Displaying 1-10 letters out of 474 published
C9ORF72 in dementia with Lewy bodies
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; firstname.lastname@example.org 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.
Conflict of Interest:
Does clinical evidence for lower motor neuron dysfunction support prion-like spreading in ALS?
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.
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.
Conflict of Interest:
Setting the Gold Standard
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.
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.
Conflict of Interest:
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. 
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. 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. 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.
1. Miró C, Ortiz T. Neurological pictures. Trigeminalepsy. J Neurol Neurosurg Psychiatry 2013;84:857-8.
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.
Conflict of Interest:
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.
Conflict of Interest:
A CASE OF RECURRENT BICKERSTAFF BRAINSTEM ENCEPHALITIS
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.
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.
Conflict of Interest:
Cerebral amyloid angiopathy-scoring methods
In their recent meta-analysis of genetics of cerebral amyloid angiopathy (CAA), Rannikmae et al, 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: 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:). 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.
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.
Conflict of Interest:
Re:The role of dopamine transporter single photon emission CT (DaT-SPECT) in the diagnosis of drug-induced Parkinsonism.
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.
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.
Re: DISCORDANT EFFECTS ON ANXIETY AND DEPRESSION OF MEDITERRANEAN DIET AND OF PHYSICAL ACTIVITY ENHANCEMENT
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) . The PREDIMED- NAVARRA trial found a favorable effect of MedDiet on cognitive function . 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 . 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) . 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 . 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.
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.
Conflict of Interest:
DISCORDANT EFFECTS ON ANXIETY AND DEPRESSION OF MEDITERRANEAN DIET AND OF PHYSICAL ACTIVITY ENHANCEMENT
We read with a great interest the article of Mart?nez-Lapiscina et al. 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. 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.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  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]  Samieri C, Grodstein F, Rosner BA,et al. Mediterranean Diet and Cognitive Function in Older Age. Epidemiology. 2013;24:490-499.  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]  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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