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INTRODUCTION
Recent studies have shown that a large hexanucleotide expansion in C9ORF72
is the most common cause of inherited Frontotemporal Lobar Degeneration
(FTLD) and Motor Neurone Disease (MND).1 In pathological terms, expansion
carriers show a distinctive molecular signature within the dentate gyrus
granule cells and CA4 pyramidal cells of the hippocampus and granule cells
of the cerebellum characterised by TDP-43-ne...
INTRODUCTION
Recent studies have shown that a large hexanucleotide expansion in C9ORF72
is the most common cause of inherited Frontotemporal Lobar Degeneration
(FTLD) and Motor Neurone Disease (MND).1 In pathological terms, expansion
carriers show a distinctive molecular signature within the dentate gyrus
granule cells and CA4 pyramidal cells of the hippocampus and granule cells
of the cerebellum characterised by TDP-43-negative, but p62-positive,
neuronal cytoplasmic inclusions (NCI).2 In clinical terms, psychosis is
one of the major clinical traits in patients with FTLD and/or MND who
carry expansions in C9ORF72.3 Given that psychosis is also common in
Dementia with Lewy bodies (DLB), we previously genetically screened 102
patients with clinically diagnosed DLB, and detected an expansion in
C9ORF72 in 2 patients.4 Consequently, we immunostained tissue sections of
hippocampus and cerebellum for p62 protein from a series of 53
pathologically confirmed cases of DLB in order to ascertain to what extent
expansions in C9ORF72 might be present in this disorder.
METHODS
Brain tissues were available from a series of 53 patients with
pathologically confirmed DLB within the Manchester Brain Bank. All had
been obtained with full ethical permission following consent by the next
of kin. Paraffin sections were cut (at a thickness of 6?m) from formalin
fixed blocks of temporal cortex (with hippocampus) and cerebellar cortex
and immunostained for p62 proteins (rabbit polyclonal antibody to p62-lck
ligand, B D Biosciences, Oxford, UK, 1:100 dilution), involving pressure
cooking the sections for antigen retrieval and employing a standard ABC
Elite kit (Vector, Burlingame, CA, USA) with DAB as chromagen.
Immunostained sections were assessed for presence of p62-immunoreactive
NCI within the dentate gyrus and CA2/3/4 regions of the hippocampus, and
within the granule cells of the cerebellum.
RESULTS
No p62-immunoreactive NCI were seen within the hippocampus or cerebellum
in any of the 53 cases.
DISCUSSION
Previously, when screening a series of 102 patients fulfilling criteria
for probable DLB we detected an expansion in C9ORF72 in two patients.4
Similar to expansion carriers with FTLD,3 both patients displayed
psychotic features, though in neither was a previous family history of
dementia recorded, nor was there pathological confirmation of DLB or other
underlying neurodegenerative disease. Therefore it was possible that these
2 individuals were misdiagnosed. Indeed, a frontotemporal dementia
phenotype that mimics DLB has been reported.5 We therefore investigated 53
pathologically confirmed cases of DLB for an expansion in C9ORF72, using
the presence of p62-immunoreactive NCI in hippocampus and cerebellum as a
surrogate marker, but did not detect any cases where relevant tissue
changes were present. Although only a few of the cases had undergone
formal genetic analysis for expansions in C9ORF72, and shown to be
negative, evidence indicates that the presence of p62-positive NCI in
these brain regions can nevertheless act robustly as a marker of the
expansion in the absence of genetic analysis. From this study, we
therefore conclude that expansions in C9ORF72 in confirmed cases of DLB
are unlikely, and in those patients bearing expansions in clinically
assessed cohorts an atypical presentation of an underlying process of
frontotemporal lobar degeneration is likely to be present.
Andrew Robinson, Yvonne Davidson, Julie S Snowden, David M A Mann
Clinical and Cognitive Sciences Research Group, Institute of Brain,
Behaviour and Mental Health, Faculty of Medical and Human Sciences,
University of Manchester, Salford Royal Hospital, Salford, M6 8HD, UK.
Correspondence to
Professor David Mann, Clinical and Cognitive Sciences Research Group,
Institute of Brain, Behaviour and Mental Health, Faculty of Medical and
Human Sciences, University of Manchester, Salford Royal Hospital, Salford,
M6 8HD, UK; david.mann@manchester.ac.uk
Contributors
DMAM conceived the study, performed microscopic analyses and prepared the
manuscript. AR and YD prepared tissue sections and performed
immunohistochemical staining. JS assisted with clinical characterization
of the cohort.
Funding
The work of the Manchester Brain Bank is supported by Alzheimers Research
UK and Alzheimer's Society under the Brains for Dementia Research (BDR)
initiative. The study was supported in part by MRC and Wellcome Trust
Neuroscience Initiative MRC G0701441).
Competing Interests
None
Ethics Approval
Ethics approval was provided by Newcastle and North Tyneside 1 Local
Research Ethics Committee under Generic Tissue Bank Ethical Agreement.?
References
1. Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat
expansion in C9ORF72 is the cause of chromosome 9p21-linked amyotrophic
lateral sclerosis-frontotemporal dementia. Neuron 2011;72:257-68.
2. Mann DMA, Rollinson S, Robinson A, et al. Dipeptide repeat proteins are
present in the p62 positive inclusions in patients with Frontotemporal
Lobar Degeneration and Motor Neurone Disease associated with expansions in
C9ORF72. Acta Neuropathol Comm 2013;1:68. DOI: 10.1186/2051-5960-1-68.
3. Snowden JS, Rollinson S, Thompson JC, et al. Distinct clinical
characteristics in patients with frontotemporal dementia and C9ORF72
mutations: a study of demographics, neurology, behaviour, cognition, and
histopathology. Brain 2012;135:693-708.
4. Snowden JS, Rollinson S, Lafon C, et al. Psychosis, C9ORF72 and
Dementia with Lewy bodies. J Neurol Neurosurg Psychiatry 2012;83:1031-2.
5. Claasen DO, Parisi JE, Giannini C, et al. Frontotemporal dementia
mimicking dementia with Lewy bodies. Cogn Behav Neurol 2008; 21:157-63.
In a recent, impressive article, Teruhiko Sekiguchi et al. (1)
hypothesize that misfolded proteins accumulating in some neurodegenerative
diseases, including Alzheimer's disease, Parkinson's disease, and
amyotrophic lateral sclerosis (ALS), can cause aggregation of their native
counterparts through a mechanism similar to the infectious prion protein's
induction of a pathogenic conformation onto its normal cellular isoform....
In a recent, impressive article, Teruhiko Sekiguchi et al. (1)
hypothesize that misfolded proteins accumulating in some neurodegenerative
diseases, including Alzheimer's disease, Parkinson's disease, and
amyotrophic lateral sclerosis (ALS), can cause aggregation of their native
counterparts through a mechanism similar to the infectious prion protein's
induction of a pathogenic conformation onto its normal cellular isoform.
Recent in vitro studies have indicated that newly formed aggregates of TAR
DNA-binding protein 43 as well as superoxide dismutase 1 (SOD1) can act as
templates for the subsequent misfolding of the respective native proteins,
and that the misfolded proteins can be intercellularly transferred in
cultured cells (2).
Neurodegeneration in ALS typically begins focally and then spreads
spatiotemporally until neurons of the respiratory system are lost. Some
researchers, therefore, suggest that ALS pathology is similarly initiated
at a single site and spreads via cell-to-cell transmission of prion-like
pathogenic conformers in a 'single seed and simple propagation' model of
ALS (2). Assuming that ALS progresses according to the proposed model, ALS
lesions will spread contiguously along the spinal segments. Using needle
electromyography (EMG), Sekiguchi et al. analyzed abnormal spontaneous
activity of pairs of muscles innervated from different spinal segments in
patients with early-stage sporadic ALS. They found that abnormal lower
motor neuron activity showed a noncontiguous pattern in many ALS patients,
suggesting that this skipping pattern of rostrocaudal spread does not
support the 'single seed' hypothesis. Instead, they proposed a 'multifocal
hits and local propagation' hypothesis. In their article, however, they do
not present the data to support their hypothesis of local disease spread
in a prion-like manner on the grounds that such data are not required from
a methodological point of view.
A motor pool refers to all of the individual motor neurons that
innervate a single muscle. Because of motor pools in the spinal cord are
clustered in distinct columns of motor neurons extending over multiple
spinal cord segments, a longitudinal study for estimating the number of
motor units from individual muscles in ALS patients may provide a
mechanistic insight into local disease spread.
Over the years a number of techniques have been developed to estimate
the number of motor units in humans by defining a motor unit as the spinal
motor neuron and its axon together with the muscle fibers it innervates.
Motor unit number estimation (MUNE) is a technique that uses EMG to
estimate the number of motor units in a muscle. Ridall PG et al.(3)
developed a Bayesian statistical methodology to analyze
electrophysiological data to provide an estimate of motor unit numbers.
This method uses mathematical equations that express the basic elements of
motor unit activation after electrical stimulation, allows for sources of
variability and uncertainty, and has the capacity to estimate a larger
number of motor units.
The exponential decimation of remaining lower motor neurons over time
and different rates of progression have recently been demonstrated using
the Bayesian MUNE (one of the most reliable methods for estimation of the
total number of motor units) in both ALS patients and SOD1-linked familial
ALS patients in all of the muscles examined (4). Furthermore, using SOD1
transgenic mice, MUNE values obtained with the Bayesian method showed a
solid correlation with the histologically determined number of remaining
lower motor neurons in the spinal cord. The exponential kinetics of
neuronal cell loss are consistent with the 'one-hit' model of
neurodegeneration described by Clarke et al. in which the death of a
neuron is initiated randomly in time by a single, rare, catastrophic event
independently of any neighboring neuron (5). Thus, the endogenous,
stochastic occurrence of the one-hit events in a homogenous population of
lower motor neurons may play a pivotal role in local disease spread. These
features are clearly distinct from those of the prion-like propagation
model of disease spread.
These findings, together with the study by Sekiguchi et al., suggest
that lower motor neuron dysfunction defined by the electrophysiological
evidence in ALS supports neither the 'simple propagation' nor the 'single
seed' hypothesis.
References:
1. Sekiguchi T et al. Spreading of amyotrophic lateral sclerosis
lesions--multifocal hits and local propagation? J Neurol Neurosurg
Psychiatry doi: 10.1136/jnnp-2013-305617
2. Polymenidou M, Cleveland DW. The seeds of neurodegeneration:
prion-like spreading in ALS. Cell 2011; 147:498-508.
3. Ridall PG, Pettitt AN, Henderson RD, McCombe PA. Motor unit
number estimation-a Bayesian approach. Biometrics. 2006; 62:1235-1250.
4. Baumann F et al. Quantitative studies of lower motor neuron
degeneration in amyotrophic lateral sclerosis: evidence for exponential
decay of motor unit numbers and greatest rate of loss at the site of
onset. Clin Neurophysiol. 2012; 123:2092-8.
5. Clarke G, Lumsden CJ. Scale-free neurodegeneration: cellular
heterogeneity and the stretched exponential kinetics of cell death. J
Theor Biol. 2005; 233:515-525.
We read the above study with interest and appreciated the thorough
analysis. Whilst the authors acknowledge in their discussion that the Wada
test is a 'silver standard', they nevertheless conclude that the Wada test
is warranted when fMRI fails to show clear left lateralisation. We would
make the following points:
1. The true "gold standard" for language dominance tests is
prediction of outc...
We read the above study with interest and appreciated the thorough
analysis. Whilst the authors acknowledge in their discussion that the Wada
test is a 'silver standard', they nevertheless conclude that the Wada test
is warranted when fMRI fails to show clear left lateralisation. We would
make the following points:
1. The true "gold standard" for language dominance tests is
prediction of outcome. The authors acknowledge this in their discussion.
2. Recent studies suggest that high-quality fMRI is somewhat more
accurate than the Wada test in predicting postoperative language outcomes.
Sabsevitz et al showed better prediction of naming outcome by fMRI than by
Wada in an unselected sample of left anterior temporal lobectomy patients.
Janecek et al demonstrated that in patients with discordant fMRI and Wada,
fMRI is generally more accurate at predicting language outcomes than the
Wada test. Thus it is erroneous to consider fMRI results as inaccurate
simply because the technique picks up more activation in the right
hemisphere. It turns out that this "non-essential activation" probably
helps patients recover.
3. For these reasons, it makes little sense to use fMRI as a
screening tool and Wada as the standard in patients with atypical language
representation.
4. The conclusion that the Wada test is warranted cannot be justified
using this methodology employing a suboptimal clinical standard.
References:
Sabsevitz DS, Swanson SJ, Hammeke TA, Spanaki MV, Possing ET, Morris
GL, Mueller WM, Binder JR. Use of preoperative functional neuroimaging to
predict language deficits from epilepsy surgery. Neurology, 2003; 60: 1788
-1792.
Janecek JK, Swanson SJ, Sabsevitz DS, Hammeke TA, Raghavan M, Mueller
W, Binder JR. Naming outcome prediction in patients with discordant Wada
and fMRI language lateralization. Epilepsy & Behavior, 2013; 27: 399-
403.
We celebrate the excitement shown by Unterberger and Bauer to our
contribution on trigeminalepsy, since they give us the chance to include
some technical data which were considered of limited interest for
clinicians. Figure 1 in our original paper shows a 4.20 seconds frame from
a conventional 32-channel video-EEG register filtered within 0.5-70 Hz.
[1]
We chose figure 1 because it unequivocally shows interictal...
We celebrate the excitement shown by Unterberger and Bauer to our
contribution on trigeminalepsy, since they give us the chance to include
some technical data which were considered of limited interest for
clinicians. Figure 1 in our original paper shows a 4.20 seconds frame from
a conventional 32-channel video-EEG register filtered within 0.5-70 Hz.
[1]
We chose figure 1 because it unequivocally shows interictal epileptic
activity, with non-rhythmic spikes of an amplitude >50 microvolts (up
to 120 microvolts) after a tactile stimulation with no subsequent pain
attack. Interictal spike activity was asymmetric, predominantly registered
in the right central and right parietal leads. Such a pattern of
interictal spikes is widely accepted as a finding that points towards
epilepsy.[2] A following simple EEG showed spike-and-wave discharges
during an episode of facial pain. Contrarily to what Unterberger and Bauer
state, our patient was awake before and after the arrow in figure 1.
Any exhausting mention of the current controversies on epilepsy, as
unintelligibly quoted by Unterberger and Bauer, is far beyond the scope of
our neurological picture. Our humble contribution claims for attention to
antidepressant selection in patients with rebel epilepsy, and invites to
further explore epilepsy as a potential differential diagnosis of
trigeminal neuralgia as Haan remarks.[3] Age of onset was critical to
consider other diagnoses than trigeminal neuralgia in our patient. As
reported in detail, a systematic approach led us to the diagnosis of
epilepsy.
2. de Curtis M, Avanzini G. Interictal spikes in focal
epileptogenesis. Prog Neurobiol 2001;63:541-67.
3. Haan J. F1000Prime Recommendation of [Miro C and Ortiz T, J Neurol
Neurosurg Psychiatr 2013, 84(8):857-8]. In F1000Prime,11 Sept
2013;doi:10.3410/f.718097750.793483143.
F1000Prime.com/718097750#eval793483143.
Sirs,
We read with interest and some kind of excitement the contribution of Mir?
and Ortiz about "Trigeminalepsy" (1). We would like to concentrate our
comments on "Figure 1 Video-EEG trace revealing spike discharges ..." No
technical details like montage, filters and time frame are indicated.
Therefore, a post hoc interpretation includes uncertainities. However, a
change of dominant activities after the arrow ("touch of...
Sirs,
We read with interest and some kind of excitement the contribution of Mir?
and Ortiz about "Trigeminalepsy" (1). We would like to concentrate our
comments on "Figure 1 Video-EEG trace revealing spike discharges ..." No
technical details like montage, filters and time frame are indicated.
Therefore, a post hoc interpretation includes uncertainities. However, a
change of dominant activities after the arrow ("touch of the cheek") is
evident. The first part of the EEG shows a state of drowsiness or light
sleep, after the touch rhythmical activities are predominant. The change
of vigilance starts with a type of arousal response the authors called
spike discharge. The pattern certainly cannot be interpreted as a seizure
pattern. Furthermore, the spiky component is not followed by a slow wave
as with interictal spikes. In summary, the published figure shows an
arousal from light sleep due to touch of the cheek. The trace is no
proving for an epileptic event and definitely not for a seizure onset
zone.
The contribution opens several other questions like the controversy about
migraine and epilepsy (2), the localizing significance of painful auras
(3), the diagnostic value of fMRI for epilepsies without corresponding
ictal EEG signs, the role of AEDs in the treatment of neuralgias and the
proof of medical refractoriness as a prerequisite for the indication of
epilepsy surgery. The exciting interpretation of trigeminal neuralgia as
focal reflex epilepsy would have justified a more complete clinical
description.
We read with great interest the review by Dr Shahrizaila and Prof
Yuki on Bickerstaff brainstem encephalitis (BBE) and Fisher syndrome (FS)
(1) and would like to refer in particular to the section about recurrent
illnesses. As stated, FS and BBE are typically monophasic and recurrent
episodes are rare. Although recurrent episodes have been described in the
literature, after a thorough literature search, only one clear do...
We read with great interest the review by Dr Shahrizaila and Prof
Yuki on Bickerstaff brainstem encephalitis (BBE) and Fisher syndrome (FS)
(1) and would like to refer in particular to the section about recurrent
illnesses. As stated, FS and BBE are typically monophasic and recurrent
episodes are rare. Although recurrent episodes have been described in the
literature, after a thorough literature search, only one clear documented
case of recurrent BBE was found. (2) In this respect, we would like to
present our case of recurrent Bickerstaff Brainstem Encephalitis.
A 35 year old male patient presented with a one day history of
progressively worsening double vision, numbness and paraesthesia of the
hands and feet and unsteady gait. A week prior to the onset of these
symptoms, he admitted to having had a diarrhoeal illness which had
resolved completely. The patient insisted that these symptoms were
identical to those preceding a "viral encephalitis" he had suffered ten
years before.
On examination at the time he was fully conscious. However he had complex
ophthalmoplegia and a wide-based, ataxic gait. Tone and power were normal
in all four limbs and he was areflexic. Interestingly, both plantar
responses were extensor. Sensory examination was normal. Initial blood
investigations, CT scan and MRI of the brain, and cerebrospinal fluid
(CSF) analysis were all normal. A clinical diagnosis of FS was made and he
was immediately started on treatment with intravenous immunoglobulins
(IvIg).
Several hours later, on the same day of admission, the patient developed
rapid deterioration in his level of consciousness. He became drowsy and
non-communicative, vomited incessantly, and developed fever. He adopted a
decorticate posture with markedly increased tone in all four limbs, the
upper limbs in flexion and the lower limb in extension. He was urgently
transferred to the Intensive Therapy Unit (ITU), intubated and ventilated.
At this point a clinical diagnosis of BBE was made. The presence of
progressive symmetrical ophthalmoplegia and ataxia, decreased level of
consciousness, pyramidal signs and normal peripheral power met the
criteria (3) for this condition.
Intravenous Methylprednisolone was added to the treatment regime. A repeat
MRI of the brain was normal. EEG showed theta activity consistent with a
non-specific encephalopathy. Nerve conduction studies showed an axonal
sensori-motor peripheral neuropathy. A serum sample for anti GQ1b
antibodies taken prior to commencing treatment with IvIg eventually
confirmed the diagnosis with a strongly positive titre (224; normal range
up to 30). C. jejuni antibodies were also positive (1:80; normal range
<1:10).
During the patient's stay in ITU, he showed no neurological improvement
despite treatment. In addition he had persistent pyrexia and evidence of
dysautonomia with sinus tachycardia and labile hypertension. An elective
tracheostomy was performed and a decision to empirically perform plasma
exchange was taken after two weeks. During the fourth week in intensive
care, the patient gradually started to regain consciousness and continued
to improve. He was eventually transferred to the neurology ward where he
underwent intensive rehabilitation and recovered fully after a period of
about six weeks. He was seen at the neurology out-patients clinic 3
months following discharge from hospital where he was found to have no
neurological deficit.
Discussion with the patient's family revealed that at 25 years of age, the
patient had suffered an identical illness and was treated in a hospital in
his home country. Review of the case notes showed that the patient had
developed abdominal pain and diarrhoea for 48 hours. Days after this
resolved he had developed speech disturbances, numbness over the trunk and
upper limbs and ataxia. There was then deterioration in level of
consciousness with decorticate posturing and respiratory insufficiency
necessitating transfer to intensive care. An MRI of the brain had shown a
possible hypointense area in the medial temporal lobe. CSF had revealed
normal protein 0.33 g/l and normal cell count. EEG had shown a slow
background with occasional high voltage signals. Apart from receiving
Ceftriaxone and Acyclovir, the patient had also received IvIg and
intravenous steroids. At the time the presumed diagnosis was that of a
viral encephalitis. In retrospect this event was more probably the
patient's first episode of BBE following a diarrhoeal illness.
There have been cases of FS or Guillaine-Barre syndrome (GBS) followed by
a second episode which involved clouding of consciousness. (4,5) However
we consider our case to be remarkable because it was recurrent BBE. To
our knowledge, there is only one other reported case of recurrent BBE. (2)
This same case showed MRI changes, namely hyperintensity on T2 weighted
images in the brainstem, with no contrast enhancement.
Furthermore we would like to highlight two other issues. The first is that
in our patient there was clear progression from a clinical diagnosis of FS
to BBE within 24 hours, giving support to the proposed "anti-GQ 1b
antibody syndrome" with the two conditions being at the ends of a clinical
spectrum. Moreover, although the outcome of BBE is more often than not
benign, the duration of unconsciousness in an immobile decorticate posture
with severe dysautonomia can lead to potentially life-threatening
complications of sepsis and thromboembolism. Therefore we feel the need to
emphasise the importance of having evidenced based and well defined
therapeutic options aimed at shortening as far as possible this period of
unconsciousness and would appreciate any contributions from your
readership relevant to this.
References:
1. Shahrizaila N, Yuki N. Bickerstaff brainstem encephalitis and
Fischer syndrome: anti-GQ1b antibody syndrome. J Neurol Neurosurg
Psychiatry 2013; 84:576-583
2. Mond?jar RR, Santos JM, Villalba EF. MRI findings in a remitting-
relapsing case of Bickerstaff encephalitis. Neuroradiology 2002; 44(5):
411-4.
3. Odaka M, Yuki N, Hirata K. Anti-GQ1b IgG antibody syndrome: clinical
and immunological range. J Neurol Neurosurg Psychiatry 2001; 70(1): 50-5.
4. Sharma V, Chan Y C, Ong, Teoh H L, Wilder- Smith E P.
Bickerstaff's brainstem encephalitis: can it recur? Journal of Clinical
Neuroscience 2006; 13(2): 277-9.
5. DONG Hui-qing, LIU Zheng, TANG Yi, LU Yan, WANG Qi and JIA Jian-
ping. Recurrent Fisher- Bickerstaff syndrome: report of a Chinese case.
Chinese Medical Journal 2011; 124(17): 2786-2788.
In their recent meta-analysis of genetics of cerebral amyloid
angiopathy (CAA), Rannikmae et al,[1] focusing on the association between
APOEe4 and sporadic CAA, stated that there is no widely accepted
standardised histopathological grading system for CAA. Although this is
true, several methods are currently used to describe the severity of CAA
in postmortem brain,[2, 3] and recently a semiquantitative scoring method
has...
In their recent meta-analysis of genetics of cerebral amyloid
angiopathy (CAA), Rannikmae et al,[1] focusing on the association between
APOEe4 and sporadic CAA, stated that there is no widely accepted
standardised histopathological grading system for CAA. Although this is
true, several methods are currently used to describe the severity of CAA
in postmortem brain,[2, 3] and recently a semiquantitative scoring method
has been suggested:[4] amyloid-beta (A-beta) deposition is scored
separately in meningeal and intracortical blood vessels on sections from
occipital, parietal, temporal, and frontal cortices: absent (0), scant A-
beta deposition (1), some circumferential A-beta deposition (2), and
widespread A-beta deposition (3). These scores are stated separately for
meningeal and intracortical blood vessels. In addition, the presence of
CAA in capillaries (capCAA) is noted (i.e., 0 and 1) and vasculopathy,
including fibrinoid necrosis, thrombosis, hemorrhage and double barreling
is assessed semiquantitatively with absent (0), occasional vessels (1),
and many vessels (2). The addition of respective scores gives a regional
total score and the overall severity of CAA across the brain may be
described by stating the mean value of all regional total scores (for
review see:[5]). Further research efforts using these or newly developed
methods will facilitate comparisons between different studies and will be
useful for the pooling of new data.
References
1. Rannikmae K, Samarasekera N, Martinez-Gonzalez NA, et al. Genetics
of cerebral amyloid angiopathy: systematic review and meta-analysis. J
Neurol Neurosurg Psychiatry 2013;84:901-908.
2. Vonsattel JP, Myers RH, Hedley-Whyte ET, et al. Cerebral amyloid
angiopathy without and with cerebral hemorrhages: a comparative
histological study. Ann Neurol 1991;30:637-649.
3. Olichney JM, Hansen LA, Hofstetter CR, et al. Cerebral infarction
in Alzheimer's disease is associated with severe amyloid angiopathy and
hypertension. Arch Neurol 1995;52:702-708.
4. Chalmers K, Love S, Ince P, et al. Validation of international
consensus criteria for the assessment of cerebral amyloid angiopathy in
post-mortem brain. In 6th Interantional Conference on Vascular Dementia
2009; Barcelona, Spain.
5. Attems J, Jellinger K, Thal DR, Van Nostrand W. Review: sporadic
cerebral amyloid angiopathy. Neuropathol Appl Neurobiol 2011;37:75-93.
We thank Dr McKinley for his correspondence on our paper entitled
"Clinical utility of dopamine transporter single photon emission computed
tomography (DaTspect) with [123I] ioflupane in diagnosis of parkinsonian
syndromes".
Although suspected drug-induced parkinsonism (DIP) was not a direct
focus of our review, we included DIP cases and discussed them as being
either suspected/uncertain parkinsonian syndromes...
We thank Dr McKinley for his correspondence on our paper entitled
"Clinical utility of dopamine transporter single photon emission computed
tomography (DaTspect) with [123I] ioflupane in diagnosis of parkinsonian
syndromes".
Although suspected drug-induced parkinsonism (DIP) was not a direct
focus of our review, we included DIP cases and discussed them as being
either suspected/uncertain parkinsonian syndromes (PS) or as subjects with
scans without dopaminergic deficit (SWEDD).
A direct discussion on DIP was not included as DaTscan is not
approved for the differential diagnosis between DIP and idiopathic
Parkinson's disease (IPD), and additional registration studies and
regulatory efforts would be needed to confirm such utility and update the
product label. We are aware that many clinicians already utilise DaTscan
in an off licensed indication for this clinical question.
DIP is a heterogeneous disorder due to a variety of drug classes
(discussed in 1). Most have clear post-synaptic dopaminergic receptor
blockade (tardive parkinsonism), but there are other cases where
dopaminegic blockers have exacerbated/unmasked prodromal pre-synaptic PD
and lastly cases where a combination of pre- and post-synaptic
dopaminergic effects are speculated (2, 3).
DaTscan would not be able to differentiate these latter two diagnoses
with both showing an abnormal scan. Similarly, a normal DaTscan does not
confirm tardive parkinisonism in this clinical context as normal DaTscan
is seen in other types of parkinsonism (e.g., psychogenic, vascular, dopa-
responsive dystonia etc.) This heterogeneity is reflected in DaTscan
studies showing a mixture of normal and abnormal scans (from <10% to
>50%) in the DIP population (2, 4).
In addition, studies demonstrated lower striatal dopamine transporter
binding in neuroleptic-naive schizophrenic patients that were not related
to anti-psychotic treatment suggesting a dopamine transporter deficit as a
potential illness trait (3), and/or implying existence of pro-Parkinsonian
risk factors independent of drugs in patients with schizophrenia.
Future research utilizing prospective and controlled study designs
are warranted to clarify the underpinning mechanisms of developing DIP,
and the direct mode of developing of parkinsonism in patients receiving
calcium channel blockers, first generation anti-histamine drugs,
valproate, lithium and other dopaminegic blockers.
References
1. Bondon-Guitton E, Perez-Lloret S, Bagheri H, Brefel C, Rascol O,
Montastruc JL. Drug-induced parkinsonism: a review of 17 years' experience
in a regional pharmacovigilance center in France. Mov Disord. 2011
Oct;26(12):2226-31.
2. Tinazzi M, Cipriani A, Matinella A, Cannas A, Solla P, Nicoletti A,
Zappia M, Morgante L, Morgante F, Pacchetti C, Sciarretta M, Dallocchio C,
Rossi S, Malentacchi M, Ceravolo R, Frosini D, Sestini S, Bovi T, Barbui
C. [???I]FP CIT single photon emission computed tomography findings in
drug-induced Parkinsonism. Schizophr Res. 2012 Aug;139(1-3):40-5.
3. Mateos JJ, Lome?a F, Parellada E, Mireia F, Fernandez-Egea E, Pavia J,
Prats A, Pons F, Bernardo M. Lower striatal dopamine transporter binding
in neuroleptic-na?ve schizophrenic patients is not related to
antipsychotic treatment but it suggests an illness trait.
Psychopharmacology (Berl). 2007 Apr;191(3):805-11.
4. Diaz-Corrales FJ, Sanz-Viedma S, Garcia-Solis D, Escobar-Delgado T, Mir
P. Clinical features and 123I-FP-CIT SPECT imaging in drug-induced
parkinsonism and Parkinson's disease. Eur J Nucl Med Mol Imaging. 2010
Mar;37(3):556-64.
Conflict of Interest:
NB: Since 2002, has received grants from GE Healthcare
(2005), Parkinson's UK (2011, 2012), MRC (2011) and the Sarah Matheson Trust
(2004); has received honoraria for lecture fees from GE Healthcare, UCB Pharma,
Teva Lundbeck, GSK, Genus Pharma; has received honoraria for advisory boards for
UCB, GSK, GE Healthcare. IDG is an employee of GE Healthcare. RAH has received
honoraria or payments for consulting, advisory services, speaking services over the
past 12 months as listed below: Abbott Laboratories, Allergan, Inc., AstraZeneca,
Biotie Therapies Corporation, Ceregene, Chelsea Therapeutics, GE Healthcare, Impax
Laboratories, Ipsen Biopharmaceuticals, Lundbeck, Med-IQ, Merck/MSD, Noven
Pharmaceuticals, Straken Pharmaceuticals, Targacept, Teva Pharmaceuticals
Industries, Teva Neuroscience, Upsher-Smith Laboratories, UCB, UCB Pharma SA,
Xenoport, RAH's institution has received research support over the past 12 months
as listed below: Abbot Laboratories, Addex Therapeutics, Allergan, AstraZeneca,
Chelsea Therapeutics, GE Healthcare, Impax Laboratories, Ipsen Biopharmaceuticals,
Merck/MSD, Merz, Michael J Fox Foundation for Parkinson's Research,
Schering-Plough, Teva Neuroscience, UCB, Vita-Pharm. RAH has received royalties in
the last 12 months: University of South Florida. In addition, RAH has consulted in
litigation with lawyers representing various current and former manufacturers of
welding consumables.
We appreciate the comments by Trovato FM et al in their Letter to the
Editor regarding our recently published trial on Mediterranean Diet
(MedDiet) and cognition (The PREDIMED-NAVARRA trial) [1]. The PREDIMED-
NAVARRA trial found a favorable effect of MedDiet on cognitive function
[1]. This protection was independent of other confounders including mood
disorders and physical activity. In a previous report, Trovato et al
s...
We appreciate the comments by Trovato FM et al in their Letter to the
Editor regarding our recently published trial on Mediterranean Diet
(MedDiet) and cognition (The PREDIMED-NAVARRA trial) [1]. The PREDIMED-
NAVARRA trial found a favorable effect of MedDiet on cognitive function
[1]. This protection was independent of other confounders including mood
disorders and physical activity. In a previous report, Trovato et al
stressed the complex relationships between cognition, mood disorders and
lifestyle factors, such as MedDiet and physical activity [2]. We concur
with them that mood disorders, MedDiet, physical activity and other
lifestyle factors jointly influence cognitive performance. Adjusting for
all these factors is the accepted strategy in observational studies to
deal with confounding. However, the PREDIMED-NAVARRA trial followed a
randomised design and the randomisation allowed us to reduce the
possibilities for residual confounding. Furthermore, when we adjusted for
some factors, including incident depression, our results did not change.
We decided to adjust for depression as a potential confounder because the
available evidence points to a protective effect of MedDiet on depression.
Recently, a meta-analysis has reported a protective effect of MedDiet on
depression (pooled RR=0.68, 95%CI: 0.54-0.86) [3]. This meta-analysis was
almost completely based on cross-sectional findings (regarding
depression), since few longitudinal studies have focused on this topic.
Among longitudinal studies, it is worthwhile to underline that Sanchez-
Villegas A et al showed that a better adherence to the MedDiet pattern was
associated with lower incidence of depression after 4.4-year of median
follow-up in the Seguimiento Universidad de Navarra (SUN) cohort study.
Interestingly, an inverse dose-response trend was found [4].
In any case, we agree with Trovato et al that an extensive clinical
research is needed to further understand the complex mechanisms by which
lifestyle-based preventive strategies can influence the risk of cognitive
impairment, depression and other chronic diseases.
REFERENCES
1. Martinez-Lapiscina EH, Clavero P, Toledo E, et al. Mediterranean
diet improves cognition: the PREDIMED-NAVARRA randomised trial. J Neurol
Neurosurg Psychiatry 2013;84:824-6.
2. Trovato GM, Catalano D, Martines GF, et al. Mediterranean diet:
Relationship with anxiety and depression. Ann Neurol 2013. Aug 8. [Epub
ahead of print]
3. Psaltopoulou T, Sergentanis TN, Panagiotakos DB, et al. Mediterranean
diet and stroke, cognitive impairment, depression: A meta-analysis. Ann
Neurol 2013. May 30 [Epub ahead of print]
4. Sanchez-Villegas A, Delgado-Rodriguez M, Alonso A, et al. Association
of the Mediterranean dietary pattern with the incidence of depression: the
Seguimiento Universidad de Navarra/University of Navarra follow-up (SUN)
cohort. Arch Gen Psychiatry 2009;66:1090-8.
We read with a great interest the article of Mart?nez-Lapiscina et
al.[1] which elegantly demonstrate how an intervention with Mediterranean
Diets enhanced with either extra-virgin olive oil or nuts supplements
appears to improve cognition compared with a generic low-fat diet.
Concurrently, elsewhere, the article in "Epidemiology" by Samieri et
al.[2] casts doubt on the available evidence that Adherence to a
Mediterran...
We read with a great interest the article of Mart?nez-Lapiscina et
al.[1] which elegantly demonstrate how an intervention with Mediterranean
Diets enhanced with either extra-virgin olive oil or nuts supplements
appears to improve cognition compared with a generic low-fat diet.
Concurrently, elsewhere, the article in "Epidemiology" by Samieri et
al.[2] casts doubt on the available evidence that Adherence to a
Mediterranean diet may help prevent cognitive decline in older age. We
agree with the limitations discussed(2) since many questions are still
open, warranting randomized trials, as the study published by your Journal
is[1].We should like to add some comment for a more comprehensive
discussion on this important subject. It is our opinion that any study on
the effects of healthier nutritional profiles, such Mediterranean Diet is
currently considered, should need more broad information within
epidemiological studies and more focused tools in interventions; among
them the assessment and the modification of sedentary habits have a very
critical relevance, throughout the life, including its cornerstones, such
as pregnancy. All behaviors are linked each other and interferences are
very likely. We reported that effectiveness of a dietary intervention is
facilitated by the enhancement of self-efficacy, i.e. by the awareness of
the benefits of the diet itself and its affordability(3). Self-efficacy,
Mediterranean diet adherence and olive oil intake were significant
independent predictors of the increase of physical activity achieved by
counseling(3). Also the epidemiology of cognitive decline has several
interrelated components: it is recognized that physical exercise has a
retarding effect on cognitive decline, and therapeutic effects are also
described(4). Patients and Methods. We performed a reappraisal of our
counseling intervention study (6 months) aimed at increasing Adherence to
Mediterranean Diet Score (AMDS; range 0-55) and at reducing sedentary
habits, assessed by detailed physical activity reports (Baecke tool) in
overweight-moderately obese subjects. The study was performed in 138
subjects,(males 61, females 77, years 49.95?14.88); suggestions and advice
on individual "healthy" food purchase, storage and cooking were given.
Reliable feedback and evidence of patients' adherence were obtained by
scheduled dietician's interviews at the beginning of the study and after
six months. Health psychology tools, i.e. GSE (General Self-Efficacy), PSM
(Psychological Stress Measure) and HAD (Hospital Anxiety Depression Scale)
validated in our population, are currently used in our preliminary and
post-intervention assessment, and not previously reported. Results.
Challenging the predictive effects of changes of Adherence to
Mediterranean Diet (?AMDS) and of changes of physical activity (?Baecke),
of ?GSE and of ?PSE vs. ?HAD, in an age-balanced model, we found that
both Mediterranean Diet Adherence and Physical Activity increase explain
(R2 0.309 ; p<0.0001) the decrease of the level of anxiety: this
provides evidence of the links among mood, cognition and stress with diet
and exercise. By Odds Ratio, the increase of AMDS is associated with
decreased hazard of Anxiety (Odds Ratio 0.653; 95% CI 0.292-1.463) so that
Mediterranean Diet is seemingly a protective factor against anxiety.
Differently, increase of Physical Activity is associated with an increased
hazard of depression (Odds Ratio 1.298; 95% CI 0.561-3.004), while the
increase of AMDS is associated with a decreased hazard of depression (Odds
Ratio 0.793 ; 95% CI 0.343-1.831); so Mediterranean Diet may be
beneficial against depression occurrence. Conclusion. Mediterranean Diet
is associated with lower hazard of depression and may be beneficial
against its occurrence and, as well, against the hazard of anxiety. No
favorable effect on depression is associated with the increase of physical
activity. Even discordant, we think that contributions along these lines
will enhance further accurate and extensive clinical research, which
should include the concurrent but not univocal effects of different
lifestyle interventions.
REFERENCES
[1] Mart?nez-Lapiscina EH, Clavero P,et al. Mediterranean diet improves
cognition: the PREDIMED-NAVARRA randomised trial. J Neurol Neurosurg
Psychiatry. 2013 May 13. [Epub ahead of print]
[2] Samieri C, Grodstein F, Rosner BA,et al. Mediterranean Diet and
Cognitive Function in Older Age. Epidemiology. 2013;24:490-499.
[3] Catalano D, Trovato GM, Pace P, Martines GF, Trovato FM. Mediterranean
diet and physical activity: An intervention study. Does olive oil exercise
the body through the mind? Int J Cardiol. 2013 May 25. [Epub ahead of
print]
[4] Buchman AS, Boyle PA, Yu L, Shah RC, Wilson RS, Bennett DA. Total
daily physical activity and the risk of AD and cognitive decline in older
adults. Neurology. 2012;78:1323-9.
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We appreciate the comments by Trovato FM et al in their Letter to the Editor regarding our recently published trial on Mediterranean Diet (MedDiet) and cognition (The PREDIMED-NAVARRA trial) [1]. The PREDIMED- NAVARRA trial found a favorable effect of MedDiet on cognitive function [1]. This protection was independent of other confounders including mood disorders and physical activity. In a previous report, Trovato et al s...
We read with a great interest the article of Mart?nez-Lapiscina et al.[1] which elegantly demonstrate how an intervention with Mediterranean Diets enhanced with either extra-virgin olive oil or nuts supplements appears to improve cognition compared with a generic low-fat diet. Concurrently, elsewhere, the article in "Epidemiology" by Samieri et al.[2] casts doubt on the available evidence that Adherence to a Mediterran...
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