Stroke recurrence in patients with atrial fibrillation: concomitant carotid artery stenosis doubles the risk.

BACKGROUND AND PURPOSE: Atrial fibrillation (AF) and significant carotid artery stenosis (CAS) often coexist in patients with acute stroke but whether CAS affects the stroke recurrence rate in anticoagulated AF patients is largely unknown. The effect of concomitant CAS on both short- and long-term prognosis after stroke in patients with AF was evaluated. METHODS: The multicentre, retrospective FibStroke registry included AF patients with an ischaemic stroke or transient ischaemic attack (TIA) during 2003-2012. In this sub-study, 165 AF patients with ischaemic stroke or TIA with significant (>50%) CAS (CAS group) and 734 AF patients without CAS (non-CAS group) were identified. The median follow-up time after an index event was 3.5 (interquartile range 3.9) years. Long-term stroke recurrence rate, 30-day mortality, CHA2 DS2 -VASc score, other risk factors and the use and intensity of anticoagulation were assessed. RESULTS: The recurrence rate of ischaemic stroke (21.2% vs. 12.7%, P = 0.005, 8.1 vs. 3.6 events per100 follow-up years) was significantly higher in CAS patients compared to the non-CAS group despite similar anticoagulation/antithrombotic therapy. CAS patients had higher mean CHA2 DS2 -VASc scores than non-CAS patients (4.3 vs. 3.3, P < 0.001). However, in a multivariate analysis CAS was shown to be an independent risk factor for stroke recurrence (hazard ratio 2.02, 95% confidence interval 1.37-3.01, P = 0.001). The 30-day all-cause mortality was significantly higher in CAS patients (7.9% vs. 1.9%, P < 0.001) and CAS was an independent risk factor also for 30-day mortality (odds ratio 3.34, 95% confidence interval 1.51-7.38, P = 0.003). CONCLUSIONS: In patients with AF, concomitant CAS was an independent risk factor for both long-term stroke recurrence and 30-day mortality.

Underuse of anticoagulation in stroke patients with atrial fibrillation--the FibStroke Study.

BACKGROUND AND PURPOSE: Current guidelines recommend oral anticoagulation (OAC) for patients with atrial fibrillation (AF) and increased risk of thromboembolic events. The reasons for not using OAC in AF patients suffering stroke or transient ischaemic attack (TIA) were assessed. METHODS: This retrospective registry included 3404 patients with previously diagnosed AF who suffered a total of 2955 ischaemic strokes and 895 TIAs during 2003-2012. RESULTS: A CHA2DS2-VASc score ≥2 and a CHADS2 score ≥2 was observed in 3590 (93.2%) and in 2784 (72.3%) of the events, respectively. Of the high-risk patients (CHADS2 ≥2) only 55.1% were on OAC before the onset of stroke or TIA. The most frequently documented reasons for withholding OAC were infrequent paroxysms of AF (14%), previous bleeding episodes (13%) and the patient's decline/independent discontinuation of treatment (9%). Moreover, patients with paroxysmal AF (40% using OAC), previous bleeding (26% using OAC) and alcohol abuse (30% using OAC) were using OAC significantly less often than patients without these characteristics. A significant increase in the proportion of high-risk patients using OAC from 49% in 2003 to 65% in 2012 was seen. CONCLUSIONS: Underuse of anticoagulation is a common contributor to ischaemic strokes and TIA episodes in patients with AF. Infrequent AF episodes, previous bleeds, patient preference and alcohol abuse were the most common reasons for not using OAC.

Abundant glial alpha-synuclein pathology in a case without overt clinical symptoms.

Screening of 1,800 brains with alpha-synuclein (alphaS) immunohistochemistry revealed five cases with abundant glial cytoplasmic inclusions (GCIs) within the white matter of the brainstem. Surprisingly, retrospective clinical assessment showed that one of these subjects did not fulfil the currently recommended clinical consensus criteria for the multiple system atrophy (MSA). One of the hallmark lesions of MSA, alphaS-positive GCIs, were widespread and abundant in this atypical case that nonetheless lacked any significant neuronal loss. If the patient had met the clinical criteria for MSA, the neuropathological phenotype would have undeniably confirmed the clinically suggested diagnosis. However, lacking overt clinical signs of MSA, the neuropathological phenotype in this subject is prone to be variably denoted or overlooked. We would therefore like to advise neuropathologists to acknowledge these cases with "occult" alpha-synucleinopathy and to inform the clinicians of such a finding. Whether these cases represent a preclinical stage of MSA or simply a biological coincidence, is yet unknown. The observation of abundant GCIs in an asymptomatic subject is, however, important, because even if these cases are rare in number, their occurrence challenge the current presumption, whereby simply the number of alphaS-positive GCIs mediates the neuronal dysfunction responsible for the clinical symptoms of MSA.

Spectral analysis of EEG in Alzheimer's disease: relation to apolipoprotein E polymorphism.

Apolipoprotein E (ApoE) epsilon 4 allele is a risk factor for late-onset Alzheimer's disease (AD) and proposed to have a direct impact on cholinergic function in AD. Slowing of the EEG is characteristic in AD and the cholinergic system has an important role in modulating EEG. Fifty-eight AD patients at the early stage of the disease and 34 age- and sex-matched controls were studied using the quantitative EEG recorded from T6-O2 derivation. AD patients were divided into two subgroups: a) according to the ApoE allele (2 epsilon, 1 epsilon 4, and 0 epsilon 4) and b) according to familial aggregation. AD subgroups did not differ in clinical severity or duration of dementia. The AD patients with the epsilon 4 allele had higher relative theta amplitude and lower relative beta amplitude than controls and patients without the epsilon 4 allele. The peak frequencies were lower in all AD subgroups compared to controls. In conclusion, we found a tendency towards more pronounced EEG slowing in AD patients carrying the epsilon 4 allele. The minor differences in EEG may suggest differences in the degree of the cholinergic deficit in these subgroups.

Subclinical cerebral complications after coronary artery bypass grafting: prospective analysis with magnetic resonance imaging, quantitative electroencephalography, and neuropsychological assessment.

OBJECTIVE: To analyze the frequency and severity of subclinical cerebral complications associated with coronary artery bypass grafting (CABG). DESIGN: A prospective controlled study using preoperative and postoperative magnetic resonance imaging (MRI) of the brain, quantitative electroencephalography (QEEG), and detailed neuropsychological and neurologic examinations as potentially sensitive indicators of subclinical cerebral injury associated with CABG. SETTING: Multimodality evaluation in a tertiary care unit (Kuopio University Hospital, Kuopio, Finland). PATIENTS: Thirty-eight patients undergoing elective CABG and 20 control patients undergoing other major vascular surgery, mostly operations on the abdominal aorta. MAIN OUTCOME MEASURES: Coronary artery bypass grafting-associated cerebral complications assessed preoperatively and postoperatively by brain MRI, QEEG, detailed neurologic examination, and a neuropsychological test battery that evaluates cognitive functions in major areas known to be vulnerable to organic impairment (learning and memory, attention, flexible mental processing, and psychomotor speed). RESULTS: There were no major neurologic complications. A mild hemisyndrome developed in 1 patient who underwent CABG and in 1 control patient. Overall, there was no decline in mean cognitive performance 3 months after surgery. Electroencephalographic slowing of 0.5 Hz or more in at least 2 channels occurred in 11 patients who underwent CABG and in 1 control patient (P=.03). The postoperative brain MRI scan revealed new small ischemic lesions in 8 patients (21%) in the CABG group but in none of the control group (P=.03). These new cerebral MRI lesions did not explain deterioration in neuropsychological test performance or the QEEG slowing. CONCLUSIONS: Coronary artery bypass grafting causes more QEEG alterations and small ischemic cerebral lesions that are detectable by MRI than does other major vascular surgery. The effect is mainly subclinical, because no statistically significant deterioration in mean neuropsychological test performance was detected.

Clinical and neuropsychological characteristics in familial and sporadic Alzheimer's disease: relation to apolipoprotein E polymorphism.

Alzheimer's disease (AD) is a heterogeneous entity presenting as sporadic and familial disease. In familial AD, there is evidence for genetic linkage to a yet undefined gene on chromosome 14 in early-onset pedigrees and on chromosome 19 in late-onset pedigrees. In a few early-onset kindreds, there were mutations in the amyloid precursor gene on chromosome 21. There is an increased frequency of apolipoprotein E (ApoE) epsilon4 allele in patients with late-onset AD. We studied the clinical presentation and profile of cognitive deficits in 58 AD patients at the early stage of the disease. We divided the AD patients into subgroups of sporadic late-onset (SLO) (> or = 65 years), familial late-onset (FLO) (> or = 65 years), sporadic early-onset (SEO) (<65 years), and familial early-onset (FEO) (<65 years) patients and into three subgroups according to their ApoE genotype zero epsilon4, one epsilon4, and two epsilon4 alleles. The AD subgroups did not differ in the global clinical severity of dementia or the duration of the disease. SLO, FLO, SEO, and FEO subgroups did not differ in clinical characteristics such as occurrence of rigidity, hypokinesia, tremor, myoclonus, hallucinations, delusions, or epileptic seizures nor in the profile of deficits on tests assessing memory, language, visuospatial, executive, and praxic functions. The epsilon4++ allele frequency was 0.43 for all AD patients and did not differ across subgroups divided according to the familial aggregation and age of onset. Patients with two epsilon4 alleles had earlier age at onset of dementia than those with no epsilon4 allele (63 +/- 9 versus 68 +/- 9 years), but otherwise the clinical symptoms and signs were not related to the ApoE genotype. However, the AD patients with two epsilon 4 alleles had lowest scores on memory tests and differed significantly from those with one or zero epsilon4 allele in the delayed list learning (p<0.05) and from those with zero epsilon4 allele in the immediate and delayed story recall. In contrast, verbal functions were better preserved in two epsilon4 patients than in those with other ApoE genotypes. This study failed to confirm the earlier reports of severe aphasia, agnosia, and apraxia in familial AD patients, but the clinical phenotype was similar irrespective to the familial aggregation. However, AD patients with two epsilon4 alleles are characterized by more severe memory loss and earlier age of onset than those without the epsilon4 allele.

Age-related cognitive decline and electroencephalogram slowing in Down's syndrome as a model of Alzheimer's disease.

We studied quantitative electroencephalogram and neuropsychological performance in an aging series of 31 patients with Down's syndrome and compared the findings with those of 36 patients with probable Alzheimer's disease and age-matched controls. We found an age-related decline of cortical functions and slowing of the electroencephalogram in Down's syndrome patients aged from 20 to 60 years. Slowing of the electroencephalogram, i.e. the decrease of the peak frequency, was significantly related to Mini-Mental status scores, and visual, praxic and speech functions, as well as memory in the Down patients, similar to the Alzheimer patients. Similar correlations were not demonstrated for young or elderly controls. This study provides neuropsychological and electrophysiological data to suggest that studying Down's syndrome patients of different ages can serve as a model for progression of Alzheimer's disease.

Volumes of hippocampus, amygdala and frontal lobe in Alzheimer patients with different apolipoprotein E genotypes.

An increased frequency of apolipoprotein E E4 allele has been reported in patients with late onset Alzheimer's disease. Apolipoprotein E participates in the transport of cholesterol and other lipids and interferes with the growth and regeneration of both peripheral and central nervous system tissues during development and after injury. Apolipoprotein E is also implicated in synaptogenesis. Apolipoprotein E isoforms differ in binding to amyloid-beta-protein and tau protein in vitro. Here, we wanted to study the effect of apolipoprotein E genotype on the magnitude of damage in the hippocampus, where a marked synapse loss exists in Alzheimer's disease. We measured by magnetic resonance imaging the volumes of the hippocampus, amygdala, and frontal lobes in the three Alzheimer subgroups: patients with 2, 1 or 0 E4 alleles. We also investigated the profile of deficits on tests assessing memory, language, visuospatial, executive, and praxic functions of these Alzheimer subgroups. All Alzheimer patients were at early stage of the disease. We found that Alzheimer patients with E4/4 genotype (N = 5) had smaller volumes of the hippocampus and the amygdala than those with E3/4 (N = 9) and those with E3/3 or E2/3 (N = 12). The difference was significant for the right hippocampus (-54% of control) and the right amygdala (-37% of control). The volumes of the frontal lobes were similar across the Alzheimer subgroups. The patients with E4/4 also showed lowest scores on delayed memory tests and differed from E3/3, 3/2 patients in the list learning test (< 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Slow-wave activity in the spectral analysis of the electroencephalogram and volumes of hippocampus in subgroups of Alzheimer's disease patients.

This study examined patients who fulfilled the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association Work Group criteria for probable Alzheimer's disease (AD; n = 35) and controls for magnetic resonance imaging and psychometric data (n = 16) and for quantitative electroencephalogram data (n = 34). A cluster analysis performed on neuropsychological variables identified 2 AD subgroups: The AD1 group (n = 12) had impaired memory and executive functions but preserved verbal and visuospatial functions. The AD2 group (n = 23) had global impairment. The AD2 group had higher theta amplitude in the temporo-occipital, centroparietal, and frontal derivation and lower peak and mean frequency than the AD1 group or controls. Both AD groups had more severe memory deficits and clearly smaller hippocampal volumes than controls. This may implicate that the degree of damage in ascending activating systems differs in these subgroups, although the damage in the hippocampus is equal.

A correlation study of CSF neuropeptides in Alzheimer's and Parkinson's disease.

The concentrations of somatostatin (SRIF), vasoactive intestinal polypeptide (VIP), beta-endorphin (beta-EP), adrenocorticotropin (ACTH) and corticotropin-releasing factor (CRF) immunoreactivity were measured in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD), patients with Parkinson's disease (PD) and controls. In order to study the mechanisms that regulate peptide levels in CSF and peptide interactions, correlations between CSF peptides were determined. Within all patient groups a number of significant correlations were shown to exist between CSF peptides. The correlations were apparently not coincidental, since there was no such relation between the concentrations of CSF peptides and CSF protein content. Neither age, sex, severity of dementia nor the presence of extrapyramidal signs could explain the number of significant correlations. These results indicate, that the correlations found between CSF peptides may be due to common regulatory mechanisms or general physiological behaviour of peptides in the CSF.

Rapidly progressive multifocal leukoencephalopathy with substantial cell-mediated inflammatory response and with cognitive decline of non-Alzheimer type in a 75-year-old female patient.

Autopsy findings of rapidly progressive and widespread multifocal leukoencephalopathy (PML) in a 75-year-old woman with no known predisposing disease are demonstrated. Originally she was given a clinical working diagnosis of syndrome of progressive supranuclear palsy (PSP). The neuropathological investigation revealed widespread white and gray matter changes consistent with PML, and the JC virus was verified by EM, in situ hybridization and immunohistochemistry. In contrast to the few chronic inflammatory cells generally seen in PML in this case there was a substantial cell-mediated inflammatory response reflected in numerous T-helper and T-killer cells. The uncommon, widespread distribution of lesions and substantial cell-mediated response reported might indicate that the rearrangement of viral genome, previously suggested of importance for viral growth in the central nervous system (CNS), is also important for viral spread within the CNS, infectivity of glial cells and for the activation of cell-mediated immunity.

Heterogeneity of cerebral blood flow: a fractal approach.

AIM: We demonstrate the heterogeneity of regional cerebral blood flow using a fractal approach and single-photon emission computed tomography (SPECT). METHOD: Tc-99m-labelled ethylcysteine dimer was injected intravenously in 10 healthy controls and in 10 patients with dementia of frontal lobe type. The head was imaged with a gamma camera and transaxial, sagittal and coronal slices were reconstructed. Two hundred fifty-six symmetrical regions of interest (ROIs) were drawn onto each hemisphere of functioning brain matter. Fractal analysis was used to examine the spatial heterogeneity of blood flow as a function of the number of ROIs. RESULTS: Relative dispersion (= coefficient of variation of the regional flows) was fractal-like in healthy subjects and could be characterized by a fractal dimension of 1.17 +/- 0.05 (mean +/- SD) for the left hemisphere and 1.15 +/- 0.04 for the right hemisphere, respectively. The fractal dimension of 1.0 reflects completely homogeneous blood flow and 1.5 indicates a random blood flow distribution. Patients with dementia of frontal lobe type had a significantly lower fractal dimension of 1.04 +/- 0.03 than in healthy controls. CONCLUSION: Within the limits of spatial resolution of SPECT, the heterogeneity of brain blood flow is well characterized by a fractal dimension. Fractal analysis may help brain scientists to assess age-, sex- and laterality-related anatomic and physiological changes of brain blood flow and possibly to improve precision of diagnostic information available for patient care.

Patient satisfaction with switching to Stalevo: an open-label evaluation in PD patients experiencing wearing-off (Simcom Study).

OBJECTIVES AND METHODS: This study investigated the ease with which 52 Parkinson's disease patients already receiving adjunct entacapone to traditional levodopa were switched to Stalevo (levodopa/carbidopa/entacapone). RESULTS: The switch to Stalevo was straightforward for most patients taking standard-release levodopa with 86% of these patients being able to replace their entire regimen without having to change the amount of levodopa taken. The majority of patients (54%, P = 0.162) preferred Stalevo; 31% preferred their prior treatment regimen; 15% had no preference. Patients found Stalevo more simple to dose (94%), more convenient to use (84%), easier to handle (84%), easier to remember (67%) and easier to swallow (59%), compared with their previous medication. CONCLUSIONS: Stalevo was well tolerated, with a low incidence of adverse events. The study shows that Stalevo is an effective, preferred and well-tolerated means of delivering levodopa/carbidopa/entacapone in one easy-to-use tablet.

Cognitive and memory deficits in untreated Parkinson's disease and amyotrophic lateral sclerosis patients: a comparative study.

We investigated the profile of cognitive and memory deficits of 22 Parkinson's disease (PD), 24 amyotrophic lateral sclerosis (ALS) patients and 26 age-matched controls. The patients were at the early phase of the disease and untreated. The ALS patients exhibited deficits in simple visuoperceptual functions and in complex visuoperceptual reasoning (Digit Symbol and Block Design tests), whereas the PD patients showed deficits only in simple visuoperceptual functions. Moreover, both ALS and PD patients had impairment in tasks requiring set shifting from one reaction to another that may suggest frontal lobe dysfunction. The ALS and PD patients also showed impairment in the task of learning a word list with effort-demanding organization of the material to be remembered. However, preserved delayed recall of logical passages suggests that memory, per se, is not impaired in ALS or in PD. The patterns of errors in a test of recognition of learned words imply, at least partially, different underlying deficits in the two diseases. An inability to inhibit irrelevant information may contribute to memory impairment in ALS patients, whereas the memory deficit in PD may derive from lowered motivation or initiating behaviour.

Neurotransmitter markers in the cerebrospinal fluid of normal subjects. Effects of aging and other confounding factors.

We have investigated neurotransmitter-related markers of the cerebrospinal fluid (CSF) in a carefully screened series of normally aging subjects in standardized conditions in order to find out the influence of age and other confounding factors on CSF measures. The levels of 3-methoxy-4-hydroxyglycol (MHPG) and the activity of acetylcholinesterase (AChE) also increased with age, while homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5 HIAA) and immunoreactivities of somatostatin (SLI), beta-endorphin (BLI) and adrenocorticotropic hormone (ACTH) were unrelated to age. The gender of subjects had no significant effect on the levels of neurotransmitter markers, while seasonal changes, as well as height and weight of the subjects seemed to cause some variations in the levels of HVA, dopamine-beta-hydroxylase (DBH) and ACTH. The study underscores the importance of standardized conditions and matched patient groups in the CSF studies.

Inhibitory and excitatory amino acids in cerebrospinal fluid of chronic epileptic patients.

We studied the levels of excitatory and inhibitory amino acids in the cerebrospinal fluid (CSF) of 28 epileptic patients (24 with partial type seizures, 4 with primary generalized seizures) and 12 controls. The levels of aspartate were 63% (p less than 0.01), glutamine 129% (p less than 0.001), and homocarnosine 127% (p less than 0.005) that of controls. The concentrations of glutamate, asparagine, total GABA, free GABA, taurine, and glycine did not differ between epileptic patients and controls. Patients with partial epilepsy had a pattern of amino acids in CSF similar to that in patients with primary generalized seizures. In the present study we did not observe increased excitation or decreased inhibition in the seizure-active brains of epileptics, as far as the CSF levels of amino acids reflect their levels in the brain.

Extrapyramidal signs in Alzheimer's disease: a 3-year follow-up study.

Occurrence of extrapyramidal signs was investigated in a follow-up study of 32 patients with probable Alzheimer's disease (AD). Bradykinesia and rigidity were observed in 39% and 11% of the neuroleptic-free patients at entry and in 72% and 61% at year 3, respectively. Tremor was not a predominant feature nor did its occurrence increase over time. Use of neuroleptics contributed to extrapyramidal signs; 75-100% of the neuroleptic-treated patients showed bradykinesia, rigidity or orofacial dyskinesia. The homovanillic acid (HVA) concentrations of the cerebrospinal fluid at entry were comparable to those of age-matched controls. Nor did HVA levels correlate with rigidity or bradykinesia in these early AD cases. Presence of bradykinesia or rigidity at the initial evaluation predicted more severe dementia and a poor prognosis over the period of 3 years, although interaction of initial clinical severity of dementia was significant. Of 15 patients with these signs 3 (20%) died and 8 (53%) needed institutional care, while of 17 patients without these signs only 1 (6%) died and 2 (12%) were institutionalized by year 3 (p less than 0.01).

Neurochemical markers in the cerebrospinal fluid of patients with Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis and normal controls.

Several neurotransmitter markers were investigated in the cerebrospinal fluid (CSF) from patients with Alzheimer's disease (AD) (n = 27), Parkinson's disease (PD) (n = 35) and ALS (n = 26) and from control subjects (n = 34) to compare the possible alterations in the biochemical profiles of these different neurodegenerative diseases. The main proportion of the patients represented an early phase of the illness at the time of the diagnosis. Correlations of the degree of dementia and the stage of the disease with CSF measures were evaluated. The CSF levels of somatostatin like-immunoreactivity (SLI) were significantly reduced in AD patients when compared with those of normals and ALS patients. The CSF concentrations of homovanillic acid (HVA) were significantly decreased for PD patients and the decrease focused on the non-demented patients. A trend of decreasing HVA values towards the most advanced stage of Parkinson's disease assessed by Webster's scale was also displayed. The content of 3-methoxy-4-hydroxyphenylglycol (MHPG) in the CSF was higher for ALS patients than for other groups. The lowest 5-hydroxy-indoleacetic acid (5HIAA) levels were observed in the PD group and the lowest acetylcholinesterase (AChE) activities were found in the PD patients with the most severe disease. Changes in CSF measures were too subtle to be beneficial for diagnostic purposes, but adequate for reflecting the different neurochemical profiles of these three degenerative neurological disorders.