Brain Atrophy Measures Research Articles

Disability independent of cerebral white matter demyelination in progressive multiple sclerosis

The pathogenic mechanisms contributing to neurological disability in progressive multiple sclerosis (PMS) are poorly understood. Cortical neuronal loss independent of cerebral white matter (WM) demyelination in myelocortical MS (MCMS) and identification of MS patients with widespread cortical atrophy and disability progression independent of relapse activity (PIRA) support pathogenic mechanisms other than cerebral WM demyelination. The three-dimensional distribution and underlying pathology of myelinated T2 lesions were investigated in postmortem MCMS brains. Postmortem brain slices from previously characterized MCMS (10 cases) and typical MS (TMS) cases (12 cases) were co-registered with in situ postmortem T2 hyperintensities and T1 hypointensities. T1 intensity thresholds were used to establish a classifier that differentiates MCMS from TMS. The classifier was validated in 36 uncharacterized postmortem brains and applied to baseline MRIs from 255 living PMS participants enrolled in SPRINT-MS. Myelinated T2 hyperintensities in postmortem MCMS brains have a contiguous periventricular distribution that expands at the occipital poles of the lateral ventricles where a surface-in gradient of myelinated axonal degeneration was observed. The MRI classifier distinguished pathologically confirmed postmortem MCMS and TMS cases with an accuracy of 94%. For SPRINT-MS patients, the MRI classifier identified 78% as TMS, 10% as MCMS, and 12% with a paucity of cerebral T1 and T2 intensities. In SPRINT-MS, expanded disability status scale and brain atrophy measures were similar in MCMS and TMS cohorts. A paucity of cerebral WM demyelination in 22% of living PMS patients raises questions regarding a primary role for cerebral WM demyelination in disability progression in all MS patients and has implications for clinical management of MS patients and clinical trial outcomes in PMS. Periventricular myelinated fiber degeneration provides additional support for surface-in gradients of neurodegeneration in MS.

Leptin bioavailability and markers of brain atrophy and vascular injury in the middle age.

We investigated the associations of leptin markers with cognitive function and magnetic resonance imaging (MRI) measures of brain atrophy and vascular injury in healthy middle-aged adults. We included 2262 cognitively healthy participants from the Framingham Heart Study with neuropsychological evaluation; of these, 2028 also had available brain MRI. Concentrations of leptin, soluble leptin receptor (sOB-R), and their ratio (free leptin index [FLI]), indicating leptin bioavailability, were measured using enzyme-linked immunosorbent assays. Cognitive and MRI measures were derived using standardized protocols. Higher sOB-R was associated with lower fractional anisotropy (FA, β=-0.114±0.02, p<0.001), and higher free water (FW, β=0.091±0.022, p<0.001) and peak-width skeletonized mean diffusivity (PSMD, β=0.078±0.021, p<0.001). Correspondingly, higher FLI was associated with higher FA (β=0.115±0.027, p<0.001) and lower FW (β=-0.096±0.029, p=0.001) and PSMD (β=-0.085±0.028, p=0.002). Higher leptin bioavailability was associated with better white matter (WM) integrity in healthy middle-aged adults, supporting the putative neuroprotective role of leptin in late-life dementia risk. Higher leptin bioavailability was related to better preservation of white matter microstructure. Higher leptin bioavailability during midlife might confer protection against dementia. Potential benefits might be even stronger for individuals with visceral obesity. DTI measures might be sensitive surrogate markers of subclinical neuropathology.

Global left frontal cortex connectivity attenuates the adverse effect of brain atrophy on global cognition in non-dementia participants

Aim: To investigate whether higher global left frontal cortex (gLFC) connectivity, a potential neural substrate of cognitive reserve (CR), mitigates the impact of brain atrophy on cognition in non-dementia participants. Methods: A total of 43 clinically diagnostic normal controls (NC), 63 subjective cognitive decline (SCD) and 30 mild cognitive impairment (MCI) were recruited, who underwent resting-state fMRI and structural MRI scans. The gLFC connectivity was defined as the average positive functional connectivity between the left frontal cortex and each voxel in the gray matter. Hippocampus, parahippocampal gyrus, and amygdala volume volumes/intracranial volume ratio (HpVR, PhgVR, and AmyVR) values were computed as measures of brain atrophy. In general linear analysis, interaction term gLFC connectivity × brain atrophy on global cognition performance were tested, which were repeated in women and men separately. The Trial registration number is NCT03370744. Results: Significant interaction effects of HpVR * gLFC connectivity (P = 0.031) and PhgVR * gLFC connectivity (P = 0.006) were observed, while AmyVR * gLFC connectivity (P = 0.088) showed a marginal significance. After accounting for APOE ε4 carrying status or diagnosis based on amyloidosis, the significant results still existed. In separate analysis, the significant interaction effects of HpVR * gLFC connectivity (P = 0.004), PhgVR * gLFC connectivity (P = 0.017), and AmyVR * gLFC connectivity (P = 0.027) were only observed in men, not in women. Conclusion: The gLFC connectivity is associated with greater resilience against the adverse effect of specified brain atrophy on global cognition, which is more effective in men.

Genetic variability of FOXP2 and its targets CNTNAP2 and PRNP in frontotemporal dementia: A pilot study in a southern Italian population

The Forkhead box P2 (FOXP2) is an evolutionary conserved transcription factor involved in the maintenance of neuronal networks, implicated in language disorders. Some evidence suggests a possible link between FOXP2 genetic variability and frontotemporal dementia (FTD) pathology and related endophenotypes. To shed light on this issue, we analysed the association between single-nucleotide polymorphisms (SNPs) in FOXP2 and FTD in 113 patients and 223 healthy controls. In addition, we investigated SNPs in two putative targets of FOXP2, CNTNAP2, Contactin-associated protein-like 2 and PRNP, prion protein genes. Overall, 27 SNPs were selected by a tagging approach. FOXP2-rs17213159-C/T resulted associated with disease risk (OR = 2.16, P = 0.0004), as well as with age at onset and severity of dementia. Other FOXP2 markers were associated with semantic and phonological fluency scores, cognitive levels (MMSE) and neuropsychological tests. Associations with language, cognitive and brain atrophy measures were found with CNTNAP2 and PRNP genetic variability. Overall, although preliminary, results here presented suggest an influence of regulatory pathways centred on FOXP2 as a molecular background of FTD affecting neurological function of multiple brain areas.

Circulating sphingolipids and subclinical brain pathology: the cardiovascular health study.

Sphingolipids are implicated in neurodegeneration and neuroinflammation. We assessed the potential role of circulating ceramides and sphingomyelins in subclinical brain pathology by investigating their association with brain magnetic resonance imaging (MRI) measures and circulating biomarkers of brain injury, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in the Cardiovascular Health Study (CHS), a large and intensively phenotyped cohort of older adults. Brain MRI was offered twice to CHS participants with a mean of 5 years between scans, and results were available from both time points in 2,116 participants (mean age 76 years; 40% male; and 25% APOE ε4 allele carriers). We measured 8 ceramide and sphingomyelin species in plasma samples and examined the associations with several MRI, including worsening grades of white matter hyperintensities and ventricular size, number of brain infarcts, and measures of brain atrophy in a subset with quantitative measures. We also investigated the sphingolipid associations with serum NfL and GFAP. In the fully adjusted model, higher plasma levels of ceramides and sphingomyelins with a long (16-carbon) saturated fatty acid were associated with higher blood levels of NfL [β = 0.05, false-discovery rate corrected P (PFDR) = 0.004 and β = 0.06, PFDR = < 0.001, respectively]. In contrast, sphingomyelins with very long (20- and 22-carbon) saturated fatty acids tended to have an inverse association with levels of circulating NfL. In secondary analyses, we found an interaction between ceramide d18:1/20:0 and sex (P for interaction = <0.001), such that ceramide d18:1/20:0 associated with higher odds for infarcts in women [OR = 1.26 (95%CI: 1.07, 1.49), PFDR = 0.03]. We did not observe any associations with GFAP blood levels, white matter grade, ventricular grade, mean bilateral hippocampal volume, or total brain volume. Overall, our comprehensive investigation supports the evidence that ceramides and sphingomyelins are associated with increased aging brain pathology and that the direction of association depends on the fatty acid attached to the sphingosine backbone.

Precise prediction of cerebrospinal fluid amyloid beta protein for early Alzheimer's disease detection using multimodal data.

Alzheimer's disease (AD) constitutes a neurodegenerative disorder marked by a progressive decline in cognitive function and memory capacity. The accurate diagnosis of this condition predominantly relies on cerebrospinal fluid (CSF) markers, notwithstanding the associated burdens of pain and substantial financial costs endured by patients. This study encompasses subjects exhibiting varying degrees of cognitive impairment, encompassing individuals with subjective cognitive decline, mild cognitive impairment, and dementia, constituting a total sample size of 82 participants. The primary objective of this investigation is to explore the relationships among brain atrophy measurements derived from magnetic resonance imaging, atypical electroencephalography (EEG) patterns, behavioral assessment scales, and amyloid β-protein (Aβ) indicators. The findings of this research reveal that individuals displaying reduced Aβ1-42/Aβ-40 levels exhibit significant atrophy in the frontotemporal lobe, alongside irregularities in various parameters related to EEG frequency characteristics, signal complexity, inter-regional information exchange, and microstates. The study additionally endeavors to estimate Aβ1-42/Aβ-40 content through the application of a random forest algorithm, amalgamating structural data, electrophysiological features, and clinical scales, achieving a remarkable predictive precision of 91.6%. In summary, this study proposes a cost-effective methodology for acquiring CSF markers, thereby offering a valuable tool for the early detection of AD.

Alzheimer's disease progression detection based on optical fluence rate measurements using alternative laser wavelengths.

Alzheimer's disease (AD) levels have increased globally, which is considered the sixth reason for deaths. So, a requirement exists for economic and quantitative methods to follow up the gradual progression of AD. The current study presents a simulation for a non-irradiated, safe, wearable, and noninvasive mobile approach for detecting the progression of Alzheimer's brain atrophy using the optical diffusion technique and for investigating the difference between the normal and the diseased brain. The virtual study was accomplished using COMSOL Multiphysics. The simulated head is implemented as the following: scalp, skull, cerebrospinal fluid, gray matter, and white matter. The optical properties of the heterogeneous tissue are observed using the fluence rate after irradiating the head with different wavelengths (630, 700, 810, 915, and 1000 nm) of lasers. Two assessment techniques were applied to evaluate the brain atrophy measurements; the first technique was an array of photodetectors, which were lined at the head posterior, while a matrix of photodetectors was applied over the head surface in the second technique. The results show that the surface photodetectors approach differentiates the normal from AD brains without measuring the brain atrophy percentages by applying 630 nm. The array of photodetectors distinguishes normal from AD brains without detecting the brain atrophy percentages when the wavelengths 630, 700, and 810 nm were applied. The line detector at 1000 nm evaluates the brain atrophy percentages with AD. The future explores applying those techniques in vivo and analyzing the information by the spectrometer for extensively safer early detection of neural disorders.

Macular vessel density in the superficial plexus is not a proxy of cerebrovascular damage in non-demented individuals: data from the NORFACE cohort

IntroductionOptical coherence tomography angiography (OCT-A) is a novel tool that allows the detection of retinal vascular changes. We investigated the association of macular vessel density (VD) in the superficial plexus assessed by OCT-A with measures of cerebrovascular pathology and atrophy quantified by brain magnetic resonance imaging (MRI) in non-demented individuals.MethodsClinical, demographical, OCT-A, and brain MRI data from non-demented research participants were included. We analyzed the association of regional macular VD with brain vascular burden using the Fazekas scale assessed in a logistic regression analysis, and the volume of white matter hyperintensities (WMH) assessed in a multiple linear regression analysis. We also explored the associations of macular VD with hippocampal volume, ventricle volume and Alzheimer disease cortical signature (ADCS) thickness assessed in multiple linear regression analyses. All analyses were adjusted for age, sex, syndromic diagnosis and cardiovascular variables.ResultsThe study cohort comprised 188 participants: 89 with subjective cognitive decline and 99 with mild cognitive impairment. No significant association of regional macular VD with the Fazekas categories (all, p > 0.111) and WMH volume (all, p > 0.051) were detected. VD in the nasal quadrant was associated to hippocampal volume (p = 0.007), but no other associations of macular VD with brain atrophy measures were detected (all, p > 0.05).DiscussionRetinal vascular measures were not a proxy of cerebrovascular damage in non-demented individuals, while VD in the nasal quadrant was associated with hippocampal atrophy independently of the amyloid status.

Exploring the effects of extended interval dosing of natalizumab and drug concentrations on brain atrophy in multiple sclerosis.

Extended interval dosing (EID) of natalizumab treatment is increasingly used in multiple sclerosis. Besides the clear anti-inflammatory effect, natalizumab is considered to have neuroprotective properties as well. This study aimed to study the longitudinal effects of EID compared to standard interval dosing (SID) and natalizumab drug concentrations on brain atrophy. Patients receiving EID or SID of natalizumab with a minimum radiological follow-up of 2 years were included. Changes in brain atrophy measures over time were derived from clinical routine 3D-Fluid Attenuated Inversion Recovery (FLAIR)-weighted magnetic resonance imaging (MRI) scans using SynthSeg. We found no differences between EID (n = 32) and SID (n = 50) for whole brain (-0.21% vs -0.16%, p = 0.42), ventricular (1.84% vs 1.13%, p = 0.24), and thalamic (-0.32% vs -0.32%, p = 0.97) annualized volume change over a median follow-up of 3.2 years. No associations between natalizumab drug concentration and brain atrophy rate were found. We found no clear evidence that EID compared to SID or lower natalizumab drug concentrations have a negative impact on the development of brain atrophy over time.

Skin autofluorescence, reflecting accumulation of advanced glycation end products, and the risk of dementia in a population-based cohort

Conditions such as hyperglycemia and oxidative stress lead to the formation of advanced glycation end products (AGEs), which are harmful compounds that have been implicated in dementia. Within the Rotterdam Study, we measured skin AGEs as skin autofluorescence, reflecting long-term accumulation of AGEs, and determined their association with the risk of dementia and with brain magnetic resonance imaging (MRI) measures. Skin autofluorescence was measured between 2013 and 2016 in 2922 participants without dementia. Of these, 1504 also underwent brain MRI, on which measures of brain atrophy and cerebral small vessel disease were assessed. All participants were followed for the incidence of dementia until 2020. Of 2922 participants (mean age 72.6 years, 57% women), 123 developed dementia. Higher skin autofluorescence (per standard deviation) was associated with an increased risk of dementia (hazard ratio 1.21 [95% confidence interval 1.01–1.46]) and Alzheimer’s disease (1.19 [0.97–1.47]), independently of age and other studied potential confounders. Stronger effects were seen in apolipoprotein E (APOE) ε4 carriers (1.34 [0.98–1.82]) and in participants with diabetes (1.35 [0.94–1.94]). Participants with higher skin autofluorescence levels also had smaller total brain volumes and smaller hippocampus volumes on MRI, and they had more often lacunes. These results suggest that AGEs may be involved in dementia pathophysiology.

CSF p-tau205: a biomarker of tau pathology in Alzheimer’s disease

Post-mortem staging of Alzheimer’s disease (AD) neurofibrillary pathology is commonly performed by immunohistochemistry using AT8 antibody for phosphorylated tau (p-tau) at positions 202/205. Thus, quantification of p-tau205 and p-tau202 in cerebrospinal fluid (CSF) should be more reflective of neurofibrillary tangles in AD than other p-tau epitopes. We developed two novel Simoa immunoassays for CSF p-tau205 and p-tau202 and measured these phosphorylations in three independent cohorts encompassing the AD continuum, non-AD cases and cognitively unimpaired participants: a discovery cohort (n = 47), an unselected clinical cohort (n = 212) and a research cohort well-characterized by fluid and imaging biomarkers (n = 262). CSF p-tau205 increased progressively across the AD continuum, while CSF p-tau202 was increased only in AD and amyloid (Aβ) and tau pathology positive (A+T+) cases (P < 0.01). In A+ cases, CSF p-tau205 and p-tau202 showed stronger associations with tau-PET (rSp205 = 0.67, rSp202 = 0.45) than Aβ-PET (rSp205 = 0.40, rSp202 = 0.09). CSF p-tau205 increased gradually across tau-PET Braak stages (P < 0.01), whereas p-tau202 only increased in Braak V–VI (P < 0.0001). Both showed stronger regional associations with tau-PET than with Aβ-PET, and CSF p-tau205 was significantly associated with Braak V–VI tau-PET regions. When assessing the contribution of Aβ and tau pathologies (indexed by PET) to CSF p-tau205 and p-tau202 variance, tau pathology was found to be the most prominent contributor in both cases (CSF p-tau205: R2 = 69.7%; CSF p-tau202: R2 = 85.6%) Both biomarkers associated with brain atrophy measurements globally (rSp205 = − 0.36, rSp202 = − 0.33) and regionally, and correlated with cognition (rSp205 = − 0.38/− 0.40, rSp202 = − 0.20/− 0.29). In conclusion, we report the first high-throughput CSF p-tau205 immunoassay for the in vivo quantification of tau pathology in AD, and a potentially cost-effective alternative to tau-PET in clinical settings and clinical trials.

Significant dose‐dependent reduction in neurofilament light chain concentration in plasma with oral tau aggregation inhibitor hydromethylthionine mesylate

AbstractBackgroundHydromethylthionine mesylate (HMTM) is a potent oral tau aggregation inhibitor. Recent results from Study TRx‐237‐039 (LUCIDITY) suggest strong effects on cognitive and functional decline and progression of brain atrophy. We investigated the effect of HMTM on change in the plasma biomarker neurofilament light chain (NfL) in LUCIDITY. NfL is a clinically accessible and established biomarker for neurodegeneration that is known to be correlated with measures of clinical decline and brain atrophy in AD and MCI due to AD (MCI‐AD).MethodLUCIDITY is a double‐blind randomised controlled Phase 3 clinical trial comparing change over 12 months in cognitive, functional and brain atrophy outcomes at HMTM doses of 16 mg/day, 8 mg/day and methylthioninium chloride (MTC) at a dose of 4 mg twice weekly as a control in a 4:1:4 randomisation, with a subsequent 12 month blinded open‐label extension phase in which all participants received 16 mg/day.ResultBaseline and 12‐month NfL plasma levels were available as randomised in 161/185 participants receiving HMTM 16 mg/day, 38/48 receiving HMTM 8 mg/day and 136/185 receiving MTC 8 mg/week. The corresponding prespecified analysis model showed a 93% reduction in the change in NfL levels relative to control for HMTM 16 mg/day overall (p = 0.0278). Reduction in NfL change in the MCI‐AD subgroup was significant also at HMTM 8 mg/day (p = 0.0242). In the AD subgroup, there were directional dose‐dependent trends that did not reach statistical significance. Change in NfL level at 12 months was significantly correlated with change in ADAS‐cog11 (p = 0.0038) and whole brain volume (p = 0.0359) over 24 months.ConclusionThese results demonstrate that the orally administered tau aggregation‐inhibitor, HMTM, is able to produce a significant dose‐dependent reduction in neurodegeneration in AD as measured by change in plasma NfL levels.

Identifying Cognitive Resilience Related Genes Among Genetic Risk Loci of Alzheimer’s Disease

AbstractBackgroundCognitive resilience (CR) in the context of Alzheimer’s disease (AD) describes the ability to maintain cognitive function despite the presence of neuropathology (Hohman et al., 2016). While most studies have focused on investigating genetic risk factors for developing AD, we here examined the association of most robust risk loci (Bellenguez et al., 2021) with CR using a neuroimaging‐based approach that incorporates measures of brain atrophy and cognition into a quantitative CR metric (van Loenhoud, 2017).MethodWe performed magnetic resonance imaging (3T) and DNA testing on n = 440 amyloid‐positive individuals in different clinical stages of AD. Employing a global cognitive composite score, we predicted gray matter volume (GM) in each voxel, adjusted for sex, age, premorbid intracranial volume, disease stage, and scanner type. To operationalize CR, W‐scores were computed for each individual based on the standardized individual difference between predicted and observed GM within temporoparietal (TP) and whole brain (WB) masks. In this approach, positive W‐scores reflect low CR, while negative W‐scores reflect high CR. A total of 83 genetic risk variants for AD (Bellenguez et al., 2021) were each tested for their association with W‐scores in a linear regression model corrected for population substructure (PC1‐5).ResultWe found an association for 6 genetic loci, of which variants rs113706587 in gene RASGEF1c and rs6943429 in gene UMAD1 were associated with higher CR (TP: p&lt;0.01, p&lt;0.02; WB: p&lt;0.02, p&lt;0.01). As expected, APOEe4 was associated with low CR (TP: p&lt;0.01, WB: p&lt;0.01), as were genetic markers of genes CLU, MINDY2 (WB: p&lt;0.04, p&lt;0.04), and BCKDK (WB: p&lt;0.05, TP: p&lt;0.04). Importantly, no association was found between APOEe2 and CR (WB: p = 0.195, TP: p = 0.139).ConclusionAmong genetic risk‐loci for AD, we identified two genetic variants associated with cognitive resilience in amyloid‐positive individuals. Interestingly, APOEe4 associated with low CR, as did genes CLU, MINDY2, and BCKDK, indicating anti‐resilience – possibly through accelerating mechanisms. In addition, our results suggest that CR against AD is independent of the protective relationship found between APOEe2 and developing AD, highlighting the relevance of investigating the mechanisms behind CR.

Plasma ADRD Biomarkers are Altered in COVID‐19 ICU Survivors

AbstractBackgroundLong Covid, which features cognitive symptoms in some people, affects an estimated 23.3 million Americans. Older adult survivors of COVID‐19‐associated critical illness are more likely to experience the cognitive symptoms of Long Covid, including deficits in attention, memory, and executive functioning. We sought to evaluate Alzheimer’s disease and related dementia (ADRD) plasma biomarkers in pilot study of older ICU survivors of COVID‐19‐related critical illness and non‐COVID critical illness.Method17 ICU survivors (13 COVID‐19, 4 non‐COVID) underwent clinical and cognitive testing, a blood sample, and a structural MRI approximately 2 months after ICU discharge. Plasma from the blood sample was extracted, and SIMOA assays were used to measure Aβ42, Aβ40, glial fibrillar acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau (pTau181). Structural MRI scans were processed using Freesurfer version 6 to measure brain atrophy (mean global cortical thickness). Plasma analyte values over three standard deviations outside the mean of the whole group were excluded (1 NfL and 1 pTau). Two‐sample t‐tests were used to compare plasma analytes between ICU groups. Pearson or Spearman correlation models were used to evaluate the relationship of target analytes with brain volumes. Covariates were tested but did not change the results.ResultSignificantly lower Aβ42/40 ratio and Aβ42 levels were observed in COVID‐19 ICU survivors relative to non‐COVID ICU survivors (Figure 1). Across all participants Aβ42/40 ratio was not associated with mean global cortical thickness, while NfL and GFAP levels were negatively associated with cortical thickness (Figure 2). However, when limited to only the COVID‐19 ICU survivors, a more ADRD‐like pattern was observed, with a trend for a positive association of Aβ42/40 ratio with cortical thickness and negative association of GFAP and NfL with cortical thickness (Figure 3).ConclusionCognitive impairment in COVID‐19 critical illness may be related to ADRD pathophysiology. Future studies in larger samples of COVID‐19 ICU survivors, as well as those with Long Covid symptoms with a history of mild to moderate COVID‐19 infection are needed to better understand these relationships.

Interactions of optic radiation lesions with retinal and brain atrophy in early multiple sclerosis.

Retrograde trans-synaptic neuroaxonal degeneration is considered a key pathological factor of subclinical retinal neuroaxonal damage in multiple sclerosis (MS). We aim to evaluate the longitudinal association of optic radiation (OR) lesion activity with retinal neuroaxonal damage and its role in correlations between retinal and brain atrophy in people with clinically isolated syndrome and early MS (pweMS). Eighty-five pweMS were retrospectively screened from a prospective cohort (Berlin CIS cohort). Participants underwent 3T magnetic resonance imaging (MRI) for OR lesion volume and brain atrophy measurements and optical coherence tomography (OCT) for retinal layer thickness measurements. All pweMS were followed with serial OCT and MRI over a median follow-up of 2.9 (interquartile range: 2.6-3.4) years. Eyes with a history of optic neuritis prior to study enrollment were excluded. Linear mixed models were used to analyze the association of retinal layer thinning with changes in OR lesion volume and brain atrophy. Macular ganglion cell-inner plexiform layer (GCIPL) thinning was more pronounced in pweMS with OR lesion volume increase during follow-up compared to those without (Difference: -0.82 μm [95% CI:-1.49 to -0.15], p = 0.018). Furthermore, GCIPL thinning correlated with both OR lesion volume increase (β [95% CI] = -0.27 [-0.50 to -0.03], p = 0.028) and brain atrophy (β [95% CI] = 0.47 [0.25 to 0.70], p < 0.001). Correlations of GCIPL changes with brain atrophy did not differ between pweMS with or without OR lesion increase ( = 5.92e-7 , p = 0.762). Faster GCIPL thinning rate is associated with increased OR lesion load. Our results support the value of GCIPL as a sensitive biomarker reflecting both posterior visual pathway pathology and global brain neurodegeneration.

Validation of brain parenchyma sonography as a marker of neurodegeneration in multiple sclerosis

BackgroundMultiple sclerosis (MS) is widely known to cause brain atrophy due to neurodegeneration. Neuroimaging investigations revealed a direct link between brain atrophy detected by MRI and impairment. Transcranial sonography is a safe, feasible and cost-effective imaging technique. In this study, we aimed to validate B-mode transcranial sonography (TCS) as a marker of neurodegeneration in MS. This study is the first study directed to set cut-off point for brain parenchyma measurement in Egyptian population. An observational, case–control study, conducted on 125 subjects; divided into 2 groups: first group, 71 healthy volunteers and patients’ group (54 patients) with relapsing–remitting multiple sclerosis (RRMS). All studied subjects were assessed using B-mode TCS. Transcranial sonography findings were categorized into: first, assessment of brain atrophy parameters by measuring diameter (cm) of third ventricle and both frontal horns of lateral ventricles. Then, the echogenicity of thalamus and brainstem structures (substantia nigra (SN), red nucleus) planimetric surface area (cm2) were assessed along with their abnormal echogenicity (cm2), while brainstem raphe was assessed semi-quantitatively for its echogenicity (intact or interrupted).ResultsQuantitative measures of brain atrophy: in normal control group the third ventricle diameter mean was 0.2 cm (± 0.08), right and left frontal horn diameter were 0.3 cm (± 0.13) and 0.28 cm (± 0.1), respectively, brain atrophy parameters could differentiate between MS patients and normal control group as a statistically significant (p< 0.001) larger ventricular diameter was found in MS patients. On the other hand, assessment of brain stem structures and thalamus showed no statistical significance between MS patients and normal control except in surface area of both red nuclei.ConclusionsBrain parenchymal sonography may be used as a tool in assessment of neurodegeneration in MS patients.

Evaluation of Brain Atrophy after One Year of Whole Brain Irradiation Using Voxel Based Morphometry

Whole-brain irradiation has often been used for metastatic brain tumors and in prophylactic irradiation, but there are few reports on the frequency of cognitive decline and brain atrophy. We attempted to adapt an objective method of measuring brain atrophy to patients after whole-brain irradiation, Using Voxel based morphometry (VBM) measured from MRI to determine if brain atrophy has occurred one year after whole brain irradiation. VBM is a method to measure the change in signal intensity when an atrophic brain is transformed into a normal brain by Deformable Image Registration. We use VBM to measure brain atrophy before and one year after irradiation in patients who received whole brain irradiation at our institution. The MRI used for the analysis was a contrast-enhanced T1-weighted image, Sagittal cross-sectional images of 1 mm thickness were obtained from the whole brain using the 3D variable flip angle turbo spin echo sequence, which is clinically used at our hospital for the cancer patient's management. The subjects were 28 patients who had undergone whole-brain irradiation at our hospital and for whom MRIs were available before treatment and after one year. The cases analyzed included patients who received prophylactic Cranial irradiation (PCI) in cases of small cell lung cancer obtained complete remission. Z-scores obtained from the medial temporal lobe were compared before and after whole brain irradiation treatment to quantitatively assess brain atrophy. The Z-score is the normalized difference between the voxel values obtained from the normal group average and the individual case. There were 15 cases of lung cancer, 5 cases of malignant lymphoma, 5 cases of breast cancer, and 3 cases of various types of cancer, with an average age of 65 years. Cases with tumors or brain edema in the vicinity of the hippocampus were excluded. Various irradiation doses were used, but the commonly used radiation doses were 23.4 Gy/13Fr (lymphoma), 25 Gy/10 Fr (PCI), 35 Gy/14 Fr (multiple metastasis). A Paired-samples one sided t-test was performed to Mean z-score of positive values within the medial temporal lobe before and one year after whole brain irradiation. This number reflects the degree of atrophy within the region of interest and is determined as mild atrophy if it is greater than 1.0. The mean Z-score was found to increase at a risk of 0.01 after whole brain irradiation. This means that brain atrophy is progressing after whole brain irradiation. Hippocampal atrophy becomes apparent about a year after whole brain irradiation. It suggests that brain atrophy occurs after radiotherapy. The problem with this study is that the effects of chemotherapy-induced brain atrophy and aging cannot be ruled out.

Towards a more precise rating of neurological disability in multiple sclerosis: A new automatic and linear quantification of limbs function.

The Expanded Disability Status Scale (EDSS) is the gold standard for evaluating clinical disability in multiple sclerosis (MS) in daily practice. However, more precise clinical assessment tools are needed. We assessed a new, automated rating of the neurological examination obtained with a mobile application (Quantified Neurological Examination - QNE). Consecutive MS patients were assessed for EDSS score and QNE application that calculates, from the description of the examination, a global score and subscores (qFSS) corresponding to the EDSS functional system scores (FSS). Brain MRI was analysed to obtain automatic measures of brain atrophy. We performed 200 examinations and included 78 patients in the MRI analysis. The global QNE score was strongly correlated with the EDSS. qFSS was statistically different according to the corresponding FSS for each function, except for the visual FSS. EDSS was predominantly correlated to the pyramidal function of the lower limbs. QNE score and qFSS had at least equivalent correlation to MRI measures than EDSS, particularly regarding the gray matter and cortical volumes. We propose an automated method to rate neurological disability in MS. While QNE strongly correlates with EDSS, it may allow a more precise way to monitor the evolution of disability.

Treatment Effect on Brain Atrophy Correlates with Treatment Effect on Cognition in Multiple Sclerosis.

The purpose of this study was to evaluate the extent to which treatment effect on magnetic resonance imaging (MRI)-derived measures of brain atrophy and focal lesions can mediate, at the trial level, the treatment effect on cognitive outcomes in multiple sclerosis (MS). We collected all published randomized clinical trials in MS lasting at least 2 years and including as end points: active MRI lesions (defined as new/enlarging T2 lesions), brain atrophy (defined as a change in brain volume between month 12 and month 24), and change in cognitive performance (assessed by the Paced Auditory Serial Addition Test [PASAT]). Relative reductions were used to quantify the treatment effect on MRI markers (lesions and atrophy), whereas the standardized mean difference (Hedges g) between baseline and follow-up cognitive assessment was used to quantify the treatment effects on cognition. A linear regression, weighted for trial size, was used to assess the relationship between the treatment effects on MRI markers and cognition. Fourteen trials including more than 8,813 patients with MS were included in the meta-regression. Treatment effect on cognition was strongly associated with the treatment effect on brain atrophy (R2 = 0.79, p < 0.001), but was not correlated with the treatment effect on active MRI lesions (R2 = 0.16, p = 0.14). Results reported here suggest that brain atrophy, a well-established MRI marker in MS clinical trials, can be used as a main outcome for clinical trials with drugs targeting cognitive impairment and neurodegeneration. ANN NEUROL 2023.

Reliability of brain atrophy measurements in multiple sclerosis using MRI: an assessment of six freely available software packages for cross-sectional analyses.

Volume measurement using MRI is important to assess brain atrophy in multiple sclerosis (MS). However, differences between scanners, acquisition protocols, and analysis software introduce unwanted variability of volumes. To quantify theses effects, we compared within-scanner repeatability and between-scanner reproducibility of three different MR scanners for six brain segmentation methods. Twenty-one people with MS underwent scanning and rescanning on three 3T MR scanners (GE MR750, Philips Ingenuity, Toshiba Vantage Titan) to obtain 3D T1-weighted images. FreeSurfer, FSL, SAMSEG, FastSurfer, CAT-12, and SynthSeg were used to quantify brain, white matterand (deep) gray matter volumes both from lesion-filled and non-lesion-filled 3D T1-weighted images. We used intra-class correlation coefficient (ICC) to quantify agreement; repeated-measures ANOVA to analyze systematic differences; and variance component analysis to quantify the standard error of measurement (SEM) and smallest detectable change (SDC). For all six software, both between-scanner agreement (ICCs ranging 0.4-1) and within-scanner agreement (ICC range: 0.6-1) were typically good, and good to excellent (ICC > 0.7) for large structures. No clear differences were found between filled and non-filled images. However, gray and white matter volumes did differ systematically between scanners for all software (p < 0.05). Variance component analysis yielded within-scanner SDC ranging from 1.02% (SAMSEG, whole-brain) to 14.55% (FreeSurfer, CSF); and between-scanner SDC ranging from 4.83% (SynthSeg, thalamus) to 29.25% (CAT12, thalamus). Volume measurements of brain, GM and WM showed high repeatability, and high reproducibility despite substantial differences between scanners. Smallest detectable change was high, especially between different scanners, which hampers the clinical implementation of atrophy measurements.