Correction to: Continuous subcutaneous apomorphine infusion in Parkinson's disease: causes of discontinuation and subsequent treatment strategies.

The published version of this article unfortunately contained a mistake in Table 2. CGI-S and CGI-I values has been interchanged. The Table is corrected here.

Continuous subcutaneous apomorphine infusion in Parkinson's disease: causes of discontinuation and subsequent treatment strategies.

Continuous subcutaneous apomorphine infusion (CSAI) is a well-recognized therapeutic option for the management of motor fluctuations in Parkinson's disease (PD), although clinical experience suggests that most patients discontinue CSAI after a variable amount of time due to several causes and circumstances. The objective of the present study was to evaluate the reasons of CSAI discontinuation and to investigate which treatment was adopted afterwards. Two independent raters retrospectively reviewed the electronic medical record of 114 patients treated with CSAI for at least 6 months. The records were reviewed regarding efficacy, safety, and evolution of CSAI treatment. Most of PD patients on CSAI had a significant improvement in their clinical condition. Lack of improvement of dyskinesia was the most frequent causes of treatment discontinuation. The second reason for CSAI discontinuation was cognitive deterioration. At CSAI discontinuation, younger patients were more likely to undergo deep brain stimulation (DBS), while older patients and patients with cognitive impairment were more likely switched to oral therapy alone (OTA). CSAI is an effective treatment that unfortunately must be discontinued in a great number of patients with advanced PD. As older age is the main limiting factor for accessing second-level therapies at CSAI discontinuation, CSAI treatment should not be postponed to older age. CSAI might be considered a good first-line and fast strategy in patients undergoing rapid deterioration of their quality of life while waiting for DBS or levodopa/carbidopa intestinal gel therapy.

Whole Exome Sequencing Study of Parkinson Disease and Related Endophenotypes in the Italian Population.

Parkinson Disease (PD) is a complex neurodegenerative disorder characterized by large genetic heterogeneity and missing heritability. Since the genetic background of PD can partly vary among ethnicities and neurological scales have been scarcely investigated in a PD setting, we performed an exploratory Whole Exome Sequencing (WES) analysis of 123 PD patients from mainland Italy, investigating scales assessing motor (UPDRS), cognitive (MoCA), and other non-motor symptoms (NMS). We performed variant prioritization, followed by targeted association testing of prioritized variants in 446 PD cases and 211 controls. Then we ran Exome-Wide Association Scans (EWAS) within sequenced PD cases (N = 113), testing both motor and non-motor PD endophenotypes, as well as their associations with Polygenic Risk Scores (PRS) influencing brain subcortical volumes. We identified a variant associated with PD, rs201330591 in GTF2H2 (5q13; alternative T allele: OR [CI] = 8.16[1.08; 61.52], FDR = 0.048), which was not replicated in an independent cohort of European ancestry (1,148 PD cases, 503 controls). In the EWAS, polygenic analyses revealed statistically significant multivariable associations of amygdala- [ß(SE) = -0.039(0.013); FDR = 0.039] and caudate-PRS [0.043(0.013); 0.028] with motor symptoms. All subcortical PRSs in a multivariable model notably increased the variance explained in motor (adjusted-R2 = 38.6%), cognitive (32.2%) and other non-motor symptoms (28.9%), compared to baseline models (~20%). Although, the small sample size warrants further replications, these findings suggest shared genetic architecture between PD symptoms and subcortical structures, and provide interesting clues on PD genetic and neuroimaging features.

Electrophysiological indices of interference resolution covary with individual fluid intelligence: investigating reactive control processes in a 3-back working memory task.

It has been proposed that the well-established relationship between working memory (WM) and fluid intelligence (gf) is mediated by executive mechanisms underlying interference control. The latter relies upon the integrity of a frontoparietal brain network, whose activity is modulated by general cognition. In regards to the chronology of this activation, only few EEG studies investigated the topic, although none of them examined the regional interaction or the effects of individual differences in gf. The current investigation sought at extending previous research by characterizing the EEG markers (temporal activation and regional coupling) of interference control and the effects of the individual variation in gf. To this end, we recorded the EEG activity of 33 participants while performing verbal and spatial versions of a 3-back WM task. In a separate session, participants were administered with a test of fluid intelligence. Interference-inducing trials were associated with an increased negativity in the frontal scalp region occurring in two separate time windows and probably reflecting two different stages of the underlying cognitive process. In addition, we found that scalp distribution of such activity differed among individuals, being the strongest activation of the left and right frontolateral sites related to high gf level. Finally, high- and low-gf participants showed different patterns in the modulation of regional connectivity (electrodes coherence in the range of 4.5-7.5Hz) according to changes in attention load among types of trials. Our findings suggest that high-gf participants may rely upon effective engagement and modulation of attention resources to face interference.

Acetyl-L-carnitine: from a biological curiosity to a drug for the peripheral nervous system and beyond.

Acetyl-L-carnitine (ALC) is a molecule derived from acetylation of carnitine in the mitochondria. Carnitine acetylation enables the function of CoA and facilitates elimination of oxidative products. Beyond this metabolic activity, ALC provides acetyl groups for acetylcholine synthesis, exerts a cholinergic effect and optimizes the balance of energy processes. Acetylcarnitine supplementation induces neuroprotective, neurotrophic and analgesic effects in the peripheral nervous system. In the recent studies, ALC, by acting as a donor of acetyl groups to NF-kb p65/RelA, enhanced the transcription of the GRM2 gene encoding the mGLU2 receptors, inducing long-term upregulation of the mGluR2, evidencing therefore that its long-term analgesic effects are dependent on epigenetic modifications. Several studies, including double-blind, placebo-controlled, parallel group studies and few open studies showed the effect of ALC in diseases characterized by neuropathies and neuropathic pain: the studies included diabetic neuropathy, HIV and antiretroviral therapy-induced neuropathies, neuropathies due to compression and chemotherapeutic agents. Double-blinded studies involved 1773 patients. Statistical evaluations evidenced reduction of pain, improvements of nerve function and trophism. In conclusion, ALC represents a consistent therapeutic option for peripheral neuropathies, and its complex effects, neurotrophic and analgesic, based on epigenetic mechanism, open new pathways in the study of peripheral nerve disease management.

Cohort study of prevalence and phenomenology of tremor in dementia with Lewy bodies.

To study prevalence, specific patterns and response to treatment of tremor in dementia with Lewy bodies (DLB), in comparison with other tremulous disorders prevalence, qualitative and quantitative features of tremor were studied in an incident cohort of 67 dopaminergic treatment naive DLB, 111 Parkinson's Disease (PD) and 34 Essential Tremor (ET) patients. Tremulous DLB patients (tDLB) were compared with tremulous PD (tPD) and ET patients and followed for 2 years. Double blind placebo-controlled acute drug challenge with L-Dopa and alcohol was performed in all ET, 24 tDLB and 27 tPD. Effects of dopaminergic chronic treatment in all tDLB and tPD patients and primidone in 8 tDLB were also assessed. Tremor occurred in 44.76 % of DLB patients. The tDLB patients presented a complex pattern of mixed tremors, characterized by rest and postural/action tremor, including walking tremor and standing overflow in 50 % tDLB. Standing tremor with overflow was characteristic of tDLB (p < 0.001). Head tremor was more frequent in tDLB than tPD and ET (p = 0.001). The tDLB tremors were reduced by acute and chronic dopaminergic treatments (p < 0.01) but not by alcohol or primidone. Tremor occurs commonly in DLB patients with a complex mixed tremor pattern which shows a significant response to acute and chronic dopaminergic treatments. Recognizing that there is a clinical category of tremulous DLB may help the differential diagnosis of tremors.

Irrelevant features of a stimulus can either facilitate or disrupt performance in a working memory task: the role of fluid intelligence.

It has been shown that fluid intelligence (gf) is fundamental to overcome interference due to information of a previously encoded item along a task-relevant domain. However, the biasing effect of task-irrelevant dimensions is still unclear as well as its relation with gf. The present study aimed at clarifying these issues. Gf was assessed in 60 healthy subjects. In a different session, the same subjects performed two versions (letter-detection and spatial) of a three-back working memory task with a set of physically identical stimuli (letters) presented at different locations on the screen. In the letter-detection task, volunteers were asked to match stimuli on the basis of their identity whereas, in the spatial task, they were required to match items on their locations. Cross-domain bias was manipulated by pseudorandomly inserting a match between the current and the three back items on the irrelevant domain. Our findings showed that a task-irrelevant feature of a salient stimulus can actually bias the ongoing performance. We revealed that, at trials in which the current and the three-back items matched on the irrelevant domain, group accuracy was lower (interference). On the other hand, at trials in which the two items matched on both the relevant and irrelevant domains, the group showed an enhancement of the performance (facilitation). Furthermore, we demonstrated that individual differences in fluid intelligence covaries with the ability to override cross-domain interference in that higher gf subjects showed better performance at interference trials than low gf subjects. Altogether, our findings suggest that stimulus features irrelevant to the task can affect cognitive performance along the relevant domain and that gf plays an important role in protecting relevant memory contents from the hampering effect of such a bias.

Apathy, but not depression, reflects inefficient cognitive strategies in Parkinson's disease.

BACKGROUND: The relationship between apathy, depression and cognitive impairment in Parkinson's disease (PD) is still controversial. The objective of this study is to investigate whether apathy and depression are associated with inefficient cognitive strategies in PD. METHODS: In this prospective clinical cohort study conducted in a university-based clinical and research movement disorders center we studied 48 PD patients. Based on clinical evaluation, they were classified in two groups: PD with apathy (PD-A group, n = 23) and PD without apathy (PD-NA group, n = 25). Patients received clinical and neuropsychological evaluations. The clinical evaluation included: Apathy Evaluation Scale-patient version, Hamilton Depression Rating Scale-17 items, the Unified Parkinson's Disease Rating Scale and the Hoehn and Yahr staging system; the neuropsychological evaluation explored speed information processing, attention, working memory, executive function, learning abilities and memory, which included several measures of recall (immediate free, short delay free, long delay free and cued, and total recall). FINDINGS: PD-A and PD-NA groups did not differ in age, disease duration, treatment, and motor condition, but differed in recall (p<0.001) and executive tasks (p<0.001). Immediate free recall had the highest predictive value for apathy (F = 10.94; p = 0.002). Depression and apathy had a weak correlation (Pearson index= 0.3; p<0.07), with three items of the depression scale correlating with apathy (Pearson index between .3 and.4; p<0.04). The depressed and non-depressed PD patients within the non-apathetic group did not differ. CONCLUSION: Apathy, but not depression, is associated with deficit in implementing efficient cognitive strategies. As the implementation of efficient strategies relies on the fronto-striatal circuit, we conclude that apathy, unlike depression, is an early expression of executive impairment in PD.

Treatment of advanced Parkinson's disease.

Patients at late stage Parkinson's disease (PD) develop several motor and nonmotor complications, which dramatically impair their quality of life. These complications include motor fluctuations, dyskinesia, unpredictable or absent response to medications, falls, dysautonomia, dementia, hallucinations, sleep disorders, depression, and psychosis. The therapeutic management should be driven by the attempt to create a balance between benefit and side effects of the pharmacological treatments available. Supportive care, including physical and rehabilitative interventions, speech therapy, occupational therapy, and nursing care, has a key role in the late stage of disease. In this review we discuss the several complications experienced by advance PD patients and their management. The importance of an integrative approach, including both pharmacological and supportive interventions, is emphasized.

Fluctuating cognition and different cognitive and behavioural profiles in Parkinson's disease with dementia: comparison of dementia with Lewy bodies and Alzheimer's disease.

To examine the occurrence of fluctuating cognition (FC) in a group of patients with Parkinson's disease with dementia (PDD), and to determine whether the presence of FC in PDD is associated with a pattern of cognitive and behavioural disturbances similar to the one shown by patients affected by dementia with Lewy bodies (DLB), a cluster analysis was carried out on the scores obtained by 27 PDD patients on the Clinician Assessment of Fluctuation Scale (CAF). The analysis separated the PDD patients into two subgroups, called PDD non-fluctuators (PDDNF; CAF 2). The two groups underwent a cognitive and behavioural evaluation. Their scores were compared with those obtained by DLB and Alzheimer's disease (AD) patients. When exploring the cognitive performance of the patients with the Dementia Rating Scale-2 (DRS-2), PDDF had a similar pattern of impairments compared to DLB, which involved prevalently the attention and initiation/perseveration domains, and which was significantly more pronounced compared to that shown by PDDNF. The main behavioural finding of the study was the similar incidence of visual hallucinations in the PDDF and DLB groups, which was significantly higher compared to PDDNF and AD. Our results confirmed the hypothesis that subgroups with different cognitive profiles exist within PDD and that the occurrence of FC is the clinical variable associated with a DLB pattern of impairment in PDD. In conclusion, our study suggests that when FC occurs in PDD this syndrome becomes clinically undistinguishable from DLB.

Behavioural assessment of dysexecutive syndrome in Parkinson's disease without dementia: a comparison with other clinical executive tasks.

The Behavioural Assessment of the Dysexecutive Syndrome (BADS) is a neuropsychological battery developed with the intent of measuring a wide range of executive impairments. Although the psychometric characteristics of BADS have previously been investigated in distinct neurological disorders, data on its validity in Parkinson's Disease (PD) without dementia are still lacking. The principal aim of the study was to address this issue. Twenty-five non-demented PD patients and 24 demographically-matched controls were administered BADS and other commonly used executive tools. Comparisons between groups indicated that two of the six BADS subtests (Temporal Judgement and Action Program) did not have sufficient sensitivity to executive impairments. However, when we explored group-predictive capabilities among the tests, the BADS total score was the most sensitive, followed by the Tower of London (TOL). We obtained similar results when we disentangled the sensitivity of the six BADS subtests. The BADS Six Elements task was the best group predictor followed by the TOL. Our findings showed that BADS is more sensitive to executive dysfunction than some of the tools commonly used to assess this construct in PD. However, we also demonstrated that, to assess executive impairments in PD without dementia adequately, this battery should be administered in combination with the TOL.

Two novel POLG1 mutations in a patient with progressive external ophthalmoplegia, levodopa-responsive pseudo-orthostatic tremor and parkinsonism.

Different mutations, or combinations of mutations, in POLG1, the gene encoding pol gammaA, the catalytic subunit of mitochondrial DNA polymerase, are associated with a spectrum of clinical presentations including autosomal dominant or recessive progressive external ophthalmoplegia (PEO), juvenile-onset ataxia and epilepsy, and Alpers-Huttenlocher syndrome. Parkinsonian features have been reported as a late complication of POLG1-associated dominant PEO. Good response to levodopa or dopamine agonists, reduced dopamine uptake in the corpus striatum and neuronal loss of the Substantia Nigra pars compacta have been documented in a few cases. Here we report two novel mutations in POLG1 in a compound heterozygous patient with autosomal recessive PEO, followed by pseudo-orthostatic tremor evolving into levodopa-responsive parkinsonism. These observations support the hypothesis that mtDNA dysfunction is engaged in the pathogenesis of idiopathic Parkinson's disease.

EEG comparisons in early Alzheimer's disease, dementia with Lewy bodies and Parkinson's disease with dementia patients with a 2-year follow-up.

EEG abnormalities have been reported for both dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). Although it has been suggested that variations in mean EEG frequency are greater in the former, the existence of meaningful differences remains controversial. No evidence is as yet available for Parkinson's disease with dementia (PDD). The aim of this study was to evaluate whether EEG abnormalities can discriminate between DLB, AD and PDD in the earliest stages of dementia and to do this 50 DLB, 50 AD and 40 PDD patients with slight cognitive impairment at first visit (MMSE > or = 20) were studied. To improve clinical diagnostic accuracy, special emphasis was placed on identifying cognitive fluctuations and REM-sleep behaviour disorder. EEG variability was assessed by mean frequency analysis and compressed spectral arrays (CSA) in order to detect changes over time from different scalp derivations. Patients' initial diagnoses were revised at a 2-year follow-up visit with neuroimaging evaluation. Initial diagnoses were confirmed in 36 DLB, 40 AD and 35 PDD patients. The most relevant group differences were observed between the AD and DLB patients in EEGs from posterior derivations (P<0.001). Dominant frequencies were 8.3 +/- 0.6 Hz for the AD group and 7.4 +/- 1.6 Hz for the DLB group, in which most of the patients (88%) exhibited a frequency band of 5.6-7.9 Hz. Dominant frequency variability also differed between the AD (1.1 +/- 0.4 Hz) and DLB groups (1.8 +/- 1.2 Hz, P<0.001). Of note, less than a half (46%) of the patients with PDD exhibited the EEG abnormalities seen in those with DLB. Graded according to the presence of alpha activity, five different patterns were identified on EEG CSA from posterior derivations. A pattern with dominant alpha bands was observed in patients with AD alone while, in those with DLB and PDD, the degree to which residual alpha and 5.6-7.9 bands appeared was related to the presence and severity of cognitive fluctuations. At follow-up, EEG abnormalities from posterior leads were seen in all subjects with DLB and in three-quarters of those with PDD. Of interest, in four patients initially labelled as having AD, in whom the occurrence of fluctuations and/or REM-sleep behaviour disorder during the 2-year follow-up had made the diagnosis of AD questionable, the initial EEG was characterized by the features observed in the DLB group. If revised consensus criteria for DLB diagnosis are properly applied (i.e. emphasizing the diagnostic weight of fluctuations and REM sleep behaviour disorder), EEG recording may act to support discrimination between AD and DLB at the earliest stages of dementia, since characteristic abnormalities may even precede the appearance of distinctive clinical features.

Delayed blink reflex in dementia with Lewy bodies.

Blink reflexes (BR) to electric stimuli of the supraorbital nerve were recorded in 26 patients with dementia with Lewy bodies (DLB), 26 patients with multiple system atrophy, 26 patients with Parkinson's disease, with or without REM sleep behaviour disorder (RBD), and in 20 patients with Alzheimer's disease and 20 with progressive supranuclear palsy without RBD, and compared with recordings in 30 healthy controls. BR were significantly delayed (p<0.001) only in DLB patients in comparison with controls and with the other groups of patients; 14 (53.8%) patients had BR latency above 2 SD of the control mean, ranging from 36.1 to 46.3 ms. BR latency was not related to the presence of RBD, while a Spearman correlation rho of 0.68 was found for scores assessing the presence of cognitive fluctuations. R2 delay was prominently (71.5%) bilateral.

Botulinum toxin treatment of lateral axial dystonia in Parkinsonism.

Lateral axial dystonia (LAD) has been described in patients with Parkinson's disease (PD), but treatment might be more controversial than treatment of LAD in other neurological conditions. Our study was designed as a blinded cross-over with botulinum toxin (BTX) and placebo in order to investigate the efficacy of BTX in PD LAD. Nine patients with LAD who failed to experience benefit from oral medications were randomly assigned to 2 groups, 4 patients received BTX and 5 placebo as a first treatment, and were switched-over to BTX or placebo in the following treatment session, performed 3 months after the first session. Each patient was evaluated at baseline, 2 and 4 weeks after injection and after 3 months follow-up with the Trunk Dystonia Disability Scale (TDDS), a Visual Analogue Scale (VAS) and a goniometric measurement of the lateral displacement. Patients were videotaped at each visit. None of the patients of the placebo group experienced benefit from treatment. BTX treatment was effective in 6 patients. One patient reported subjective benefit, with improvement of VAS score and mild improvement of TDDS score, but with no improvement of flexion degree. Two patients did not report any benefit. Four patients opted to continue to receive BTX treatment for 2 years after the cross-over study. Our study shows that BTX could be considered a possible treatment for LAD in parkinsonism.

End-of-dose deterioration in non ergolinic dopamine agonist monotherapy of Parkinson's disease.

The study was designed to investigate the possible occurrence of "wearing-off" (WO) during dopamine agonist (DA) monotherapy. Sixty patients with "de novo" idiopathic PD were randomised into one of two DA monotherapy branches to receive oral ropinirole at 15 mg per day, or pramipexole at 2.1 mg per day. DA doses could be increased in the following two years but levodopa could not be added until the study ended. WO was assessed by self-evaluation charts confirmed by a blinded observation of a 30% or greater deterioration in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score. Proc Mixed and Kaplan-Meier curves evaluated treatment variables as a function of time. T-tests were used to compare post-hoc variables reclassified according to WO occurrence. Thirty patients received ropinirole, and 30 pramipexole monotherapy. Eighteen patients (30%) experienced "wearing-off" 15-21 months after beginning monotherapy. No differences were observed between treatments. WO phenomena was observed 3.4+/-0.3 hours after intake of the morning or afternoon dose and consisted of UPDRS score worsening by 11.1+/-2.1 points (69-111% more than "on" score). Statistical evaluation gave evidence of differences between patients who experienced WO and those who did not: UPDRS motor scores obtained at admission to the study were higher (by 3.4+/-0.2 points, p=0.01 t-test) and DA doses at 6-12 months were higher in fluctuating patients. UPDRS motor scores deteriorated, however. similarly and there were no differences, in UPDRS scores recorded in ON conditions, between fluctuating and non-fluctuating patients at the end of the study. Our findings provide evidence of WO phenomena in patients with early PD receiving non-ergolinic DA monotherapy.