Visual hallucinations in Parkinson's disease are associated with thinning of the inner retina.

Visual hallucinations (VH) are common in patients with Parkinson's disease (PD), yet the underlying pathophysiological mechanisms are still unclear. We aimed to explore the association of the presence of VH with inner retinal thinning and, secondarily, with visual acuity. To this end, we included 40 PD patients in this exploratory study, of whom 14 had VH, and 22 age- and sex-matched healthy controls. All participants were interviewed for the presence of VH by a neurologist specialized in movement disorders and underwent a thorough ophthalmologic examination, including measurement of the best-corrected visual acuity (BCVA) and optical coherence tomography to obtain macular scans of the combined ganglion cell layer and inner plexiform layer (GCL-IPL). Patients with VH had a thinner GCL-IPL than patients without VH, which persisted after correction for age, disease stage, levodopa equivalent daily dose (LED) and cognitive function. Furthermore, BCVA was lower in the PD group with VH than in the PD group without VH, although only a trend remained after correction for age, disease stage, LED and cognitive function. Taken together, in patients with PD, visual hallucinations appear to be associated with a thinning of the inner retinal layers and, possibly, with reduced visual acuity. Further research using a longitudinal design is necessary to confirm these findings and to establish the causality of these relationships.

Medial temporal lobe atrophy relates more strongly to sleep-wake rhythm fragmentation than to age or any other known risk.

Atrophy of the medial temporal lobe of the brain is key to memory function and memory complaints in old age. While age and some morbidities are major risk factors for medial temporal lobe atrophy, individual differences remain, and mechanisms are insufficiently known. The largest combined neuroimaging and whole genome study to date indicates that medial temporal lobe volume is most associated with common polymorphisms in the GRIN2B gene that encodes for the 2B subunit (NR2B) of the NMDA receptor. Because sleep disruption induces a selective loss of NR2B from hippocampal synaptic membranes in rodents, and because of several other reports on medial temporal lobe sensitivity to sleep disruption, we hypothesized a contribution of the typical age-related increase in sleep-wake rhythm fragmentation to medial temporal lobe atrophy. Magnetic resonance imaging and actigraphy in 138 aged individuals showed that individual differences in sleep-wake rhythm fragmentation accounted for more (19%) of the variance in medial temporal lobe atrophy than age did (15%), or any of a list of health and brain structural indicators. The findings suggest a role of sleep-wake rhythm fragmentation in age-related medial temporal lobe atrophy, that might in part be prevented or reversible.

Cognitive functioning in patients with carotid artery occlusion; a systematic review.

INTRODUCTION: Patients with complete occlusion of the internal carotid artery (CAO) are vulnerable to cerebral hypoperfusion. Since cerebral hypoperfusion is associated with accelerated cognitive decline, patients with CAO may have an increased risk of cognitive impairment. We aimed to assess the prevalence and profile of cognitive impairment in patients with CAO and to explore the relation between hemodynamic impairment and cognitive functioning. METHODS: We systematically searched Medline and EMBASE for studies including patients with symptomatic or asymptomatic CAO subjected to cognitive testing that were published between 1980 and 2017. We did not include patients with carotid stenosis. We obtained data on type of study, patient characteristics, cerebral imaging and neuropsychological testing. In addition, we extracted data on potential causes of systemic hemodynamic impairment and the presence and stage of cerebral hemodynamic impairment. We assessed methodological quality of included studies with the Newcastle-Ottawa Scale. RESULTS: We found eight studies comprising 244 patients (mean age 61 years, 76% male, 93% symptomatic CAO). The proportion of patients with cognitive impairment ranged from 54 to 71% in four studies; in the other four studies patients with CAO performed worse on cognitive testing than controls, but results were not quantified. Impairment was reported in all cognitive domains. We found no data on the association between systemic hemodynamic impairment and cognitive functioning. Studies that assessed whether cerebral hemodynamic impairment was associated with cognitive functioning showed conflicting results. CONCLUSION: In patients with CAO, cognitive impairment is present in about half to two-thirds of patients and is not restricted to specific cognitive domains. The effect of systemic and cerebral hemodynamic impairment on cognitive functioning in patients with CAO deserves further study.

Safety and feasibility of post-stroke care and exercise after minor ischemic stroke or transient ischemic attack: MotiveS & MoveIT.

BACKGROUND: Despite the beneficial effect of cardiac rehabilitation after myocardial infarction, a rehabilitation program to improve cardiorespiratory fitness and influence secondary prevention has not been implemented for ischemic stroke and transient ischemic attack (TIA). OBJECTIVE: To investigate the safety and feasibility of a post-stroke care including an exercise program after minor ischemic stroke or TIA. METHODS: In a randomised controlled trial, 20 patients with a recent minor stroke or TIA without cardiac contraindications were randomly assigned to one of the two interventions; post-stroke care without exercise or post-stroke care with exercise. Patients were evaluated at baseline, 6 and 12 months. RESULTS: Eighteen patients completed the intervention. In none of the patients cardiopulmonary contraindications for the maximal exercise test and exercise program were found. No cardiovascular events occurred during the maximal exercise tests and exercise program. After one year, significantly more patients in the post-stroke care with exercise group achieved the composite endpoint of optimal medical therapy. CONCLUSIONS: Post-stroke care including an exercise program is safe and feasible in the acute phase after minor stroke or TIA and might be a way to increase effectiveness of secondary stroke prevention. We are currently conducting a larger trial to validate these results.

A randomised controlled trial of aerobic exercise after transient ischaemic attack or minor stroke to prevent cognitive decline: the MoveIT study protocol.

INTRODUCTION: Patients with transient ischaemic attack (TIA) or stroke are at risk for cognitive impairment and dementia. Currently, there is no known effective strategy to prevent this cognitive decline. Increasing evidence exists that physical exercise is beneficial for cognitive function. However, in patients with TIA or stroke who are at risk of cognitive impairment and dementia, only a few trials have been conducted. In this study, we aim to investigate whether a physical exercise programme (MoveIT) can prevent cognitive decline in patients in the acute phase after a TIA or minor ischaemic stroke. METHODS AND ANALYSIS: A single-blinded randomised controlled trial will be conducted to investigate the effect of an aerobic exercise programme on cognition compared with usual care. 120 adult patients with a TIA or minor ischaemic stroke less than 1 month ago will be randomly allocated to an exercise programme consisting of a 12-week aerobic exercise programme and regular follow-up visits to a specialised physiotherapist during the period of 1 year or to usual care. Outcome measures will be assessed at the baseline, and at the 1-year and 2-year follow-up. The primary outcome is cognitive functioning measured with the Montreal Cognitive Assessment (MoCA) test and with additional neuropsychological tests. Secondary outcomes include maximal exercise capacity, self-reported physical activity and measures of secondary prevention. ETHICS AND DISSEMINATION: The study received ethical approval from the VU University Amsterdam Ethics committee (2011/383). The results of this study will be published in peer-reviewed journals and presented at international conferences. We will also disseminate the main results to our participants in a letter. TRIAL REGISTRATION NUMBER: The Nederlands Trial Register NTR3884.

The auditory oddball paradigm in patients with vascular cognitive impairment: a prolonged latency of the N2 complex.

OBJECTIVE: The event-related potential (ERP) evoked by the auditory oddball paradigm has been investigated mainly in patients with Alzheimer's disease and in patients with different causes of subcortical dementia. Subcortical ischemic vascular disease (SIVD) seems to be an important cause of vascular cognitive impairment (VCI) frequently not fulfilling the criteria for dementia. Recognition of VCI is needed in order to provide adequate care and therapy. The aim of this study was to investigate the diagnostic value of the different elements of this response (N(1), N(2) complex and P(3) latencies) in a group of elderly patients with VCI caused by SIVD. METHODS: The study population consisted of patients with a clinical and neuropsychological diagnosis of VCI caused by SIVD (n = 38) and healthy control subjects (n = 53) aged 60 years or older. The mean Mini Mental State Examination score of both groups was 27.6, and the mean HIV Dementia Scale score was 6.1 in the patient group and 12.3 in the control group. In all subjects, the ERP was recorded under standardized conditions, and the latencies and amplitudes of N(1), N(2) and P(3) were analyzed by two clinical neurophysiologists in consensus. Both were blinded to the diagnosis. RESULTS: The N(2) latency was significantly longer in patients with VCI than in age-matched controls, whereas the latencies of the P(3) and N(1) were not significantly different. The peak-to-peak amplitude of the N(2) complex to the P(3) wave was significantly lower in the patient group. White matter abnormalities on MRI were not significantly correlated with the N(2) latency. CONCLUSION: Our findings suggest that the latency of the N(2) complex is prolonged and the peak-to-peak amplitude of the N(2) complex to the P(3) wave is lowered in patients with VCI caused by SIVD.

[Disorders of concentration and memory in young adults and middle-aged persons]. / Concentratie- en geheugenstoornissen op jongvolwassen en middelbare leeftijd.

Four patients, two women aged 29 and 52 and two men aged 46 and 25, respectively, consulted a neurologist for attention and memory disorders. Further investigation revealed that the symptoms were caused by metachromatic leucodystrophy, Graves' disease, Huntington's disease, and a psychological background, respectively. The first patient became dependent in 1.5 years, the second recovered after treatment, the third was independent with slowly progressive symptoms after 1 year, and the fourth was advised to consult a psychologist. Disorders of attention and memory in relatively young people deserve a detailed evaluation at the very first visit, involving the elaboration of an initially extensive differential diagnosis. Too early a separation between a psychic and an organic pathogenesis should be avoided. Indications for the presence of a neurological condition include: consultation at the initiative of others, a relatively brief duration of symptoms without a clear provoking factor, the absence of a psychiatric history or life event, cognitive dysfunction in several areas, abnormal behaviour and an incriminating family history.

Effect of hydroxychloroquine on progression of dementia in early Alzheimer's disease: an 18-month randomised, double-blind, placebo-controlled study.

BACKGROUND: Results of epidemiological studies, neuropathological observations, and in-vitro experiments all suggest that inflammatory mechanisms contribute to the destructive lesions in Alzheimer's disease. We aimed to establish the effect of the anti-inflammatory drug hydroxychloroquine on the progression of dementia. METHODS: We did a double-blind, parallel-group, multicentre trial in which we randomly assigned 168 patients with early Alzheimer's disease to hydroxychloroquine (200 or 400 mg dependent on bodyweight), or placebo for 18 months. Outcome measures were related to activities of daily living, cognitive function, and behavioural abnormalities. Analysis was by intention to treat. RESULTS: At 18 months, mean scores for the interview for deterioration in daily life in dementia in patients on hydroxychloroquine (22.6 [SD 11.4]) did not differ from those for patients on placebo (21.3 [10.5]). Also, mean scores on the cognitive subscale of the Alzheimer's disease assessment scale were closely similar in hydroxychloroquine (26.4 [14.9]) and placebo (25.7 [14.3]) treated patients, as were behavioural changes, measured by the revised memory and behavioural problems checklist (36.3 [12.0] and 34.2 [12.4], respectively). Explorative analyses did not suggest any specific subgroup that benefited from hydroxychloroquine. The frequency and nature of serious adverse events and side-effects were much the same in both groups. 155 (92%) patients completed all assessments over the entire study. INTERPRETATION: Anti-inflammatory treatment with hydroxychloroquine for 18 months does not slow the rate of decline in minimal or mild Alzheimer's disease.

A new mutation in the prion protein gene: a patient with dementia and white matter changes.

The authors describe the clinical characteristics, MRI abnormalities, and molecular findings in a patient with a novel variant of a two-octarepeat insertion mutation in the prion protein gene. This patient presented with moderately progressive dementia of presenile onset and gait ataxia. MRI showed extensive cortical atrophy and white matter abnormalities. The mutation consists of a two-octarepeat insertion mutation and irregularities in the nucleotide sequence of the octarepeat region.

Autosomal dominant diffuse leukoencephalopathy with neuroaxonal spheroids.

OBJECTIVE: To provide clinical, MRI, and histopathologic findings in a rare white matter disorder with autosomal dominant inheritance, so-called hereditary diffuse leukoencephalopathy with spheroids (HDLS). BACKGROUND: Progressive leukoencephalopathies often constitute a diagnostic dilemma in both children and adults. In some cases, histopathologic examination of brain tissue is required for a classifying diagnosis. METHODS: Clinical history, MRI, and autopsy findings were reviewed in three patients with HDLS: a father, his daughter, and an unrelated patient. RESULTS: Clinical history consisted of an adult-onset neurologic deterioration with signs of frontal lobe dysfunction, epilepsy, spasticity, ataxia, and mild extrapyramidal disturbances. MRI findings included cerebral atrophy and patchy white matter changes, most pronounced in the frontal and frontoparietal area with extension through the posterior limb of the internal capsule into the pyramidal tracts of the brainstem. Autopsy in two patients revealed a leukoencephalopathy with frontoparietal and frontal preponderance and numerous neuroaxonal spheroids in the abnormal white matter. The pyramidal tracts were affected throughout the brainstem. CONCLUSION: Similar clinical and histopathologic findings have been reported in members of a Swedish pedigree. The homogeneity of the findings strongly suggests that HDLS is a distinct disease entity. In the absence of a biochemical or genetic marker, a definitive diagnosis requires histopathologic confirmation in one of the affected family members. Neuroaxonal spheroids.

[Vascular brain damage: an important and recognizable cause of cognitive and behavioral disorders]. / Vasculaire hersenschade: een belangrijke en te herkennen oorzaak van cognitieve stoornissen en gedragsstoornissen.

Four patients presented symptoms of a dementia syndrome. A man aged 67 showed gradual aggravation of disorders of memory and gait, as well as subcortical infarctions. A man aged 65 had disorders of concentration non compatible with the infarctions on the MRI scan, which disappeared after discontinuation of use of flunarizine. A woman aged 55 and a man aged 52 had changes of character and infarctions in the frontal lobe. Vascular dementia is, contrary to what most criteria suggest, often a subcortical syndrome. The relationship between cerebrovascular pathology on CT and MRI scans and cognitive and behavioural disorders is often hard to establish. If the criteria for vascular dementia are applied blindly, other causes of the subcortical dementia syndrome can be missed. The present criteria offer almost no room for detecting the subtle cognitive and behavioural disorders of cerebrovascular pathology. It is important to recognize the early changes of a threatened brain, because treatment and prevention might be effective in preventing further damage.

The diagnostic value of magnetic resonance imaging and technetium 99m-HMPAO single-photon-emission computed tomography for the diagnosis of Alzheimer disease in a community-dwelling elderly population.

The objective of this study was to assess the diagnostic value for Alzheimer disease (AD) of single-photon-emission computed tomography (SPECT) and magnetic resonance imaging (MRI), separately and in combination. The study was part of a two-stage population-based study of mental functioning among noninstitutionalized 65-to 85-year-olds living in Amsterdam, The Netherlands. Participants (n = 51) were randomly selected within strata of cognitive function to obtain a sample of AD patients (n = 10) and clinically normal subjects (n = 41), of whom 22 displayed some cognitive impairment and fulfilled criteria for "minimal dementia" according to the Cambridge Examination for Mental Disorders of the Elderly. Coronal T1-weighted MRI was used to visualize the medial temporal lobe. Medial temporal lobe atrophy (MTA) was assessed qualitatively on a 0-4 scale. Regional cerebral blood flow on SPECT was assessed with the use of technetium 99m-HMPAO in three manually drawn regions of interest (frontal, parietal, and temporoparietal). Ratios were calculated by using the cerebellum as the reference area. MTA differed significantly between AD patients and clinically normal subjects (p = 0.0009), with sensitivity for AD of 70% and a specificity of 76%. None of the three SPECT ratios differed between normal and AD subjects. The temporoparietal/cerebellar ratio had a sensitivity of 30% and a specificity of 71% as a cutoff of 0.76. When both tests were positive the combined sensitivity was low (20%), but the false-positive rate was also very low (5%). A negative result on MRI or any SPECT ratio yielded a high specificity (93%-98%) but also a high false-negative rate (60-80%). Adding SPECT to MRI seems useful only if a diagnosis of AD is suspected clinically and confirmation is needed. When the clinical probability that AD is absent is high, normal results on either MRI or SPECT may confirm this notion. Given the fact that structural imaging should be performed in a clinical workup for dementia, using MRI only would be the most cost-effective approach.

Visual assessment of medial temporal lobe atrophy on magnetic resonance imaging: interobserver reliability.

We conducted an interobserver study to assess agreement on visual rating of medial temporal lobe atrophy on coronal T1-weighted MRI. A total of 100 studies of elderly individuals, using two different MRI techniques (spin echo and inversion recovery sequences), were analysed by four raters (three neurologists and one neuroradiologist) using a five-point rating scale. Complete agreement was found in 37% of the total sample. Interobserver agreement as expressed by kappa values was 0.44 (95% CI = 0.34-0.54) and 0.51 (95% CI = 0.41-0.61) for the two techniques. After dichotomizing medial temporal lobe atrophy into present or absent, a post hoc analysis revealed higher complete agreement (70%), with kappa values of 0.59 (95% CI = 0.51-0.67) and 0.62 (95% CI = 0.48-0.075), for the two techniques (all four raters). From this study we conclude that visual rating of medial temporal lobe atrophy on MRI in the coronal plane yields fair to good agreement among observers. We recommend this type of visual rating for use in clinical settings when a quick judgement on the presence of medial temporal lobe atrophy is needed.

Diagnosing Alzheimer's disease in elderly, mildly demented patients: the impact of routine single photon emission computed tomography.

Based on the observation of bilateral temporoparietal hypoperfusion in Alzheimer's disease (AD), single photon emission computed tomography (SPECT) is advocated by some as a powerful diagnostic tool in the evaluation of demented patients. We studied whether routine brain SPECT in elderly, mildly demented outpatients increases the a priori diagnostic sensitivity and specificity of a careful clinical examination. 99mTc-HMPAO SPECT imaging was performed in 110 patients for a first evaluation for dementia. A semiquantitative measure of temporoparietal (TP) perfusion was calculated as the ratio of the activity in the temporoparietal cortex to activity in the cerebellum. A diagnosis of probable AD according to the McKhann criteria was made in 68 patients (mean age of 79.3 years) based on the results of a clinical examination, ancillary investigations and a 6-month follow-up. TP perfusion was significantly lower in AD patients than in 18 age-matched, non-demented controls. However, at a specificity of 89%, sensitivity was only 43% for detecting probable AD. The clinicians judged that SPECT had contributed to the final diagnosis in only 8% of the demented patients investigated. Routine brain SPECT in elderly, mildly demented outpatients does not contribute substantially to diagnostic accuracy after a careful clinical examination using current diagnostic criteria. Clinical guidelines have to be developed for the use of SPECT in patients with (suspected) dementia.