MRI Atrophy Research Articles

Predictive value of phospho-tau/total-tau ratio in amyloid-negative Mild Cognitive Impairment

BackgroundIn patients with Mild Cognitive Impairment and normal biomarkers of amyloid-β deposition, prognostication remains challenging. MethodsWe aimed at identifying clinical features, patterns of brain atrophy, and risk of subsequent conversion to dementia in a clinical cohort of consecutive patients with Mild Cognitive Impairment and normal CSF amyloid-β1-42 presenting to our Cognitive Neurology Clinic who were followed prospectively over an average of 25 months. We stratified them as Converters/Non-Converters to dementia based on clinical follow-up and compared baseline clinical features, CSF biomarkers, and pattern of atrophy on MRI data between groups. ResultsAmong 111 eligible patients (mean age 65,61 years; 56,8% were male), 41 patients developed a clinical diagnosis of dementia. Subjects with low baseline p/t-tau had twofold risk of future conversion compared to high p/t-tau ratio subjects (HR = 2.0, p = 0.026). When stratifying converters according to CSF p/t-tau ratio cut off value (0,17), those with values lower than the cut-off had significantly more MRI atrophy at baseline relative to Non-Converters in limbic structures. ConclusionIn Mild Cognitive Impairment patients with negative CSF amyloid biomarker, CSF p/t-tau ratio may be useful to identify those at greater risk of subsequent conversion, possibly because of TDP43-related underlying pathology.

Genetic origin of patients having spastic paraplegia with or without other neurologic manifestations

BackgroundHereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases characterized by lower-limb spastic paraplegia with highly genetic and clinical heterogeneity. However, the clinical sign of spastic paraplegia can also be seen in a variety of hereditary neurologic diseases with bilateral corticospinal tract impairment. The purpose of this study is to identify the disease spectrum of spastic paraplegia, and to broaden the coverage of genetic testing and recognize clinical, laboratorial, electrophysiological and radiological characteristics to increase the positive rate of diagnosis.MethodsTwenty-seven cases were screened out to have definite or suspected pathogenic variants from clinically suspected HSP pedigrees through HSP-associated sequencing and/or expanded genetic testing. One case was performed for enzyme detection of leukodystrophy without next-generation sequencing. In addition, detailed clinical, laboratorial, electrophysiological and radiological characteristics of the 28 patients were presented.ResultsA total of five types of hereditary neurological disorders were identified in 28 patients, including HSP (15/28), leukodystrophy (5/28), hereditary ataxia (2/28), methylmalonic acidemia/methylenetetrahydrofolate reductase deficiency (5/28), and Charcot-Marie-tooth atrophy (1/28). Patients in the HSP group had chronic courses, most of whom were lower limbs spasticity, mainly with axonal neuropathy, and thinning corpus callosum, white matter lesions and cerebellar atrophy in brain MRI. In the non-HSP groups, upper and lower limbs both involvement was more common. Patients with homocysteine remethylation disorders or Krabbe’s disease or autosomal recessive spastic ataxia of Charlevoix-Saguenay had diagnostic results in laboratory or imaging examination. A total of 12 new variants were obtained.ConclusionsHSP had widespread clinical and genetic heterogeneity, and leukodystrophy, hereditary ataxia, Charcot-Marie-Tooth atrophy and homocysteine remethylation disorders accounted for a significant proportion of the proposed HSP. These diseases had different characteristics in clinical, laboratorial, electrophysiological, and radiological aspects, which could help differential diagnosis. Genetic analysis could ultimately provide a clear diagnosis, and broadening the scope of genetic testing could improve the positive rate of diagnosis.

Correlation of Cerebral Atrophy and White Matter Hyperintensity Burden in MRI with Clinical Cognitive Decline

Objective: Dementia is a disease of gradual memory and cognitive loss that affects an individual’s day-to-day activities and is caused by permanent brain damage. Majority of patients are from the elderly population and only2 to 10 % of affected population is less than 65 years.Materials and Methods: We obtained a correlation of severity of white matter hyperintensity (WMH) burden in MRI with severity of clinically assessed cognitive decline. And also analysed the severity of cerebral atrophy in MRI with severity of clinically assessed cognitive decline.Results: In our study Fazekas scoring for WMHs showed a sensitivity of 87.5% and specificity of 83.3% on correlation with clinical cognitive decline assessed by ADAS-Cog. Also, MTA scale for cerebral atrophy showed a sensitivity of 72% and specificity of 88% on correlation with clinical cognitive decline assessed by ADAS-Cog. Significant P-value have been obtained for both the above visual rating scales of MRI (Fazekas and MTA) by linear regression, on correlation with clinically assessed cognitive decline.Conclusion: White matter disease assessed by Fazekas scale and cerebral atrophy by MTA scale on MRI brain correlated well with cognitive decline clinically assessed by neuropsychological tests.

Quantitative Gradient Echo MRI Identifies Dark Matter as a New Imaging Biomarker of Neurodegeneration that Precedes Tisssue Atrophy in Early Alzheimer's Disease.

Background: Currently, brain tissue atrophy serves as an in vivo MRI biomarker of neurodegeneration in Alzheimer’s disease (AD). However, postmortem histopathological studies show that neuronal loss in AD exceeds volumetric loss of tissue and that loss of memory in AD begins when neurons and synapses are lost. Therefore, in vivo detection of neuronal loss prior to detectable atrophy in MRI is essential for early AD diagnosis.Objective: To apply a recently developed quantitative Gradient Recalled Echo (qGRE) MRI technique for in vivo evaluation of neuronal loss in human hippocampus.Methods: Seventy participants were recruited from the Knight Alzheimer Disease Research Center, representing three groups: Healthy controls [Clinical Dementia Rating® (CDR®) = 0, amyloid β (Aβ)-negative, n = 34]; Preclinical AD (CDR = 0, Aβ-positive, n = 19); and mild AD (CDR = 0.5 or 1, Aβ-positive, n = 17).Results: In hippocampal tissue, qGRE identified two types of regions: one, practically devoid of neurons, we designate as “Dark Matter”, and the other, with relatively preserved neurons, “Viable Tissue”. Data showed a greater loss of neurons than defined by atrophy in the mild AD group compared with the healthy control group; neuronal loss ranged between 31% and 43%, while volume loss ranged only between 10% and 19%. The concept of Dark Matter was confirmed with histopathological study of one participant who underwent in vivo qGRE 14 months prior to expiration.Conclusion: In vivo qGRE method identifies neuronal loss that is associated with impaired AD-related cognition but is not recognized by MRI measurements of tissue atrophy, therefore providing new biomarkers for early AD detection.

Evaluation of the relationship between retinal nerve layer thickness and corpus callosum atrophy in MRI with memory impairment in patients with multiple sclerosis.

ABSTRACTIntroduction:Multiple sclerosis (MS) is a chronic neurological disease in which demyelination and loss of axons lead to disruption of communication between neurons in the central nervous system. Cognitive impairment occurs in a significant proportion of patients with MS. Therefore, the aim of this study was to investigate the relationship between retinal nerve fiber layer (RNFL) thickness and corpus callosum atrophy in magnetic resonance imaging with memory disorders in patients with MS.Methods:This descriptive analytical study was performed on patients with a diagnosis of relapsing–remitting multiple sclerosis referred to the clinic of Ali Ibn Abi Talib Hospital in Zahedan, Iran. An information form that includes a Mini–Mental State Examination was first prepared, by which the patient’s memory impairment is measured. After recording the data, the data were collected using an information form and finally analyzed by SPSS software version 22 using an independent t-test.Results:In this study, 80 patients with MS primary progressive multiple sclerosis were included in the study, of which 53 were female and 27 were male. The mean age of patients was 45.1 ± 5.9 years, which did not show a statistically significant difference (P = 0.536). The mean RNFL thickness in patients with memory impairment was significantly lower than that in patients without memory impairment. The mean corpus callosum thickness was found to be significantly lower in patients with memory impairment than in patients without memory impairment.Conclusion:All in all, the results of this study showed that the thickness of RNFL and the corpus callosum in patients with memory impairment was significantly lower than that in patients without memory impairment.

Deep medullary veins are associated with widespread brain structural abnormalities

Our aim is to investigate the association of cerebral deep medullary veins (DMVs) with white matter microstructural integrity and regional brain atrophy in MRI. In a community-based cohort of 979 participants (mean age 55.4 years), DMVs were identified on susceptibility-weighted imaging. Brain structural measurements including gray matter and hippocampus volumes, as well as diffusion tensor metrics, were evaluated. The mean (SD)number of DMVs was 19.0 (1.7). A fewer number of DMVs was related to lower fractional anisotropy and higher mean diffusivity in multiple voxels on the white matter skeleton (threshold-free cluster enhancement corrected p < 0.05, adjusted for age and sex). Also, fewer DMVs were significantly related to a lower gray matter fraction and a hippocampal fraction (0.10 and 0.11 per DMV, respectively; SE, 0.03 for both; p < 0.001 for both). A significant correlation between DMVs’ reduction and cortical atrophy was observed in the bilateral occipital lobes, temporal lobes, hippocampus, and frontal lobes (p < 0.001, adjusted for age, sex, and total intracranial volume). Our results provided evidence that cerebral small venules disease play a role in brain parenchymal lesions and neurodegenerative processes.

Alzheimer’s disease spectrum profiled by CSF and imaging biomarkers: Tau PET best predicts cognitive decline

AbstractBackgroundThe concept of pathophysiologically profiling individuals based on their biomarker status for Aβ42 (A) or tau (T) deposition and neurodegeneration (N) is attracting interest in the Alzheimer’s disease research field. All three processes can be monitored by either cerebrospinal fluid (CSF) sampling or imaging (PET/MRI). We aimed to test the comparability of the CSF and imaging biomarkers in each AT(N) category and their ability to predict longitudinal cognitive decline.MethodA subset of data from 254 patients who had had PET investigations with amyloid‐β and tau tracers, and CSF sampling at the same time point, and a structural MRI within one year was selected from the Alzheimer’s Disease Neuroimaging Initiative trial data. The participants were grouped by clinical diagnosis at that time: cognitively normal (n=88), subjective memory concern (n=82), early (n=35) or late (n=31) mild cognitive impairment, and Alzheimer’s disease (n=18). Agreement between the modalities for A, T and N was assessed with Cohen’s Kappa statistic. Linear mixed‐effects models were used to predict subsequent decline in the episodic memory composite score.ResultBiomarkers for A in PET and CSF showed moderate agreement (Kappa=0.42‐64). Biomarkers for T in PET and CSF showed fair agreement (Kappa&lt;0.40), except in the Alzheimer’s disease group where agreement was moderate (Kappa=0.64). The N biomarkers (CSF vs atrophy in MRI) showed evidence of discordance across all groups (Kappa&lt;0.26). Baseline tau PET positivity predicted longitudinal decline in episodic memory irrespective of the p‐Tau181 (CSF) status (estimate=‐0.02, p≤0.05), but the same was not seen for isolated p‐Tau181 (CSF) positivity (estimate=0.00, p=0.58). Baseline tau and amyloid‐β PET positivity biomarkers predicted decline in episodic memory (estimate=‐0.02, p≤0.0001), but isolated amyloid‐β PET positivity did not (estimate=‐0.01, p=0.09). Isolated tau PET positivity was not observed in the absence of amyloid‐β PET positivity, with the exception of one participant with PET values close to the cutoff point.ConclusionWhile results for amyloid‐β are relatively similar using CSF or imaging, CSF and imaging results for tau and neurodegeneration are not interchangeable. Tau PET positivity was superior to phosphorylated tau and amyloid‐β PET in predicting cognitive decline in the Alzheimer’s disease continuum.

Quantifying patterns of pathology: A characterization of the 3D spatial distribution of tau tangles and amyloid plaques in Alzheimer’s disease using multi‐modal image registration with a scattering transform

AbstractBackgroundVolumetric measures of MRI scans have consistently shown medial temporal lobe (MTL) atrophy in individuals across the spectrum of AD. However, these measures are not considered to be specific for AD, partly because a direct link to tau and amyloid pathology has not been demonstrated (Jack et. al, 2018). To address this limitation, we developed multi‐modal image registration and analysis tools to integrate neuropathological data from 2D histology images with 3D postmortem MRI images in the same brain region, in order to quantify the density of tangles and plaques.MethodsWe imaged tissue excised from the MTL at 0.125 mm resolution with an 11T MR scanner (fig 1a) and manually segmented it into subregions (fig 1b). We sliced the tissue into 10um thick sections, 1mm apart, and digitally imaged them with a light microscope after staining for amyloid (6E10) or tau (PHF‐1) (fig 1c). Locations of tangles and plaques on histology were estimated with a deep convolutional neural network (UNET) trained on a smaller set of annotated data (fig 1d). To align histology images with the MRI images, we first computed scattering transforms of histology to capture high resolution textural information (fig 1e). This was then used to find both optimal spatial and intensity profile transformations between the two imaging modalities (fig 1f). We rigidly aligned MRI images to the Mai Paxinos atlas for interpretability.ResultsWe localized tau tangles and amyloid plaques from histology sections of a person with severe AD, and in corresponding 3D MRI images of the brain tissue from the same individual. We quantified density of particles per region. Initial findings demonstrated the highest amount of tau in the entorhinal cortex, subiculum, and CA1 (fig 2) compared to other subregions in the MTL, consistent with Braak staging. No obvious differential distribution of amyloid was observed.ConclusionOur detailed localization of tangles and plaques in 3D offers the opportunity to study spatial distribution of pathology within brain regions among patients that span the spectrum of disease, which will foster more robust comparison with MRI atrophy, and potentially shed new light on the progression of AD.

A novel MRI approach for evaluation of microstructural neurodegeneration in early Alzheimer disease

AbstractBackgroundCurrently, brain tissue atrophy serves as in vivo structural MRI biomarker of neurodegeneration in Alzheimer Disease (AD). However, postmortem histopathological studies show that neuronal loss in AD exceeds volumetric loss of tissue and that AD‐related memory loss begins when neurons are lost. Hence, in vivo detection of neurodegeneration preceding detectable atrophy is essential for early AD diagnosis.MethodOur innovative approach to assessing neuronal damage in vivo is based on (a) quantitative Gradient Recalled Echo (qGRE) MRI technique and (b) genetically‐informed relationships between qGRE metrics and major components of brain tissue cellular structure (neurons/neurites and glia) that were obtained using gene expression profiles across the human brain provided by the Allen Human Brain Atlas. Seventy participants were recruited from the Knight Alzheimer Disease Research Center, representing three groups: Healthy controls [Clinical Dementia Rating® (CDR®)=0, amyloid β (Aβ)‐negative), n=34] HC; Preclinical AD (CDR=0, Aβ‐positive, n=19), PC; and mild AD (CDR=0.5 or 1, Aβ‐positive, n=17), AD.ResultPreliminary data show that qGRE identified new biomarkers in AD brain characterizing tissues with significantly lower (termed Dark Matter) and relatively preserved (termed Viable Tissue) concentrations of neurons. The fraction of Dark Matter showed clinically important and significant differences between HC and PC groups in hippocampus, middle temporal, fusiform, postcentral, and inferior parietal brain regions. However, no HC vs. PC group difference was detected by the volumetric measurements (Figure 1). Further, measurements of the Dark Matter fraction in the hippocampus showed strong associations with Cerebrospinal fluid (CSF) amyloid Aβ42 (r=‐0.52), CSF ptau (r=0.60), 18F‐AV1415‐PET tau imaging (r=0.60), and PiB‐PET amyloid imaging (r=0.60). These associations were significantly stronger compared with volumetric measurements: CSF amyloid Aβ42 (r=0.18), CSF ptau (r=‐0.24), PET tau imaging (r=‐0.39), and PiB‐PET amyloid imaging (r=‐0.17)). Importantly, the Dark Matter fraction had a significant inter‐regional association (r=0.87) with neuronal count in the hippocampal subfields obtained from histopathological study of one participant who underwent in vivo qGRE 14 months prior to expiration (Figure 2).ConclusionqGRE‐based measurements identify the microstructural changes in early AD‐related neurodegeneration that are not recognized by structural MRI atrophy measurements, therefore providing new biomarkers for early AD detection.

Baseline MRI atrophy predicts 2-year cognitive outcomes in early-onset Alzheimer's disease.

MRI atrophy predicts cognitive status in AD. However, this relationship has not been investigated in early-onset AD (EOAD, < 65years) patients with a biomarker-based diagnosis. Forty eight EOAD (MMSE ≥ 15; A + T + N +) and forty two age-matched healthy controls (HC; A-T-N-) from a prospective cohort underwent full neuropsychological assessment, 3T-MRI scan and lumbar puncture at baseline. Participants repeated the cognitive assessment annually. We used linear mixed models to investigate whether baseline cortical thickness (CTh) or subcortical volume predicts two-year cognitive outcomes in the EOAD group. In EOAD, hemispheric CTh and ventricular volume at baseline were associated with global cognition, language and attentional/executive functioning 2years later (p < 0.0028). Regional CTh was related to most cognitive outcomes (p < 0.0028), except verbal/visual memory subtests. Amygdalar volume was associated with letter fluency test (p < 0.0028). Hippocampal volume did not show significant associations. Baseline hemispheric/regional CTh, ventricular and amygdalar volume, but not the hippocampus, predict two-year cognitive outcomes in EOAD.

Alzheimer's disease MRI patterns: Cognitive, structural and cerebrospinal fluid correlates

While hippocampal atrophy represents the prototypical MRI finding in Alzheimer's Disease (AD), also other MRI atrophy patterns are commonly found in this population. The differences in clinical and imaging longitudinal evolution associated with the diverse MRI atrophy patterns, however, are poorly understood. Here, we decided to assess the clinical and radiological atrophy progression in AD subjects stratified according to baseline MRI atrophy patterns.

Clinical Phenotype and Mutation Spectrum of Alzheimer's Disease with Causative Genetic Mutation in a Chinese Cohort.

BackgroundAlzheimer’s disease with a causative genetic mutation (AD-CGM) is an uncommon form, characterized by a heterogeneous clinical phenotype and variations in the genotype of racial groups affected.ObjectiveWe aimed to systemically describe the phenotype variance and mutation spectrum in the large sample size of the Peking Union Medical College Hospital (PUMCH) cohort, Beijing, China.MethodsNext-generation sequencing (NGS) was carried out in 1108 patients diagnosed with dementia. A total of 40 Han Chinese patients with three AD gene mutations were enrolled. A systemic review of all the patients was performed, including clinical history, neurocognitive assessment, brain magnetic resonance imaging, and cerebrospinal fluid (CSF) biomarkers.ResultsWe studied the following gene mutation variants: 12 AβPP, 13 PSEN1, and 9 PSEN2, and 23 among them were novel. Most of them were early-onset, but PSEN1 mutation carriers had the youngest onset age. The commonest symptoms were similar to those of AD, including an amnestic syndrome, followed by psychiatric symptoms and movement disorder. On MRI, parietal and posterior temporal atrophy was prominent in PSEN1 and PSEN2 mutation carriers, while AβPP mutation carriers had more vascular changes. The CSF biomarkers profile was indistinguishable from sporadic AD.ConclusionWe identified a small group of AD-CGM subjects representing 3.6% among more than 1000 demented patients in the PUMCH cohort. These subjects usually presented with early-onset dementia and exhibited significant clinical and genetic heterogeneity. Identification required complete screening of genetic mutations using NGS. Although family history was usually present, we found non-familial cases of all three genetic mutations.

Decreased Retinal Vascular Density in Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI): An Optical Coherence Tomography Angiography (OCTA) Study.

BackgroundTo explore the retinal vascular density changes in Alzheimer’s disease (AD) and mild cognitive impairment (MCI) patients using optical coherence tomography angiography (OCTA).MethodsWe recruit 62 AD patients, 47 MCI patients, and 49 cognitively healthy controls (HC) in this study. All participants in the study received a comprehensive ophthalmological and neurological evaluation, including global cognitive screening, as well as the Mini-Mental State Examination (MMSE), and completed the following eye examinations: visual acuity (VA), intraocular pressure (IOP), examination with slit-lamp, fundus photography (Version 1.5.0.0, NIDEK CO, LTD) and Optical coherence tomography imaging (software ReVue version 2017.1.0.155, Optovue Inc., Fremont, CA, United States). The visual rating scales for atrophy and white matter lesion in MRI was evaluated for all the patients with AD and MCI.ResultsIn the AD patient group, the superficial vascular density in the superior, inferior and whole retina was 44.64 ± 3.34, 44.65 ± 3.55, and 44.66 ± 3.36, respectively. These values were 44.24 ± 3.15, 43.72 ± 3.16, and 44 ± 3.07, respectively, in the MCI patient group. After multivariate analysis of the generalized linear model, adjustments for the confounding factors of sex, age, hypertension, diabetes and the quality index of OCTA image, the superficial vascular density in the AD and MCI patient groups was significantly lower than that in the HC group (P < 0.05): 46.94 ± 2.04, 46.67 ± 2.26, and 46.82 ± 2.08, respectively. No difference in the area of the FAZ among the three groups was observed (AD group: 0.34 ± 0.11 mm2; MCI group: 0.36 ± 0.12 mm2; control group: 0.33 ± 0.12 mm2, p > 0.05). The ganglion cell complex (GCC) thickness, inner parafovea thickness, and peripapillary retinal nerve fiber layer (p-RNFL) thickness were associated with the superficial vascular density. We found no significant correlation between the global cognition (MMSE scores) or between the Fazekas score and retinal OCT angiogram flow density.ConclusionThe superficial vascular density in the AD and MCI patient groups was significantly lower than that in the HC group. Our findings suggest the retinal microvascular dysfunction occurred in MCI and AD.

Automated quantitative MRI volumetry reports support diagnostic interpretation in dementia: a multi-rater, clinical accuracy study

ObjectivesWe examined whether providing a quantitative report (QReport) of regional brain volumes improves radiologists’ accuracy and confidence in detecting volume loss, and in differentiating Alzheimer’s disease (AD) and frontotemporal dementia (FTD), compared with visual assessment alone.MethodsOur forced-choice multi-rater clinical accuracy study used MRI from 16 AD patients, 14 FTD patients, and 15 healthy controls; age range 52–81. Our QReport was presented to raters with regional grey matter volumes plotted as percentiles against data from a normative population (n = 461). Nine raters with varying radiological experience (3 each: consultants, registrars, ‘non-clinical image analysts’) assessed each case twice (with and without the QReport). Raters were blinded to clinical and demographic information; they classified scans as ‘normal’ or ‘abnormal’ and if ‘abnormal’ as ‘AD’ or ‘FTD’.ResultsThe QReport improved sensitivity for detecting volume loss and AD across all raters combined (p = 0.015* and p = 0.002*, respectively). Only the consultant group’s accuracy increased significantly when using the QReport (p = 0.02*). Overall, raters’ agreement (Cohen’s κ) with the ‘gold standard’ was not significantly affected by the QReport; only the consultant group improved significantly (κs 0.41➔0.55, p = 0.04*). Cronbach’s alpha for interrater agreement improved from 0.886 to 0.925, corresponding to an improvement from ‘good’ to ‘excellent’.ConclusionOur QReport referencing single-subject results to normative data alongside visual assessment improved sensitivity, accuracy, and interrater agreement for detecting volume loss. The QReport was most effective in the consultants, suggesting that experience is needed to fully benefit from the additional information provided by quantitative analyses.Key Points• The use of quantitative report alongside routine visual MRI assessment improves sensitivity and accuracy for detecting volume loss and AD vs visual assessment alone.• Consultant neuroradiologists’ assessment accuracy and agreement (kappa scores) significantly improved with the use of quantitative atrophy reports.• First multi-rater radiological clinical evaluation of visual quantitative MRI atrophy report for use as a diagnostic aid in dementia.

Neuroimaging correlates of gait abnormalities in progressive supranuclear palsy

Progressive supranuclear palsy is a neurodegenerative disorder characterized primarily by tau inclusions and neurodegeneration in the midbrain, basal ganglia, thalamus, premotor and frontal cortex. Neurodegenerative change in progressive supranuclear palsy has been assessed using MRI. Degeneration of white matter tracts is evident with diffusion tensor imaging and PET methods have been used to assess brain metabolism or presence of tau protein deposits. Patients with progressive supranuclear palsy present with a variety of clinical syndromes; however early onset of gait impairments and postural instability are common features. In this study we assessed the relationship between multimodal imaging biomarkers (i.e., MRI atrophy, white matter tracts degeneration, flortaucipir-PET uptake) and laboratory-based measures of gait and balance abnormalities in a cohort of nineteen patients with progressive supranuclear palsy, using univariate and multivariate statistical analyses. The PSP rating scale and its gait midline sub-score were strongly correlated to gait abnormalities but not to postural imbalance. Principal component analysis on gait variables identified velocity, stride length, gait stability ratio, length of gait phases and dynamic stability as the main contributors to the first component, which was associated with diffusion tensor imaging measures in the posterior thalamic radiation, external capsule, superior cerebellar peduncle, superior fronto-occipital fasciculus, body and splenium of the corpus callosum and sagittal stratum, with MRI volumes in frontal and precentral regions and with flortaucipir-PET uptake in the precentral gyrus. The main contributor to the second principal component was cadence, which was higher in patients presenting more abnormalities on mean diffusivity: this unexpected finding might be related to compensatory gait strategies adopted in progressive supranuclear palsy. Postural imbalance was the main contributor to the third principal component, which was related to flortaucipir-PET uptake in the left paracentral lobule and supplementary motor area and white matter disruption in the superior cerebellar peduncle, putamen, pontine crossing tract and corticospinal tract. A partial least square model identified flortaucipir-PET uptake in midbrain, basal ganglia and thalamus as the main correlate of speed and dynamic component of gait in progressive supranuclear palsy. Although causality cannot be established in this analysis, our study sheds light on neurodegeneration of brain regions and white matter tracts that underlies gait and balance impairment in progressive supranuclear palsy.

Cerebral Amyloid Angiopathy in Amyloid-Positive Patients from a Memory Clinic Cohort.

The overlap between cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD) is frequent and relevant for patients with cognitive impairment. To assess the role of the diagnosis of CAA on the phenotype of amyloid-β (Aβ) positive patients from a university-hospital memory clinic. Consecutive patients referred for suspected cognitive impairment, screened for Aβ pathological changes in cerebrospinal fluid (CSF), with available MRI and neuropsychological results were included. We determined the association between probable CAA and clinical, neuropsychological (at presentation and after a mean follow-up of 17 months in a sub-sample) and MRI (atrophy, white matter hyperintensities, perivascular spaces) characteristics. Of 218 amyloid-positive patients, 8.3% fulfilled criteria for probable CAA. A multivariable logistic regression showed an independent association of probable CAA with lower Aβ1-42 (adjusted odds ratio [aOR] = 0.94, 95% confidence interval [95% CI] = 0.90-0.98, p = 0.003), and Aβ1-40 (aOR = 0.98, 95% CI=0.97-0.99 p = 0.017) levels in CSF, and presence of severe burden of enlarged perivascular spaces (EPVS) in the centrum semiovale (aOR = 3.67, 95% CI = 1.21-11.15, p = 0.022). Linear mixed-model analysis showed that both groups significantly deteriorated in global clinical severity, executive function and memory. Nevertheless, the presence of probable CAA did not differently affect the rate of cognitive decline. The presence of probable CAA in Aβ positive patients was associated with lower Aβ1-42 and Aβ1-40 CSF levels and increased centrum semiovale EPVS burden, but did not independently influence clinical phenotype nor the rate of cognitive decline within our follow-up time window.

Disentangling neurodegeneration subtypes of Alzheimer’s disease using data‐driven methods

AbstractBackgroundResearch on understanding heterogeneity in Alzheimer’s disease (AD) has traditionally relied on ‘a priori’ categorizations of recognized clinical or pathologic disease variants. More recently, application of clustering methods to high‐dimensional spatial features from neuroimaging data has allowed data‐driven discovery of AD subtypes based on differentiated regional patterns of neurodegeneration.MethodsWe provide an up‐to‐date review of structural MRI studies that leveraged data‐driven approaches to examine heterogeneity in regional neurodegeneration patterns among AD patients. Findings will be discussed in relation to different families of clustering methods employed across studies. We further present primary data from our ongoing studies characterizing AD neurodegeneration subtypes by means of FDG‐PET as a potentially more sensitive molecular imaging marker of neurodegenerative processes.ResultsData‐driven studies across multiple independent cohorts and employed methodologies provide converging evidence for the existence of distinct MRI atrophy subtypes that broadly resemble the differentiation into atypical medial temporal‐ vs neocortical‐predominant patterns characterizing established neuropathological subtypes. These studies not only allowed for a regionally more detailed characterization of the respective atrophy patterns, but also pointed to the existence of more differentiated atrophy profiles within these broad subtype categories. Concordantly, our cluster analyses of FDG‐PET data confirmed a broad distinction into AD subtypes characterized by medial temporal/limbic‐ vs neocortical‐predominant hypometabolism, and at a higher resolution further distinguished a rare frontal variant from the typical temporo‐parietal neocortical pattern (Fig‐1). In a pilot imaging‐pathologic association study based on ante‐mortem FDG‐PET of 34 pathologic AD cases, the neocortical‐predominant subtype was more likely to have neocortical tau Braak stage VI and to have higher CERAD ratings of cortical neuritic plaques, whereas Thal amyloid phase and diffuse plaque ratings did not differ from the limbic‐predominant subtype. The limbic‐predominant subtype had a higher burden of comorbid cerebrovascular disease, but TDP‐43 or Lewy body comorbidity did not differ significantly between subtypes.ConclusionsData‐driven approaches applied to neuroimaging data can give an unbiased and regionally detailed estimate of the distinct neurodegeneration subtypes present among AD dementia patients. Methodological consensus on the optimal clustering techniques and input features is needed to define the most robust subtype‐defining neurodegeneration patterns to be used for patient stratification.

Genome‐wide analysis of longitudinal Alzheimer’s disease biomarker endophenotypes

AbstractBackgroundAlzheimer’s disease (AD) is characterized by a pathophysiological cascade, in part detectable using imaging and fluid biomarkers, that evolves over many years. Our goal was to study the interaction between genetic risk and longitudinal trajectories of selected AD endophenotypes using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset.MethodLongitudinal data included amyloid beta (PET and CSF), total tau and phosphorylated tau (CSF), FDG PET (3 ROIs), MRI measures of atrophy (8 ROIs) and white matter hyperintensities (WMHI), and composite scores from cognitive tests for memory and executive function (full list of endophenotypes, sample size, and covariates in Table 1). Genetic association with longitudinal phenotypes was performed using Linear Mixed Modelling (LMM; LME4 R package), modeling the SNP main effect and SNP x time effects, with time x subject as a random effect and participant age as the time variable. SNP P‐values from the LMM were analyzed for gene enrichment using MAGMA, with a 10kb boundary around genes for SNP to gene assignment. A stringent significance threshold was set to P ≤ 6.25 × 10−9 based on Bonferroni correction for the top 8 principal components explaining 85% of variance across all tested phenotypes. LD trimming was performed to identify top SNPs for genetic regions. MAGMA gene based association was FDR corrected to P ≤ 0.05.ResultMultiple genetic regions (26) were associated with the main SNP effect, including the APOE ε4 locus, which was significant on all measures except WMHI. Time interaction identified the APOE ε4 allele as study wide significant with cognitive measures and 5 MRI ROIs. Apart from APOE, 7 SNPs were identified that met genome‐wide significance, including SNPs intronic to BORCS5, HLA‐DPA1, and GRIN3A (Figure 1). Gene based association identified 21 genes, 14 primarily associated with MRI atrophy measures, 3 WMHI, 2 with CSF tau, 1 with amyloid PET, and 1 with cognitive measures (Figure 2).ConclusionGenetic association analysis of longitudinal trajectories of AD biomarker phenotypes identified both genes and pathways previously implicated with AD, as well as several novel loci. These findings may point to new targets for diagnostic and therapeutic development.

Influences of Folate Supplementation on Homocysteine and Cognition in Patients with Folate Deficiency and Cognitive Impairment.

Although folate deficiency was reported to be associated with hyperhomocysteinemia, influence of folate supplementation on cognition remains controversial. Therefore, we explored the effects of folate supplementation on the cognition and Homocysteine (Hcy) level in relatively short periods in patients with folate deficiency and cognitive impairment. Enrolled 45 patients (mean age of 79.7 ± 7.9 years old) with folate deficiency (<3.6 ng/mL) with cognitive impairment underwent Mini-Mental State Examination (MMSE), and laboratory examinations, including folate, vitamin B12, and Hcy. The degree of hippocampal atrophy in MRI was estimated using a voxel-based specific regional analysis system for Alzheimer’s disease (VSRAD). Patients were administrated folate (5 mg/day), then Hcy, and MMSE score were re-examined after 28 to 63 days. Mean Hcy significantly decreased from 25.0 ± 18.0 to 11.0 ± 4.3 nmol/mL (p < 0.001). Average MMSE scores also significantly changed from 20.1 ± 4.7 to 22.2 ± 4.3 (p < 0.001). The degree of change in the MMSE score and basic Hcy or Hcy change was significantly positively correlated, while degree of hippocampal atrophy in MRI did not. Although several factors should be taken into account, folate supplementation ameliorated cognitive impairment, at least for a short period, in patients with folate deficiency.

Neurotoxicity after hematopoietic stem cell transplant in multiple sclerosis.

ObjectiveAccelerated brain volume loss has been noted following immunoablative autologous hematopoietic stem cell transplantation (IAHSCT) for multiple sclerosis. As with other MS treatments, this is often interpreted as ‘pseudoatrophy’, related to reduced inflammation. Treatment‐related neurotoxicity may be contributory. We sought objective evidence of post‐IAHSCT toxicity by quantifying levels of Neurofilament Light Chain (sNfL) and Glial Fibrillary Acidic Protein (sGFAP) before and after treatment as markers of neuroaxonal and glial cell damage.MethodsSera were collected from 22 MS patients pre‐ and post‐IAHSCT at 3, 6, 9, and 12 months along with 28 noninflammatory controls. sNfL and sGFAP quantification was performed using the SiMoA single‐molecule assay.ResultsPre‐IAHSCT levels of sNfL and sGFAP were elevated in MS patients compared with controls (geometric mean sNfL 21.8 vs. 6.4 pg/mL, sGFAP 107.4 vs. 50.7 pg/mL, P = 0.0001 for both). Three months after IAHSCT, levels of sNfL and sGFAP increased from baseline by 32.1% and 74.8%, respectively (P = 0.0029 and 0.0004). sNfL increases correlated with total busulfan dose (P = 0.034), EDSS score worsening at 6 months (P = 0.041), and MRI grey matter volume loss at 6 months (P = 0.0023). Subsequent NfL levels reduced to less than baseline (12‐month geometric mean 11.3 pg/mL P = 0.0001) but were still higher than controls (P = 0.0001). sGFAP levels reduced more slowly but at 12 months were approaching baseline levels (130.7 pg/mL).InterpretationThere is direct evidence of transient CNS toxicity immediately after IAHSCT which may be chemotherapy mediated and contributes to transient increases in MRI atrophy.