Timely referral for device-aided therapy in Parkinson's disease. Development of a screening tool.

BACKGROUND: Timely referral of Parkinson's disease (PD) patients to specialized centers for treatment with device-aided therapies (DAT) is suboptimal. OBJECTIVE: To develop a screening tool for timely referral for DAT in PD and to compare the tool with the published 5-2-1 criteria. METHODS: A cross-sectional, observational study was performed in 8 hospitals in the catchment area of a specialized movement disorder center in the Northern part of the Netherlands. The target population comprised PD patients not yet on DAT visiting the outpatient clinic of participating hospitals. The primary outcome was apparent eligibility for referral for DAT based on consensus by a panel of 5 experts in the field of DAT. Multivariable logistic regression modelling was used to develop a screening tool for eligibility for referral for DAT. Potential predictors were patient and disease characteristics as observed by attending neurologists. RESULTS: In total, 259 consecutive PD patients were included, of whom 17 were deemed eligible for referral for DAT (point prevalence: 6.6%). Presence of response fluctuations and troublesome dyskinesias were the strongest independent predictors of being considered eligible. Both variables were included in the final model, as well as levodopa equivalent daily dose. Decision curve analysis revealed the new model outperforms the 5-2-1 criteria. A simple chart was constructed to provide guidance for referral. Discrimination of this simplified scoring system proved excellent (AUC after bootstrapping: 0.97). CONCLUSIONS: Awaiting external validation, the developed screening tool already appears promising for timely referral and subsequent treatment with DAT in patients with PD.

Clinical applicability of quantitative atrophy measures on MRI in patients suspected of Alzheimer's disease.

OBJECTIVES: Neurodegeneration in suspected Alzheimer's disease can be determined using visual rating or quantitative volumetric assessments. We examined the feasibility of volumetric measurements of gray matter (GMV) and hippocampal volume (HCV) and compared their diagnostic performance with visual rating scales in academic and non-academic memory clinics. MATERIALS AND METHODS: We included 231 patients attending local memory clinics (LMC) in the Netherlands and 501 of the academic Amsterdam Dementia Cohort (ADC). MRI scans were acquired using local protocols, including a T1-weighted sequence. Quantification of GMV and HCV was performed using FSL and FreeSurfer. Medial temporal atrophy and global atrophy were assessed with visual rating scales. ROC curves were derived to determine which measure discriminated best between cognitively normal (CN), mild cognitive impairment (MCI), and Alzheimer's dementia (AD). RESULTS: Patients attending LMC (age 70.9 ± 8.9 years; 47% females; 19% CN; 34% MCI; 47% AD) were older, had more cerebrovascular pathology, and had lower GMV and HCV compared to those of the ADC (age 64.9 ± 8.2 years; 42% females; 35% CN, 43% MCI, 22% AD). While visual ratings were feasible in > 95% of scans in both cohorts, quantification was achieved in 94-98% of ADC, but only 68-85% of LMC scans, depending on the software. Visual ratings and volumetric outcomes performed similarly in discriminating CN vs AD in both cohorts. CONCLUSION: In clinical settings, quantification of GM and hippocampal atrophy currently fails in up to one-third of scans, probably due to lack of standardized acquisition protocols. Diagnostic accuracy is similar for volumetric measures and visual rating scales, making the latter suited for clinical practice. In a real-life clinical setting, volumetric assessment of MRI scans in dementia patients may require acquisition protocol optimization and does not outperform visual rating scales. KEY POINTS: • In a real-life clinical setting, the diagnostic performance of visual rating scales is similar to that of automatic volumetric quantification and may be sufficient to distinguish Alzheimer's disease groups. • Volumetric assessment of gray matter and hippocampal volumes from MRI scans of patients attending non-academic memory clinics fails in up to 32% of cases. • Clinical MR acquisition protocols should be optimized to improve the output of quantitative software for segmentation of Alzheimer's disease-specific outcomes.

Rivastigmine for minor visual hallucinations in Parkinson's disease: A randomized controlled trial with 24 months follow-up.

BACKGROUND: Visual hallucinations are common in patients with Parkinson's disease and represent probably the major independent predictor for cognitive deterioration and nursing home placement. OBJECTIVE: To investigate if treatment of minor visual hallucinations in Parkinson's disease with rivastigmine delays the progression to psychosis. METHODS: A multicenter, randomized, double-blind, placebo-controlled trial was conducted which aimed to recruit 168 patients with Parkinson's disease reporting minor visual hallucinations 4 weeks before it. Important exclusion criteria were Parkinson's disease dementia, current delirium, and treatment with antipsychotics or drugs that have significant anti-cholinergic side effects. Subjects were randomized to rivastigmine capsules, 3-6 mg twice a day, or placebo for 24 months. The primary outcome was the time to Parkinson's disease psychosis, which was defined as the need to start with antipsychotics. RESULTS: The trial was stopped prematurely because of slow recruitment. Ninety-one patients were randomized: 46 patients were assigned to rivastigmine and 45 patients to placebo. No effect of rivastigmine could be demonstrated on the transition time to psychosis or dementia during the 24-month follow-up period. After 6 months of study treatment, cognition, mood, motor performance, and non-motor performance did not differ significantly between the rivastigmine-group and the placebo-group. CONCLUSIONS: Because the study was terminated early, it was insufficiently powered to properly evaluate the primary outcome. The limited data of the study favor a wait and see approach instead of early treatment with rivastigmine in PD patients with minor VH.

["I can't complete my payment form anymore" : Visual disorders in posterior cortical atrophy]. / "Ik kan mijn acceptgiro niet meer invullen" : Visuele stoornissen bij posterieure corticale atrofie.

Visual problems occur frequently in elderly patients and are often caused by ophthalmological problems. In this clinical lesson we show that visual problems can also be caused by posterior cortical atrophy (PCA). PCA is a clinico-radiological syndrome that is often caused by Alzheimer's disease and other neurodegenerative diseases as Lewy body dementia and corticobasal degeneration. It is characterized by progressive decline in visual information processing. In addition, there is relative retention of memory and language in early stages. Brain imaging shows atrophy of the posterior brain areas.

[White matter abnormalities following attempted suicide]. / Wittestofafwijkingen na een zelfmoordpoging.

BACKGROUND: Delayed post-hypoxic leukoencephalopathy (DPHL) is a demyelinating disorder characterized by neuropsychiatric symptoms occurring a few days to some weeks following cerebral hypoxia. CASE DESCRIPTION: A 50-year old female patient showed rapidly progressive cognitive deterioration with apathy, mutism and regressive behaviour a few weeks after a suicide attempt with carbon monoxide (CO). This eventually leads to a state of akinetic mutism. Magnetic resonance imaging (MRI) of the brain showed diffuse white matter abnormalities. These MRI findings combined with CO intoxication and the clinical picture were highly suggestive for DPHL. CONCLUSION: This case emphasizes that a neurological cause should be considered if rapidly progressive neuropsychiatric symptoms occur, and that after suspected auto intoxication it is important to take possible hypoxia and its after-effects into consideration. Recognition of DPHL is important so that unnecessary invasive diagnostics and treatment can be avoided. Considering the favorable natural course of DPHL appropriate measures should be taken in order to provide supportive care and rehabilitation.

Assessing mental flexibility: neuroanatomical and neuropsychological correlates of the Trail Making Test in elderly people.

The Trail Making Test part B (TMT-B) is highly sensitive to age-related changes in the brain and cognitive function. However, the precise contribution of periventricular hyperintensities (PVH), deep white matter hyperintensities (DWMH), and medial temporal lobe atrophy (MTA) to task performance remains unspecified. Similarly, diminished performance may be due to deficient flexibility functions, but also to other age-related cognitive decline (e.g., mental slowing). The aim of the present study was to determine neuroanatomical (PVH, DWMH, MTA) and neuropsychological (working memory, executive function, speed and attention, episodic memory) predictors of TMT-B performance in elderly people. Results showed that MTA was the strongest predictor of TMT-B performance. The predictive value of the neuropsychological scores differed among the various TMT-B variables. For example, all neuropsychological domains predicted the TMT-B total completion time, whereas only executive function predicted the ratio score (TMT-B/A). We conclude that MTA is a very important predictor of TMT-B performance in elderly people. Furthermore, multiple cognitive functions are involved in TMT-B performance and a mild decline in any of these functions may result in diminished TMT-B performance. Therefore it is crucial to use the ratio score when one wishes to examine executive function ability.

Fragmentation of the rest-activity rhythm correlates with age-related cognitive deficits.

Aging affects both cognitive performance and the sleep-wake rhythm. The recent surge of studies that support a role of sleep for cognitive performance in healthy young adults suggests that disturbed sleep-wake rhythms may contribute to 'age-related' cognitive decline. This relationship has however not previously been extensively investigated. The present correlational study integrated a battery of standardized cognitive tests to investigate the association of mental speed, memory, and executive function with actigraphically recorded sleep-wake rhythms in 144 home-dwelling elderly participants aged 69.5 +/- 8.5 (mean +/- SD). Multiple regression analyses showed that the partial correlations of the fragmentation of the sleep-wake rhythm with each of the three cognitive domains (r = -0.16, -0.19, and -0.16 respectively) were significant. These associations were independent from main effects of age, implying that a unique relationship between the rest-activity rhythm and cognitive performance is present in elderly people.

The role of white matter hyperintensities and medial temporal lobe atrophy in age-related executive dysfunctioning.

Various studies support an association between white matter hyperintensities (WMH) and deficits in executive function in nondemented ageing. Studies examining executive functions and WMH have generally adopted executive function as a phrase including various functions such as flexibility, inhibition, and working memory. However, these functions include distinctive cognitive processes and not all may be affected as a result of WMH. Furthermore, atrophy of the medial temporal lobe (MTA) is frequently observed in ageing. Nevertheless, in previous studies of nondemented ageing MTA was not considered when examining a relationship between white matter and executive function. The goal of the present study was to examine how WMH and MTA relate to a variety of executive functions, including flexibility, fluency, inhibition, planning, set shifting, and working memory. Strong correlations were observed between WMH and MTA and most of the executive functions. However, only MTA was related to flexibility and set shifting performance. Regression analysis furthermore showed that MTA was the strongest predictor of working memory, after which no further significant association with WMH was noted. Alternatively, both MTA and periventricular hyperintensities independently predicted inhibition performance. These findings emphasize the importance of MTA when examining age-related decline in executive functioning.

White matter hyperintensities and working memory: an explorative study.

White matter hyperintensities (WMH) are commonly observed in elderly people and may have the most profound effect on executive functions, including working memory. Surprisingly, the Digit Span backward, a frequently employed working memory task, reveals no association with WMH. In the present study, it was investigated whether more detailed analyses of WMH variables and study sample selection are important when establishing a possible relationship between the Digit Span backward and WMH. To accomplish this, the Digit Span backward and additional working memory tests, WMH subscores, and cardiovascular risk factors were examined. The results revealed that performance on the Digit Span backward test is unrelated to WMH, whereas a relationship between other working memory tests and WMH was confirmed. Furthermore, a division between several white matter regions seems important; hyperintensities in the frontal deep white matter regions were the strongest predictor of working memory performance.

Neuroimaging and correlates of cognitive function among patients with heart failure.

BACKGROUND/AIMS: We purposed to investigate the relationship between cerebral abnormalities detected by magnetic resonance imaging (MRI) and cognitive performance in nondemented outpatients with heart failure (HF). METHODS: In 58 patients with HF neuropsychological assessment was performed including tests of mental speed, executive functions, memory, language and visuospatial functions. Deep, periventricular and total white matter hyperintensities (WMH), lacunar and cortical infarcts, global and medial temporal lobe atrophy (MTA) were investigated on MRI of the brain. Correlations between MRI findings and the cognitive measures were calculated. RESULTS: MTA correlated with memory (r = -0.353, p < 0.01), with executive functions (r = -0.383, p < 0.01) and the Mini Mental State Examination (r = -0.343, p < 0.05). Total WMH and deep WMH were found to correlate with depression and anxiety scores, but not with cognitive measures. Age, estimated premorbid intelligence and MTA were independent predictors of diminished cognitive performance. CONCLUSIONS: In HF patients, MTA was related to cognitive dysfunction, involving memory impairment and executive dysfunction, whereas WMH was related to depression and anxiety.

Profile of cognitive impairment in chronic heart failure.

OBJECTIVES: To determine the frequency and pattern of cognitive dysfunction in outpatients with chronic congestive heart failure (CHF) and to identify the corresponding demographic and clinical correlates. DESIGN: Case-control study. SETTING: Outpatient clinic in a community hospital. PARTICIPANTS: Sixty-two outpatients with CHF, 53 controls diagnosed with cardiovascular disease uncomplicated by CHF (cardiac controls), and 42 healthy controls were investigated. MEASUREMENTS: Neuropsychological assessment included tests of mental speed, executive function, memory, language, and visuospatial function. Composite z-scores for five cognitive domains and mean z-score for overall cognitive performance were computed. The cutoff score to indicate cognitive impairment was defined as the overall healthy participants' cognitive z-score minus 2 standard deviations. Independent demographic and clinical predictors of cognitive impairment were identified using linear regression analysis. RESULTS: Patients with CHF showed a pattern of general cognitive impairment, including impairment of executive function, memory, language, mental speed, and attention. Twenty-five percent (P=.04) of patients with CHF were classified as cognitively impaired, compared with 15% of the cardiac controls and 4% of the healthy controls. Independent predictors of cognitive impairment in patients with CHF were estimated intelligence, New York Heart Association class, and presence of the apolipoprotein (Apo)E epsilon4 allele. CONCLUSION: Cognitive dysfunction is relatively common in patients with CHF, with deficits being most prominent in the domains of executive function, memory, language, and mental speed. Disease severity and ApoE genotype are likely to be important determinants for cognitive impairment in patients with chronic CHF.

Brain magnetic resonance imaging abnormalities in patients with heart failure.

BACKGROUND: Although heart failure (HF) is a common cardiovascular disorder, to date little research has been conducted into possible associations between HF and structural abnormalities of the brain. AIMS: To determine the frequency and pattern of magnetic resonance imaging (MRI) abnormalities in outpatients with chronic HF, and to identify any demographic and clinical correlates. METHODS: Brain MRI scans were compared between a sample of 58 HF patients, 48 controls diagnosed with cardiovascular disease uncomplicated by HF (cardiac controls) and 42 healthy controls. Deep, periventricular and total white matter hyperintensities (WMH), lacunar and cortical infarcts, global and medial temporal lobe atrophy (MTA) were investigated. RESULTS: Compared to cardiac and healthy controls, HF patients had significantly more WMH, lacunar infarcts and MTA, whereas cardiac controls only had more MTA, compared to healthy controls. Age and left ventricular ejection fraction (LVEF) were independently associated with total WMH. Age and systolic hypotension were associated with MTA in HF patients and cardiac controls. CONCLUSION: Our results suggest that cardiac dysfunction contributes independently to the development of cerebral MRI abnormalities in patients with HF. Age and low LVEF are the principal predictors of cerebral WMH in patients with HF and in cardiac controls.

Cognitive impairment and MRI correlates in the elderly patients with type 2 diabetes mellitus.

BACKGROUND: exact mechanisms underlying cognitive dysfunction in diabetes mellitus (DM) remain unclear. Imaging studies of the brain could help to identify possible structural brain lesions underlying cognitive dysfunction. OBJECTIVE: to describe a detailed neuropsychological profile in patients functioning independently with type 2 DM. Secondly, correlations were studied between cognitive impairment and brain lesions on magnetic resonance imaging (MRI), i.e. periventricular hyperintensities (PVH), deep white matter lesions (DWML), medial temporal lobe atrophy (MTA), cerebral atrophy and lacunar infarcts. In addition, the influence of relevant disease variables of DM was studied. METHODS: 92 patients with type 2 DM (mean age 73.2 +/- 5.7 years, mean duration 13.8 +/- 10.8 years) and 44 control subjects (mean age 72.9 +/- 5.3 years) were included and underwent an extensive neuropsychological test battery and an MRI of the brain. RESULTS: neuropsychological scores were worse for each cognitive domain except for memory functions after adjustment for hypertension in a group of elderly patients with type 2 DM compared to healthy control subjects. Only PVH were independently associated with motor speed, whereas all other MRI measures were not independently associated with cognitive impairment. Interactions between the different MRI measures were not present. Glycosylated haemoglobin (HbA(1c)) and duration of DM were significantly associated with cognitive dysfunction. CONCLUSIONS: the data of this cross-sectional study show that type 2 DM is associated with diminished cognitive function in different cognitive domains, while memory is less affected after adjustment for hypertension. The association of cognitive impairment with MRI measures is equivocal, whereas HbA(1c) and duration of DM were significantly associated with cognitive dysfunction.

Brain lesions on MRI in elderly patients with type 2 diabetes mellitus.

BACKGROUND AND PURPOSE: Diabetes mellitus (DM) type 2 has been associated with poor cognitive performance and dementia, particularly in elderly patients. The exact mechanisms underlying the cognitive dysfunction in DM remain unclear. Imaging studies of the brain could be helpful to give more insight into possible structural brain lesions underlying these cognitive dysfunctions. Therefore, we performed a study in independently living patients with DM type 2 in order to investigate the association between DM and brain imaging abnormalities. METHODS: The study population consisted of 45 patients with DM type 2 without hypertension (mean age 73.4 +/- 5.1 years, mean duration 16.5 +/- 11.5 years), 45 patients with DM type 2 and hypertension (mean age 73.5 +/- 6.1 years, mean duration 11.9 +/- 9.2 years) and 44 control subjects (mean age 73.1 +/- 5.4 years). All patients and control subjects underwent an MRI of the brain. White matter lesions (WML), cerebral atrophy and medial temporal lobe atrophy were rated by a standardized visual rating scale. Lacunar infarcts were defined as focal hypo-intensities on fluid-attenuated inversion recovery sequences with a hyperintense rim around it. RESULTS: WML occurred more frequently in diabetic patients with hypertension as well as without hypertension. Significantly more deep WML were found in DM patients with and without hypertension when compared to control subjects, whereas no difference was found in the occurrence of periventricular hyperintensities. In all 3 groups, lacunar infarcts occurred sporadically. A trend towards higher atrophy scores was seen in patients with DM compared to control subjects. CONCLUSIONS: The data of this cross-sectional study suggest that type 2 DM is an independent risk factor for deep WML in the independently living elderly patients.

Pain intensity and pain affect in relation to white matter changes.

Since aging is a risk factor for both dementia and the occurrence of painful conditions, with the number of aged people increasing in the next decades, an increase in the number of elderly people suffering from both conditions can be anticipated. Reliable pain assessment in this population is restricted by reduced communicative and cognitive capacity, with serious consequences for effective pain treatment. White matter changes are frequently observed in the various subtypes of dementia as well as in normal aging, and may play a crucial role in pain processing. In healthy elderly people, reliable pain assessment can be accomplished, which enables examining the relationship between pain experience and white matter changes. A normal structure and function of the white matter is extremely important for dorsolateral prefrontal cortex (DLPFC) functioning, which has recently been linked to pain inhibition. The present study focused on the relation between white matter changes and both pain intensity and pain affect in elderly people without dementia. The Coloured Analogue Scale (CAS) and the Number of Words Chosen-Affective (NWC-A) were applied to measure pain intensity and pain affect, respectively. The presence of white matter changes was significantly related to a higher score on the NWC-A but not the CAS score. These results suggest that pain experience may change as a result of aging and that white matter changes might be indicative for these alterations.

Validation of the HIV Dementia Scale in an elderly cohort of patients with subcortical cognitive impairment caused by subcortical ischaemic vascular disease or a normal pressure hydrocephalus.

INTRODUCTION: Most cognitive screening instruments are tailored to detect symptoms of cortical dysfunction in the elderly. Therefore, subcortical cognitive dysfunction may be missed using these tests. The aim of this study was to validate the Human Immunodeficiency Virus (HIV) Dementia Scale (HDS), a screening test developed to detect subcortical cognitive dysfunction in young HIV-infected patients, in a group of elderly patients with subcortical cognitive impairment (SCI) caused by subcortical ischaemic vascular disease (SIVD) or a normal pressure hydrocephalus (NPH). MATERIALS AND METHODS: 53 patients with SCI caused by SIVD or an NPH and 54 age-matched control subjects without cognitive impairment were included. All subjects underwent the HDS and the Mini-Mental State Examination (MMSE). A neuropsychological examination was used as the best reference test for the diagnosis of SCI. RESULTS: The mean HDS score (maximum 16) was 5.1 +/- 3.5 in the SCI patients and 13.0 +/- 2.4 in the controls (p < 0.0001). The mean MMSE score (maximum 30) was 26.5 +/- 3.1 in the SCI group and 28.6 +/- 1.4 in the controls (p < 0.0001). Among subjects who had an MMSE score of more than 26 points, SCI patients (n = 35) also scored significantly lower on the HDS than controls (n = 50), mean scores being 6.2 +/- 3.4 and 13.0 +/- 2.4, respectively (p < 0.0001). A receiver-operating characteristics curve was used to detect the optimal sensitivity and specificity of the HDS. A cut-off score of 9 yielded 91% sensitivity (95% CI: 79-97) and 96% specificity (95% CI: 87-99). With this cut-off score, the positive predictive value was 96% (95% CI: 86-99) and the negative predictive value was 91% (95% CI: 81-97). CONCLUSIONS: These results suggest that the HDS is able to detect SCI in an elderly population with SIVD or NPH and a normal MMSE score, and warrant its further development as a screening tool for SCI.