Stroke Prevention in Atrial Fibrillation: Our Current Failures and Required Research.

Nonvalvular atrial fibrillation is a common rhythm disorder of middle-aged to older adults that can cause ischemic strokes and systemic embolism. Lifelong use of oral anticoagulants reduces the risk of these ischemic events but increases the risk of major and clinically relevant hemorrhages. These medications also require strict compliance for efficacy, and they have nontrivial failure rates in higher-risk patients. Left atrial appendage closure is a nonpharmacological method to prevent ischemic strokes in atrial fibrillation without the need for lifelong anticoagulant use, but this procedure has the potential for complications and residual embolic events. This workshop of the Roundtable of Academia and Industry for Stroke Prevention discussed future research needed to further decrease the ischemic and hemorrhagic risks among patients with atrial fibrillation. A direct thrombin inhibitor, factor Xa inhibitors, and left atrial appendage closure are FDA-approved approaches whereas factor XIa inhibitors are currently being studied in phase 3 randomized controlled trials for stroke prevention. The benefits, risks, and shortcomings of these treatments and future research required in different high-risk patient populations are reviewed in this consensus statement.

Left ventricular hypertrophy and left atrial size are associated with ischemic strokes among non-vitamin K antagonist oral anticoagulant users.

BACKGROUND: Ischemic strokes (IS) occurring in patients taking non-vitamin K antagonist oral anticoagulants (NOACs) are becoming increasingly more frequent. We aimed to determine the clinical, echocardiographic, and neuroimaging markers associated with developing IS in patients taking NOACs for atrial fibrillation. METHODS: From a quaternary care center, clinical/radiologic data were collected from consecutive NOAC users with IS and age-matched controls without IS. Brain MRIs were reviewed for markers of cerebral small vessel disease. Variables with significant differences between groups were entered into a multivariable regression model to determine predictors of IS. Among IS patients, a Cox regression analysis was constructed to determine predictors of IS recurrence during follow-up. RESULTS: 112 patients with IS and 94 controls were included in the study. Variables significantly different between groups included apixaban use, dabigatran use, prior cerebrovascular events, hemoglobin A1c (HbA1c), left ventricular hypertrophy, left atrial volume index, and severe white matter hyperintensities. After multivariable adjustment, prior cerebrovascular events (aOR 23.86, 95% CI [6.02-94.48]), HbA1c levels (aOR 2.36, 95% CI [1.39-3.99]), left ventricular hypertrophy (aOR 2.73, 95% CI [1.11-6.71]) and left atrial volume index (aOR 1.05, 95% CI [1.01-1.08]) increased the risk of stroke, whereas apixaban use appeared to decrease the risk (aOR 0.38, 95% CI [0.16-0.92]). Malignancy was associated with IS recurrence (aHR 4.90, 95% CI [1.35-18.42]) after adjustment for age and chronic renal failure. CONCLUSIONS: Prior cerebrovascular events, diabetes, left ventricular hypertrophy, and increased left atrial size are risk factors for developing an IS among NOAC users.

Mechanistic Implications of Cortical Superficial Siderosis in Patients With Mixed Location Intracerebral Hemorrhage and Cerebral Microbleeds.

BACKGROUND AND OBJECTIVES: Hypertensive cerebral small vessel disease (HTN-cSVD) is the predominant microangiopathy in patients with a combination of lobar and deep cerebral microbleeds (CMBs) and intracerebral hemorrhage (mixed ICH). We tested the hypothesis that cerebral amyloid angiopathy (CAA) is also a contributing microangiopathy in patients with mixed ICH with cortical superficial siderosis (cSS), a marker strongly associated with CAA. METHODS: Brain MRIs from a prospective database of consecutive patients with nontraumatic ICH admitted to a referral center were reviewed for the presence of CMBs, cSS, and nonhemorrhagic CAA markers (lobar lacunes, centrum semiovale enlarged perivascular spaces [CSO-EPVS], and multispot white matter hyperintensity [WMH] pattern). The frequencies of CAA markers and left ventricular hypertrophy (LVH), a marker for hypertensive end-organ damage, were compared between patients with mixed ICH with cSS (mixed ICH/cSS[+]) and without cSS (mixed ICH/cSS[-]) in univariate and multivariable models. RESULTS: Of 1,791 patients with ICH, 40 had mixed ICH/cSS(+) and 256 had mixed ICH/cSS(-). LVH was less common in patients with mixed ICH/cSS(+) compared with those with mixed ICH/cSS(-) (34% vs 59%, p = 0.01). The frequencies of CAA imaging markers, namely multispot pattern (18% vs 4%, p < 0.01) and severe CSO-EPVS (33% vs 11%, p < 0.01), were higher in patients with mixed ICH/cSS(+) compared with those with mixed ICH/cSS(-). In a logistic regression model, older age (adjusted odds ratio [aOR] 1.04 per year, 95% CI 1.00-1.07, p = 0.04), lack of LVH (aOR 0.41, 95% CI 0.19-0.89, p = 0.02), multispot WMH pattern (aOR 5.25, 95% CI 1.63-16.94, p = 0.01), and severe CSO-EPVS (aOR 4.24, 95% CI 1.78-10.13, p < 0.01) were independently associated with mixed ICH/cSS(+) after further adjustment for hypertension and coronary artery disease. Among ICH survivors, the adjusted hazard ratio of ICH recurrence in patients with mixed ICH/cSS(+) was 4.65 (95% CI 1.38-11.38, p < 0.01) compared with that in patients with mixed ICH/cSS(-). DISCUSSION: The underlying microangiopathy of mixed ICH/cSS(+) likely includes both HTN-cSVD and CAA, whereas mixed ICH/cSS(-) is likely driven by HTN-cSVD. These imaging-based classifications can be important to stratify ICH risk but warrant confirmation in studies incorporating advanced imaging/pathology.

Peak width of skeletonized mean diffusivity and cognitive performance in cerebral amyloid angiopathy.

Background: Cerebral Amyloid Angiopathy (CAA) is a cerebral small vessel disease that can lead to microstructural disruption of white matter (WM), which can be measured by the Peak Width of Skeletonized Mean Diffusivity (PSMD). We hypothesized that PSMD measures would be increased in patients with CAA compared to healthy controls (HC), and increased PSMD is associated with lower cognitive scores in patients with CAA. Methods: Eighty-one probable CAA patients without cognitive impairment who were diagnosed with Boston criteria and 23 HCs were included. All subjects underwent an advanced brain MRI with high-resolution diffusion-weighted imaging (DWI). PSMD scores were quantified from a probabilistic skeleton of the WM tracts in the mean diffusivity (MD) image using a combination of fractional anisotropy (FA) and the FSL Tract-Based Spatial Statistics (TBSS) algorithm (www.psmd-marker.com). Within CAA cohort, standardized z-scores of processing speed, executive functioning and memory were obtained. Results: The mean of age and sex were similar between CAA patients (69.6 ± 7.3, 59.3% male) and HCs (70.6 ± 8.5, 56.5% male) (p = 0.581 and p = 0.814). PSMD was higher in the CAA group [(4.13 ± 0.94) × 10-4 mm2/s] compared to HCs [(3.28 ± 0.51) × 10-4 mm2/s] (p < 0.001). In a linear regression model corrected for relevant variables, diagnosis of CAA was independently associated with increased PSMD compared to HCs (ß = 0.45, 95% CI 0.13-0.76, p = 0.006). Within CAA cohort, higher PSMD was associated with lower scores in processing speed (p < 0.001), executive functioning (p = 0.004), and memory (0.047). Finally, PSMD outperformed all other MRI markers of CAA by explaining most of the variance in models predicting lower scores in each cognitive domain. Discussion: Peak Width of Skeletonized Mean Diffusivity is increased in CAA, and it is associated with worse cognitive scores supporting the view that disruption of white matter has a significant role in cognitive impairment in CAA. As a robust marker, PSMD can be used in clinical trials or practice.

Improving detection of cerebral small vessel disease aetiology in patients with isolated lobar intracerebral haemorrhage.

BACKGROUND AND PURPOSE: We evaluate whether non-haemorrhagic imaging markers (NHIM) (white matter hyperintensity patterns, lacunes and enlarged perivascular spaces (EPVS)) can discriminate cerebral amyloid angiopathy (CAA) from hypertensive cerebral small vessel disease (HTN-cSVD) among patients with isolated lobar intracerebral haemorrhage (isolated-LICH). METHODS: In patients with isolated-LICH, four cSVD aetiologic groups were created by incorporating the presence/distribution of NHIM: HTN-cSVD pattern, CAA pattern, mixed NHIM and no NHIM. CAA pattern consisted of patients with any combination of severe centrum semiovale EPVS, lobar lacunes or multiple subcortical spots pattern. HTN-cSVD pattern consisted of any HTN-cSVD markers: severe basal ganglia PVS, deep lacunes or peribasal ganglia white matter hyperintensity pattern. Mixed NHIM consisted of at least one imaging marker from either pattern. Our hypothesis was that patients with HTN-cSVD pattern/mixed NHIM would have a higher frequency of left ventricular hypertrophy (LVH), which is associated with HTN-cSVD. RESULTS: In 261 patients with isolated-LICH, CAA pattern was diagnosed in 93 patients, HTN-cSVD pattern in 53 patients, mixed NHIM in 19 patients and no NHIM in 96 patients. The frequency of LVH was similar among those with HTN-cSVD pattern and mixed NHIM (50% vs 39%, p=0.418) but was more frequent in HTN-cSVD pattern compared with CAA pattern (50% vs 20%, p<0.001). In a regression model, HTN-cSVD pattern (OR: 7.38; 95% CI 2.84 to 19.20) and mixed NHIM (OR: 4.45; 95% CI 1.25 to 15.90) were found to be independently associated with LVH. CONCLUSION: Among patients with isolated-LICH, NHIM may help differentiate HTN-cSVD from CAA, using LVH as a marker for HTN-cSVD.

Clinical and neuroimaging risk factors associated with the development of intracerebral hemorrhage while taking direct oral anticoagulants.

BACKGROUND AND AIMS: Intracerebral hemorrhage (ICH) associated with direct oral anticoagulant (DOAC) usage confers significant mortality/disability. We aimed to understand the clinical and neuroimaging features associated with developing ICH among DOAC users. METHODS: Clinical and radiological data were collected from consecutive DOAC users with ICH (DOAC-ICH) and age-matched controls without ICH from a single referral center. The frequency/distribution of MRI markers of hemorrhage risk were assessed. Baseline demographics and neuroimaging markers were compared in univariate tests. Significant associations (p < 0.1) were entered into a multivariable regression model to determine predictors of ICH. RESULTS: 86 DOAC-ICH and 94 ICH-free patients were included. Diabetes, coronary artery disease, prior ischemic stroke, smoking history, and antiplatelet usage were more common in ICH patients than ICH-free DOAC users. In the neuroimaging analyses, severe white matter hyperintensities (WMHs), lacunes, cortical superficial siderosis (cSS), and cerebral microbleeds (CMBs) were more common in the ICH cohort than the ICH-free cohort. In the multivariable regression, diabetes [OR 3.53 95% CI (1.05-11.87)], prior ischemic stroke [OR 14.80 95% CI (3.33-65.77)], smoking history [OR 3.08 95% CI (1.05-9.01)], CMBs [OR 4.07 95% CI (1.45-11.39)], and cSS [OR 39.73 95% CI (3.43-460.24)] were independently associated with ICH. CONCLUSIONS: Risk factors including diabetes, prior stroke, and smoking history as well as MRI biomarkers including CMBs and cSS are associated with ICH in DOAC users. Although screening MRIs are not typically performed prior to initiating DOAC therapy, these data suggest that patients of high-hemorrhagic risk may be identified.

The Boston criteria version 2.0 for cerebral amyloid angiopathy: a multicentre, retrospective, MRI-neuropathology diagnostic accuracy study.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is an age-related small vessel disease, characterised pathologically by progressive deposition of amyloid ß in the cerebrovascular wall. The Boston criteria are used worldwide for the in-vivo diagnosis of CAA but have not been updated since 2010, before the emergence of additional MRI markers. We report an international collaborative study aiming to update and externally validate the Boston diagnostic criteria across the full spectrum of clinical CAA presentations. METHODS: In this multicentre, hospital-based, retrospective, MRI and neuropathology diagnostic accuracy study, we did a retrospective analysis of clinical, radiological, and histopathological data available to sites participating in the International CAA Association to formulate updated Boston criteria and establish their diagnostic accuracy across different populations and clinical presentations. Ten North American and European academic medical centres identified patients aged 50 years and older with potential CAA-related clinical presentations (ie, spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes), available brain MRI, and histopathological assessment for CAA diagnosis. MRI scans were centrally rated at Massachusetts General Hospital (Boston, MA, USA) for haemorrhagic and non-haemorrhagic CAA markers, and brain tissue samples were rated by neuropathologists at the contributing sites. We derived the Boston criteria version 2.0 (v2.0) by selecting MRI features to optimise diagnostic specificity and sensitivity in a prespecified derivation cohort (Boston cases 1994-2012, n=159), then externally validated the criteria in a prespecified temporal validation cohort (Boston cases 2012-18, n=59) and a geographical validation cohort (non-Boston cases 2004-18; n=123), comparing accuracy of the new criteria to the currently used modified Boston criteria with histopathological assessment of CAA as the diagnostic standard. We also assessed performance of the v2.0 criteria in patients across all cohorts who had the diagnostic gold standard of brain autopsy. FINDINGS: The study protocol was finalised on Jan 15, 2017, patient identification was completed on Dec 31, 2018, and imaging analyses were completed on Sept 30, 2019. Of 401 potentially eligible patients presenting to Massachusetts General Hospital, 218 were eligible to be included in the analysis; of 160 patient datasets from other centres, 123 were included. Using the derivation cohort, we derived provisional criteria for probable CAA requiring the presence of at least two strictly lobar haemorrhagic lesions (ie, intracerebral haemorrhages, cerebral microbleeds, or foci of cortical superficial siderosis) or at least one strictly lobar haemorrhagic lesion and at least one white matter characteristic (ie, severe visible perivascular spaces in centrum semiovale or white matter hyperintensities in a multispot pattern). The sensitivity and specificity of these criteria were 74·8% (95% CI 65·4-82·7) and 84·6% (71·9-93·1) in the derivation cohort, 92·5% (79·6-98·4) and 89·5% (66·9-98·7) in the temporal validation cohort, 80·2% (70·8-87·6) and 81·5% (61·9-93·7) in the geographical validation cohort, and 74·5% (65·4-82·4) and 95·0% (83·1-99·4) in all patients who had autopsy as the diagnostic standard. The area under the receiver operating characteristic curve (AUC) was 0·797 (0·732-0·861) in the derivation cohort, 0·910 (0·828-0·992) in the temporal validation cohort, 0·808 (0·724-0·893) in the geographical validation cohort, and 0·848 (0·794-0·901) in patients who had autopsy as the diagnostic standard. The v2.0 Boston criteria for probable CAA had superior accuracy to the current Boston criteria (sensitivity 64·5% [54·9-73·4]; specificity 95·0% [83·1-99·4]; AUC 0·798 [0·741-0854]; p=0·0005 for comparison of AUC) across all individuals who had autopsy as the diagnostic standard. INTERPRETATION: The Boston criteria v2.0 incorporate emerging MRI markers of CAA to enhance sensitivity without compromising their specificity in our cohorts of patients aged 50 years and older presenting with spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes. Future studies will be needed to determine generalisability of the v.2.0 criteria across the full range of patients and clinical presentations. FUNDING: US National Institutes of Health (R01 AG26484).

Corpus callosum lesions are associated with worse cognitive performance in cerebral amyloid angiopathy.

The impact of vascular lesions on cognition is location dependent. Here, we assessed the contribution of small vessel disease lesions in the corpus callosum to vascular cognitive impairment in cerebral amyloid angiopathy, as a model for cerebral small vessel disease. Sixty-five patients with probable cerebral amyloid angiopathy underwent 3T magnetic resonance imaging, including a diffusion tensor imaging scan, and neuropsychological testing. Microstructural white-matter integrity was quantified by fractional anisotropy and mean diffusivity. Z-scores on individual neuropsychological tests were averaged into five cognitive domains: information processing speed, executive functioning, memory, language and visuospatial ability. Corpus callosum lesions were defined as haemorrhagic (microbleeds or larger bleeds) or ischaemic (microinfarcts, larger infarcts and diffuse fluid-attenuated inversion recovery hyperintensities). Associations between corpus callosum lesion presence, microstructural white-matter integrity and cognitive performance were examined with multiple regression models. The prevalence of corpus callosum lesions was confirmed in an independent cohort of memory clinic patients with and without cerebral amyloid angiopathy (n = 82). In parallel, we assessed corpus callosum lesions on ex vivo magnetic resonance imaging in cerebral amyloid angiopathy patients (n = 19) and controls (n = 5) and determined associated tissue abnormalities with histopathology. A total number of 21 corpus callosum lesions was found in 19/65 (29%) cerebral amyloid angiopathy patients. Corpus callosum lesion presence was associated with reduced microstructural white-matter integrity within the corpus callosum and in the whole-brain white matter. Patients with corpus callosum lesions performed significantly worse on all cognitive domains except language, compared with those without corpus callosum lesions after correcting for age, sex, education and time between magnetic resonance imaging and neuropsychological assessment. This association was independent of the presence of intracerebral haemorrhage, whole-brain fractional anisotropy and mean diffusivity, and white-matter hyperintensity volume and brain volume for the domains of information processing speed and executive functioning. In the memory clinic patient cohort, corpus callosum lesions were present in 14/54 (26%) patients with probable and 2/8 (25%) patients with possible cerebral amyloid angiopathy, and in 3/20 (15%) patients without cerebral amyloid angiopathy. In the ex vivo cohort, corpus callosum lesions were present in 10/19 (53%) patients and 2/5 (40%) controls. On histopathology, ischaemic corpus callosum lesions were associated with tissue loss and demyelination, which extended beyond the lesion core. Together, these data suggest that corpus callosum lesions are a frequent finding in cerebral amyloid angiopathy, and that they independently contribute to cognitive impairment through strategic microstructural disruption of white-matter tracts.

Cerebellar atrophy and its implications on gait in cerebral amyloid angiopathy.

OBJECTIVE: Recent data suggest that cerebral amyloid angiopathy (CAA) causes haemorrhagic lesions in cerebellar cortex as well as subcortical cerebral atrophy. However, the potential effect of CAA on cerebellar tissue loss and its clinical implications have not been investigated. METHODS: Our study included 70 non-demented patients with probable CAA, 70 age-matched healthy controls (HCs) and 70 age-matched patients with Alzheimer's disease (AD). The cerebellum was segmented into percent of cerebellar subcortical volume (pCbll-ScV) and percent of cerebellar cortical volume (pCbll-CV) represented as percent (p) of estimated total intracranial volume. We compared pCbll-ScV and pCbll-CV between patients with CAA, HCs and those with AD. Gait velocity (metres/second) was used to investigate gait function in patients with CAA. RESULTS: Patients with CAA had significantly lower pCbll-ScV compared with both HC (1.49±0.1 vs 1.73±0.2, p<0.001) and AD (1.49±0.1 vs 1.66±0.24, p<0.001) and lower pCbll-CV compared with HCs (6.03±0.5 vs 6.23±0.6, p=0.028). Diagnosis of CAA was independently associated with lower pCbll-ScV compared with HCs (p<0.001) and patients with AD (p<0.001) in separate linear regression models adjusted for age, sex and presence of hypertension. Lower pCbll-ScV was independently associated with worse gait velocity (ß=0.736, 95% CI 0.28 to 1.19, p=0.002) in a stepwise linear regression analysis including pCbll-CV along with other relevant variables. INTERPRETATION: Patients with CAA show more subcortical cerebellar atrophy than HC or patients with AD and more cortical cerebellar atrophy than HCs. Reduced pCbll-ScV correlated with lower gait velocity in regression models including other relevant variables. Overall, this study suggests that CAA causes cerebellar injury, which might contribute to gait disturbance.

Effect of vascular amyloid on white matter disease is mediated by vascular dysfunction in cerebral amyloid angiopathy.

We postulated that vascular dysfunction mediates the relationship between amyloid load and white matter hyperintensities (WMH) in cerebral amyloid angiopathy (CAA). Thirty-eight cognitively healthy patients with CAA (mean age 70 ± 7.1) were evaluated. WMH was quantified and expressed as percent of total intracranial volume (pWMH) using structural MRI. Mean global cortical Distribution Volume Ratio representing Pittsburgh Compound B (PiB) uptake (PiB-DVR) was calculated from PET scans. Time-to-peak [TTP] of blood oxygen level-dependent response to visual stimulation was used as an fMRI measure of vascular dysfunction. Higher PiB-DVR correlated with prolonged TTP (r = 0.373, p = 0.021) and higher pWMH (r = 0.337, p = 0.039). Prolonged TTP also correlated with higher pWMH (r = 0.485, p = 0.002). In a multivariate linear regression model, TTP remained independently associated with pWMH (p = 0.006) while PiB-DVR did not (p = 0.225). In a bootstrapping model, TTP had a significant indirect effect (ab = 0.97, 95% CI: 0.137-2.461), supporting that the association between PiB-DVR and pWMH is mediated by TTP response. There was no longer a direct effect independent of the hypothesized pathway. Our study suggests that the effect of vascular amyloid load on white matter disease is mediated by vascular dysfunction in CAA. Amyloid lowering strategies might prevent pathophysiological processes leading to vascular dysfunction, therefore limiting ischemic brain injury.

Idiopathic primary intraventricular hemorrhage and cerebral small vessel disease.

BACKGROUND: Although primary intraventricular hemorrhage is frequently due to trauma or vascular lesions, the etiology of idiopathic primary intraventricular hemorrhage (IP-IVH) is not defined. AIMS: Herein, we test the hypothesis that cerebral small vessel diseases (cSVD) including hypertensive cSVD (HTN-cSVD) and cerebral amyloid angiopathy are associated with IP-IVH. METHODS: Brain magnetic resonance imaging from consecutive patients (January 2011 to September 2019) with non-traumatic intracerebral hemorrhage from a single referral center were reviewed for the presence of HTN-cSVD (defined by strictly deep or mixed-location intracerebral hemorrhage/cerebral microbleeds) and cerebral amyloid angiopathy (applying modified Boston criteria). RESULTS: Forty-six (4%) out of 1276 patients were identified as having IP-IVH. Among these, the mean age was 74.4 ± 12.2 years and 18 (39%) were females. Forty (87%) had hypertension, and the mean initial blood pressure was 169.2 ± 40.4/88.8 ± 22.2 mmHg. Of the 35 (76%) patients who received a brain magnetic resonance imaging, two (6%) fulfilled the modified Boston criteria for possible cerebral amyloid angiopathy and 10 (29%) for probable cerebral amyloid angiopathy. Probable cerebral amyloid angiopathy was found at a similar frequency when comparing IP-IVH patients to the remaining patients with primary intraparenchymal hemorrhage (P-IPH) (27%, p = 0.85). Furthermore, imaging evidence for HTN-cSVD was found in 8 (24%) patients with IP-IVH compared to 209 (28%, p = 0.52) patients with P-IPH. CONCLUSIONS: Among IP-IVH patients, cerebral amyloid angiopathy was found in approximately one-third of patients, whereas HTN-cSVD was detected in 23%-both similar rates to P-IPH patients. Our results suggest that both cSVD subtypes may be associated with IP-IVH.

The role of biomarkers and neuroimaging in ischemic/hemorrhagic risk assessment for cardiovascular/cerebrovascular disease prevention.

Stroke prevention in patients with atrial fibrillation is arguably one of the fastest developing areas in preventive medicine. The increasing use of direct oral anticoagulants and nonpharmacologic methods such as left atrial appendage closure for stroke prevention in these patients has increased clinicians' options for optimal care. Platelet antiaggregants are also commonly used in other ischemic cardiovascular and or cerebrovascular conditions. Long term use of oral anticoagulants for atrial fibrillation is associated with elevated risks of major bleeds including especially brain hemorrhages, which are known to have extremely poor outcomes. Neuroimaging and other biomarkers have been validated to stratify brain hemorrhage risk among older adults. A thorough understanding of these biomarkers is essential for selection of appropriate anticoagulant or left atrial appendage closure for stroke prevention in patients with atrial fibrillation. This article will address advances in the stratification of ischemic and hemorrhagic stroke risk among patients with atrial fibrillation and other conditions.

Lacunes, Microinfarcts, and Vascular Dysfunction in Cerebral Amyloid Angiopathy.

OBJECTIVE: To analyze the relationship of lacunes with cortical cerebral microinfarcts (CMIs), to assess their association with vascular dysfunction, and to evaluate their effect on the risk of incident intracerebral hemorrhage (ICH) in cerebral amyloid angiopathy (CAA). METHODS: The count and topography of lacunes (deep/lobar), CMIs, and white matter hyperintensity (WMH) volume were retrospectively analyzed in a prospectively enrolled CAA cohort that underwent high-resolution research MRIs. The relationship of lacunes with CMIs and other CAA-related markers including time to peak (TTP) of blood oxygen level-dependent signal, an established measure of vascular dysfunction, was evaluated in multivariate models. Adjusted Cox regression models were used to investigate the relationship between lacunes and incident ICH. RESULTS: The cohort consisted of 122 patients with probable CAA without dementia (mean age, 69.4 ± 7.6 years). Lacunes were present in 31 patients (25.4%); all but one were located in lobar regions. Cortical CMIs were more common in patients with lacunes compared to patients without lacunes (51.6% vs 20.9%, p = 0.002). TTP was not associated with either lacunes or CMIs (both p > 0.2) but longer TTP response independently correlated with higher WMH volume (p = 0.001). Lacunes were associated with increased ICH risk in univariate and multivariate Cox regression models (p = 0.048 and p = 0.026, respectively). CONCLUSIONS: Our findings show a high prevalence of lobar lacunes, frequently coexisting with CMIs in CAA, suggesting that these 2 lesion types may be part of a common spectrum of CAA-related infarcts. Lacunes were not related to vascular dysfunction but predicted incident ICH, favoring severe focal vessel involvement rather than global ischemia as their mechanism.

Assessment of Cerebral Vasomotor Reactivity in Patients With Primary Open-angle Glaucoma and Ocular Hypertension Using the Breath-Holding Index.

PRCIS: Patients with ocular hypertension (OHT) do not show impaired cerebral vasodilation responses to hypercapnia but patients with primary open-angle glaucoma (POAG) do. Impaired vasoreactivity in patients with POAG may have neuronal or vascular origins and increase stroke risk. PURPOSE: To investigate changes in cerebral blood flow and cerebral vasomotor reactivity using the breath-holding index in patients with POAG and OHT, to examine whether these parameters contribute to the risk of ischemic stroke. METHODS: Thirty patients with POAG, 30 patients with OHT, and 30 age- and sex-matched healthy control subjects were included in this university hospital-based, cross-sectional, and observational study. Eyes with a greater degree of visual field loss and/or more severe optic disc damage were selected for the study in patients with POAG, whereas in patients with OHT and controls, the study eye was chosen randomly. The mean blood flow velocity and breath-holding index were measured in the middle cerebral artery ipsilaterally in patient and control groups, by using transcranial Doppler ultrasonography. RESULTS: The mean blood flow velocity and breath-holding indexes were significantly lower in patients with POAG than in the control group (all P<0.05). In the OHT group, the mean blood flow velocity and breath-holding indexes were not different from those in the control group. CONCLUSIONS: Patients with POAG have impaired vasodilation response to hypercapnia. Presumably, the neuronal changes and deterioration of the endothelium-mediated vasodilatation in patients with glaucoma may disrupt the regulation of arteries and potentially present functional insufficiency on vasoreactivity. Moreover, impaired cerebral vascular regulation may contribute to the increased risk of stroke in patients with POAG.

White matter atrophy in cerebral amyloid angiopathy.

OBJECTIVE: We postulated that cerebral amyloid angiopathy (CAA) is associated with white matter atrophy (WMA) and that WMA can be related to cognitive changes in CAA. METHODS: White matter volume expressed as percent of intracranial volume (pWMV) of prospectively enrolled patients without dementia diagnosed with probable CAA was compared to age-matched healthy controls (HC) and patients with Alzheimer disease (AD). Cognitive scores were also sought to understand the potential effects of WMA on cognitive function. RESULTS: Patients with CAA (n = 72) had significantly lower pWMV (27.97% ± 2.63) when compared to age-matched HC (n = 72; mean difference [MD], 2.38%; p < 0.0001) and patients with AD (n = 72; MD, 1.57%; p < 0.0001). Differences were most pronounced in the posterior occipital regions in both comparisons. When comparisons were restricted to groups of patients with CAA but no intracerebral hemorrhage (n = 32) or hypertension (n = 32), and age-matched HC and AD, the significant differences were unaltered. Within the CAA cohort, higher age, lobar microbleed counts, and presence of hypertension were associated with lower pWMV (p = 0.0007, p = 0.031, and p = 0.003, respectively). All associations remained independent in multivariable analyses. Within the CAA cohort, higher pWMV independently correlated with better scores of executive function. CONCLUSIONS: Patients with CAA show WMA when compared to age-matched HC and patients with AD. WMA independently correlates with the number of lobar microbleeds, a marker of CAA severity. Consistent spatial patterns of WMA especially in posterior regions might be related to CAA. The association between WMA and measures of executive function suggests that WMA might represent an important mediator of CAA-related neurologic dysfunction.

Alexithymia is a non motor symptom of essential tremor regardless of the presence of depression and anxiety.

OBJECTIVE: Essential tremor (ET) is one of the most common movement disorders. Aside from tremor, patients may exhibit other motor features as well as non-motor features, including neuropsychiatric symptoms. The cerebellum and cerebellar connections are thought to play a key role in the pathophysiology of ET. Cognitive and affective disturbances can occur in the context of cerebellar disease. Our aim was to study the prevalence and clinical correlates of alexithymia and its relationship to depression and anxiety in ET patients and control subjects (CS). METHOD: We enrolled 100 ET patients and 100 age- and gender-matched CS. The Toronto Alexithymia Scale-20 (TAS-20), the Beck depression inventory-II and the Beck anxiety inventory were administered. RESULTS: Alexithymia levels were significantly higher in ET patients than CS (respective mean TAS-20 scores = 50.63 ± 9.79 vs. 44.05 ± 12.51, p < 0.001).  There were robust associations between alexithymia, depressive symptoms, and anxiety but, after excluding the ET patients and the CS who had moderate or severe depression or who had moderate or severe anxiety, the total alexithymia score remained significantly higher in the ET than the CS group (46.78 ± 9.19 vs. 41.18 ± 11.79, p ≤ 0.01). CONCLUSION: This study suggests that prevalence of alexithymia is significantly higher in ET patients. Alexithymia might be another non-motor neuropsychiatric symptom of the disease.  Further studies are needed to confirm and expand upon our findings.

Evaluation of retinal alterations in Parkinson disease and tremor diseases.

Optical coherence tomography (OCT) has been suggested as a method for detection of retinal alterations in neurodegenerative diseases. The usefulness of OCT as a diagnostic tool to differentiate Parkinson's disease (PD) from other tremor diseases, remains unknown. We aimed to evaluate morphological changes of the retina in patients with PD, essential tremor (ET), essential tremor-Parkinson's disease (ET-PD) using OCT. Forty-two eyes of 21 patients with PD, 24 eyes of 12 patients with ET, 24 eyes of 12 patients with ET-PD and 44 eyes of 22 age-matched healthy controls were included in the study. All participants underwent detailed neurological and ophthalmological examination. Measurements in all quadrants of macula and retinal nerve fiber layer (RNFL) thickness using OCT were recorded. There was no significant difference among the groups regarding age, sex. The average RNFL thickness was thinner in PD patients than that of ET (p = 0.032). The RNFL thickness in superior quadrant was lower in PD group compared with the ET and control group (p = 0.001, p = 0.016). Significant differences were observed in most of the macular thickness parameters excluding foveolar and foveal thickness (p = 0.865, 0.394). Correlations were found among several OCT parameters and disease duration or severity in all patient groups (p > 0.05). Retinal alterations were found in PD patients compared to ET. However, no significant retinal changes were detected by OCT in patients with ET and ET-PD compared to controls. According to our data, retinal assessments by OCT do not seem to be satisfactory for differentiation of these disorders.

Investigation of risk factors, topographic location and stroke mechanisms of unilateral isolated and posterior cerebral ARTERY thalamic infarcts.

BACKGROUND AND PURPOSE: In this study, we aimed to examine the risk factors, topographic features and stroke mechanisms of acute ischemic unilateral infarcts of thalamus. METHODS: Patient with isolated thalamic infarct and those with posterior cerebral artery (PCA) infarction who were admitted to our hospital between January 2014 and January 2017 with acute unilateral thalamic infarction (TI) were included in this study (isolated thalamic infarction/ isolated TI; thalamic and posterior cerebral artery infarction/PCA+TI). Demographic characteristics and vascular risk factors of the patients were determined. Thalamic infarct areas were recorded topographically as anterior, posteromedial, ventrolateral, posterolateral, more than one area, and variant areas. Stroke mechanism was determined according to the criteria of "Trial of Org 10172 in Acute Stroke Treatment" (TOAST). Patients with isolated TI and PCA TI were compared according to risk factors, stroke mechanism and infarct topography. RESULTS: Forty-three patients with a mean age of 63.3 ± 14.5 years were included in the study. Twenty-eight patients (60.1%) were found to have isolated TI and the remaining 15 patients (34.9%) had PCA+TI. 32.1% of patients with isolated TI had sensory symptoms on presentation, and 60% of patients with PCA-TI had sensorimotor symptoms. The mean age, the mean score on National Institutes of Health Stroke Scale (NIHSS) and the mean frequency of atrial fibrillation were higher in PCA+TI patients than in isolated-TI patients (p: 0.04, p: 0.004, p: 0.02 respectively). 32.6% of the patients had ventrolateral, 30.2% had posteromedial involvement. Ventrolateral topography was seen in 46.7% of the PCA+TI patients, while posteromedial topography was seen in 39.3% of the isolated-TI patients. 53.6% of the isolated-TI had small vessel disease etiology, while 40% of the PCA+TI had cardioembolic etiology, and the other 40% had large artery atherosclerosis. CONCLUSION: Our study showed that the most ommon stroke mechanism in patients with thalamic infarction is the small vessel disease. Isolated TI and PCA+TI patients differ in terms of etiologic mechanism and infarct topography. Variant territorial involvement and multiple area involvements can be quite common in thalamic infarcts.