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
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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 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
Kagi and colleagues (1) provide a review but not a critique of a
controversial technique. For a technique to have diagnostic utility it
needs sensitivity to the disease and reproducibility; DAT-SPECT
unfortunately falls down on each.
The review describes the test as around 100% sensitive as a diagnostic
tool in detecting PD. The authors conclude that the normal scans in 5-15%
of patients with de-novo PD are normal becau...
Kagi and colleagues (1) provide a review but not a critique of a
controversial technique. For a technique to have diagnostic utility it
needs sensitivity to the disease and reproducibility; DAT-SPECT
unfortunately falls down on each.
The review describes the test as around 100% sensitive as a diagnostic
tool in detecting PD. The authors conclude that the normal scans in 5-15%
of patients with de-novo PD are normal because
"some patients with dystonic tremor are
misdiagnosed as PD" rather than that the test
itself may not be perfect. The gold standard is not clinical opinion, DAT
scan or PET scan, but post mortem. It can be shown, from knowledge and
understanding of the technique's parameters
(2), that DAT-SPECT has both false negatives and false positives, the
predictive value of a result varying according to the composition of the
population being tested. We know that tremor-dominant patients may have
slow progression (3), and that their DAT-SPECT scan may be less abnormal
than the akinetic-rigid patient (4). Many of the
SWEDD's (though I prefer the term false-
negative) may be tremor-dominant and slowly progressing. Only a very long
time (not the one or two years quoted here) and a post-mortem will provide
the evidence that they do or do not have idiopathic
Parkinson's disease.
The authors do not consider the issue of reproducibility, a key problem in
DAT-SPECT (2). How useful is a technique in which a result can vary by
40% from day to day (2)? Some SWEDD's will
undoubtedly be due to technical error.
Tolosa has undermined the confidence in the technique that he expresses in
this review by an earlier publication (5). In 2007 he reported 6
"uncertain
parkinsonism" patients in whom the DAT-scan
changed between first and second scan, over a two year period. Five went
from abnormal to normal; presumably either the first scan was falsely
positive or the second scan was falsely negative. In the sixth patient
the scan changed from normal to abnormal; presumably, the first was a
false negative.
The authors write that DAT-SPECT has not been validated as a screen for
persons at risk of developing PD. It has, and its limitations
(particularly the low predictive value of positive results in a normal
population) mean that it will not be useful (2). They also write that its
use in longitudinal monitoring of disease progression has not been
considered; in 2002 a large US review group did just that (6). Despite
this, many SPECT progression studies have been carried out in
Parkinson's disease (eg CALM, ELLDOPA,CEP-
1347). The extra information that has been gained by this addition to
clinical progression studies may not have justified the radiation exposure
of so many patients on two or more occasions.
Despite my misgivings over the technique there may be one clinical
application. Falsely positive DAT-SPECT scans are relatively uncommon in
a de-novo Parkinsonian population (2) and so the scan, if reproducible,
could be helpful in distinguishing the organic from the non-organic. A
good clinician may instead prefer to rely on their own judgement and the
fullness of time.
Finally it should be noted that Dr Tolosa was chief investigator on a
large recent study (5) funded by GE Healthcare, a manufacturer of a DAT-
SPECT pharmaceutical agent. Its omission as a possible conflict of
interest may have been an oversight but, if not, it might have been better
for him to declare this so that the reader could make their own judgement.
1. Kagi G, Bhatia KP, Tolosa E . The role of DAT-SPECT in
movement disorders. J Neurol Neurosurg Psychiatry. 2010 Jan;81(1):5-12.
2. Morrish P. Controversies in Neuroimaging.
Parkinson's disease: Diagnosis and Clinical
Management 2nd edition. 2008,Eds Factor and Weiner. Demos Publishing.
28;317-326.
3. Hoehn MM, Yahr MD. Parkinsonism:onset, progression and mortality.
Neurology 1967, 17; 427-42.
4. Spiegel J, Hellwig D, Samnick S et al. Striatal FP-CIT uptake differs
in the subtypes of early Parkinson's disease.
J Neural Transm 2007, 114(3):331-5.
5. Tolosa E, Borght TV, Moreno E et al. Accuracy of DaTSCAN([123]I-
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
6. Ravina B, Eidelberg D, Ahlskog JE et al. The role of radiotracer
imaging in Parkinson's disease. Neurology 2002;
64(2) 208-15
Conflict of Interest:
In 2002 I received payment from Amersham International, manufacturers of a DAT-SPECT product, (via a grant from the Movement Disorders Society)for an article appearing as a supplement in Movement Disorders
The recently published Italian Longitudinal Study on Aging [1] has
indicated Metabolc Syndrome (MetS) subjects had a three fold increased
risk of Vascular Dementia (VaD), but not of Alzheimer Disease (AD) or
other dementias, compared with those without MetS only after adjustment
for traditional risk factors. Additionally, authors have indicated that
among the five components identifying MetS, hypertension had the higher
incidence rate for VaD and low HDL cholesterol for AD in the whole study
sample. Finally they reported a synergistic effect due to MetS vs its
individual components on the risk of VaD. Previously, several studies have
shown that MetS increases the risk of cognitive decline [2], AD [3], VaD
[4] and dementia overall [5].
AD is characterised by gradual onset and continuing cognitive decline,
with cognitive deficits not attributed to other central nervous system
medical conditions; VaD is accompanied by evidence of cerebrovascular
disease (CVD) etiologically related to the dementia. The two clinical
entities share most of the components of MetS, including hypertension,
hyperlipidemia, diabetes mellitus (DM), and obesity [6,7]. MetS increases
the risk of future DM and CVD, conditions associated with VaD and AD
[1,6,7].
Although the Italian study has not shown increased risk of AD in MetS
patients [1], current evidence indicates an association between AD and
CVD. Casserly and Topol suggested that vascular risk factors converge to
increase the presence of misfolded neurotoxic amyloid-b peptide (Ab),
after a substantial incubation period, eventually causing AD [8]. Insulin
has an important role in the metabolism of Ab and tau-protein and
consequently result in increased formation of senile plaques [9]. Silent
strokes and subcortical ischemic lesions have been linked to cognitive
decline and dementia and the most probable underlying pathophysiologic
mechanism is cerebral hypoperfusion due to atherosclerosis [10]. Roman and
Royall suggested the ischemic lesions as the main contributor to late-
onset dementia clinically diagnosed as AD [11].
AD can be distinguished either as inherited early-onset disease or as a
late-onset disease accounting for 90-95% of all cases [12]. The inherited
presenile forms have been associated with specific mutations of several
genes encoding the amyloid precursor protein (APP) or proteolytic enzymes,
which cleave APP. Regarding risk factors, pathogenesis and
neuropathological findings, the vast majority of AD cases are of late-
onset. It is most likely that vascular disease co-exists with the amyloid
deposition.
The mechanism by which MetS could increase the risk of dementia of
degenerative or vascular origin is not yet fully elucidated. In our review
concerning MetS and AD we have reinforced the hypothesis that AD and VaD
share common vascular underlying mechanisms [7,8]. However, previous
studies concerning the risk for AD in MetS patients produced inconclusive
results [3,5]. Further studies are needed to support or reject a common
vascular hypothesis for AD and VaD.
References
1. Solfrizzi V, Scafato E, Capurso C et al. Metabolic syndrome and the
risk of vascular dementia. The Italian Longitudinal Study on Aging. J
Neurol Neurosurg Psychiatry. 2009 Dec 3, doi:10.1136/jnnp.2009.181743.
2. Yaffe K, Kanaya A, Lindquist K et al. The metabolic syndrome,
inflammation, and risk of cognitive decline. JAMA 2004;292:2237-2242.
3. Razay, G., Vreugdenhil, A., Wilcock, G. The metabolic syndrome and
Alzheimer disease. Arch. Neurol. 2007;64:93-96.
4. Raffaitin C, Gin H, Empana JP et al. Metabolic syndrome and risk for
incident Alzheimer disease or vascular dementia: the Three-City Study.
Diabetes Care. 2009;32:169-74.
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;20:2255-2260.
6. Kivipelto M, Helkala EL, Laakso MP et al. Midlife vascular risk factors
and Alzheimer disease in later life: longitudinal, population based study.
BMJ. 2001:322:1447-1451.
7. Milionis HJ, Florentin M, Giannopoulos S. Metabolic syndrome and
Alzheimer disease: a link to a vascular hypothesis? CNS Spectr.
2008;13:606-613.
8. Casserly I, Topol E. Convergence of atherosclerosis and Alzheimer
disease: inflammation, cholesterol, and misfolded proteins. Lancet.
2004;363:1139-1146.
9. de la Monte SM, Wands JR. Review of insulin and insulin-like growth
factor expression, signaling, and malfunction in the central nervous
system: relevance to Alzheimer's disease. J Alzheimers Dis. ,2005;7:45-61.
10. de la Torre JC. Alzheimer disease as a vascular disorder: nosological
evidence. Stroke. 2002;33:1152-1162.
11. Roman GC, Royall DR. A diagnostic dilemma: is "Alzheimers dementia"
Alzheimers disease, vascular dementia, or both? Lancet Neurol. 2004;3:141
12. Ritchie K, Lovestone S. The dementias. Lancet. 2002;360:1759-1766
Dear Editor,
we read with great interest the paper by Attarian et al on response to
Intravenous immunoglobulin (IVIg) therapy in patients with chronic ataxic
neuropathies and anti-GD1b antibodies.
We would like to share our experience with a patient with chronic ataxic
demyelinating polyneuropathy and antibodies to disialogangliosides who
responded to Rituximab therapy.
A 69-year-old man presented in August 2006 with sub...
Dear Editor,
we read with great interest the paper by Attarian et al on response to
Intravenous immunoglobulin (IVIg) therapy in patients with chronic ataxic
neuropathies and anti-GD1b antibodies.
We would like to share our experience with a patient with chronic ataxic
demyelinating polyneuropathy and antibodies to disialogangliosides who
responded to Rituximab therapy.
A 69-year-old man presented in August 2006 with subacute ataxic gait and
paresthesias at four limbs. He had been diagnosed in January 2006 with low
-grade B-cell-lymphoma after a bone marrow biopsy done to ascertain an IgM
monoclonal gammopathy. The neurological examination showed ataxic gait,
reduced sense of touch/pain from knees and elbows down; severe
hypopallesthesia and areflexia at lower limbs; distal weakness at right
leg. Electrodiagnostic studies revealed sensory-motor demyelinating
polyneuropathy. Cerebrospinal fluid analysis showed increased proteins (70
mg/L). In ELISA the IgM strongly reacted with GD1a (>100000), GD1b, GM2
(51200) and sulfatide (>100000) (normal range <3600). Antibodies to
myelin-associated glycoprotein (MAG) and GM1 were negative. Sural nerve
biopsy showed loss of large myelinated fibers with clusters of
regeneration and segmental demyelinations. Immunofluorescence did not
show deposits of immunoglobulins. Being the patient overweight (150
kilograms) and affected with a severe heart disease, IVIg were not
considered due to the fear of volume overload. Given the coexistence of
low-grade B-cell-lymphoma, the patient underwent therapy with Rituximab
(375 mg/m2 for 4 weeks), a chimeric anti-CD20 monoclonal antibody, with
benefit: the patient became able to walk independently also on toes and
hills, strength was 5/5 MRC in all the limbs, hypoesthesia was limited to
feet and hands. Antibody titers significantly decreased. In July 2007 the
patient underwent a second Rituximab course with benefit; in the following
months, however, hypoesthesia gradually spread up to elbows and knees,
and antibody titers were back to high titers. Strength remained preserved.
In March 2009 the patient underwent a third Rituximab course, with a
prompt and enduring effect. At last neurological evaluation (November
2009) the patient had regained full functionality at all limbs; the gait
was normal and strength preserved; hypopallesthesia and areflexia at lower
limbs persisted.
Sensory ataxic neuropathies are known to occur in patients with IgM
paraproteins and anti-GD1b antibodies, consistent with the preferential
localization of GD1b in primary sensory neurons. Anti-GD1a antibodies are
instead mostly associated with motor neuropathy. Sensory-motor peripheral
neuropathy and IgM paraproteinemia may be associated with antibodies to
sulfatide, sometimes coexisting or cross-reacting with antibodies to MAG.
Our patient had a demyelinating chronic ataxic polyneuropathy with the
unusual coexistence of antibodies to disialogangliosides and sulfatide
likely produced by the same monoclonal malignancy and responsive to
Rituximab therapy.
The short-term effect of IVIg and the subsequent need of frequent
treatments in patient affected with chronic polyneuropathy requiring long-
term treatment, may be overcome by the use of Rituximab, especially in
the cases associated with IgM monoclonal gammopathy. As already
demonstrated in anti-MAG polyneuropathy, the high cost of Rituximab may be
balanced by its long-lasting effects.
I read with interest the article by Geraldes et al.[1] on the use of
transcranial magnetic stimulation (TMS) in psychogenic paralysis. The
Authors showed in a young lady with a reversible left body limbs paresis
due to conversion disorders (CD), a significant increase of corticomotor
threshold and reduction in amplitude of motor evoked potentials (MEP) in
the affected side. These changes were resto...
I read with interest the article by Geraldes et al.[1] on the use of
transcranial magnetic stimulation (TMS) in psychogenic paralysis. The
Authors showed in a young lady with a reversible left body limbs paresis
due to conversion disorders (CD), a significant increase of corticomotor
threshold and reduction in amplitude of motor evoked potentials (MEP) in
the affected side. These changes were restored with the normalization of
clinical pictures. Geraldes et al. concluded that neurophysiological
changes were due to brain modulation proper of CD moreover they affirm
that in no previous study corticomotor threshold was investigated.
In a previous TMS-psychogenic palsy larger (21 patients) study [2]
corticomotor threshold and MEP amplitude were explored without any
significant differences respect to the unaffected side nor to the controls
group. CD frequently represents a great challenge for neurologist and TMS
contribute to speed up this diagnosis in psychogenic paralysis [2].
Although the hypothesis of Geraldes et al. may be intriguing, their TMS
findings could confuse the already complex diagnostic pathway in patients
with psychogenic paralysis.
Geraldes R, Coelho M, Rosa MM, Severino L, Castro J, de Carvalho M.
Abnormal transcranial magnetic stimulation in a patient with presumed
psychogenic paralysis.J Neurol Neurosurg Psychiatry. 2008 ;79(12):1412-
1413.
Cantello R, Boccagni C, Comi C, Civardi C, Monaco F. Diagnosis of
psychogenic paralysis: the role of motor evoked potentials. J Neurol. 2001
;248: 889-897.
I read with interest the excellent review on Charcot-Marie-Tooth
disease (CMT) by Reilly and Shy (1). I wish to make a brief comment on CMT
associated with dynamin 2 gene mutations. This CMT subtype is currently
classified within dominant intermediate CMT type B (DI-CMTB), as
electrophysiological study characteristically shows motor conduction
velocities in the intermediate range (25-45 m/s). There are, however,
three re...
I read with interest the excellent review on Charcot-Marie-Tooth
disease (CMT) by Reilly and Shy (1). I wish to make a brief comment on CMT
associated with dynamin 2 gene mutations. This CMT subtype is currently
classified within dominant intermediate CMT type B (DI-CMTB), as
electrophysiological study characteristically shows motor conduction
velocities in the intermediate range (25-45 m/s). There are, however,
three recent pedigrees associated to mutations in the PH or M domain of
the gene causing a well defined axonal phenotype (2-4). CMT subtypes
(CMT1, CMT2A, etc.) are used to characterise specific causes of each of
the larger categories (1). As demonstrated in the case of several CMT
causative gene mutations, including dynamin 2, this system is not perfect
(1). CMT caused by dynamin 2 mutations could be classified either within
DI-CMTB, or within CMT2 in which case this calls for a new acronym
(following the order of publication this might be CMT2M).
References
1. Reilly MM, Shy ME. Diagnosis and new treatments in genetic
neuropathies. J Neurol Neurosurg Psychiatry 2009; 80: 1304-14.
2. Fabrizi GM, Ferrarini M, Cavallaro T, et al. Two novel mutations in
dynamin-2 cause axonal Charcot-Marie-Tooth disease. Neurology 2007; 69:
291-5.
3. Gallardo E, Claeys KG, Nelis E, et al. Magnetic resonance imaging
findings of leg musculature in Charcot-Marie-Tooth disease type 2 due to
dynamin 2 mutation. J Neurol 2008; 255:986-92.
4. Claeys KG, Zuchner S, Kennerson M, et al. Phenotypic
spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy. Brain
2009; 132: 1741-52.
To the editor:
I read with interest the case report recently published in your journal.
In this paper, Gregoire and colleagues describe a 24-year-old man with
strokes without systemic involvement as the presenting feature of Fabry
disease. They conclude that a pure cerebrovascular presentation of Fabry
disease without prior multisystem involvement (mainly, cardiomyopathy,
skin lesions or renal involvement) has not previo...
To the editor:
I read with interest the case report recently published in your journal.
In this paper, Gregoire and colleagues describe a 24-year-old man with
strokes without systemic involvement as the presenting feature of Fabry
disease. They conclude that a pure cerebrovascular presentation of Fabry
disease without prior multisystem involvement (mainly, cardiomyopathy,
skin lesions or renal involvement) has not previously been clearly
described.
Recently, data from 2446 patients in the Fabry Registry were analyzed to
identify clinical characteristics of patients experiencing stroke during
the natural history period (before enzyme replacement therapy) [1]. A
total of 138 patients (86 of 1243 males [6.9%] and 52 of 1203 females
[4.3%]) experienced strokes. Median age at first stroke was 39.0 years in
males and 45.7 years in females. Most patients (70.9% of males and 76.9%
of females) had not experienced renal or cardiac events before their first
stroke. Fifty percent of males and 38.3% of females experienced their
first stroke before being diagnosed with Fabry disease.
So, stroke in Fabry disease frequently occurs before diagnosis and in the
absence of other key signs of the disease.
1. Sims K, Politei J, Banikazemi M, Lee P. Stroke in Fabry disease
frequently occurs before diagnosis and in the absence of other clinical
events: natural history data from the Fabry Registry. Stroke 2009
Mar;40:788-94.
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...
Kagi and colleagues (1) provide a review but not a critique of a controversial technique. For a technique to have diagnostic utility it needs sensitivity to the disease and reproducibility; DAT-SPECT unfortunately falls down on each. The review describes the test as around 100% sensitive as a diagnostic tool in detecting PD. The authors conclude that the normal scans in 5-15% of patients with de-novo PD are normal becau...
Metabolic syndrome and the dementias: a link between Alzheimer disease and vascular dementia?
Sotirios Giannopoulos, Athanassios P. Kyritsis, Maria Kosmidou, Haralampos J. Milionis
Departments of Neurology & Internal Medicine University of Ioannina School of Medicine, Ioannina, Greece
Key words: metabolic syndrome; Alzheimer disease; vascular dementia; cerebrovascular disease;
Au...
Dear Editor, we read with great interest the paper by Attarian et al on response to Intravenous immunoglobulin (IVIg) therapy in patients with chronic ataxic neuropathies and anti-GD1b antibodies. We would like to share our experience with a patient with chronic ataxic demyelinating polyneuropathy and antibodies to disialogangliosides who responded to Rituximab therapy. A 69-year-old man presented in August 2006 with sub...
Dear Editor,
I read with interest the article by Geraldes et al.[1] on the use of transcranial magnetic stimulation (TMS) in psychogenic paralysis. The Authors showed in a young lady with a reversible left body limbs paresis due to conversion disorders (CD), a significant increase of corticomotor threshold and reduction in amplitude of motor evoked potentials (MEP) in the affected side. These changes were resto...
I read with interest the excellent review on Charcot-Marie-Tooth disease (CMT) by Reilly and Shy (1). I wish to make a brief comment on CMT associated with dynamin 2 gene mutations. This CMT subtype is currently classified within dominant intermediate CMT type B (DI-CMTB), as electrophysiological study characteristically shows motor conduction velocities in the intermediate range (25-45 m/s). There are, however, three re...
To the editor: I read with interest the case report recently published in your journal. In this paper, Gregoire and colleagues describe a 24-year-old man with strokes without systemic involvement as the presenting feature of Fabry disease. They conclude that a pure cerebrovascular presentation of Fabry disease without prior multisystem involvement (mainly, cardiomyopathy, skin lesions or renal involvement) has not previo...
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