A New Visual Scale to Assess White Matter Hyperintensities Within Cholinergic Pathways

P3-151: White matter hyperintensities within cholinergic pathways in Alzheimer's disease affecting the clock drawing test performance

Background Cerebral small vessel disease (CSVD) is associated with an increased risk of stroke, dementia, and death. The risk of CSVD in people with HIV (PWH) is twice the general population but the CSVD risk in PWH with substance abuse is poorly defined. With national surveys showing approximately two-thirds of PWH admitting to using an illicit drug in their lifetime, the evaluation of CSVD risk in this population is needful.Table 1:Demographic and Clinical information of CSVD in PWH with substance use disorder (N=23) Methods We retrospectively analyzed brain magnetic resonance imaging (MRI) findings of PWH attending our ambulatory HIV needle exchange clinic. Brain MRIs done in the previous 5 years before study analysis were included. CSVD was determined by Cerebral small vessel disease score (0 to 4), assigning 1 point each for the following: (i) presence of lacunar infarct, (ii) microbleeds, (iii) prominent perivascular spaces, and (iv) white matter hyperintensities. The findings suggestive of CSVD such as age-related white matter changes and chronic microvascular ischemia were also included in the CSVD assessment. Substance use disorder (uncontrolled use of a substance despite harmful consequences) was determined to be present if this was included on the patient diagnosis list.Table 2:Cerebral Small Vessel disease Score in PWH with substance use disorder. 5 participants had a CSVD score of 0 but "age related white matter disease" on Brain MRI Results 51 patients (PWH with substance use disorder) were included in the analysis. 23 participants out of this group had brain MRI imaging out of which 12 (52.2%) had CSVD. The mean age was 50 years. The demographic and clinical data of the cohort are shown in Table 1. The CSVD score ranged from 0 to 3 with an average score of 1. Table 2 illustrates the CSVD score of the cohort. 5 participants had a CSVD score of 0 but a brain MRI report of “age-related white matter changes”. The Pearson Correlation between age and CSVD score was 0.057 with a p-value of 0.86. Conclusion 52% of PWH who use substance have CSVD on MRI brain imaging. This could translate to an increased risk of stroke, cognitive impairment, and death if not recognized early and aggressively addressed. CSVD score provides objective quantification of CSVD but age-related white matter changes, which are not captured on this score may be equally important especially as PWH continues to age. A systematic approach for screening for CSVD in PWH with substance use disorder is warranted to minimize the unfavorable outcomes associated with this cohort. Disclosures All Authors: No reported disclosures

White matter hyperintensities (WMHs) have been associated with neurological complications including cognitive impairment. WMHs have been often described in HIV positive subjects and they have been linked to neurocognitive impairment, cerebrospinal fluid (CSF) residual viral replication and biomarkers of monocyte activation. Aim of this study was to grade WMHs in HIV-positive individuals using a simple visual scale and to explore their severity with clinical, neurocognitive and biomarker characteristics. Brain MRIs were retrospectively evaluated by two reviewers who rated WMHs following the "age-related white matter changes (ARWMC)" scale. 107 adult HIV-positive patients receiving lumbar punctures for clinical reasons were included. 70 patients (66.6%) were diagnosed with WMHs. Average WMH scores were higher in treated [7 (1-11)] vs. naïve individuals [3 (0-6)] (p = 0.008). Higher WHMs scores were observed in patients with chronic renal impairment along with chronic hepatitis (naïve) and longer HIV duration (treated participants). No consistent associations between plasma, CSF biomarkers and WMHs scores were found. 45 patients underwent full neurocognitive tests and WMHs scores were non-significantly higher in patients diagnosed with HAND [6.5 (0.5-8.3) vs. 1.5 (0-7), p = 0.165]; screening (IHDS and FAB), visuo-spatial (Corsi's) and auditory-verbal memory (disillabic words repetition) tests scored worse in patients with higher WMHs. In our population of HIV-positive patients with low CD4 nadir and partial CD4 cell recovery the burden of WMHs was associated with the duration of HIV infection and with commonly observed comorbidities (such as renal and hepatic impairment). Given the association with worse neurocognition, further studies on tailored interventions are needed.

Segmentation of age-related white matter changes in a clinical multi-center study

BackgroundBone health may be associated with cerebral small vessel disease. This study aims to explore the correlation between bone turnover biomarkers (BTMs) and parathyroid hormone (PTH) with the severity of white matter hyperintensities (WMH).Materials and methodsWe retrospectively analyzed 213 inpatients from the Neurology Department of Beijing Jishuitan Hospital between June 2021 and May 2022. The WMH burden was assessed semi-quantitatively using the age-related white matter changes scale and the Fazekas scale, with the latter separately evaluating periventricular WMH (PWMH) and deep WMH (DWMH). Participants were categorized into two groups based on WMH severity. Binary logistic regression was performed to investigate the relationship, and subgroup analyses were conducted across subgroups stratified by sex, hypertension, and diabetes.ResultsPatients with severe WMH, PWMH, and DWMH had significantly higher β-carboxy-terminal cross-linked telopeptide of type 1 collagen (β-CTX) and PTH levels compared to those in the mild groups. After adjusting for confounding factors, elevated β-CTX levels remained associated with severe WMH (OR: 4.44, 95% CI: 1.33–14.81) and severe PWMH (OR: 6.37, 95% CI: 1.80–22.47), while increased PTH levels were associated with severe DWMH (OR: 1.02, 95% CI: 1.01–1.05). Subgroup analysis showed a significant relationship between PTH and the severity of WMH and PWMH in patients with diabetes (p for interaction < 0.05).Conclusionβ-CTX was independently linked to WMH/PWMH severity, and PTH to DWMH severity, pointing to a possible bone–cerebrovascular axis. Larger prospective and interventional studies should confirm these markers as potential CSVD biomarkers and treatment targets.

The relation of white matter hyperintense lesions to episodic memory impairment in patients with Parkinson’s disease (PD) is still controversial. We aimed at evaluating the relation between white matter hyperintense lesions and episodic memory decline in patients with PD. In this multicentric prospective study, twenty-one normal controls, 15 PD patients without mild cognitive impairment (MCI) and 13 PD patients with MCI were selected to conduct a clinico-radiological correlation analysis. Performance during episodic memory testing, age-related white matter changes score, total manual and automated white matter hyperintense lesions volume and lobar white matter hyperintense lesions volumes were compared between groups using the Kruskal-Wallis and Wilcoxon signed-rank tests, and correlations were assessed using the Spearman test. MCI PD patients had impaired free recall. They also had higher total, left prefrontal and left temporal white matter hyperintense lesions volumes than normal controls. Free recall performance was negatively correlated with the total white matter hyperintense lesions volume, either manually or automatically delineated, but not with the age-related white matter changes score. Using automated segmentation, both the left prefrontal and temporal white matter hyperintense lesions volumes were negatively correlated with the free recall performance. Early episodic memory impairment in MCI PD patients may be related to white matter hyperintense lesions, mainly in the prefrontal and temporal lobes. This relation is influenced by the method used for white matter hyperintense lesions quantification. Automated volumetry allows for detecting those changes.

Background: Pathological findings of cerebral amyloid angiopathy (CAA) and Alzheimer’s disease (AD) coexist frequently. Both diseases are associated with β-amyloid deposition and dementia. We aimed to evaluate frequency and clinicoradiological profile of AD patients with multiple microbleeds (MBs) Methods: We reviewed clinical charts and magnetic resonance imaging (MRI) findings in patients with probable AD from 2009 to 2012, according to the DSM-IV. Brain MRI was performed at 1.5 T using protocols, including T2*-weighted gradient-echo or susceptibility-weighted imaging. MBs were defined as rounded, hypointense foci ≤ 10 mm in size in the brain parenchyma. MBs topography was divided into the lobar (L) and the deep/infratentorial (D/I) region. Multiple MBs were defined as the number ≥ 8 in the L or the D/I territory. White matter hyperintensities (WMH) were assessed using the age-related white matter changes scale. Clinicoradiological findings were examined for ≥ 1 year. Prevalence and clinicoradiological profiles were studied in patients with multiple L MBs or multiple D/I MBs. Results: Five hundred fifty patients (238 men and 312 women) were participated in the present study. Mean age (SD) was 78.4 (7.7) years, 78.3 (8.1) in men and 78.6 (7.5) in woman. A total of 132 patients (55 men and 78 women) had at least MB. Prevalence of total MBs was 24.0%, 23.1 in men and 25.0 in women. Multiple L MBs existed in 49 patients (8.9%), 15 men (6.3) and 34 women (10.9). Multiple D/I MBs were found in 44 patients (8.0%), 23 men (9.7) and 21 women (6.7). Clinical profiles of multiple L MBs revealed sudden deterioration, rapid progression, non-hypertension, higher rates of symptomatic subcortical hemorrhage and onset of CAA-associated leukoencephalopathy. Radiological hallmarks exhibited increased number and size of MBs, high score of WMH and asymptomatic subcortical hemorrhage. Clinicoradiological features of multiple D/I MBs exhibited higher rates of hypertension and variable degrees of WMH. Conclusions: The present study indicated that prevalence of multiple MBs was 16.9% in Japanese patients with AD. The clinicoradiological profile suggested severe degree of CAA in patients with multiple L MBs (8.9%) and hypertensive changes in patients with multiple D/I MBs (8.0%).

Amyloid-related imaging abnormalities (ARIA) consist of ARIA-E (with effusion or edema) and ARIA-H (hemosiderin deposits [HDs]). To address accurate ascertainment of ARIA identification, a final magnetic resonance imaging (MRI) reading was performed on patients with mild-to-moderate Alzheimer's disease randomized to bapineuzumab IV or placebo during two Phase III trials (APOE ɛ4 allele carriers or noncarriers). Final MRI central review consisted of a systematic sequential locked, adjudicated read in 1,331 APOE ɛ4 noncarriers and 1,121 carriers by independent neuroradiologists. Assessment of ARIA-E, ARIA-H, intracerebral hemorrhages, and age-related white matter changes is described. In the Final Read, treatment-emergent ARIA-E were identified in 242 patients including 76 additional cases not noted previously in real time. Overall, incidence proportion of ARIA-E was higher in carriers (active 21.2%; placebo 1.1%) than in noncarriers (pooled active 11.3%; placebo 0.6%), and was more often identified in homozygote APOE ɛ4 carriers than heterozygotes (34.5% versus 16.9%). Incidence rate of ARIA-E increased with increased dose in noncarriers. Frequency of ARIA-E first episodes was highest after the first and second bapineuzumab infusion and declined after repeated infusions. Incidence of total HDs <10 mm (cerebral microhemorrhages) was higher in active groups versus placebo. ARIA was detected more often on MRI scans when every scan was reviewed by trained neuroradiologists and results adjudicated. There was increased incidence of ARIA-E in bapineuzumab-treated carriers who had a microhemorrhage at baseline. ARIA-E was a risk factor for incident ARIA-H and late onset ARIA-E was milder radiologically. Age-related white matter changes did not progress during the study.

This study aimed to characterize age-related white matter changes by evaluating patterns of overlap between the linear association of age with fractional anisotropy (FA) with mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Specifically, we assessed patterns of overlap between diffusion measures of normal appearing white matter by covarying for white matter hyperintensity (WMH) load, as WMHs are thought to increase with age and impact diffusion measures. Seventy-nine healthy adults aged between 18 and 75 years took part in the study. Diffusion tensor imaging (DTI) data were based on 61 directions acquired with a b-value of 2,000. We found five main patterns of overlap: FA alone (15.95%); FA and RD (31.90%); FA and AD (12.99%); FA, RD, and AD (27.93%); and FA, RD, and MD (8.79%). We showed that cognitively healthy aging adults had low WMH load, which subsequently had minimal effect on diffusion measures. We discuss how patterns of overlap may reflect underlying biological changes observed with aging such as loss of myelination, axonal damage, as well as mild microstructural and chronic white matter impairments. This study contributes to understanding the underlying causes of degeneration in specific regions of the brain and highlights the importance of considering the impact of WMHs in aging studies of white matter.

Background and PurposeThe relationship between plasma level of total homocysteine (tHcy) and white matter hyperintensities (WMHs), especially in patients with acute ischemic stroke (AIS), is controversial. The present study investigated the association between these two as well as WMH locations in a large cohort of patients with AIS.MethodsConsecutive patients were reviewed from a prospective ischemic stroke database. Clinical data, including tHcy level and WMHs, were assessed. WMHs were assessed using the Fazekas scale and Age-Related White Matter Changes (ARWMC) visual grading scale. The association between tHcy and WMH locations was investigated by using multivariate logistic regression analyses.ResultsA total of 923 out of 1,205 patients were examined. The average age was 58.9 ± 11.9 years; 31.6% were female. Elevated tHcy level was significantly associated with WMHs. For the highest tHcy quartile, the odds ratio (OR) (95% confidence interval; CI) was 1.891 (1.257; 2.843) according to the Fazekas scale and 1.781 (1.185; 2.767) according to the ARWMC scale when compared to the lowest quartile. However, in a subgroup analysis, only WMHs in the periventricular area and left or right frontal areas were found to be independently associated with tHcy level. For the highest tHcy quartile, the OR (95% CI) was 1.761 (1.172; 2.648) for the periventricular WMHs, 1.768 (1.134; 2.756)for the left frontal WMHs, and 1.890 (1.206; 2.960)for the right frontal WMHs.ConclusionsIn patients with AIS, plasma tHcy level is related to WMHs, especially WMHs distributed within the periventricular and frontal areas.

Clinical correlates of cerebral white matter hyperintensities in cognitively normal older adults

Objective To explore the pathogenesis of age⁃related white matter changes (ARWMC), and to investigate the correlation between ARWMC and the number of circulating endothelial progenitor cells (EPCs) and cognitive function in order to provide evidence for early prevention and treatment of ARWMC and cognitive impairment in elderly people. Methods Forty patients with ARWMC were confirmed by CT or MRI. The number of circulating EPCs was measured by flow cytometry. The cognitive function was evaluated by Mini ⁃ Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). One way analysis of variance (ANOVA) of completely random design and χ2 test of R × C tabular data were used to select single factor. Logistic regression (backward) was performed to determine the risk factors for ARWMC. Results Flow cytometry showed that the number of circulating EPCs reduced in patients with ARWMC, especially in severe group (29.50 ± 6.26), and there was statistically significant difference compared with control group (70.50 ± 8.71) and mild⁃to⁃moderate group (58.99 ± 7.78; P = 0.000, for all). The number of circulating EPCs was negatively correlated with the severity of ARWMC (r = ⁃ 0.562, P = 0.001). The scores of MMSE (23.85 ± 2.35) and the scores of MoCA (19.80 ± 3.38) in severe group were significantly lower than control group (27.10 ± 1.80, 26.60 ± 1.23, respectively) and mild⁃to⁃moderate group (25.80 ± 2.02, 23.30 ± 2.87, respectively), and there was statistically significant difference between groups (P < 0.05, for all). Cognitive impairment was mainly presented on visuoconstructional and executive functions, delayed recall and orientation. Conclusion The change of the number of circulating EPCs can be a predictive factor for ARWMC, and it is a potential predictor of the severity of ARWMC. The decrease of the circulating EPCs may be an important pathogenesis of ARWMC, and also the important causation of cognitive impairment in elderly people. DOI：10.3969/j.issn.1672-6731.2010.03.015

The response to donepezil in patients with Alzheimer's disease varies, and it is important to identify the potential responder before therapy. Cerebral white matter changes (WMC) are frequently observed in older patients, and the effect of WMC on therapeutic response remains controversial. The present study aimed to investigate the relationships between the location of WMC, severe WMC and the response to donepezil. Among 418 patients with Alzheimer's disease receiving donepezil, 196 patients were eligible for analysis. Five brain areas on each side were analyzed using computed tomography scans and the Age-Related White Matter Changes Rating Scale before therapy. The Cognitive Abilities Screening Instrument was used annually. Patients were defined as responders if their baseline Cognitive Abilities Screening Instrument score minus their follow-up Cognitive Abilities Screening Instrument score was ≤0. There was no significant difference in demographic data between responder and non-responder groups. Patients in the responder group had significantly less involvement of WMC in the frontal area (P = 0.0213) and nearly a trend for less involvement of WMC in the basal ganglia (P = 0.1103). After adjustment for age, sex, education, polymorphism of apolipoprotein E, hypertension and diabetes, WMC in the frontal area (OR 0.446, P = 0.0139) and basal ganglia (OR 0.243, P = 0.0380) were significantly associated with a reduced therapeutic response. Patients with WMC in the frontal area and basal ganglia had significant decreases in their therapeutic response to donepezil. The location of WMC, independent of their severity, might be associated with the therapeutic response in patient with Alzheimer's disease. Geriatr Gerontol Int 2018; 18: 123-129.

BackgroundIncreasing life expectancy necessitates the better understanding of the neurophysiological underpinnings of age-related cognitive changes. The majority of research examining structural-cognitive relationships in aging focuses on the role of age-related changes to grey matter integrity. In the current study, we examined the relationship between age-related changes in white matter and language production. More specifically, we concentrated on word-finding failures, which increase with age.Methodology/Principal FindingsWe used Diffusion tensor MRI (a technique used to image, in vivo, the diffusion of water molecules in brain tissue) to relate white matter integrity to measures of successful and unsuccessful picture naming. Diffusion tensor images were used to calculate Fractional Anisotropy (FA) images. FA is considered to be a measure of white matter organization/integrity. FA images were related to measures of successful picture naming and to word finding failures using voxel-based linear regression analyses. Successful naming rates correlated positively with white matter integrity across a broad range of regions implicated in language production. However, word finding failure rates correlated negatively with a more restricted region in the posterior aspect of superior longitudinal fasciculus.Conclusions/SignificanceThe use of DTI-MRI provides evidence for the relationship between age-related white matter changes in specific language regions and word finding failures in old age.

To assess and compare age-related diffusion changes in the white matter in different cerebral lobes, as quantified by diffusion-weighted imaging (DWI) and high b-value q-space imaging (QSI). Seventy-three cases without neurological symptoms or imaging abnormalities were grouped by age as young (<30 years, n = 20), middle-aged (30-49 years, n = 19), old (50-69 years, n = 18), and very old (> 70 years, n = 16) and imaged by a 1.5-T MR scanner for DWI and QSI. Apparent diffusion coefficient (ADC) and mean displacement (MDP) values were calculated in the white matter of frontal, parietal, and temporal lobes and compared using Dunnett's test, with the young group as a control. MDP values in frontal and parietal lobes were significantly higher in old and very old age groups than in the young, while those in the temporal lobes were significantly higher only in the very old group. ADC values were significantly higher in all three lobes in the very old group. QSI is more sensitive than DWI to age-related myelin loss in white matter.