Patients with Scans
without Evidence of Dopaminergic Deficit (SWEDD) in the ELLDOPA Study.
Neurology64 (Suppl 1):(Abstract).
2 Marshall VL, Patterson J, Hadley DM, Grosset KA, Grosset DG. Successful
antiparkinsonian medication withdrawal in patients with Parkinsonism and normal
FP-CIT SPECT. Mov Disord. 2006;21:2247-50.
3 Schwingenschuh P, Ruge D, Edwards MJ, Terranova C, Katschnig P, Carrillo F, Silveira-
Moriyama L, Schneider SA, Kagi G, Palomar FJ, Talelli P, Dickson J, Lees AJ, Quinn N,
Mir P, Rothwell JC, Bhatia KP. Distinguishing SWEDDs patients with asymmetric resting
tremor from Parkinson's disease: A clinical and electrophysiological study. Mov Disord.
DOI 10.1002/mds.23019 2010.4.
4 Morrish P. Controversies in Neuroimaging. Parkinson's disease: Diagnosis and
Clinical Management 2nd edition. 2008,Eds Factor and Weiner. Demos Publishing.
28;317-326.
5 . Morrish PK. The harsh realities facing the use of SPECT imaging in monitoring disease
progression in Parkinson's disease. J Neurol Neurosurg Psychiatry 2003;74:1447
6 Booij J, Habraken JB, Bergmans P, Tissingh G, Winogrodzka A, Wolters EC, Janssen AG,Stoof JC, van Royen EA. Imaging of dopamine transporters with iodine-123-FP-CIT SPECT in healthy controls and patients with Parkinson's disease. J Nucl.Med 1998;39:1879-84.
7. Tolosa E, Borght TV, Moreno E. Accuracy of DaTSCAN (123I-Ioflupane) SPECT in diagnosis of patients with clinically uncertain parkinsonism: 2-year follow-up of an open-label study. Mov Disord. 2007;22:2346-51.
8. Winogrodzka A, Bergmans P, Booij J, van Royen EA, Janssen AG, Wolters EC. [123I]FP- CIT SPECT is a useful method to monitor the rate of dopaminergic degeneration in early- stage Parkinson's disease. J Neural Transm 2001; 108(8-9):1011-1019.
9 Tolosa E, Gaig C, Santamaria J, Compta Y. Diagnosis and the premotor phase of Parkinson disease . Neurology 2009;72 (suppl 2) :S12-S20.
10 Ravina B, Eidelberg D, Ahlskog JE, Albin RL, Brooks DJ, Carbon M, Dhawan V, Feigin A,
Fahn S, Guttman M, Gwinn-Hardy K, McFarland H, Innis R, Katz RG, Kieburtz K, Kish
SJ, Lange N, Langston JW, Marek K, Morin L, Moy C, Murphy D, Oertel WH, Oliver G,
Palesch Y, Powers W, Seibyl J, Sethi KD, Shults CW, Sheehy P, Stoessl AJ, Holloway R .
The role of radiotracer imaging in Parkinson's disease. Neurology 2005; 64(2) 208-15.
Conflict of Interest:
Eduardo Tolosa was the principal investigator on an international trial on the value of DaTSCAN SPECT in parkinsonism 7 . For this he received no personal compensation. He has in the past received honoraria for lecturing in symposia on imaging in Parkinson disease sponsored by GE Healthcare
I enjoyed reading the paper of Sascha Kopke et al. [1] on the
efficacy of an evidence-based information program for people with recently
diagnosed multiple sclerosis. I noticed, however that the odds ratio (OR)
for the primary endpoint (achieving 'informed choice') is incorrect, both
in the Abstract and in the Results.
Abstract: 'For the primary endpoint, a significant difference was
shown with 50 of 85 (59%) pa...
I enjoyed reading the paper of Sascha Kopke et al. [1] on the
efficacy of an evidence-based information program for people with recently
diagnosed multiple sclerosis. I noticed, however that the odds ratio (OR)
for the primary endpoint (achieving 'informed choice') is incorrect, both
in the Abstract and in the Results.
Abstract: 'For the primary endpoint, a significant difference was
shown with 50 of 85 (59%) participants in the intervention group achieving
informed choice after 6 months compared with 18 of 89 (20%) in the control
group (OR 0.2 (95% CI 0.1 to 0.4), p<0.001).'
Results: 'The intervention led to significantly more participants
with informed choice during 6 months of follow-up (figure 2A), with 50
participants (58.8%) in the IG compared with 18 (20.2%) in the CG
(difference 38.6% (95% CI 24.1% to 53.1%); OR 0.18 (95% CI 0.09 to 0.35),
p<0.001)'.
The OR is should in fact be 5.63 (95% CI 2.87-11.05) meaning that
patients who received the evidence-based information program achieved
informed choice 5.6 times more often than patients who received the
control treatment.
The correct OR (a ratio of ratios) is easily arrived at from
examination of the 2 x 2 table below.
Informed choice- Intervention group: Control group
Yes- 50 : 18
No- 35 : 71
First ratio (informed choice achieved): 50/18 = 2.78.
Second ratio (informed choice not achieved): 35/71 = 0.49.
Ratio of the two ratios (OR): 2.78/0.49 = 5.67.
A simpler but less intuitive formula is: 50 x 71/18 x 35 = 5.67.
Errors are part of science, and sometimes even obvious ones can pass
unnoticed in quality peer-reviewed journals. The OR provides information
that both clinicians and patients can use for decision making. I hope this
letter contributes to making clearer the main findings of this important
paper.
I would like to commend the authors on this informative review on the
utility of dopamine transporter SPECT in the diagnostic workup of
Parkinsonian syndromes. I acknowledge that this review is set in the
context of the labelled indications for DaTSCAN as outlined by the EMA and
FDA however from a pragmatic perspective I would like to highlight the
utility of dopamine transporter SPECT in differentiating drug-induced
Par...
I would like to commend the authors on this informative review on the
utility of dopamine transporter SPECT in the diagnostic workup of
Parkinsonian syndromes. I acknowledge that this review is set in the
context of the labelled indications for DaTSCAN as outlined by the EMA and
FDA however from a pragmatic perspective I would like to highlight the
utility of dopamine transporter SPECT in differentiating drug-induced
Parkinsonism from Idiopathic Parkinson's disease (or other
neurodegenerative Parkinsonian syndromes) where diagnostic uncertainty
exists. Phenomenology can be unrewarding when trying to differentiate
drug-induced Parkinsonism, a common cause of Parkinsonism in the elderly,
from Idiopathic Parkinson's disease. The presence of normal dopamine
transporter SPECT imaging can be reassuring for both the clinician and the
patient when confirming a drug-induced aetiology (1). An important caveat
however is that dopamine antagonists and related agents can unmask
incipient Parkinson's disease thus regular examination and followup remain
perhaps the most important tools in the investigation of Parkinsonism.
Reference:
1. Cummings JL, Henchcliffe C, Schaier S et al. The role of
dopaminergic imaging in patients with symptoms of dopaminergic system
neurodegeneration. Brain 2011: 134; 3146-3166.
Metabolic Syndrome and Alzheimer's Disease:
Contrasting Epidemiological Evidence and Possible Underlying Mechanisms
We thank Giannopoulos and colleagues for their interesting Letter. At
present, cumulative evidence suggested that metabolic syndrome (MetS), a
constellation of interrelated metabolic derangements increasing the risk
of cerebrovascular disease (CVD) and diabetes, has been shown to be
in...
Metabolic Syndrome and Alzheimer's Disease:
Contrasting Epidemiological Evidence and Possible Underlying Mechanisms
We thank Giannopoulos and colleagues for their interesting Letter. At
present, cumulative evidence suggested that metabolic syndrome (MetS), a
constellation of interrelated metabolic derangements increasing the risk
of cerebrovascular disease (CVD) and diabetes, has been shown to be
independently associated with predementia and dementia syndromes. In
particular, MetS appeared to increase the risk for age-related cognitive
decline (ARCD), while for mild cognitive impairment (MCI) and its
progression to dementia the findings were too limited to draw any
conclusion [1-3]. Furthermore, several studies suggested that MetS may be
linked to the risk of developing dementia and VaD [4-7], while contrasting
findings existed of the possible role of MetS in developing AD [5-10].
Several individual components of MetS have been linked to risk of
developing dementia and cognitive impairment. Among the five MetS
components, hyperglycemia, lower high density lipoprotein (HDL) levels,
and elevated triglyceride levels were the components with increased risk
for predementia syndromes. Furthermore, hypertriglyceridemia was the
component with increased risk of dementia syndromes, particularly VaD [6].
However, the suggested association between MetS and AD was not
confirmed by four large longitudinal and population-based studies, the
Honolulu-Asia Aging Study , the Three-City Study, the Italian Longitudinal
Study on Aging, and the cohort of Medicare recipients residing in northern
Manhattan, in which no association between MetS and AD was found [5-8].
These results did not support those from population-based and case-control
studies in which MetS appeared to increase the risk of AD [9, 10].
However, the Kuopio Study was only cross-sectional and, consequently,
cannot address the question of whether MetS predicts AD [9], while the
case-control study demonstrated a link between MetS and AD, but important
limitations were the relatively small sample and the design of the study
[10]. In fact, it was not possible to distinguish between those factors
that may precede the development of AD and have a causal role and those
factors that may have been altered as a consequence of the disease. There
was also a selection bias because AD patients were selected from memory
clinics; therefore, there could be a spurious identification of risk
factors associated with clinic attendance rather than the disease itself
[10].
Notwithstanding the association between MetS an AD should be confirmed in
other larger studies with longer follow-up periods, we are completely
agree with Giannopoulos and colleagues on the growing evidence of a series
of underlying mechanisms related to this suggested association. These
suggestions proposed in a particular group of patients the presence of a "metabolic-cognitive
syndrome", i.e. a MetS plus cognitive
impairment of degenerative or vascular origin. This could represent a
pathophysiological model in which to study in depth the mechanisms linking
MetS and MetS components with dementia, particularly AD, and predementia
syndromes (ARCD or MCI), suggesting a possible integrating view of the
MetS components and their influence on cognitive decline. The potential
mechanisms linking the continuum of obesity, hyperinsulinemia,
hypertension, hyperlipidemia, and type 2 diabetes mellitus are multiple,
overlapping, and highly correlated. Therefore, it has been suggested a
role of these factors in the development of cognitive decline and
dementia, including underlying mechanisms, supporting their influence on ß-amyloid (A ß) peptide
metabolism and tau protein hyperphosphorylation, the principal
neuropathological hallmarks of AD. For example, recent work reveals that
leptin may be linked to AD through modulation of
A ß production and clearance [11]. Leptin was
found to reduce production of A ß, apparently through a reduction in ß-secretas activity, as well as to increase apolipoprotein E (APOE)-mediated clearance of Aß fibrils.
Recently, findings from the Health ABC study confirmed the neuroprotective role of leptin levels in the elderly individuals, against cognitive
decline, but also suggested that leptin resistance may play a role in the cognitive impairment [12]. Moreover, once established a leptin resistance
status, this influenced negatively not only cognitive performances but
also the metabolic response. In fact, leptin has been shown to have an
antidiabetic function through control of intracellular fatty acid
metabolism, maintenance of glucose sensitivity, and prevention of islet
lipotoxicity [13]. This double action of leptin on cognitive performances
and metabolism suggested not only the link but also the complexity of
mechanisms subtending to a metabolic-cognitive syndrome.
Furthermore, among MetS components, peripheral insulin resistance could be
the primary pathophysiological mechanism of MetS, although the definitions
of MetS and its components do not include any reference to insulin
resistance or hyperinsulinemia. In AD, an age-related desynchronization of
biological systems may result, involving cortisol and noradrenaline axes
associated with stress components, reactive oxygen species, and membrane
damage, and causing an insulin resistant brain state with decreased
glucose/energy metabolism and the increased formation of
hyperphosphorylated tau protein and A ß[14]. These interactive effects may provide clues to shared etiologies among metabolic
disorders [15]. For example, weight loss through lifestyle interventions
or medications may alter adipokine activity, improve hyperinsulinemia,
inflammation, glucose tolerance, blood pressure, lipids, and the risk of
CVD. Considerable interest has also arisen regarding the effects of
lifestyle interventions such as exercise and dietary/nutraceutical
manipulations. Pharmacological interventions currently under study include
statins, antihypertensive therapies, and insulin-sensitizing drugs. If
MetS and its components are associated with increased risk of developing
cognitive impairment, then early identification and treatment of these
individuals might offer avenues for disease course modification.
References
1. Roberts RO, Geda YE, Knopman DS, et al. Metabolic syndrome,
inflammation, and nonamnestic mild cognitive impairment in older persons:
a population-based study. Alzheimer Dis Assoc Disord 2009; [post author
corrections] DOI: 10.1097/WAD.0b013e3181a4485c.
2. Solfrizzi V, Scafato E, Capurso C, et al; Italian Longitudinal Study on
Aging Working Group Metabolic syndrome, mild cognitive impairment, and
progression to dementia. The Italian Longitudinal Study on Aging.
Neurobiol Aging 2009; [Epub ahead of print]
DOI:10.1016/j.neurobiolaging.2009.12.012.
3. Yaffe K, Weston AL, Blackwell T, Krueger KA The metabolic syndrome and
development of cognitive impairment among older women. Arch Neurol 66: 324
-328 (2009).
4. Roriz-Cruz M, Rosset I, Wada T, et al. Cognitive impairment and frontal
-subcortical geriatric syndrome are associated with metabolic syndrome in
a stroke-free population. Neurobiol Aging 2007;28:1723-36.
5. Kalmijn S, Foley D, White L, et al. Metabolic cardiovascular syndrome
and risk of dementia in Japanese-American elderly men: the Honolulu-Asia
aging study. Arterioscler Thromb Vasc Biol
2000;20:2255-60.
6. Raffaitin C, Gin H, Empana JP, et al. Metabolic syndrome and risk for
incident Alzheimer's disease or vascular dementia: the Three-City Study.
Diabetes Care 2009;32:169-74.
7. Solfrizzi V, Scafato E, Capurso C, et al.; Italian Longitudinal Study
on Aging Working Group. Metabolic syndrome and the risk of vascular
dementia. The Italian Longitudinal Study on Aging. J Neurol Neurosurg.
Psychiatry 2009; [Epub ahead of print] DOI: 10.1136/jnnp.2009.181743.
8. Muller M, Tang MX, Schupf N, et al. Metabolic syndrome and dementia
risk in a multiethnic elderly cohort. Dement Geriatr Cogn Disord
2007;24:185-92.
9. Vanhanen M, Koivisto K, Moilanen L, et al. Association of metabolic
syndrome with Alzheimer disease: a population-based study. Neurology
2006;67:843-47.
10. Razay G, Vreugdenhil A, Wilcock G. The metabolic syndrome and
Alzheimer disease. Arch Neurol 2007;64:93-6.
11. Fewlass DC, Noboa K, Pi-Sunyer FX, ey al. Obesity-related leptin
regulates Alzeimer's Abeta. FASEB J
2004;18:1870-8.
12. Holden KF, Lindquist K, Tylavsky FA, et al; Health ABC study. Serum
leptin level and cognition in the elderly: Findings from the Health ABC
Study. Neurobiol Aging 2009;30:1483-9.
13. Shimabukuro M, Koyama K, Chen G, et al. Direct antidiabetic effect of
leptin through triglyceride depletion of tissues. Proc Natl Acad Sci USA
1997;94:4637-4641.
14. Salkovic-Petrisica M, Osmanovica J, Grunblattb E, et al. Insulin
resistant brain state generates multiple long-term morphobiological
abnormalities including hyperphosphorylated tau protein and amyloid- ß. J Alzheimer Dis 2009;18:729-50.
15. Craft S. The role of metabolic disorders in Alzheimer disease and
vascular dementia: two roads converged. Arch Neurol 2009;66:300-5.
We thank Dr. Solari for pointing out an aspect of possible
misunderstanding, but surely not incorrectness. We agree that the reverse
odds ratio of 5.63 (95% CI 2.87 to 11.05, p<0.001) would more clearly
refer to the odds of achieving informed choice. Still the reported odds
ratio of 0.18 (95% CI 0.09 to 0.35, p<0.001) gives exactly the same
information and is probably more intuitively underst...
We thank Dr. Solari for pointing out an aspect of possible
misunderstanding, but surely not incorrectness. We agree that the reverse
odds ratio of 5.63 (95% CI 2.87 to 11.05, p<0.001) would more clearly
refer to the odds of achieving informed choice. Still the reported odds
ratio of 0.18 (95% CI 0.09 to 0.35, p<0.001) gives exactly the same
information and is probably more intuitively understood as an odds ratio
below 1 usually represents a positive intervention effect by avoiding an
unwanted outcome, i.e. in this study avoiding the "absence of informed
choice". Therefore, it needs to be stressed that this is not an instance
of "errors as part of science" as implied by Dr. Solari, but simply a
matter of reporting.
Furthermore, the proposed way of calculating the odds ratio is rather
unusual, as odds are normally calculated within exposure groups and not
within outcome groups. The latter would describe the odds to be in the
control or in the intervention group, which clearly does not make sense as
we want to describe the odds of achieving the outcome. Of course, the odds
ratio will be the same for both approaches.
We would like to thank Mr Rajendran his detailed and elaborate
comment regarding our trial on the initial monotherapy of epilepsy with
levetiracetam or lamotrigine (Rosenow et al JNNP 2012) . It is always a
good sign when a clinical study finds the interest not only of those
already actively contributing to a field of research but also of junior
colleagues which have not previously published in the area of clinical
epil...
We would like to thank Mr Rajendran his detailed and elaborate
comment regarding our trial on the initial monotherapy of epilepsy with
levetiracetam or lamotrigine (Rosenow et al JNNP 2012) . It is always a
good sign when a clinical study finds the interest not only of those
already actively contributing to a field of research but also of junior
colleagues which have not previously published in the area of clinical
epilepsy. It appears that Mr Rajendran misunderstood some of the data
presented by us especially regarding three major topics: 1) The number of
protocol violations and number of patients in the per protocol analysis
set, 2) the basics of hypothesis testing, and 3) the meaning of ITT and PP
analysis in clinical trial analysis. We would like to use the opportunity
to clarify these issues in a point by point fashion for him and the
interested readership of JNNP.
1) The number of protocol violations and number of patients in
the per protocol analysis set.
We frankly described in our article that the proportion of patients with
protocol violations was relatively high (about 40%). Unfortunately, Mr.
Rajendran mixed up the number of patients in our per protocol analysis
set: Levetiracetam, n=116 and Lamotrigine, n=129 with the number of
patients with protocol violations: Levetiracetam, n=90 (43.7%) and
Lamotrigine, n=74 (36.5%). Therefore, there were about 40% of protocol
violations and we did not reflect on the power.
2) The basics of hypothesis testing.
Hypothesis testing aims at refusing the nullhypothesis and as a result at
accepting the alternative hypothesis. We did not aim "to demonstrate that
the null hypothesis is indeed true" this would indeed by an unusual
approach. We summarised statistically correctly in our discussion that "we
found no significant differences between LEV and LTG".
3) The meaning of ITT and PP analysis in clinical trial
analysis.
We performed our primary analysis on the basis of the ITT-set and the PP-
set which is fully in accordance with ICH E9. Both analyses should be
performed, ?so that any differences between them can be the subject of
explicit discussion and interpretation" (ibid, S. 26). We did not find
differences between the results of the analyses and therefore, we drew the
conclusion that "it is unlikely, that the protocol violation rate did
influence the results of the primary endpoint". This interpretation is
much less assertive as Mr. Rajendran summarized our interpretation and
from our point of view it is fully justified by the results.
I thank Dr. Civardi and his group, who have demonstrated a large
experience with the practical use of Motor Evoked Potentials, for their
interest in our article describing a patient with presumed psychogenic
left hemiparalysis and abnormal transcranial magnetic stimulation (TMS)
(1). Our initial aim in performing TMS to our patient was exactly to prove
that MEPs were normal, as suggested by other authors (including Dr.
C...
I thank Dr. Civardi and his group, who have demonstrated a large
experience with the practical use of Motor Evoked Potentials, for their
interest in our article describing a patient with presumed psychogenic
left hemiparalysis and abnormal transcranial magnetic stimulation (TMS)
(1). Our initial aim in performing TMS to our patient was exactly to prove
that MEPs were normal, as suggested by other authors (including Dr.
Civardi and coworkers). However, in our patient, there was a non-
significant difference between left and right hemisphere MEP amplitudes,
but the cortico-motor threshold was 170% higher in the right hemisphere.
The similar F-waves size between sides excluded a difference in lower
motor neuron excitability. These changes reverted after the patient has
recovered and the diagnosis of conversive disorder has been explained. Dr.
Civardi refers to an important retrospective study on TMS in psychogenic
paralysis, since it shows that normal TMS can reassure the neurologist
regarding the absence of a structural CNS dysfunction (2). In this work a
single evaluation was made in 21 patients, 15 of which had a
unilateral/asymmetric paralysis. From this group only 9 patients had the
final diagnosis of conversive disorder. Although Dr. Civardi states, in
his letter, that no differences between hemispheres were found, this is
not reported in the referred paper (only mean values are shown).
By the time of our report, only a few papers addressed changes on MEPs
related to immobilization and reports on voluntary inhibition of movement
mainly analysed the ability to inhibit prepared movements and did not
specifically analysed MEP thresholds (3,4). As previously stated,
conclusions from a single case should be cautious; especially when we now
know that cognitive processes such as motor imagering may influence the
results (5). Studies making comparisons between normal controls and
patients with conversive paresis should clearly state controls test
conditions (was there an indication to be quiet, to think of movement and
inhibiting it, etc), otherwise subtle differences may be neglected. We
recently had another patient with conversive hemiparesis in whom the
affected hemisphere showed a strikingly increased cortico-motor threshold
in the involved hemisphere. This fact may be conflicting with the existing
literature, however it fits with the functional imaging data, and should
be further investigated, namely with well defined task protocols.
1. Geraldes R, Coelho M, Rosa MM, Severino L, Castro J, de Carvalho
M. Abnormal transcranial magnetic stimulation in a patient with presumed
psychogenic paralysis. JNNP; 2008; 79:1412-1413
2. Cantello R, Boccagni C, Civardi C, Monaco F. Diagnosis of psychogenic
paralysis: the role of motor evoked potentials. J Neurol; 2001; 248:889-
897
3. Crews RT, Kamen G. Motor-evoked potentials following imagery and limb
disuse. Int J Neurosci.2006;116(5):639-513.
4. Cocon JP, Stinear CM, Byblow WD. Intracortical inhibition during
volitional inhibition of prepared action. J Neurophysiol. 2006; 95(6):3371
-83
5. Liepert J, Hassa T, Tuscher O, Schmidt R. Abnormal motor
excitability in patients with psychogenic paresis. A TMS study. J Neurol.
2009; 256(1):121-6.
The meta-analysis by Xu et al is a valiant effort to map the evidence
for modifiable risk factors of Alzheimer's disease (AD) (1). We
acknowledge this huge effort, however, we have serious concerns regarding
the systematic appraisal and the synthesis of the available data.
On top of the critique by Drs. Wu and Brayne (e-letter), a
comprehensive assessment of the article and its results can reveal
critical error...
The meta-analysis by Xu et al is a valiant effort to map the evidence
for modifiable risk factors of Alzheimer's disease (AD) (1). We
acknowledge this huge effort, however, we have serious concerns regarding
the systematic appraisal and the synthesis of the available data.
On top of the critique by Drs. Wu and Brayne (e-letter), a
comprehensive assessment of the article and its results can reveal
critical errors in data collection and the analysis of the available
evidence. An experienced methodologist could easily spot from the forest
plots in the supplementary material that all risk factors are in the same
direction, an observation that cannot be explained by chance.
Therefore, we tried to re-analyze the meta-analyses using data
reported in the supplementary material of this paper and, indeed, the
summary effect estimates could not be replicated. We figured out that the
authors have inadvertently used the extracted ORs (at least for binary
exposures) derived from the individual studies as is, without transforming
them into the logarithmic scale as it is required, leading to
miscalculations of the summary effect sizes. Thus, most if not all
inferences in the paper are based on these false summary estimates
resulting in misleading conclusions.
Besides the aforementioned analytical errors, we are afraid that the
extraction of relevant data points from the primary studies may suffer
from crucial errors as well. We summarise here potential problems for the
association between "ever vs never alcohol use" and AD as it illustrated
in supplementary material (page 184). Unfortunately, in 4 out of the 11
eligible studies the extracted estimates were wrong. Specifically, in 2
studies the authors included an estimate for the comparison of "wine
drinkers vs no drinkers" even though an estimate for "ever vs never
alcohol consumption" was available (2,3). In one study they inadvertently
reported the estimate for a comparison of tuberculosis history (4) instead
of the alcohol use, whereas in another study they extracted an estimate
for an occupational exposure to alcohols and phenols (as organic solvents)
(5). Moreover, it seems that the study "Lindsay, 2002" (3) has overlapping
populations with the study "CHSA, 1994" (6) and therefore it should not be
considered twice. Additionally, in one of the included studies (7) the
authors have captured an estimate that is most probably is a typo. In the
primary study, an OR of 4.10 (95% CI 0.60-80.50) is reported. Our back
calculations (based on the point estimate and the lower confidence
interval) have shown that the upper CI most probable was 28.05 and this
was not corrected by Xu et al, influencing the weight of this study in the
meta-analysis.
Taking all these discrepancies into account we tried to repeat the
meta-analysis for the exposure to alcohol and AD. The summary OR
(estimated by our team using correct analytical methods, correct effect
estimates and after the exclusion of the study with overlapping sample)
was 0.79 (95% CI: 0.63-0.98) for fixed effects and 0.84 (95% CI: 0.57-
1.24) for random effects models with I2=57%. In contrast the authors
presented a summary OR of 0.63 (95% CI, 0.48-0.79) under the fixed-effects
model with I2=11.3%. We have observed similar discrepancies for several
other risk factors. Obviously using these effects to calculate the
population attributable fractions led to the false conclusion that 66% of
the Alzheimer's disease cases could be prevented. Indeed, a more
conservative and thorough estimation of the population attributable risk
for modifiable risk factors of AD indicated that known risk factors are
responsible for only 28.2% (95% CI, 14.2% to 41.5%) of total AD cases
worldwide (8).
Furthermore, inclusion of studies with overlapping samples was also
observed in meta-analyses of key risk factors. For example, in the meta-
analysis of type 2 diabetes mellitus, the authors included three studies
on Cardiovascular Health Cognition Study (Kuller et al 2003, Becker et al
2009 and Irie et al 2008) and another two studies on Baltimore
Longitudinal Study of Aging (Moffat et al 2004, Dal et al 2005). However,
only the study with the longest follow-up period should be included in the
analysis for each of these cohort studies. The same caveat was observed in
the meta-analysis for educational attainment.
Additionally, for other risk factors (e.g socioeconomic status and
educational attainment) the authors have not harmonized the exposure of
interest, presenting separate meta-analyses for "high level versus low
level" and for "low level versus high level" of exposure.
Finally, we should express our concerns regarding the search strategy
applied from the authors. For example in the case of coffee or caffeine
drinking, a previous published meta-analysis in 2015 (9) includes more
studies and yields non-significant effect estimates (5 studies in the
paper by Kim et al and 4 studies in the paper by Xu et al). The authors
report a significant random-effects OR of 0.54 (95% CI: 0.39 to 0.69)
compared to 0.78 [95% CI: 0.78 to 1.22) by Kim et al which is clearly non-
significant. Several similar examples exist throughout the manuscript
(e.g. current vs. never statin use, NSAIDs use, ever vs. never smokers).
Having all these caveats in mind the editorial team of the journal
should thoroughly re-assess all the available evidence presented in this
paper.
References
1. Xu W, Tan LL, Wang H-F, Jiang T, Tan M-S, Tan LL, et al. Meta-
analysis of modifiable risk factors for Alzheimer's disease. J Neurol
Neurosurg Psychiatry. 2015;86(12):1299-306.
2. Tyas SL, Manfreda J, Strain LA, Montgomery PR. Risk factors for
Alzheimer's disease: a population-based, longitudinal study in Manitoba,
Canada. Int J Epidemiol. 2001 Jun;30(3):590-7.
3. Lindsay J, Laurin D, Verreault R, H?bert R, Helliwell B, Hill GB,
et al. Risk factors for Alzheimer's disease: a prospective analysis from
the Canadian Study of Health and Aging. Am J Epidemiol. 2002;156(5):445-
53.
4. Harmanci H, Emre M, Gurvit H, Bilgic B, Hanagasi H, Gurol E, et
al. Risk factors for Alzheimer disease: a population-based case-control
study in Istanbul, Turkey. Alzheimer Dis Assoc Disord. 2003;17(3):139-45.
5. Kukull WA, Larson EB, Bowen JD, McCormick WC, Teri L, Pfanschmidt
ML, et al. Solvent exposure as a risk factor for Alzheimer's disease: a
case-control study. Am J Epidemiol. 1995;141(11):1059-71.
6. The Canadian Study of Health and Aging: risk factors for
Alzheimer's disease in Canada. Neurology. 1994;44(11):2073-80.
7. Harwood DG, Barker WW, Loewenstein DA, Ownby RL, St George-Hyslop
P, Mullan M, et al. A cross-ethnic analysis of risk factors for AD in
white Hispanics and white non-Hispanics. Neurology. 1999;52(3):551-6.
8. Norton S, Matthews FE, Barnes DE, Yaffe K, Brayne C. Potential
for primary prevention of Alzheimer's disease: An analysis of population-
based data. Lancet Neurol. 2014;13(8):788-94.
9. Kim Y-S, Kwak SM, Myung S-K. Caffeine intake from coffee or tea
and cognitive disorders: a meta-analysis of observational studies.
Neuroepidemiology. 2015;44(1):51-63.
I have some comments concerning the report by S. Jesse, D.R. Thal and A.C. Ludolph, recently published in JNNP September 15 2015, pag. 1166-1168 "Thiamine deficiency in Amyotrophic Lateral Sclerosis". In a research dated 1981 Rindi et al. showed that in 12 CSF samples obtained from different healthy subjects, without any clinical disorder involving thiamin status, the only thiamin compounds detected after electrophoretic...
ASPIRIN FOR ACUTE MIGRAINE HEADACHES IN ADULTS
OLD IS STILL GOOD IF NOT GOLD The review article on use of aspirin for acute migraine headaches in adults and an editorial on the same is worth appreciation and is an excellent documentations, specially for poor patients of third world countries. Of course the authors have revised and given the message through an esteemed journal to the neurologists in particular...
I enjoyed reading the paper of Sascha Kopke et al. [1] on the efficacy of an evidence-based information program for people with recently diagnosed multiple sclerosis. I noticed, however that the odds ratio (OR) for the primary endpoint (achieving 'informed choice') is incorrect, both in the Abstract and in the Results.
Abstract: 'For the primary endpoint, a significant difference was shown with 50 of 85 (59%) pa...
I would like to commend the authors on this informative review on the utility of dopamine transporter SPECT in the diagnostic workup of Parkinsonian syndromes. I acknowledge that this review is set in the context of the labelled indications for DaTSCAN as outlined by the EMA and FDA however from a pragmatic perspective I would like to highlight the utility of dopamine transporter SPECT in differentiating drug-induced Par...
Metabolic Syndrome and Alzheimer's Disease: Contrasting Epidemiological Evidence and Possible Underlying Mechanisms
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Dear Editor,
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We would like to thank Mr Rajendran his detailed and elaborate comment regarding our trial on the initial monotherapy of epilepsy with levetiracetam or lamotrigine (Rosenow et al JNNP 2012) . It is always a good sign when a clinical study finds the interest not only of those already actively contributing to a field of research but also of junior colleagues which have not previously published in the area of clinical epil...
I thank Dr. Civardi and his group, who have demonstrated a large experience with the practical use of Motor Evoked Potentials, for their interest in our article describing a patient with presumed psychogenic left hemiparalysis and abnormal transcranial magnetic stimulation (TMS) (1). Our initial aim in performing TMS to our patient was exactly to prove that MEPs were normal, as suggested by other authors (including Dr. C...
The meta-analysis by Xu et al is a valiant effort to map the evidence for modifiable risk factors of Alzheimer's disease (AD) (1). We acknowledge this huge effort, however, we have serious concerns regarding the systematic appraisal and the synthesis of the available data.
On top of the critique by Drs. Wu and Brayne (e-letter), a comprehensive assessment of the article and its results can reveal critical error...
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