Ischemic Small Vessel Disease Research Articles

MRI-Proven Incident Ischemia: A New Marker of Disease Progression in Small Vessel Diseases.

In ischemic cerebral small vessel diseases (cSVD), recurrent ischemic stroke is rare (2%-3% per year). Because acute ischemia may not always lead to stroke in cSVD due to the small size of lesions, acute stroke may not reliably reflect ischemic activity or the risk of further clinical worsening, as both incident lacunes and incidental diffusion-weighted imaging-positive lesions can occur without stroke symptoms. We aimed to evaluate the total ischemic activity by measuring the incidence of magnetic resonance imaging (MRI)-proven incident ischemia, independent of the presence of stroke symptoms in a large cohort of cSVD. DHU-LAC is an ongoing French multicenter cohort study of MRI-proven ischemic stroke presumably due to cSVD. We report data on patients recruited between June 2018 and October 2023. In DHU-LAC, patients are enrolled within 15 days of stroke onset and are cared for according to current guidelines. During the first 6 months, patients are systematically reassessed clinically and by brain MRI: (1) at any time if stroke symptoms occur and (2) at the end of the period. We defined MRI-proven incident ischemia as either recurrent ischemic stroke or at least 1 incident lacune or incidental diffusion-weighted imaging-positive lesion on brain MRI at 6 months. Two hundred forty-nine patients were included, of whom 172 had available data at both inclusion and after 6 months. They were aged 63±6 years, 28% were women, and 65% had hypertension. Six (3%) had a recurrent ischemic stroke, but 25 more (15%) had at least 1 incident lacune or incidental diffusion-weighted imaging-positive lesion on brain MRI. MRI-proven ischemia occurs about 5× more frequently than ischemic stroke in cSVD. As data confirming the detrimental clinical effect of both incident lacunes and incidental diffusion-weighted imaging-positive lesions accumulate, MRI-proven incident ischemia may become a plausible outcome for future clinical trials in cSVD. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03552926.

The Role of Hypertension in Cognitive Dysfunction

Cognitive impairment and subsequent dementia are considered significant health challenges. In patients with established dementia, it is argued that hypertension is the main risk factor for small vessel ischemic disease and additional cortical white matter lesions. Cognitive domains and impairments associated with hypertension include learning, memory, attention, abstract reasoning, mental flexibility, psychomotor skills, and executive function. It is uncontrolled hypertension in midlife—but not late life—that is associated with worse cognitive impairment. Advanced imaging techniques confirm the effect of uncontrolled hypertension in developing dementia. Functional changes in the arterial system and an increase in arterial stiffness could be involved in the onset of dementia. In most studies, it is argued that better blood pressure control and duration of antihypertensive medication are associated with the incidence of dementia. In this review, the available data on the relationship between cognitive dysfunction and hypertension are examined.

A - 103 Exploring the Diagnostic Criteria for Alcohol-Related Dementia: a Case Study

Abstract Objective Excessive and chronic alcohol use can cause structural/functional abnormalities in the brain, including cognitive impairment (CI) (Harper, 2009). Despite these established risks, alcohol-related dementia (ARD) has received little recognition, mainly due to lack of a distinct pathophysiological profile. Through a case differential approach (concussion vs. ARD), the authors aim to clarify diagnostic criteria for ARD. Methods A 56-year-old right-handed male presented to the emergency room after fall with head strike (no loss of consciousness) with alcohol withdrawal delirium. Symptoms of cerebellar ataxia and CI of 6-month duration were noted. Past medical history was significant for alcohol use (four standard units per day), hyperlipidemia, tobacco use, and depression/anxiety. Neuroimaging revealed cerebral atrophy and chronic small vessel ischemic disease. A neuropsychological evaluation (NPE) was conducted 18 days post-fall. Results NPE revealed relative weaknesses in working memory, complex attention, and visual abstraction. Impairments were noted in visuospatial organization/planning, processing speed, basic attention, verbal fluency, and verbal memory. Motor examination was evident for intention tremor. Conclusion Brain changes associated with ARD include volume loss, altered glucose metabolism, reduced neuronal density, changes in frontal lobe function, and white matter loss. In contrast, individuals affected by concussions may encounter challenges with attention/concentration, processing speed, and working memory. Distinguishing a clear diagnostic profile for ARD is difficult due to high rates of concomitant concussion in this population. The patient’s deficits exceed those expected due to concussion alone, with an anticipated cognitive recovery timeframe of 7–14 days (Iverson, 2006). Furthermore, neuroimaging and NPE results support the diagnostic hypothesis of ARD.

Association between optic disc pallor and lacunar stroke

ObjectiveTo test for associations between optic disc pallor and two clinical variables: ischaemic stroke subtype (cortical and lacunar) and cerebral small vessel disease (SVD) scores in a cohort of hospital...

Could the Early Detection of Atrial Fibrillation Reduce the Risk of Developing Dementia?

Atrial fibrillation (AF) and dementia are major global public health issues and share common risk factors, especially after the age of 65 and regardless of the presence of stroke. Despite accounting for potential confounders, AF appears to be an independent risk factor for cognitive decline and dementia. The mechanisms are likely to be multifactorial and may include AF-related ischemic stroke, cerebral hypoperfusion, microbleeds, systemic inflammation, genetic factors, and small vessel disease, leading to brain atrophy and white matter damage. The early aggressive management of AF and comorbidities may reduce the risk of dementia. Indeed, the early detection of AF-related cognitive impairment should allow for the early implementation of measures to prevent the development of dementia, mainly through integrative approaches involving the correction of risk factors and maintenance of rhythm control. Well-designed prospective studies are needed to determine whether early detection and AF treatment can prevent dementia and identify whether optimal integrative measures are effective in preventing cognitive impairment and dementia.

ω-3 PUFA for Secondary Prevention of White Matter Lesions and Neuronal Integrity Breakdown in Older Adults

Older adults with lower intake and tissue levels of long-chain ω-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA; 20:5) and docosahexaenoic acid (DHA; 22:6) have more brain white matter lesions (WMLs), an association suggesting that small-vessel ischemic disease, a major contributor to the development of dementia, including Alzheimer disease, may be preventable through ω-3 treatment. To determine whether ω-3 treatment reduces WML accumulation in older adults without dementia harboring WMLs and with suboptimal ω-3 status. This quadruple-blinded, placebo-controlled, randomized clinical trial with treatment stratification by apolipoprotein E ε4 allele (APOE*E4) carrier status used linear mixed-effects models to estimate mean annual change between groups. The study was conducted at Oregon Health & Science University, a major academic medical center in the Pacific Northwest, from May 2014 to final participant visit in September 2019. Data analysis concluded in July 2022. Participants were adults without dementia aged 75 years and older with WMLs greater than or equal to 5 cm3 and plasma ω-3 PUFA less than 5.5 weight percentage of total. Three-year treatment with 1.65 g of ω-3 PUFA (975 mg of EPA and 650 mg of DHA) vs a soybean oil placebo matched for taste, smell, and appearance. The primary outcome was annual WML progression measured using magnetic resonance imaging. Secondary outcomes included diffusion tensor imaging of fractional anisotropy (DTI-FA), representing neuronal integrity breakdown. A total of 102 participants (62 women [60.8%]; mean age, 81 years [range, 75-96 years]) were equally randomized, 51 per treatment group. Although the ω-3 group had less annual WML accumulation than the placebo group, the difference was not statistically significant (1.19 cm3 [95% CI, 0.64-1.74 cm3] vs 1.34 cm3 [95% CI, 0.80-1.88 cm3]; P = .30). Similarly, the ω-3 group had less annual DTI-FA decline than the placebo group, but the difference was not statistically significant (-0.0014 mm2/s [95% CI, -0.0027 to 0.0002 mm2/s] vs -0.0027 mm2/s [95% CI, -0.0041 to -0.0014 mm2/s]; P = .07). Among APOE*E4 carriers, the annual DTI-FA decline was significantly lower in the group treated with ω-3 than the placebo group (-0.0016 mm2/s [95% CI, -0.0032 to 0.0020 mm2/s] vs -0.0047 mm2/s [95% CI, -0.0067 to -0.0025 mm2/s]; P = .04). Adverse events were similar between treatment groups. In this 3-year randomized clinical trial, ω-3 treatment was safe and well-tolerated but failed to reach significant reductions in WML accumulation or neuronal integrity breakdown among all participants, which may be attributable to sample size limitations. However, neuronal integrity breakdown was reduced by ω-3 treatment in APOE*E4 carriers, suggesting that this treatment may be beneficial for this specific group. ClinicalTrials.gov Identifier: NCT01953705.

P.030 Remote ischemic conditioning in acute ischemic stroke and small vessel disease – a feasibility study

Background: We tested the hypothesis that delivering remote ischemic conditioning (RIC) with an adjunct tissue reflectance sensor (TRS) device may be feasible in patients with acute ischemic stroke (AIS) and cerebral small vessel disease (cSVD). Methods: AIS patients with neurological deficits within 7 days of symptom onset were screened for moderate to severe cSVD. Eligible patients were randomized 2:1 to receive intervention RIC or sham RIC (7 days). The primary outcome measure was intervention feasibility. It was assessed as an intervention-related comfort by a 5-point Likert scale during each session (1-very uncomfortable, 5-very comfortable). The secondary outcome measure was assessment of TRS derived dermal blood concentration and blood oxygenation changes during RIC. Results: Forty-seven (32 intervention, 15 sham) patients were enrolled at a median (IQR) 39.7 (25-64) hours after symptom onset, with mean±SD age of 75±12 years, 22 (46.8%) were females and median baseline NIHSS of 5(3-7). The Likert scale was 3.5 (3-4) in the intervention group and 4 (4-5) in the sham group. The TRS derived blood concentration and blood oxygenation changes were proportionate in the intervention arm and absent in the sham arm. Conclusions: RIC treatment with TRS is feasible in patients with AIS+cSVD. The efficacy of RIC needs further assessment.

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.

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)

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.

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.

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.

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.