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We evaluated elagolix and leuprolide from the patient’s perspective for the treatment of endometriosis-related pain. Preference weights from a published discrete choice experiment were used to evaluate preferences for treatment profiles simulating elagolix (150 mg/day and 200 mg/twice-daily dosages) and leuprolide for the treatment of moderate to severe endometriosis-related pain. Sensitivity analyses were conducted by varying the range of risk for pregnancy-related problems, moderate to severe hot flashes, and bone fracture across scenarios. The 200 mg twice daily dosage of elagolix is more likely to be preferred over leuprolide by patients with moderate to severe endometriosis-related pain in all scenarios explored in the evaluation and sensitivity analyses. The probability that an average respondent would select a treatment was sensitive to increases in risk of moderate to severe hot flashes for leuprolide and possible variations in the risk of pregnancy-related problems for both treatments but was not influenced by an increased risk of bone fracture. Patients’ preferences for treatment of endometriosis-related pain should be evaluated using the benefits and risks of each pharmacological option. Respondents were more likely to prefer the treatment profile similar to 200 mg twice daily elagolix over that of leuprolide in all scenarios.

Yaban hayatı türlerine yönelik koruma ve yönetim çalışmalarının etkin bir şekilde gerçekleştirilebilmesi için türlerin kullandığı habitat büyüklüklerinin belirlenmesi, habitat tercihlerinde rol oynayan değişkenlerin tespit edilmesi ve izlenmesi gerekmektedir. Geleneksel arazi envanter yöntemleri ile bu verilerin toplaması hem maliyetli hem de zaman alıcı bir süreçtir. Bu yöntemlerin aksine, geniş alanlar için sürekli veri akışı sağlayan uydu görüntülerinin kullanılması hem zaman açısından hem de maliyet açısından fayda sağlamaktadır. Bu sebeple, Akdağ (Simav) yöresinde gerçekleştirilen bu çalışmada, Landsat-8 OLI uydu görüntüsü yardımıyla, Karaca (Capreolus capreolus L.) türünün tercih ettiği habitat büyüklüğünün ve bu tercihinde rol oynayan değişkenlerin belirlenmesi amaçlanmıştır. Dolaylı sayım teknikleri kullanılarak yürütülen arazi çalışmaları esnasında, 32 adet türe ait var verisi kaydedilmiştir. Definiens yazılımı yardımıyla, Çoklu Çözünürlüklü Segmentasyon işlemi uygulanılarak, uydu görüntüsü farklı yamalara ayrılmıştır. Bu işlemin ardından, Satranç Daması Segmentasyonu uygulanılarak, uydu görüntüsü 16, 64, 256 1024 piksele sahip farklı karelajlara ayrılmıştır. Her bir karelaj içerisinde, Definiens yazılımı yardımıyla 9 farklı algoritma ve ArcGIS yazılımı ile 6 farklı yama parametresi olmak üzere toplam 15 farklı değişken elde edilmiştir. MaxEnt yazılımı ile türe ait var verileri ve uydu görüntüsünden elde edilen değişkenler kullanılarak her bir karelaj boyutu için model oluşturulmuş ve haritalandırılmıştır. Farklı piksel sayılarına sahip karelajların modellerine ait eğitim veri seti AUC ve test veri seti AUC değerleri sırasıyla, 16 (0,712, 0,698) , 64 (0,864, 0, 825), 256 (0,802, 0.795) 1024 (0.792, 0.779) olarak elde edilmiştir. Elde edilen modeller içerisinde, 64 piksele sahip karelaj için oluşturulan model, tür için en uygun model olarak seçilmiştir. Modeli oluşturan değişkenler, zıtlık(2), kenar zıtlığı ve GLCM entropi olarak belirlenmiştir. Sonuç olarak, gerçekleştirilen bu çalışma ile türün tercih ettiği habitat büyüklüğüne ve tercihinde rol oynayan değişkenlere uydu görüntüsü aracılığıyla erişilebileceği tespit edilmiştir.

Alzheimer’s disease (AD) patients treated with rivastigmine transdermal patch have shown statistically significant differences versus placebo on the AD Assessment scale-cognitive subscale (ADAS-cog). In this retrospective analysis of a double-blind, placebo- and active-controlled, 24-week clinical trial, the specific effects of rivastigmine patch on individual ADAS-cog items and cognitive domains (memory, language, and praxis) were explored. The mean baseline to week 24 changes were calculated for each ADAS-cog item and domain in this exploratory, hypothesis-generating analysis. Patients on 9.5 mg/24 h rivastigmine patch, 17.4 mg/24 h rivastigmine patch, and 3 to 12 mg/d rivastigmine capsules showed improvements over placebo on the memory and praxis ADAS-cog subscales. The rivastigmine patch groups also showed improvements on the language subscale. Significant differences versus placebo were seen on several individual item scores in the rivastigmine-treated groups. Rivastigmine patch was associated with improvements on the memory, praxis, and language domains of cognition in patients with mild-to-moderate AD.

SUMMARY Background and objective: Rivastigmine is approved in the USA for the treatment of mild to moderate Alzheimer's disease and Parkinson's disease dementia (PDD). Executive function (EF) deficits are a core symptom of PDD. The current objective was to investigate the effects of rivastigmine capsules versus placebo on EF in PDD, focusing on secondary outcome measures from a large, international, randomized, double-blind, placebo-controlled, 24-week trial (EXPRESS, CENA713B2311). Methods: Secondary outcomes included Delis–Kaplan Executive Function System (D-KEFS) measures of EF. Data from three D-KEFS subtests (Card Sorting, Letter Fluency, Color–Word Interference), plus the Symbol Digit Modalities Test were analyzed in the observed case (OC) population. Changes from baseline in the rivastigmine versus placebo groups were evaluated using the van Elteren test blocking for country. Results: Of 541 patients in the EXPRESS study, 402, 71, 97, and 65 patients provided data for Letter Fluency, Card Sorting and Color-Word Interference subtests, and the Symbol Digit Modalities Test, respectively. On Letter Fluency, rivastigmine was associated with improvements in correct responses, set loss errors, and responses made (all P < 0.05), but not repetition errors. Higher Card Sorting recognition description score (P= 0.03), and more correct substitutions on the Symbol Digit Modalities Test (P= 0.02) were also recorded. Conclusion: Rivastigmine was associated with significant improvements over placebo on EF tests evaluating flexibility of thinking, problem solving and planning in patients with PDD. These findings support the hypothesis that rivastigmine may affect frontal subcortical circuits, which potentially contributes to observed clinical improvement associated with EF.

Rivastigmine has been shown to improve cognition in patients with Parkinson’s disease dementia (PDD). To further explore the impact of anticholinesterase therapy on PDD, Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) items were assessed in a retrospective analysis of a 24-week, double-blind, placebo-controlled trial of rivastigmine. Mean changes from baseline at week 24 were calculated for ADAS-cog item scores and for 3 cognitive domain scores. A total of 362 patients were randomized to 3 to 12 mg/d rivastigmine capsules and 179 to placebo. Patients with PDD receiving rivastigmine improved versus placebo on items: word recall, following commands, ideational praxis, remembering test instructions, and comprehension of spoken language (P < .05), with standardized mean differences ranging from 0.04 to 0.30. Rivastigmine also showed significant effects versus placebo on all domains: memory, language, and praxis. The ADAS-cog is sensitive to broad cognitive changes in PDD. Overall, rivastigmine was associated with improvements on individual cognitive items and general cognitive domains.

A nine-year old girl admitted to our clinic with two months history of itchy skin eruption, initially started on the arms and then disseminated to all the body including the face. Dermatological examination revealed extensive papulosquamous lesions covered with hemorrhagic crust and central necrosis. Clinically the diagnosis was thought to be pityriasis lichenoides et varioliformis acuta (PLEVA) and a skin biopsy was performed from a lesion which revealed exocytosis and spongiosis in epidermis, edema and exocytosis of erythrocytes in papillary dermis, perivascular lymphocytic infiltration in dermis. In laboratory evaluation, oropharyngeal culture was positive for Streptococcus pyogenes. The analysis of urine sample revealed leucocyturia and Escherichia coli grew on urine culture. Therapy with erythromycin, which was found to be sensitive against both pathogens, and also the main therapeutic agent for PLEVA started 250mg tb 4x1 orally, since the histopathological findings were also compatible with PLEVA. A rapid response was achieved and more than half of the lesions were found to be regressed in ten days. In this report, a child of PLEVA with a rapid and dramatic response to erythromycin therapy is described with a brief literature review.

Disease-specific assessments are not currently available for patients with Parkinson’s disease dementia (PDD). This study evaluated the criterion-related validity and test—retest reliability of the Alzheimer’s Disease Assessment scale cognitive subscale (ADAS-cog) in terms of sensitivity for differentiation between mild and moderate severity impairment in PDD. Six other dementia rating scales and cognitive tests were also examined. A total of 113 patients with PDD or Alzheimer disease were recruited into this 4-week, multicenter study, segregated into 2 severity groups based on Mini-Mental State Examination (MMSE) score. Mean ADAS-cog scores showed a statistically significant separation between mild and moderate severity patients in both dementias (P < .001). For the ADAS-cog, test—retest Spearman correlation coefficients were significant for each dementia type and severity. This study demonstrated the criterion-related validity and test—retest reliability for ADAS-cog in patients with PDD and strong correlations with MMSE. This supports the validity of previous results obtained with these measures in studies of patients with PDD.

The primary objective of the open-label extension was to evaluate the long-term safety and tolerability of a transdermal rivastigmine patch up to 1 year, as a novel approach to treatment in Alzheimer disease. This was a 28-week extension to a 24-week, double-blind, double-dummy, placebo-controlled, and active-controlled study evaluating rivastigmine patches [9.5 mg/24 h (10 cm2) and 17.4 mg/24 h (20 cm2)] and oral capsules (3 to 6 mg twice-daily). Patients entering the extension were switched directly to 9.5 mg/ 24 h rivastigmine patch and increased to 17.4 mg/24 h patch, irrespective of their double-blind study treatment. Primary measures included safety and tolerability assessments, including adverse events and serious adverse events. Of 1195 patients randomized to treatment, 870 (72.8%) completed the double-blind study and entered the open-label extension. During weeks 1 to 4 of the extension, 9.5 mg/24 h rivastigmine patch was well tolerated overall by patients formerly randomized to rivastigmine capsule or patch groups: < or =2.5% reported nausea and < or =1.9% reported vomiting. No unexpected safety issues arose, and skin tolerability was good; similar to the double-blind study. During the 28-week, open-label extension phase, the patch seemed to be well tolerated with a favorable safety profile.

Rivastigmine is now widely approved for the treatment of mild to moderately severe dementia in Parkinson's disease (PDD). However, since anticholinergic drugs have a role in the management of tremor in patients with Parkinson's disease (PD), concerns have been raised that the use of cholinergic drugs might worsen PD. The current analyses were performed to examine the potential of rivastigmine to affect tremor and other motor symptoms in patients with PDD.The safety profile of rivastigmine was evaluated using a database from a 24-week, randomized, double-blind, placebo-controlled trial in 541 PDD patients (362 randomized to rivastigmine, 179 to placebo), and 334 PDD patients who subsequently entered an open-label 24-week extension on rivastigmine.During the double-blind trial, the adverse event (AE) of emerging or worsening tremor was reported in 10.2% of patients in the rivastigmine group, compared with 3.9% in the placebo group (p = 0.012). Tremor was most frequently reported during the titration phase of rivastigmine treatment, although this was not reflected in total motor Unified Parkinson's Disease Rating Scale (UPDRS) part III scores. Dose dependence of this AE was not observed. At the end of the double-blind phase, six (1.7%) rivastigmine-treated patients had discontinued the study because of tremor. In the open-label extension in which all patients received rivastigmine, tremor was reported by 6.9% of patients: 3.8% and 12.2% of whom had previously received double-blind rivastigmine and placebo, respectively (p = 0.006), suggesting that first exposure to rivastigmine leads to a transient increase in tremor. Three (0.9%) of the 334 patients who entered the open-label extension phase discontinued because of tremor. Incidences of worsening parkinsonism, bradykinesia and rigidity were all5% in both treatment groups (all p-values not statistically significant, rivastigmine vs placebo). In the 48-week observation of rivastigmine treatment, there was no evidence of adverse long-term motor outcomes. Post-hoc analysis showed that similar improvements in the symptoms of dementia, including the ability to perform activities of daily living, were seen regardless of whether exacerbation of tremor was reported during the study.Rivastigmine did not induce clinically significant exacerbation of motor dysfunction in patients with PDD. Rest tremor incidence as an AE was a transient phenomenon during dose titration of rivastigmine. There was no indication that exposure to long-term rivastigmine was associated with a worsening of PD.

Two subtypes of Alzheimer’s disease (AD) have been commonly identified: early- and late-onset forms. Previous studies suggest that early-onset AD patients have more neuritic plaques (NPs) and neurofibrillary tangles (NFTs). In the current study, NP and NFT counts were performed for 8 brain regions in 25 subjects with definite AD. A repeated-measures analysis of variance of mean regional NP and NFT counts for early- and late-onset groups was performed. A significant between-subject effect indicating greater overall NP and NFT burden in the early-onset group was observed (NP: F = 6.8, df = 1, P = .015; NFT: F = 7.5, df = 1, P = .012). This analysis supports the hypothesis that early-onset AD is associated with greater pathologic burden than late-onset AD. This suggests that late-onset AD patients have less cognitive reserve than early-onset patients and require fewer pathologic changes to exhibit cognitive deterioration.

Objective: To explore the profile of neuropsychiatric symptoms in patients with dementia associated with Parkinson’s disease (PDD). Methods: 537 patients with PDD drawn from an international multicentre clinical trial of rivastigmine were assessed using the 10-item Neuropsychiatric Inventory (NPI). A cluster analysis was used to investigate the inter-relationship of NPI items. Associations between the clusters and demographic and clinical variables were analysed. Results: 89% of the patients presented at least one symptom on the NPI, 77% had two or more symptoms and 64% had at least one symptom with a score ⩾4. The most common symptoms were depression (58%), apathy (54%), anxiety (49%) and hallucinations (44%). Patients with more severe dementia and advanced Parkinson’s disease had more neuropsychiatric symptoms. Nearly 60% of the care givers reported at least one NPI symptom to be of at least moderate severe distress. Five NPI clusters were identified: one group with few and mild symptoms (52%); a mood cluster (11%, high scores on depression, anxiety and apathy); apathy (24%; high apathy and low scores on other items); agitation (5%, high score on agitation and high total NPI score); and a psychosis cluster (8%; high scores on delusions and hallucinations). The psychosis and agitation clusters had the lowest Mini-Mental State Examination score and the highest Unified Parkinson’s Disease Rating Scale and care giver distress scores. Conclusion: Neuropsychiatric symptoms are common in patients with PDD. The profile of these symptoms differs from that in other types of dementia. Subgroups with different neuropsychiatric profiles were identified. These subgroups may be associated with distinct neurobiological changes, which should be explored in future studies.

Apathy is the most commonly observed behavioral disturbance in Alzheimer’s disease (AD) and has been suggested to be frontally mediated. Neuritic plaque (NP) and neurofibrillary tangle (NFT) counts were performed for 8 brain regions in 29 subjects with definite AD. Neuropsychiatric Inventory (NPI) for autopsied subjects was obtained from questioning of caregivers of subjects included in the study. Chronic apathy and total NPI composite scores correlated with anterior cingulate NFT counts (r = 0.518, p = 0.01, and r = 0.438, p = 0.032). This analysis suggests that chronic apathy in AD correlates with a greater anterior cingulate NFT burden and that chronic behavioral changes are more reflective than acute changes of disease pathology.

In patients with dementia associated with Parkinson's disease (PD), the efficacy and safety of rivastigmine, an inhibitor of acetylcholinesterase and butyrylcholinesterase, were previously demonstrated in a 24-week double-blind placebo-controlled trial. Our objective was to determine whether benefits were sustained over the long term. Following the double-blind trial, all patients were permitted to enter an active treatment extension study, during which they received rivastigmine 3-12 mg/day. Standard safety assessments were performed. Efficacy assessments included the Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog) and other measures of cognition, daily function, neuropsychiatric symptoms, and executive function. Of 433 patients who completed the double-blind trial, 334 entered and 273 completed the active treatment extension. At 48 weeks, the mean ADAS-cog score for the whole group improved by 2 points above baseline. Placebo patients switching to rivastigmine for the active treatment extension experienced a mean cognitive improvement similar to that of the original rivastigmine group during the double-blind trial. The adverse event profile was comparable to that seen in the double-blind trial. Long-term rivastigmine treatment appeared well tolerated and may provide sustained benefits in dementia associated with PD patients who remain on treatment for up to 48 weeks.

Frontal-subcortical circuits form the principal network, which mediate motor activity and behavior in humans. Five parallel frontal-subcortical circuits link the specific areas of the frontal cortex to the striatum, basal ganglia and thalamus. These frontal-subcortical circuits originate from the supplementary motor area, frontal eye field, dorsolateral prefrontal region, lateral orbitofrontal region and anterior cingulate portion of the frontal cortex. The open afferent and efferent connections to the frontal-subcortical circuits mediate coordination between functionally similar areas of the brain. Specific chemoarchitecture and multiple neurotransmitter interactions modulate the functional activity of each circuit. Dorsolateral prefrontal circuit lesions cause executive dysfunction, orbitofrontal circuit lesions lead to personality changes characterized by disinhibition and anterior cingulate circuit lesions present with apathy. The neurobiological correlates of neuropsychiatric disorders including depression, obsessive-compulsive disorder, schizophrenia and substance abuse, imply involvement of frontal-subcortical circuits.

BACKGROUND– Dementia and depression are both common disorders of the elderly. It may be difficult to differentiate dementia from depression, and the two conditions commonly coexist. Understanding the relationship between the two disorders is critically important for diagnosis and optimal management of older patients with cognitive impairment and mood changes. REVIEW SUMMARY– Depression may produce cognitive impairment. This cognitive decline, known as the dementia syndrome of depression (DOD), usually is reversed by treatment of the depressive disorder. However, some patients with DOD develop dementia in the following few years. Depression might be a risk factor for Alzheimer disease (AD) or a harbinger of its occurrence. It also may co-occur with AD. Patients with AD and depression differ biologically from those without mood changes. Neuroimaging studies in patients with depression and AD show impaired metabolism in the frontal lobes. Depression exaggerates the functional impairment, decreases quality of life, and increases caregiver distress of patients with AD. In patients presenting with dementia and depression, metabolic imbalances and toxic side effects of drugs should be ruled out. Depression in dementia is treatable with appropriate antidepressant therapy. CONCLUSIONS– Depression and dementia are closely related. Depression can precede, be a risk factor for, or coexist as a part of the clinical presentation of dementia. There are syndrome-specific histopathologic and neurochemical changes in the brains of patients with depression and AD. Depression in dementia is treatable. Treatment of mood changes may help improve functional activity, reduce caregiver distress, and enhance the quality of life of patients.

Using a retrospective data analysis, the authors investigated the relationships between instrumental activities of daily living (IADLs) and neuropsychiatric symptoms, cognitive impairment, and medical illness burden in patients with Alzheimer's disease (AD). One hundred forty-three patients fulfilling the clinical criteria for probable or possible AD in an outpatient clinic were assessed for IADLs, neuropsychiatric symptoms, cognitive impairment, and medical illness burden with the Functional Activities Questionnaire (FAQ), Neuropsychiatric Inventory (NPI), Mini-Mental State Exam (MMSE), and Cumulative Illness Rating Scale–Geriatric (CIRS-G). Both MMSE and NPI scores related significantly to IADLs as measured by the FAQ. Several psychiatric symptoms were correlated significantly with IADLs. FAQ scores had no correlation with CIRS-G. Neuropsychiatric findings also were associated significantly with MMSE and had a weak correlation with CIRS-G scores. IADLs changed with cognition and neuropsychiatric disturbances in AD. Medical illness burden had little influence on functional status and a limited impact on neuropsychiatric symptoms.

Few studies evaluate neuropathological correlates of behavioral changes in Alzheimer disease (AD). We identified 31 autopsy patients with a diagnosis of definite AD. Behavioral changes were assessed with the Neuropsychiatric Inventory. Brain sections were collected from bilateral orbitofrontal and left anterior cingulate, superior temporal, inferior parietal, occipital, and hippocampal cortices for quantification of neurofibrillary tangles (NFTs) and diffuse and neuritic plaques. Sections from frontal, cingulate, and hippocampal cortices were reviewed for the presence of Lewy bodies (LBs). Hypothesis-driven correlational analyses were performed by the bootstrap method. Subgroup analyses contrasted a group with high scores of one specific behavior to a group with low scores after equating groups for other behaviors. NFT burden in the left orbitofrontal cortex across all 31 patients significantly correlated with agitation scores (r = 0.41, p < 0.015) and NFTs correlated significantly (r = 0.66, p = 0.004) with higher agitation scores in the subgroup analysis. Left anterior cingulate NFTs, although not within our hypotheses, also showed a significant relationship to agitation within the subgroups (r = 0.76, p = 0.0003; Bonferroni p = 0.02). Seven patients, including three in the agitation subgroup, had cortical LBs. Aberrant motor behavior and NFT density in the left orbitofrontal cortex showed a significant relationship for the entire group (r = 0.38, p < 0.03) and for subgroups (r = 0.49, p = 0.04), whereas apathy and left anterior cingulate NFTs showed a significant relationship only for the entire group (r = 0.25, p < or = 0.01). These observations suggest that agitation and aberrant motor behavior are correlates of greater NFT pathology in the orbitofrontal cortex in AD, whereas increasing apathy may relate to greater NFT burden in the anterior cingulate.

It has been proposed that excitotoxic damage by glutamatergic hyperactivity is responsible for neurodegeneration in Alzheimer's disease. Lamotrigine (LTG) inhibits presynaptic glutamate release and is considered to be effective in treatment of other neurodegenerative disorders by its cerebroprotective properties. We used LTG in 11 patients with the diagnosis of probable Alzheimer's disease. 300 mg/day administration of LTG improved word recognition, naming and depressed mood on Alzheimer Disease Assessment Scale (ADAS).

Background and objective: Rivastigmine is approved in the USA for the treatment of mild to moderate Alzheimer's disease and Parkinson's disease dementia (PDD). Executive function (EF) deficits are a core symptom of PDD. The current objective was to investigate the effects of rivastigmine capsules versus placebo on EF in PDD, focusing on secondary outcome measures from a large, international, randomized, double‐blind, placebo‐controlled, 24‐week trial (EXPRESS, CENA713B2311). Methods: Secondary outcomes included Delis–Kaplan Executive Function System (D‐KEFS) measures of EF. Data from three D‐KEFS subtests (Card Sorting, Letter Fluency, Color–Word Interference), plus the Symbol Digit Modalities Test were analyzed in the observed case (OC) population. Changes from baseline in the rivastigmine versus placebo groups were evaluated using the van Elteren test blocking for country. Results: Of 541 patients in the EXPRESS study, 402, 71, 97, and 65 patients provided data for Letter Fluency, Card Sorting and Color‐Word Interference subtests, and the Symbol Digit Modalities Test, respectively. On Letter Fluency, rivastigmine was associated with improvements in correct responses, set loss errors, and responses made (all P < 0.05), but not repetition errors. Higher Card Sorting recognition description score (P= 0.03), and more correct substitutions on the Symbol Digit Modalities Test (P= 0.02) were also recorded. Conclusion: Rivastigmine was associated with significant improvements over placebo on EF tests evaluating flexibility of thinking, problem solving and planning in patients with PDD. These findings support the hypothesis that rivastigmine may affect frontal subcortical circuits, which potentially contributes to observed clinical improvement associated with EF.

Hallucinations in Alzheimer's disease (AD) may indicate greater cortical cholinergic deficits. Rivastigmine has shown larger treatment benefits versus placebo in dementia with Lewy bodies and Parkinson's disease dementia patients with hallucinations. In this retrospective, hypothesis-generating analysis, we investigated whether hallucinations in AD were associated with greater treatment benefits with rivastigmine. Data were pooled from two randomized, double-blind, 6-month, mild-to-moderate AD trials comparing rivastigmine with placebo. Co-primary efficacy parameters were the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog) and Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus). Efficacy data were analyzed for two sub-populations: those with and those without hallucinations at baseline. Of 927 patients, 194 (21%) reported hallucinations at baseline. Hallucinators tended to have greater decline on placebo on all outcome measures. On the ADAS-cog, mean rivastigmine - placebo differences of 3.7 points in hallucinators and 2.2 points in non-hallucinators were reported at 6 months (both p < 0.001). In hallucinators, a significant rivastigmine - placebo difference of -1.0 points (a beneficial effect) was seen on the CIBIC-plus at 6 months (p< 0.001). Non-hallucinators showed a smaller significant treatment difference of -0.3 points (p< 0.05). Interaction testing suggested that differences in treatment effects were significant between hallucinators and non-hallucinators. Hallucinations predicted greater treatment responses to oral rivastigmine.

Oral cholinesterase inhibitors (ChEIs) are associated with side effects such as nausea and vomiting. The use of transdermal patches for ChEI delivery may help to minimize these problems. The objective of this review was to consider available data from patients switching from oral ChEIs to transdermal rivastigmine treatment, and to suggest practical guidelines for patients wishing to do this. Literature database and reference list searches were performed to identify suitable publications. Data from two clinical trials and a series of open observational studies, in which patients were switched to the rivastigmine patch from oral rivastigmine, donepezil tablets, or galantamine, were evaluated. Adverse events were tabulated. In the studies reported here, nausea was reported in up to 3.2% and vomiting in up to 1.9% of patients switching to the rivastigmine patch from oral rivastigmine. Similar rates (up to 3.8% of patients for nausea and 0.8% of patients for vomiting) were reported when switching to the rivastigmine patch from donepezil tablets, and no nausea or vomiting was reported in a case study of patients switching to the rivastigmine patch from galantamine tablets. Switching regimes used in clinical trials appeared well tolerated. Data support recommendations for patients on high rivastigmine capsule doses to switch directly to the 9.5 mg/24 h rivastigmine patch, while those on lower oral rivastigmine doses should start on the 4.6 mg/24 h patch for 4 weeks before increasing to the 9.5 mg/24 h patch. This latter regimen is recommended for patients on other oral cholinesterase inhibitors if switching is medically indicated or requested by the patient or the caregiver.

Background and Objectives: Transdermal patches provide non-invasive, continuous drug delivery, and offer significant potential advantages over oral treatments. With all transdermal treatments a proportion of patients will experience some form of skin reaction. The rivastigmine patch has been approved for the treatment of mild-to-moderate Alzheimer’s disease (AD) since July 2007 in the US. The aim of the component of the trial reported here was to evaluate the skin tolerability of the rivastigmine transdermal patch in patients with mild-to-moderate AD. Methods: The pivotal IDEAL trial was a 24-week, randomized, double-blind, placebo-controlled, multicentre trial of the efficacy and tolerability of the rivastigmine transdermal patch in 1195 patients with mild-to-moderate AD. This was followed by a 28-week open-label extension. Although not prospectively defined as a secondary assessment, during both phases of the study the condition of the patients’ skin at the application site was evaluated. These data are reviewed in this article. Results: During the 24-week, double-blind phase of the study, 89.6% of patients in the target 9.5 mg/24 h patch treatment group had recorded ‘no, slight or mild’ signs or symptoms for their most severe application-site reaction. Erythema and pruritus were the most commonly reported reactions. No patient in any patch treatment group experienced a skin reaction that was reported as a serious adverse event. In the 9.5 mg/24 h treatment group, 2.4% of patients discontinued treatment due to an application-site reaction. During the 28-week open-label extension, the skin tolerability profile was similar to that seen in the double-blind phase. Overall, 3.7% of patients discontinued treatment due to application-site skin reactions. There was no indication that the severity of the skin reactions increased over time. Conclusion: Overall, the data support a favourable skin tolerability profile for the rivastigmine transdermal patch, and provide reassurance that the benefits of rivastigmine patch therapy for patients with AD are not confounded by significant skin irritation problems. Nevertheless, care should be taken to follow manufacturer’s advice about patch application, such as daily rotation of the application site, to minimize the risk of skin reactions.

Summary Objective To assess the effect of rivastigmine in patients with mild cognitive impairment (MCI) on the time to clinical diagnosis of Alzheimer's disease (AD) and the rate of cognitive decline. Methods The study was a double-blind, randomised, placebo-controlled trial of up to 48 months. All patients had MCI operationally defined by having cognitive symptoms, a global clinical dementia rating stage of 0·5, a score of less than 9 on the New York University delayed paragraph recall test, and by not meeting the diagnostic criteria for AD. Primary efficacy variables were time to clinical diagnosis of AD, and change in performance on a cognitive test battery. This study is registered with the US National Institutes of Health clinical trials database (ClinicalTrials.gov), number NCT00000174. Findings Of 1018 study patients enrolled, 508 were randomly assigned to rivastigmine and 510 to placebo; 17·3% of patients on rivastigmine and 21·4% on placebo progressed to AD (hazard ratio 0·85 [95% CI 0·64–1·12]; p=0·225). There was no significant difference between the rivastigmine and placebo groups on the standardised Z score for the cognitive test battery measured as mean change from baseline to endpoint (−0·10 [95% CI −0·63 to 0·44], p=0·726). Serious adverse events were reported by 141 (27·9%) rivastigmine-treated patients and 155 (30·5%) patients on placebo; adverse events of all types were reported by 483 (95·6%) rivastigmine-treated patients and 472 (92·7%) placebo-treated patients. The predominant adverse events were cholinergic: the frequencies of nausea, vomiting, diarrhoea, and dizziness were two to four times higher in the rivastigmine group than in the placebo group. Interpretation There was no significant benefit of rivastigmine on the progression rate to AD or on cognitive function over 4 years. The overall rate of progression from MCI to AD in this randomised clinical trial was much lower than predicted. Rivastigmine treatment was not associated with any significant safety concerns.

Objective: To compare the profile of cognitive impairment in Alzheimer’s disease (AD) with dementia associated with Parkinson’s disease (PDD). Methods: Neuropsychological assessment was performed in 488 patients with PDD and 488 patients with AD using the Mini-Mental State Examination (MMSE) and the Alzheimer9s Disease Assessment Scale-cognitive subscale (ADAS-cog). Logistic regression analysis was used to investigate whether the diagnosis could be accurately predicted from the cognitive profile. Additionally, the cognitive profiles were compared with a normative group using standardised effect sizes (Cohen’s d). Results: Diagnosis was predicted from the cognitive profile, with an overall accuracy of 74.7%. Poor performance of the AD patients on the orientation test in ADAS-cog best discriminated between the groups, followed by poor performance of the PDD patients on the attentional task in MMSE. Both groups showed memory impairment, AD patients performing worse than PDD patients. Conclusion: The cognitive profile in PDD differs significantly from that in AD. Performance on tests of orientation and attention are best in differentiating the groups.

Background About 40% of the patients with Parkinson's disease (PD) have depressive symptoms, either major depression (MD) or subthreshold depression. Depression was found to be associated with age and age at onset of PD, female gender, more severe parkinsonism, in particular with left-sided and akinetic-rigid symptoms, more functional impairment and cognitive impairment. However, the findings are inconsistent and partly contradictory and most of the studies focused on major depression in PD without dementia. The aim of this study was to examine the relationship between subthreshold depression and other clinical features in 538 PD patients with dementia but without MD drawn from a randomized, placebo-controlled multicentre trial of rivastigmine in PD. Results One hundred and sixteen patients (21%) had subthreshold depression. Depression was associated with a younger age and age at onset and female gender, but not with severity of parkinsonism, cognition or activities of daily living or laterality of motor symptoms. However, in male patients, an association between depression and left-sided parkinsonism was found. Conclusion In contrast to previous findings in PD patients with major depression but without dementia, we found no relationship between subthreshold depression and other clinical symptoms in patients with PDD. Copyright © 2007 John Wiley & Sons, Ltd.

Objective: To investigate the effects of attentional deficits on activities of daily living (ADL) in patients with dementia associated with Parkinson’s disease (PDD). Method: 461 patients were assessed neuropsychologically. Factor analyses were used to differentiate attention from other cognitive functions and to differentiate different aspects of ADL functions. The effects of the attentional measure on ADL were examined using sequential multiple regression, controlling for age, sex, education, severity of motor symptoms and other cognitive functions. Results: Three cognitive factors were identified, with one factor emerging as a measure of vigilance and focused attention. This factor predicted different aspects of ADL status even after controlling for motor functions and other cognitive factors. The attention factor was the single strongest cognitive predictor of ADL status, matching the strength of the effects of motor functions on ADL status. Conclusion: Impaired attention is an important determinant of ADL functions in patients with PDD.

Functional status, reflected by measures of activities of daily living (ADLs), deteriorates as Alzheimer disease (AD) progresses. Decline in activities of daily living may be mediated by executive and frontal lobe dysfunction. The objective of this study was to examine the relationship between activities of daily living and pathologic burden in Alzheimer disease. Twenty two subjects with definite Alzheimer disease were selected from the UCLA ADRC neuropathology database. A total activities of daily living score was derived from the Retrospective Collateral Dementia Interview-Revised (RCDI-R) questionnaire, which was administered to caregivers of autopsied subjects included in the study. Neuritic plaque (NP) and neurofibrillary tangle (NFT) counts were performed for 8 brain regions. There was a significant positive correlation between total activities of daily living score (higher scores indicate more disability) and mean neuritic plaques and neurofibrillary tangle counts (r = 0.671, P = 0.001, and r = 0.542, P = 0.009, resp), as well as CA1 and prosubiculum neuritic plaques and neurofibrillary tangle counts, right and left orbital frontal neuritic plaques counts, and occipital neuritic plaques count. Total activities of daily living score did not correlate with age at death, age at symptom onset, dementia duration, gender, or education. Deteriorating activities of daily living in Alzheimer Disease subjects correlate with greater overall pathologic burden and possibly selectively with involvement of the medial temporal, occipital, and orbital frontal regions.

In patients with dementia associated with Parkinson's disease (PD), the efficacy and safety of rivastigmine, an inhibitor of acetylcholinesterase and butyrylcholinesterase, were previously demonstrated in a 24-week double-blind placebo-controlled trial. Our objective was to determine whether benefits were sustained over the long term. Following the double-blind trial, all patients were permitted to enter an active treatment extension study, during which they received rivastigmine 3-12 mg/day. Standard safety assessments were performed. Efficacy assessments included the Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog) and other measures of cognition, daily function, neuropsychiatric symptoms, and executive function. Of 433 patients who completed the double-blind trial, 334 entered and 273 completed the active treatment extension. At 48 weeks, the mean ADAS-cog score for the whole group improved by 2 points above baseline. Placebo patients switching to rivastigmine for the active treatment extension experienced a mean cognitive improvement similar to that of the original rivastigmine group during the double-blind trial. The adverse event profile was comparable to that seen in the double-blind trial. Long-term rivastigmine treatment appeared well tolerated and may provide sustained benefits in dementia associated with PD patients who remain on treatment for up to 48 weeks.

The authors aimed to use baseline data of an ongoing large, prospective study in subjects with mild cognitive impairment (MCI) to investigate the impact of APOE genotype on the symptom profile of the condition.Cognitive assessments included the AD Assessment Scale cognitive subscale (ADAS-cog), the Mini-Mental State Examination (MMSE), and a cognitive battery for assessment of memory, attention, and executive function. Behavioral assessments included the Neuropsychiatric Inventory and Beck Depression Inventory. Activities of daily living were assessed by the AD Cooperative Study Activities of Daily Living (ADCS-ADL) scale. Hippocampal volumes were measured with MRI.A total of 494 of 1,018 study subjects provided APOE data. Approximately 40% of the subjects were APOE epsilon4 carriers. APOE epsilon4 carriers had lower MMSE (p = 0.01) and higher ADAS-cog (p0.0001) scores than noncarriers, indicating worse cognitive impairment. APOE epsilon4 carriers also had greater deficits on New York University delayed paragraph recall and Buschke free and cued selective reminding tests, and on the ADCS-ADL scale (p0.001). They also had smaller hippocampal volumes (p = 0.002). Behavioral scores were similar across the subgroups.MCI subjects carrying the APOE epsilon4 allele showed distinct cognitive and imaging profiles, which appeared to resemble those of early Alzheimer patients. APOE epsilon4 genotype was associated with greater impairments in memory and functional activities as well as hippocampal atrophy.

The authors investigated neuropsychiatric symptoms in mild cognitive impairment (MCI) from baseline data of the Investigation in the Delay to Diagnosis of AD with Exelon (InDDEx) study (n = 1,010). Neuropsychiatric symptoms were reported in 59% of subjects (Neuropsychiatric Inventory [NPI]). NPI+ subjects had significantly greater impairment on global, cognitive, and functional scores than NPI− subjects. The presence of neuropsychiatric symptoms appears to be a marker of MCI severity.

Stroke in childhood is rare and has its own characteristic findings. Vertebrobasilar ischemia due to trauma in this age group has been described, but its specific features have not yet been clearly defined. Dissection of vertebral artery is one of the causes of vertebrobasilar ischemia that is very uncommonly detected in the intracranial portion of the posterior circulation in childhood. We report a 14-year-old boy with a history of neck trauma and transient vertigo attacks who presented with brainstem and cerebellar ischemic findings. Due to the large left cerebellar infarct size compressing the fourth ventricle, we performed emergent posterior fossa decompression. Digital cerebral subtraction angiography revealed left vertebral artery dissection beginning at the V1 portion to the level of V4 and distal thrombosis of basilar artery. After 2 months, he was discharged from the hospital with minor neurologic deficit with anticoagulation therapy. Due to better outcome in childhood, early investigation for intracranial dissection should be included in the evaluation of posterior circulation infarcts in this age group.

After generalized or partial seizures, transient lesions may appear on magnetic resonance (MR) images. The mechanisms of MR changes might be a defect in cerebral autoregulation and blood-brain permeability. We report a patient with partial and secondary generalized tonic-clonic seizures. After her first seizure which was generalized tonic-clonic in nature, we detected multiple high signal intensities over the frontal cortical area on proton density images which were enhanced with gadolinium on T1-weighted images. The first and repeated EEGs showed no abnormalities or epileptic discharges. We started carbamezapine (600 mg/d) and excluded systemic diseases like vasculitis, infections, aetiological factors causing cerebrovascular diseases. In the follow-up, she was seizure free under antiepileptic therapy and no other neurological deficit. Repeated MR scans after 24 months from her first seizure revealed no pathologic signal intensities. Although the pathophysiology is unknown, recognition of reversible lesions helps diagnostic and therapeutic approaches to abnormal MR findings after seizures.