Ischemic Small Vessel Disease Research Articles

The interplay between White Matter Hyperintensities and regional β‐Amyloid on Defaults Mode Network

AbstractBackgroundCerebral small vessel ischemic disease (SVID) has been suggested to contribute to the pathogenesis of Alzheimer’s disease (AD). Yet, the mechanistic role of SVID in potentially contributing to AD pathology is unclear. The main objective of this study was to test the hypothesis that axonal SVID influences amyloid β (Aβ) levels within connected default mode network (DMN) tracts and cortical regions in cognitively unimpaired older adults.MethodRegional Standard Uptake Value ratios (SUVr) from Aβ‐PET, and white matter hyperintensity (WMH) volumes from 3D MRI FLAIR images were analyzed across a sample of 72 clinically‐unimpaired (Mini‐Mental State Examination (MMSE) ≥ 26), aged participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI3). The association of WMH volumes in major fiber tracts projecting from cortical DMN regions and Aβ‐PET SUVr in the connected cortical DMN regions were analyzed using linear regression models adjusted for age, sex, ApoE and total brain volumes.ResultThe regression analyses demonstrate that increased WMH volumes in the superior longitudinal fasciculus (SLF) was associated with increased regional SUVr in the inferior parietal lobule (IPL) (p = 0.011).ConclusionThe findings suggest that the relation between Aβ parietal cortex is partially driven by SVID in downstream axonal pathways in pAD. The biological relationships and interplay between Aβ and white matter microstructure alterations that precede overt WMH development across the continuum of AD progression warrants further study.

Pseudo‐longitudinal trajectories of cerebrovascular disease biomarkers in adults with Down syndrome across the lifespan

AbstractBackgroundAdults with Down syndrome (DS) overproduce amyloid precursor protein, develop amyloid plaques at an early age, and are diagnosed with Alzheimer’s disease (AD) dementia at a high frequency. There is emerging evidence that cerebrovascular disease is elevated across the AD continuum in older adults with DS, independent of age and vascular risk, but it is unknown when cerebrovascular disease emerges across the lifespan.MethodAdults with DS from the multisite Alzheimer’s Biomarker Consortium‐Down Syndrome study (ABC‐DS; n = 241; age = 25‐72, 44±10; 45% women; 77/11/12% Cognitively‐Stable/MCI‐DS/AD dementia) underwent harmonized MRI and received a cognitive diagnosis at a consensus conference. Cross‐sectional white matter hyperintensity volume (WMH; ischemic small vessel disease), enlarged perivascular space score (PVS; impaired toxin clearance), chronic infarcts (large vessel disease), and microbleeds (hemorrhagic small vessel disease/cerebral amyloid angiopathy) were fit against piece‐wise, left null regression models with age to estimate the age inflection point at which these cerebrovascular markers emerged. The residuals for each biomarker (i.e., more than expected for their age) were then regressed on diagnosis.ResultTotal WMH volume (0.01‐31.7, 4±4.6 cm3), enlarged PVS score (0‐26, 8±5), infarcts (15% have at least one), and microbleeds (12% have at least one) were present in this lifespan sample of adults with DS. There was a significant inflection point in the fourth decade of life for total WMH (37±6, p = 7E‐3), enlarged PVS (31±6, p = 3E‐6), and infarcts (31±9, p = 2E‐3), but not microbleeds (36±21, p = 0.7). Regionally, there were significant inflection points for frontal (36±6, p = 3E‐3), parietal (36±7, p = 0.02), and occipital (42±6, p = 0.02), but not temporal WMH (33±14, p = 0.3). AD dementia was associated with higher residuals in parietal (0.5±0.2, p = 0.02) and occipital WMH (0.6±0.3, p = 0.02).ConclusionIn adults with DS, there is cerebrovascular pathology on MRI that emerges around the same age as what has been reported for amyloid PET positivity and tau PET accumulation in this population. More posterior small vessel disease for a given age may arise with a diagnosis of AD, suggesting a cerebrovascular process in AD pathogenesis. Longitudinal assessment in relation to AD biomarkers, including amyloid and tau PET, will provide additional insight.

CORRELATION OF BRAIN MAGNETIC RESONANCE IMAGING INCLUDING DIFFUSION-WEIGHTED IMAGING WITH NEUROCOGNITIVE OUTCOME IN CORONARY ARTERY BYPASS GRAFTING (CABG) PATIENTS

Objectives: This study aims to evaluate the new lesions on magnetic resonance imaging including diffusion-weighted imaging (MRI-DWI) in patients undergoing coronary artery bypass grafting (CABG) and its relationship with neurocognitive outcome. Methods: In this prospective study, bilateral carotid and vertebral Doppler study was done before CABG surgery and the brain MRI protocol including fluid attenuation inversion recovery and DWI was applied 1–4 days before surgery and 6–12 weeks after surgery. Neuropsychological examinations were administered to both groups before and 6–12 weeks after surgery. Results: A total of 66 patients were included in the study. On pre-operative angiogram, CABG had less double-vessel (31.8%) and more triple-vessel disease (65.15%). MRI brain with DWI was performed preoperatively in 50 (75.75%) of 66 CABG patients. Before surgery, no diffusion abnormalities were found on DW images. In those who underwent MRI, no lesions were found in 21 (31.82%) CABG patients. Bilateral small vessel ischemic disease (SVID) or periventricular lucencies was seen in 23 (34.85%) CABG patients. Bilateral SVID with lacunar infarct was seen in 4 (6.06%) CABG patients. Lacunar infarct and wedge infarct were seen in 1 (1.52%) patient each. At follow-up, MRI brain with DWI was performed only in 54 (81.82%) CABG patients. There was no significant change found postoperatively on brain MRI imaging. There was also no significant difference before and after CABG patients in cognitive function. Conclusion: This study concluded that CABG has no relation in the form of brain MRI changes with the cognition function of the patients.

Assessment of remote ischemic conditioning delivery with optical sensor in acute ischemic stroke: Randomised clinical trial protocol.

Remote ischemic conditioning (RIC) is delivered by a blood pressure cuff over the limb, raising pressure 50 mmHg above the systolic blood pressure, to a maximum of 200 mmHg. The cuff is inflated for five minutes and then deflated for five minutes in a sequential ischemia-reperfusion cycle 4-5 times per session. Elevated pressure in the limb may be associated with discomfort and consequently reduced compliance. Continuous assessment of relative blood concentration and oxygenation with a tissue reflectance spectroscopy (a type of optical sensor device) placed over the forearm during the RIC sessions of the arm will allow us to observe the effect of inflation and deflation of the pressure cuff. We hypothesize, in patients with acute ischemic stroke (AIS) and small vessel disease, RIC delivered together with a tissue reflectance sensor will be feasible. The study is a prospective, single-center, randomized control trial testing the feasibility of the device. Patients with AIS within 7 days from symptoms onset; who also have small vessel disease will be randomized 2:1 to intervention or sham control arms. All patients randomized to the intervention arm will receive 5 cycles of ischemia/reperfusion in the non-paralyzed upper limb with a tissue reflectance sensor and patients in the sham control arm will receive pressure by keeping the cuff pressure at 30 mmHg for 5 minutes. A total of 51 patients will be randomized, 17 in the sham control arm and 34 in the intervention arm. The primary outcome measure will be the feasibility of RIC delivered for 7 days or at the time of discharge. The secondary device-related outcome measures are fidelity of RIC delivery and the completion rate of intervention. The secondary clinical outcome includes a modified Rankin scale, recurrent stroke and cognitive assessment at 90 days. RIC delivery together with a tissue reflectance sensor will allow insight into the blood concentration and blood oxygenation changes in the skin. This will allow individualized delivery of the RIC and improve compliance. ClinicalTrials.gov Identifier: NCT05408130, June 7, 2022.

1002 Bilateral Nonarteritic Anterior Ischemic Optic Neuropathy (NAION) in a Patient with Obstructive Sleep Apnea (OSA)

Abstract Introduction Nonarteritic Anterior Ischemic Optic Neuropathy (NAION) is an ischemic insult to the anterior portion of the optic nerve with unclear etiology. Several small sized studies and case reports have demonstrated association between OSA and NAION. In this case, we present a patient with bilateral NAION who was later diagnosed with OSA which may signify this important clinical association. Report of case(s) A 57-year-old man with history of hypertension, presented to the ophthalmology clinic for sudden painless decreased visual acuity of the right eye for one-month duration. He had no history of head trauma or other neurological deficits on his initial presentation. He reported having “bad vision” in his left eye for the entire of his life. Funduscopic evaluation revealed bilateral optic disc edema more in the left eye. Laboratory workup including CBC, CMP and HbA1C were within normal limits. Brain MRI showed only mild nonspecific scattered subcortical and deep periventricular hyperintensities suggestive of chronic small vessel ischemic disease and no acute infarct or masses. MRI of the orbits was normal. A diagnosis of bilateral Nonarteritic Anterior Ischemic Optic Neuropathy (NAION) was highly suggested based on the clinical history and examination findings. A referral to a sleep clinic was made to evaluate for possible sleep apnea. A polysomnogram confirmed obstructive sleep apnea with AHI of 7.2/h, REM AHI of 7.7/h and supine AHI 14.9/h. Nocturnal hypoxemia associated with the respiratory events with time of O2 saturation < 88% for 29 minutes. Patient was referred for a titration study to determine the appropriate PAP pressure to treat his sleep disordered breathing. Conclusion This case adds to the current evolving evidence of the link between OSA with NAION. It signifies the importance of having an index of suspicion, among both sleep specialists and ophthalmologists, to recognize patients who may have one of the conditions and consider screening for the other, which may lead to earlier diagnosis and improved outcomes. Support (if any)  

VERY LATE-ONSET SCHIZOPHRENIA-LIKE PSYCHOSIS: CASE REPORT AND CRITICAL LITERATURE REVIEW.

Late-life psychosis presents a challenge, wherein a wide range of differential diagnoses should be considered. Very late-onset schizophrenia-like psychosis (VLOSLP) is a nosological entity that remains a conundrum. We provide a comprehensive literature review on the neurobiological underpinnings of VLOSLP. We describe a case that typifies the clinical presentation of VLOSLP. Although not pathognomonic, certain features, namely the two-stage progression of psychotic episode, partition delusions, multimodal hallucinations, and absent formal thought disorder or negative symptoms, are quite suggestive of VLOSLP. Several medical causes that might cause late-life psychosis, including neuroinflammatory/immunology diseases, were ruled out. Neuroimaging revealed basal ganglia lacunar infarctions along with chronic white matter small-vessel ischemic disease. The diagnosis of VLOSLP is based on clinical evidence, and the aforementioned clinical features support this diagnostic hypothesis. This case adds to the growing body of evidence pertaining to the relevance of cerebrovascular risk factors in the pathophysiology of VLOSLP, alongside age-specific neurobiological processes. We hypothesized that microvascular brain lesions disrupt the frontal-subcortical circuitry and uncover other core neuropathological processes. Future research should focus on identifying a specific biomarker that would allow clinicians to more accurately diagnose VLOSLP, differentiate it from other overlapping clinical entities such as dementia or post-stroke psychosis, and provide a tailored treatment for the patient.

Fragile-X-associated Tremor/Ataxia Syndrome in a Woman with Full Mutation: A Case Report (P5-11.009)

<h3>Objective:</h3> To describe the first case of FXTAS in a full mutation woman without Fragile X syndrome. <h3>Background:</h3> Fragile-X-associated tremor/ataxia syndrome (FXTAS) is caused by expanded trinucleotide (CGG) repeats between 55–199 (premutation) in the <i>Fragile X Mental Retardation 1 (FMR1) gene</i>. Core clinical features of FXTAS include cerebellar ataxia, intention tremor and Parkinsonism. In contrast, a full mutation of CGG repeats&gt;200 repeats with methylation of the gene leads to fragile X syndrome, which is characterized by early intellectual disability, autistic features, and seizures. <i>FMR1</i> premutation carrier women presenting as FXTAS have been reported. This is the first report of a woman with a full mutation presenting with FXTAS. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> A 65-year-old woman presented with problems with dexterity and shuffling gait. The patient also complained of urinary urgency, constipation, anxiety, depression, and mild cognitive complaints. The patient’s son was diagnosed with fragile X syndrome at 14 months. Neurological exam of the patient showed parkinsonism, action tremor and limb ataxia. MRI brain demonstrated chronic ischemic small vessel disease and mildly reduced brain volume. <i>FMR1 CGG</i> repeat sizes were 20 and &gt;200. The 20 repeat allele was seen on the active X chromosome (representing non-random X-inactivation), while the &gt;200 repeat allele was fully methylated on Southern blot. Testing for Parkinson’s disease-associated genes were negative. <h3>Conclusions:</h3> This is the first report of a woman with a <i>FMR1</i> full mutation presenting with signs and symptoms of FXTAS. Several cases of FXTAS have been reported in <i>FMR1</i> full mutation men with fragile X syndrome due to mosaicism of repeat sizes and the presence of a premutation allele. Full mutation adults with complete methylation have not been reported to have FXTAS. The clinical presentation of this case might be due to size or methylation mosaicism in brain. Alternatively, one could also consider a different disease mimicking FXTAS. <b>Disclosure:</b> Dr. Kazanci has nothing to disclose. The institution of Dr. Berry-Kravis has received research support from NIH. The institution of Dr. Berry-Kravis has received research support from Ovid. The institution of Dr. Berry-Kravis has received research support from Zynerba. The institution of Dr. Berry-Kravis has received research support from Roche. The institution of Dr. Berry-Kravis has received research support from CDC. The institution of Dr. Berry-Kravis has received research support from FRAXA Research Foundation. The institution of Dr. Berry-Kravis has received research support from GeneTx. The institution of Dr. Berry-Kravis has received research support from Angelman Syndrome Foundation. The institution of Dr. Berry-Kravis has received research support from Acadia. The institution of Dr. Berry-Kravis has received research support from GW. The institution of Dr. Berry-Kravis has received research support from Anavex. The institution of Dr. Berry-Kravis has received research support from Rett Syndrome Research Trust. The institution of Dr. Berry-Kravis has received research support from Ultragenyx. The institution of Dr. Berry-Kravis has received research support from Mallinckrodt. The institution of Dr. Berry-Kravis has received research support from Together Strong Foundation. The institution of Dr. Berry-Kravis has received research support from Orphazyme. The institution of Dr. Berry-Kravis has received research support from Ionis. The institution of Dr. Berry-Kravis has received research support from Taysha. The institution of Dr. Berry-Kravis has received research support from Erydel. The institution of Dr. Berry-Kravis has received research support from Tetra. The institution of Dr. Berry-Kravis has received research support from Neuren. The institution of Dr. Berry-Kravis has received research support from FRAXA Research Foundation. Dr. Hall has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Academy of Neurology. Dr. Hall has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier - Parkinsonism and Related Disorders. Dr. Hall has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Annals of Neurology. The institution of Dr. Hall has received research support from Parkinson’s Foundation. The institution of Dr. Hall has received research support from CHDI. The institution of Dr. Hall has received research support from Biohaven. The institution of Dr. Hall has received research support from Neurocrine. The institution of Dr. Hall has received research support from Uniqure. Dr. Hall has received personal compensation in the range of $500-$4,999 for serving as a Study section with NIH.

Segmentation of incident lacunes during the course of ischemic cerebral small vessel diseases.

Lacunes represent key imaging markers of cerebral small vessel diseases (cSVDs). During their progression, incident lacunes are related to stroke manifestations and contribute to progressive cognitive and/or motor decline. Assessing new lesions has become crucial but remains time-consuming and error-prone, even for an expert. We, thus, sought to develop and validate an automatic segmentation method of incident lacunes in CADASIL caused by cysteine mutation in the EGFr domains of the NOTCH3 gene, a severe and progressive monogenic form of cSVD. Incident lacunes were identified based on difference maps of 3D T1-weighted MRIs obtained at the baseline and 2 years later. These maps were thresholded using clustering analysis and compared with results obtained by expert visual analysis, which is considered the gold standard approach. The median number of lacunes at the baseline in 30 randomly selected patients was 7 (IQR = [2, 11]). The median number of incident lacunes was 2 (IQR = [0, 3]) using the automatic method (mean time-processing: 25 s/patient) and 0.5 (IQR = [0, 2]) using the standard visual approach (mean time-processing: 8 min/patient). The complementary analysis of segmentation results is enabled to quickly remove false positives detected in specific locations and to identify true incident lesions not previously detected by the standard analysis (2 min/case). A combined approach based on automatic segmentation of incident lacunes followed by quick corrections of false positives allowed to reach high individual sensitivity (median at 0.66, IQR = [0.21, 1.00]) and global specificity scores (0.80). The automatic segmentation of incident lacunes followed by quick corrections of false positives appears promising for properly and rapidly quantifying incident lacunes in large cohorts of cSVDs.

Efficacy on Cerebral Function of Acetyl-L-Carnitine in Non-Dementia Patient With Multiple Ischemic Small Vessel Disease: A Single Photon Emission Computed Tomography (SPECT) Study

Efficacy on Cerebral Function of Acetyl-L-Carnitine in Non-Dementia Patient With Multiple Ischemic Small Vessel Disease: A Single Photon Emission Computed Tomography (SPECT) Study

Monogenic Causes in Familial Stroke Across Intracerebral Hemorrhage and Ischemic Stroke Subtypes Identified by Whole-Exome Sequencing

Whole exome sequencing (WES) has been used to detect rare causative variants in neurological diseases. However, the efficacy of WES in genetic diagnosis of clinically heterogeneous familial stroke remains inconclusive. We prospectively searched for disease-causing variants in unrelated probands with defined familial stroke by candidate gene/hotspot screening and/or WES, depending on stroke subtypes and neuroimaging features at a referral center. The clinical significance of each variant was determined according to the American College of Medical Genetics guidelines. Among 161 probands (mean age at onset 53.2 ± 13.7 years; male 63.4%), 33 participants (20.5%) had been identified with 19 pathogenic/likely pathogenic variants (PVs; WES applied 152/161 = 94.4%). Across subtypes, the highest hit rate (HR) was intracerebral hemorrhage (ICH, 7/18 = 38.9%), particularly with the etiological subtype of structural vasculopathy (4/4 = 100%, PVs in ENG, KRIT1, PKD1, RNF213); followed by ischemic small vessel disease (SVD, 15/48 = 31.3%; PVs in NOTCH3, HTRA1, HBB). In contrast, large artery atherosclerosis (LAA, 4/44 = 9.1%) and cardioembolism (0/11 = 0%) had the lowest HR. NOTCH3 was the most common causative gene (16/161 = 9.9%), presenting with multiple subtypes of SVD (n = 13), ICH (n = 2), or LAA (n = 1). Importantly, we disclosed two previously unreported PVs, KRIT1 p.E379* in a familial cerebral cavernous malformation, and F2 p.F382L in a familial cerebral venous sinus thrombosis. The contribution of monogenic etiologies was particularly high in familial ICH and SVD subtypes in our Taiwanese cohort. Utilizing subtype-guided hotspot screening and/or subsequent WES, we unraveled monogenic causes in 20.5% familial stroke probands, including 1.2% novel PVs. Genetic diagnosis may enable early diagnosis, management and lifestyle modification.Graphical Among 161 familial stroke probands, 33 (20.5%) had been identified pathogenic or likely pathogenic monogenic variants related to stroke. The positive hit rate among all subtypes was high in intracerebral hemorrhage (ICH) and ischemic small vessel disease (SVD). Notably, two previously unreported variants, KRIT1 p.E379* in a familial cerebral cavernous malformation and F2 p.F382L in familial cerebral venous sinus thrombosis, were disclosed. CVT cerebral venous thrombosis; HTN Hypertensive subtype; LAA large artery atherosclerosis; SV structural vasculopathy; U Undetermined.

Associations between cortical microinfarcts, hippocampal atrophy, and cerebral small vessel disease

AbstractBackgroundBrain cortical microinfarcts (CMI) are negatively correlated with cognitive function in both normal aging and Alzheimer’s disease (AD). High‐field structural magnetic resonance imaging (MRI) has facilitated in vivo detection of CMIs but their significance and underlying pathological mechanism remain uncertain. Here we assessed correlations between CMIs and medial temporal lobe (MTL) cortical thickness, white matter hyperintensity (WMH) volume, and relative periventricular white matter cerebral blood flow (PVWM CBF) in healthy individuals. PVWM CBF is thought to provide a measure of cerebral small vessel function.Method76 cognitively intact subjects age 65 ± 15 years were scanned using a hybrid 7T/3T protocol. CMIs were counted by visual inspection on T1‐weighted MP2RAGE (0.7mm3) and FLAIR (0.8mm3) scans obtained at 7T. T1‐weighted MPRAGE, FLAIR and 3D arterial spin labeling (ASL) data were also acquired at 3T and were used to calculate cortical thickness, WMH volume, and regional CBF. Spearman and Pearson bivariate tests were used for statistical analyses.Result185 CMIs were detected in 63 of 76 (83%) 7T scans (range:0‐8, 66% multiple CMIs). Age and sex were not significantly correlated with CMI number.A significant positive Pearson correlation was seen between the number of CMIs and log‐transformed WMH volume (r(74)= 0.23, p=0.04) and a more significant negative correlation between the number of CMIs and PVWM CBF normalized to global CBF was also observed (r(74)= ‐0.37, p=0.003).Significant negative correlations between CMI number and mean cortical thickness in Brodmann area 35 (BA35) (r(73)= ‐0.24, p=0.04) and parahippocampal cortex (r(73)= ‐0.26, p=0.03) was observed with nonsignificant trends in BA36 and entorhinal cortex.ConclusionSignificant correlations between the CMI number and both relative PVWM CBF and WMH volume suggests a contribution of small vessel ischemic disease in the development of CMIs. The negative correlation between CMIs and MTL cortical thickness supports the possibility of a mutual underlying pathway for CMIs and Alzheimer’s disease that may be mediated by cerebral amyloid angiopathy.

Cerebrovascular diseases and cognitive impairment: therapy approaches

The issue of cerebral vascular pathology is one of the most important social problems in the modern world, and Russia is no exception. Cerebrovascular diseases are distinguished by high prevalence, mortality and disability rates. They are of great importance from a health perspective of not only each individual, but total nation. Acute or chronic disorders of cerebral circulation naturally results from atherosclerosis of the major arteries of the head, hypertensive disease, and other cardiovascular diseases. These factors cause pathology of large and small cerebral vessels, which leads to chronic cerebral ischemia and (or) acute cerebrovascular accident with damage to various brain structures. Cognitive impairment is probably the most common presentation of cerebrovascular insufficiency. The severity of cognitive impairment can vary significantly depending on the stage of the condition and the severity of the underlying vascular disease - from mild cognitive impairment to dementia. Vascular cognitive impairment can be caused by several mechanisms. Small vessel ischemic disease is one of the pathological conditions that cause the development of cognitive impairment and dementia. Other presentations of cerebrovascular disorders can include multi-infarction, hypoperfusion, hemorrhagic, hereditary and mixed dementia. Current strategies for the management of patients with vascular cognitive impairment and dementia include symptomatic treatment, risk factor management, and non-pharmacological approaches aimed at preventing their progression.

AFFECTIVE TRAJECTORIES: RISK OF DEMENTIA AND UNDERLYING STRUCTURAL BRAIN VARIABLES IN OLDER WOMEN

Abstract Understanding how trajectories of positive and negative affect relate to dementia risk and underlying structural brain variables is important for dementia prevention. We examined associations between annually assessed Positive and Negative Affect Scale subscales and dementia risk (2000-18) among cognitively-intact community-dwelling women (N=948; aged 72.9±3.7) from the Women’s Health Initiative Study of Cognitive Aging (years 2000-2010) and Magnetic Resonance Imaging Study (2005-2006). Joint latent class mixture models were constructed to identify latent classes of women with similar trajectories of affect and dementia risk over time. Multinomial and logistic regressions examined whether structural MRI measures predicted latent class membership (adjusted for sociodemographic, lifestyle, clinical characteristics, and intracranial volume). Two latent classes of positive affect (high stable:88% and decreasing:12%) and four classes of negative affect (Minimal stable:75%; high stable:4%; emerging:12%; moderate decreasing:9%) were identified. With the high stable trajectory as referent, women with decreasing positive affect were more likely to develop dementia (HR=4.33;p&amp;lt;.001). The odds of being classified as this high-dementia risk group were increased among women with more (per SD) global small vessel ischemic disease (SVID;OR=1.42;p&amp;lt;.001), deep white matter SVID (OR=1.93;p&amp;lt;.001), and smaller parahippocampal volumes (OR=1.41;p=.016). For negative affect, with minimal stable negative affect as referent, women with smaller hippocampal volumes were more likely to be classified as having moderate decreasing negative affect (OR=1.45;p=.024) while emerging negative affect was associated with higher dementia risk (HR=2.00;p=.014). These findings highlight the importance of changes in affect in later-life with dementia risk and potential underlying role of cerebrovascular disease and medial temporal lobe structures.

Antithrombotic therapy to prevent cognitive decline in people with small vessel disease on neuroimaging but without dementia.

Cerebral small vessel disease is a progressivedisease of the brain'sdeep perforating blood vessels.It is usually diagnosed based on lesions seen on brain imaging. Cerebral small vessel disease is a common cause of stroke but can also cause a progressive cognitive decline. As antithrombotic therapy is anestablished treatment for stroke prevention, we sought to determinewhether antithrombotic therapy might also be effective in preventing cognitive decline in people with small vessel disease. To assess the effects of antithrombotic therapy for prevention of cognitive decline in people with small vessel disease on neuroimaging but without dementia. We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Review Group's Specialised Register, and the Cochrane Stroke Group's Specialised Register; the most recent search was on 21 July 2021. We also searched MEDLINE, Embase, four other databases and two trials registries. We searched the reference lists of the articles retrieved from these searches. As trials with a stroke focus may include relevant subgroup data, we complemented these searches with a focussed search of all antithrombotic titles in the Cochrane Stroke Group database. SELECTION CRITERIA: We included randomised controlled trials (RCT) of people with neuroimaging evidence of at least mild cerebral small vessel disease (defined here as white matter hyperintensities, lacunes of presumed vascular origin and subcortical infarcts) but with no evidence of dementia. The trials had to compareantithrombotic therapy of minimum 24 weeks' duration to no antithrombotic therapy (either placebo or treatment as usual), or comparedifferent antithrombotic treatment regimens. Antithrombotic therapy could include antiplatelet agents (as monotherapyor combination therapy), anticoagulants or a combination. Two review authors independently screened all the titlesidentified by the searches. We assessed full texts for eligibility for inclusion according to our prespecified selection criteria, extracted data to a proforma and assessed risk of bias using the Cochrane tool for RCTs. We evaluated the certainty of evidence using GRADE. Due to heterogeneity across included participants, interventions and outcomes of eligible trials, it was not possible to perform meta-analyses. We included threeRCTs (3384 participants). One study investigated the effect of antithrombotic therapy in participants not yet on antithrombotic therapy; two studies investigated the effect of additional antithrombotic therapy, one in a population already taking a single antithrombotic agent and one in a mixed population (participants on an antithrombotic drug and antithrombotic-naive participants). Intervention and follow-up durations varied from 24 weeks to four years. Jia 2016 was a placebo-controlled trial assessing 24 weeks of treatment with DL-3-n-butylphthalide (a compound with multimodal actions, including a putative antiplatelet effect) in 280 Chinese participants with vascular cognitive impairment caused by subcortical ischaemic small vessel disease, but without dementia. There was very low-certainty evidence for a small difference in cognitive test scores favouring treatment with DL-3-n-butylphthalide, as measured by the 12-item Alzheimer's Disease Assessment Scale-Cognitive subscale (adjusted mean difference -1.07, 95% confidence interval (CI) -2.02 to -0.12), but this difference may not be clinically relevant. There was also very low-certainty evidence for greater proportional improvement measured with the Clinician Interview-Based Impression of Change-Plus Caregiver Input (57% with DL-3-n-butylphthalide versus 42% with placebo; P = 0.01), but there was no difference in other measures of cognition (Mini-Mental State Examination and Clinical Dementia Rating) or function. There was no evidence of a difference in adverse events between treatment groups. The SILENCE RCT compared antithrombotic therapy (aspirin) and placebo during four years of treatment in 83 participants with 'silent brain infarcts' who were on no prior antithrombotic therapy. There was very low-certainty evidence for no difference between groups across various measures of cognition and function, rates of stroke or adverse events. The Secondary Prevention of Subcortical Stroke Study (SPS3) compared dual antiplatelet therapy (clopidogrel plus aspirin) to aspirin alone in 3020 participants with recent lacunar stroke. There was low-certainty evidence of no effect on cognitive outcomes as measured by the Cognitive Abilities Screening Instruments (CASI) assessed annually over five years. There was also low-certainty evidence of no difference in the annual incidence of mild cognitive decline between the two treatment groups (9.7% with dual antiplatelet therapy versus 9.9% with aspirin), or the annual stroke recurrence rate(2.5% with dual antiplatelet therapy versus 2.7% with aspirin). Bleeding risk may be higher with dual antiplatelet therapy (hazard ratio (HR) 2.15, 95% CI 1.49 to 3.11; low certainty evidence), but there may be no significant increase in intracerebral bleeding risk(HR 1.52, 95% CI 0.79 to 2.93; low-certainty evidence). None of the included trials assessed the incidence of new dementia. We found no convincing evidence to suggest any clinically relevant cognitive benefit of using antithrombotic therapy in addition tostandard treatment in people with cerebral small vessel disease but without dementia, but there may be an increased bleeding risk with this approach. There was marked heterogeneityacross the trials and the certainty of the evidence was generally poor.

Correlation of CT perfusion with MRI brain in symptomatic carotid artery stenosis

BackgroundCerebral white matter disease and large vessel cerebral steno-occlusive are both associated with high incidence of strokes and mortality. There is a lack of literature correlating the cerebral perfusion downstream of a stenotic lesion with white matter changes in the cerebral hemispheres. The aim of this study was to correlate the white matter changes in magnetic resonance imaging (MRI) with computed tomography (CT) perfusion parameters in patients with symptomatic carotid stenosis. MethodsA total of 50 patients with symptomatic carotid stenosis underwent MRI brain and CT Perfusion. Percentage differences in cerebral blood flow (CBF) and mean transit time (MTT) were correlated with symmetric and asymmetric small vessel ischemic disease (SVID) on MRI. Receiver operating characteristic (ROC) curve analysis was performed to determine sensitivity and specificity for different values of percentage CBF and MTT difference. ResultsA total of 17 patients with symmetrical SVID had a mean CBF difference of 6.58 (SD of 3.17) and mean MTT difference of 11.61 (SD of 4.32). 33 patients with asymmetrical SVID had a mean CBF difference of 34.73 (SD of 6.87) and mean MTT difference of 44.63 (SD of 9.12). ROC curve analysis showed percentage CBF and MTT differences of 12.5% and 26.5% respectively to be associated with 100% specificity and sensitivity. ConclusionIn patients with symptomatic carotid stenosis, CT perfusion parameters correlate with MRI features of SVID.

A clinical case report on haloperidol-induced extrapyramidal symptoms in schizophrenia with small vessels ischemic disease

Background : schizophrenia is a severe mental disorder that may cause disability and has a major effect on an individual’s life. Multiple sclerosis is a chronic disease that affects the central nervous system. Schizophrenia and Multiple sclerosis both have a similar influence on the well-being of life. The onset of both diseases may be at the acute or sub-acute level characterized by progressive disability. Both diseases lack of signs and symptoms, common symptoms are seen like headache, and fever in the early stage. Some studies noted that patients with multiple sclerosis have an increased risk of developing schizophrenia. Factors that influence the occurrence of multiple sclerosis and schizophrenia-like gender, ethnicity, geography, and season. Presentation of case : A case 41 years male reported in psychiatric OPD with his wife at that time client was disoriented as verbalization by his wife patient had the complaint of slurred speech, and difficulty in walking, the patient had difficulty performing daily activities for 8 days. Also, the patient complains of sleep disturbances, difficulty in initiating sleep, and shows violent behaviours, he takes the knife out, threatens his wife, has suspicious behaviors towards his wife, and mutters to self. The patient was a known case of schizophrenia for 8 years. The investigation carried out such as history taken a physical examination of muscle stiffness on limbs lower presented, mental status examination of hallucination (visual ), and suspicious, incorporate behaviour present. The patient removed his clothes during the mental status examination. In MRI- small vessel ischemic disease. The psychiatrist diagnosed as extrapyramidal symptoms induced by haloperidol with schizophrenia with small vessels ischemic disease. The patient was treated with Tab. risperidone 3mg OD, tab clozapine 12.5mg hs, tab quetiapine 200mg HS, Tab. Lorazepam 2mg. HS. And symptoms were minimized after a two week of improving the patient’s condition. Prognosis: The patient was treated with antipsychotics, antianxiety and neurotransmitter agents, and supportive therapy, and the patient’s prognosis was improved. Conclusion: Primary managing entails correct diagnosis, risk factor reduction, and supportive therapy. The least likely to result in extrapyramidal symptoms are second-generation antipsychotics, which can be used depending on the patient’s condition.

Associations between cortical microinfarcts and MRI markers of neurodegeneration and cerebrovascular disease in aging

AbstractBackgroundCortical microinfarcts (CMI) are associated with cognitive impairment in both healthy aging and dementia, though the mechanisms underlying CMIs remain uncertain. Here we assessed correlations between CMIs and medial temporal lobe (MTL) cortical thickness, white matter hyperintensity (WMH) volume, and cerebral blood flow (CBF) in older subjects.MethodNeuroimaging data from 55 cognitively intact older subjects scanned using a hybrid 7T/3T protocol were analyzed. CMIs were manually identified on T1‐weighted MP2RAGE data (0.7mm isotropic resolution) obtained at 7T (Figure 1). Cortical thickness, WMH volume and whole brain CBF were obtained with T1‐weighted, FLAIR and 3D background suppressed arterial spin labeling (ASL) imaging, all acquired at 3T and were available from N=39, 49 and 48 subjects of the N=55 subjects respectively. Spearman’s bivariate nonparametric test was used for statistical analyses.ResultCohort demographics and imaging results are summarized in Table 1. 111 CMIs were detected in 43 of 55 (78%) of 7T T1‐weighted and FLAIR MRI scans (range:0‐6, 56% multiple CMIs). Age and sex were not significantly correlated with the number of CMIs. A negative correlation between the number of CMIs and mean BA36 cortical thickness was observed (r(37)= ‐0.348, p=0.03) (Figure 2). A similar trend was also observed in entorhinal and parahippocampal cortices. No significant correlation was seen between the number of CMIs and WMH volume. No significant correlation was observed between the number of CMIs and CBF in whole brain, gray matter, or white matter.ConclusionThe percentage of subjects showing CMIs is higher than previous 3T studies suggesting improved sensitivity of high‐resolution 7T MRI for detection of CMIs. Contrary to prior reports the lack of correlation between the number of CMIs and either WMH volume or CBF suggests that cerebrovascular insufficiency and small vessel ischemic disease may not be the underlying pathologic mechanisms causing CMIs, at least in cognitively intact older subjects. However, the negative correlation between CMIs and MTL cortical thickness supports the possibility of a mutual underlying pathway for Alzheimer’s disease and CMIs that may be mediated by cerebral amyloid angiopathy.

Fish intake and MRI burden of cerebrovascular disease in older adults

AbstractBackgroundCerebrovascular disease (CVD), a major contributor of cognitive aging, is characterized by subclinical damage visualized on brain MRI, including covert brain infarcts, white matter hyperintensities (WMH) and dilated perivascular spaces (dPVS). Few protective factors for brain vascular health, that may help prevent stroke and dementia, have been identified so far. Fish intake may prevent ischemic events and small vessel disease. When investigating factors with a pleiotropic effect such as fish, there is interest to capture pathophysiological burden globally, combining biomarkers into a single metric. Here, we investigated the association of fish intake with a global indicator of the MRI burden of CVD among older adults.MethodThis Three‐City Dijon study included 1,623 participants (≥65 years) without history of dementia, stroke or cardiovascular disease, who had completed a Food Frequency Questionnaire and underwent brain MRI with automated assessment of WMH, visual detection of covert infarcts, and grading of dPVS. A global indicator of CVD burden was estimated using a factorial analysis of mixed data; association of fish intake with the indicator was assessed by adjusted linear regression.ResultThe proportions of participants consuming fish less than once a week, once a week, 2 to 3 times and more than 4 times per week were 11%, 37%, 47% and 6%, respectively. The continuous CVD burden indicator, derived from the first dimension of the factorial analysis (32.4% of explained variance), was associated with a higher WMH load, more infarcts and higher dPVS severity. Higher fish intake was associated with a lower CVD burden indicator (P for trend &lt;0.001). Compared to participants consuming fish less than once a week, the CVD indicator decreased by ‐0.19 units (95% CI, ‐0.37; ‐0.005) for those consuming fish 2‐3 times per week and by ‐0.31 units (‐0.59; ‐0.03) for ≥4 times per week. These effect estimates of eating fish at least twice a week were equivalent to having a 4 to 5 years younger brain in terms of vascular health (β = 0.05 units (0.03; 0.06) for each one year increase of age).ConclusionFish consumption may promote brain vascular health before manifestation of overt brain disease.

Adherence to a MIND-Like Dietary Pattern, Long-Term Exposure to Fine Particulate Matter Air Pollution, and MRI-Based Measures of Brain Volume: The Women's Health Initiative Memory Study-MRI.

Background:Previous studies suggest that certain dietary patterns and constituents may be beneficial to brain health. Airborne exposures to fine particulate matter [particulate matter with aerodynamic diameter ()] are neurotoxic, but the combined effects of dietary patterns and have not been investigated.Objectives:We examined whether previously reported association between exposure and lower white matter volume (WMV) differed between women whose usual diet during the last 3 months before baseline was more or less consistent with a Mediterranean–DASH Intervention for Neurodegenerative Delay (MIND)-like diet, a dietary pattern that may slow neurodegenerative changes.Methods:This study included 1,302 U.S. women who were 65–79 y old and free of dementia in the period 1996–1998 (baseline). In the period 2005–2006, structural brain magnetic resonance imaging (MRI) scans were performed to estimate normal-appearing brain volumes (excluding areas with evidence of small vessel ischemic disease). Baseline MIND diet scores were derived from a food frequency questionnaire. Three-year average exposure prior to MRI was estimated using geocoded participant addresses and a spatiotemporal model.Results:Average total and temporal lobe WMVs were [95% confidence interval (CI): 0.001, 1.48) and (95% CI: 0.002, 0.37) higher, respectively, with each 0.5-point increase in the MIND score and were (95% CI: , ) and (95% CI: , ) lower, respectively, with each interquartile range (IQR) () increase in . The inverse association between per IQR and WMV was stronger () among women with MIND scores below the median (for total WMV, ; 95% CI: , ), but absent in women with scores above the median (; 95% CI: , 3.72), with similar patterns for WMV in the frontal, parietal, and temporal lobes. For total cerebral and hippocampus brain volumes or WMV in the corpus callosum, the associations with were not significantly different for women with high MIND scores and women with low MIND scores.Discussion:In this cohort of U.S. women, exposure was associated with lower MRI-based WMV, an indication of brain aging, only among women whose usual diet was less consistent with the MIND-like dietary pattern at baseline. https://doi.org/10.1289/EHP8036

Interactions Between Kidney Function and Cerebrovascular Disease: Vessel Pathology That Fires Together Wires Together.

The kidney and the brain, as high-flow end organs relying on autoregulatory mechanisms, have unique anatomic and physiological hemodynamic properties. Similarly, the two organs share a common pattern of microvascular dysfunction as a result of aging and exposure to vascular risk factors (e.g., hypertension, diabetes and smoking) and therefore progress in parallel into a systemic condition known as small vessel disease (SVD). Many epidemiological studies have shown that even mild renal dysfunction is robustly associated with acute and chronic forms of cerebrovascular disease. Beyond ischemic SVD, kidney impairment increases the risk of acute cerebrovascular events related to different underlying pathologies, notably large artery stroke and intracerebral hemorrhage. Other chronic cerebral manifestations of SVD are variably associated with kidney disease. Observational data have suggested the hypothesis that kidney function influences cerebrovascular disease independently and adjunctively to the effect of known vascular risk factors, which affect both renal and cerebral microvasculature. In addition to confirming this independent association, recent large-scale human genetic studies have contributed to disentangling potentially causal associations from shared genetic predisposition and resolving the uncertainty around the direction of causality between kidney and cerebrovascular disease. Accelerated atherosclerosis, impaired cerebral autoregulation, remodeling of the cerebral vasculature, chronic inflammation and endothelial dysfunction can be proposed to explain the additive mechanisms through which renal dysfunction leads to cerebral SVD and other cerebrovascular events. Genetic epidemiology also can help identify new pathological pathways which wire kidney dysfunction and cerebral vascular pathology together. The need for identifying additional pathological mechanisms underlying kidney and cerebrovascular disease is attested to by the limited effect of current therapeutic options in preventing cerebrovascular disease in patients with kidney impairment.