Progression Of Gray Matter Atrophy Research Articles

Identification of different MRI atrophy progression trajectories in epilepsy by subtype and stage inference.

Artificial intelligence (AI)-based tools are widely employed, but their use for diagnosis and prognosis of neurological disorders is still evolving. Here we analyse a cross-sectional multicentre structural MRI dataset of 696 people with epilepsy and 118 control subjects. We use an innovative machine-learning algorithm, Subtype and Stage Inference, to develop a novel data-driven disease taxonomy, whereby epilepsy subtypes correspond to distinct patterns of spatiotemporal progression of brain atrophy.In a discovery cohort of 814 individuals, we identify two subtypes common to focal and idiopathic generalized epilepsies, characterized by progression of grey matter atrophy driven by the cortex or the basal ganglia. A third subtype, only detected in focal epilepsies, was characterized by hippocampal atrophy. We corroborate external validity via an independent cohort of 254 people and confirm that the basal ganglia subtype is associated with the most severe epilepsy.Our findings suggest fundamental processes underlying the progression of epilepsy-related brain atrophy. We deliver a novel MRI- and AI-guided epilepsy taxonomy, which could be used for individualized prognostics and targeted therapeutics.

Functional and structural brain MRI changes associated with cognitive worsening in multiple sclerosis: a 3-year longitudinal study.

Heterogeneous processes may contribute to cognitive impairment in multiple sclerosis (MS). To apply a longitudinal multiparametric MRI approach to identify mechanisms associated with cognitive worsening in MS patients. 3T brain functional and structural MRI scans were acquired at baseline and after a median follow-up of 3.4years in 35 MS patients and 22 healthy controls (HC). Associations between cognitive worsening (reliable change index score < -1.25 at the Rao's battery) and longitudinal changes in regional T2-hyperintense white matter (WM) lesions, diffusion tensor microstructural WM damage, gray matter (GM) atrophy and resting state (RS) functional connectivity (FC) were explored. At follow-up, HC showed no clusters of significant microstructural WM damage progression, GM atrophy or changes in RS FC. At follow-up, 10 MS patients (29%) showed cognitive worsening. Compared to cognitively stable, cognitively worsened MS patients showed more severe GM atrophy of the right anterior cingulate cortex and bilateral supplementary motor area (p < 0.001). Cognitively worsened vs cognitively stable MS patients showed also decreased RS FC in the right hippocampus of the right working memory network and in the right insula of the default mode network. Increased RS FC in the left insula of the executive control network was found in the opposite comparison (p < 0.001). No significant regional accumulation of focal WM lesions nor microstructural WM abnormalities occurred in both patients' groups. GM atrophy progression in cognitively relevant brain regions combined with functional impoverishment in networks involved in cognitive functions may represent the substrates underlying cognitive worsening in MS.

Functional and Structural MRI Changes Associated With Cognitive Worsening in Multiple Sclerosis: A 3-Year Longitudinal Study (P11-3.003)

<h3>Objective:</h3> To apply a multiparametric MRI approach to identify mechanisms associated with cognitive worsening in multiple sclerosis (MS). <h3>Background:</h3> Heterogeneous processes may contribute to cognitive impairment in MS; however, its association with brain structural and functional MRI changes still need to be fully explored. <h3>Design/Methods:</h3> Brain dual-echo, 3D T1-weighted, diffusion-weighted imaging, and resting state (RS) functional MRI scans were acquired at baseline and after median follow up of 3.4 years in 35 MS patients and 22 healthy controls (HC). Associations between cognitive worsening at Rao’s battery and longitudinal changes in T2-hyperintense lesion location, WM microstructural damage, gray matter (GM) atrophy and RS functional connectivity (FC) were explored using tract-based spatial statistic, tensor-based morphometry and independent component analysis. <h3>Results:</h3> Fifteen (43%) MS patients were cognitively impaired at baseline and 10 (29%) showed cognitive deterioration at follow-up. At baseline, compared to HC, MS patients showed widespread WM damage and GM atrophy, and decreased RS FC in some clusters of executive control (ECN) and working memory networks (WMN). At follow-up, annualized volume loss of caudate nucleus was significantly higher in MS patients with vs without cognitive deterioration (−1.2% vs −0.2%, p&lt;0.05). No significant between-group differences in lesion location, WM microstructural changes or GM atrophy were found. Compared to stable MS patients, worsened patients showed decreased RS FC in right hippocampus of right WMN and in right insula of default mode network. In the opposite comparison, increased RS FC in left insula of ECN was found. <h3>Conclusions:</h3> While cognitively-stable MS patients showed increased RS FC in left insula, possibly reflecting a compensatory mechanism, cognitive deterioration in MS patients was associated with decreased RS FC in several functional brain networks, with limited GM atrophy progression. Our study suggests that, in MS patients already characterized by substantial structural damage, cognitive deterioration might be secondary to functional network collapse. <b>Disclosure:</b> Dr. Azzimonti has nothing to disclose. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bristol Myers Squibb . Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi Genzyme. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Paola Valsasina has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for ACCMED. Elisabetta Pagani has nothing to disclose. Olga Marchesi has nothing to disclose. Dr. Tedone has nothing to disclose. Carmen Vizzino has nothing to disclose. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). Maria Assunta Rocca has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva. The institution of Maria Assunta Rocca has received research support from Italian Ministry of Health, MS Society of Canada and Fondazione Italiana Sclerosi Multipla.

Clinical value of cerebrospinal fluid neurofilament light chain in semantic dementia

BackgroundSemantic dementia (SD) is a neurodegenerative disorder characterised by progressive language problems falling within the clinicopathological spectrum of frontotemporal lobar degeneration (FTLD). The development of disease-modifying agents may be facilitated...

A longitudinal study of speech production in primary progressive aphasia and behavioral variant frontotemporal dementia

We examined longitudinal change in language expression during a semi-structured speech sample in 48 patients with primary progressive aphasia (PPA) or behavioral variant frontotemporal dementia (bvFTD) and related this to longitudinal neuroimaging of cortical thickness available in 25 of these patients. All patient groups declined significantly on measures of both speech fluency and grammar, although patients with nonfluent/agrammatic PPA (naPPA) declined to a greater extent than patients with the semantic variant, the logopenic variant, and bvFTD. These patient groups also declined on several neuropsychological measures, but there was no correlation between decline in speech expression and decline in neuropsychological performance. Longitudinal decline in grammaticality, assessed by the number of well-formed sentences produced, was associated with longitudinal progression of gray matter atrophy in left frontal operculum/insula and bilateral temporal cortex.

Longitudinal progression of grey matter atrophy in non-amnestic Alzheimer's disease.

Recent models of Alzheimer's disease progression propose that disease may be transmitted between brain areas either via local diffusion or long-distance transport via white matter fibre pathways. However, it is unclear whether such models are applicable in non-amnestic Alzheimer's disease, which is associated with domain-specific cognitive deficits and relatively spared episodic memory. To date, the anatomical progression of disease in non-amnestic patients remains understudied. We used longitudinal imaging to differentiate earlier atrophy and later disease spread in three non-amnestic variants, including logopenic-variant primary progressive aphasia (n = 25), posterior cortical atrophy (n = 20), and frontal-variant Alzheimer's disease (n = 12), as well as 17 amnestic Alzheimer's disease patients. Patients were compared to 37 matched controls. All patients had autopsy (n = 7) or CSF (n = 67) evidence of Alzheimer's disease pathology. We first assessed atrophy in suspected sites of disease origin, adjusting for age, sex, and severity of cognitive impairment; we then performed exploratory whole-brain analysis to investigate longitudinal disease spread both within and outside these regions. Additionally, we asked whether each phenotype exhibited more rapid change in its associated disease foci than other phenotypes. Finally, we investigated whether atrophy was related to structural brain connectivity. Each non-amnestic phenotype displayed unique patterns of initial atrophy and subsequent neocortical change that correlated with cognitive decline. Longitudinal atrophy included areas both proximal to and distant from sites of initial atrophy, suggesting heterogeneous mechanisms of disease spread. Moreover, regional rates of neocortical change differed by phenotype. Logopenic-variant patients exhibited greater initial atrophy and more rapid longitudinal change in left lateral temporal areas than other groups. Frontal-variant patients had pronounced atrophy in left insula and middle frontal gyrus, combined with more rapid atrophy of left insula than other non-amnestic patients. In the medial temporal lobes, non-amnestic patients had less atrophy at their initial scan than amnestic patients, but longitudinal rate of change did not differ between patient groups. Medial temporal sparing in non-amnestic Alzheimer's disease may thus be due in part to later onset of medial temporal degeneration than in amnestic patients rather than different rates of atrophy over time. Finally, the magnitude of longitudinal atrophy was predicted by structural connectivity, measured in terms of node degree; this result provides indirect support for the role of long-distance fibre pathways in the spread of neurodegenerative disease. 10.1093/brain/awz091_video1 awz091media1 6041544065001.

Dynamic gray matter volume changes in pediatric multiple sclerosis: A 3.5 year MRI study.

To assess, using MRI, the spatial patterns of gray matter (GM) atrophy in pediatric patients with multiple sclerosis (MS), their dynamic changes over time, and their clinical relevance. Sixty-eight pediatric patients with MS (30 with a clinical and MRI follow-up after 3.5 years) and 26 healthy controls (HC) underwent clinical and MRI evaluation. To overcome difficulties in obtaining longitudinal scans in pediatric HC, a group of 317 pediatric HC from an NIH-funded MRI Study of Normal Brain Development was used to estimate GM developmental trajectories. In pediatric patients with MS, deviations from normative GM volume values at the voxel level were assessed at baseline and during the follow-up, using linear mixed-effects models. Correlations between GM volume deviations and disability, IQ, and white matter (WM) lesion volumes (LV) were estimated. Pediatric patients with MS showed failures in GM development in several cortical and subcortical regions, as well as GM atrophy progression in most of these regions, which were only partially related to focal WM LV. Significant correlations were found between regional GM atrophy (particularly of deep GM regions) and disability, whereas higher IQ was associated with reduced deviations from age-expected GM volumes of specific GM regions at baseline and during the follow-up. Impaired GM maturation occurs in pediatric patients with MS, which is only partially driven by WM inflammation, suggesting that early neurodegenerative phenomena contribute to disability. High IQ, a measure of reserve, may offer protection by promoting remodeling of GM pruning in this young age.

Self-reported urinary impairment identifies 'fast progressors' in terms of neuronal loss in multiple system atrophy.

MSA is an adult-onset, sporadic, progressive parkinsonian syndrome characterised by the presence of akinesia, cerebellar dysfunction, autonomic failure and pyramidal signs. Annualized-whole-brain atrophy rate (a-WBAR) is an informative way to quantify disease progression. In this longitudinal work we investigate the correlations of a-WBAR with clinical scales for motor impairment, autonomic disability and cognitive decline in MSA and explore how atrophy progresses within the brain. Fourty-one MSA patients were studied using Structural Imaging Evaluation with Normalization of Atrophy (SIENA). SIENA is an MRI-based algorithm that quantifies brain tissue volume. Clinical parameters were explored using the 18-item Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale, the Hoehn and Yahr Scale, the Frontal Assessment Battery and the Natural History and Neuroprotection in Parkinson Plus Syndromes scale (sub-items for orthostatic and urinary functions). The mean (±SD) age was 60.4 years ± 7.7 and a-WBAR was 1.65% ± 0.9. Demographics and clinical ratings at the time of the first scan were non-significantly associated with a-WBAR. The only exception was the baseline urinary score with a weak but significant association (R2 = 0.15, p = 0.04). Progression of grey matter atrophy was detected in the left superior temporal gyrus, right middle frontal gyrus, right frontopolar region and midbrain. Urinary impairment at baseline may help to identify 'fast progressors' in terms of neuronal loss, particularly in the frontal and temporal lobes. Thus, urinary impairment should be recognized as a key target for disease modifying therapeutic interventions in MSA.

Effect of glatiramer acetate on cerebral grey matter pathology in patients with relapsing-remitting multiple sclerosis

IntroductionIn this two year longitudinal study we compare the progression of grey matter (GM) damage in MS patients treated with glatiramer acetate (GA) for relapsing-remitting multiple sclerosis (RRMS) respect to untreated patients. MethodsWe studied thirty-five treated with GA and thirty-five untreated RRMS subjects matched for age, gender, disease duration and EDSS. Each patient underwent neurological examination every 6 months and 3-Tesla MRI at study entry (T0), after 1 year (T1) and 2 years (T2). At T0, T1 and T2, the number of new cortical lesions (CLs) was assessed on double inversion recovery images. By using the longitudinal stream of FreeSurfer, the cortical thickness and volume changes of several cerebral structures were evaluated after 2 years. ResultsThe mean number of new CLs was significantly lower in GA group compared to untreated patients both at T1 (0.9 ± 1.0 vs 1.7 ± 1.0, p < 0.05) and at T2 (1.4 ± 1.3 vs 2.9 ± 1.8, p < 0.001). Volume loss of thalamus (−0.5% ± 0.2% vs. −1.1% ± 0.4%; p < 0.001), globus pallidus (−4.4% ± 3.1% vs. −8.2% ± 4.5%; p < 0.001), hippocampus (−0.7% ± 0.3% vs. −1.5% ± 0.5%; p < 0.001) and cerebellum (−0.5% ± 0.3% vs. −0.9% ± 0.4%; p < 0.001) was also lower in the GA group. A more pronounced cortical thinning was observed in cingulate (p = 0.04), cuneus and frontomarginal gyrus (p = 0.01 for both comparisons) of the untreated patients. ConclusionOur findings suggest that GA exerts its immunomodulatory action at the level of GM either reducing the accumulation of CLs and slowing down the GM atrophy progression. Despite a confirmation in a larger sample size is required, our results suggest a possible effect of GA on GM damage.

Serotonin Selective Reuptake Inhibitor Treatment Improves Cognition and Grey Matter Atrophy but not Amyloid Burden During Two-Year Follow-Up in Mild Cognitive Impairment and Alzheimer's Disease Patients with Depressive Symptoms.

Late-life depression, even when of subsyndromal severity, has shown strong associations with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Preclinical studies have suggested that serotonin selective reuptake inhibitors (SSRIs) can attenuate amyloidogenesis. Therefore, we aimed to investigate the effect of SSRI medication on amyloidosis and grey matter volume in subsyndromal depressed subjects with MCI and AD during an interval of two years. 256 cognitively affected subjects (225 MCI/ 31 AD) undergoing [18F]-AV45-PET and MRI at baseline and 2-year follow-up were selected from the ADNI database. Subjects with a positive depression item (DEP(+); n = 73) in the Neuropsychiatric Inventory Questionnaire were subdivided to those receiving SSRI medication (SSRI(+); n = 24) and those without SSRI treatment (SSRI(-); n = 49). Longitudinal cognition (Δ-ADAS), amyloid deposition rate (standardized uptake value, using white matter as reference region (SUVRWM), and changes in grey matter volume were compared using common covariates. Analyses were performed separately in all subjects and in the subgroup of amyloid-positive subjects. Cognitive performance in DEP(+)/SSRI(+) subjects (Δ-ADAS: -5.0%) showed less deterioration with 2-year follow-up when compared to DEP(+)/SSRI(-) subjects (Δ-ADAS: +18.6%, p < 0.05), independent of amyloid SUVRWM at baseline. With SSRI treatment, the progression of grey matter atrophy was reduced (-0.9% versus -2.7%, p < 0.05), notably in fronto-temporal cortex. A slight trend towards lower amyloid deposition rate was observed in DEP(+)/SSRI(+) subjects versus DEP(+)/SSRI(-). Despite the lack of effect to amyloid PET, SSRI medication distinctly rescued the declining cognitive performance in cognitively affected patients with depressive symptoms, and likewise attenuated grey matter atrophy.

Neocortical origin and progression of gray matter atrophy in nonamnestic Alzheimer's disease

Amnestic Alzheimer's disease (AD) is characterized by early atrophy of the hippocampus and medial temporal lobes before spreading to the neocortex. In contrast, nonamnestic Alzheimer's patients have relative sparing of the hippocampus, but the pattern in which the disease spreads is unclear. We examined spreading disease in nonamnestic AD using a novel magnetic resonance imaging–based analysis adapted from pathologic staging studies, applied here to cross-sectional imaging data. We selected 240 T1-weighted scans from 129 patients with pathology confirmed by autopsy or cerebrospinal fluid, and atrophy maps were computed relative to 238 scans from 115 elderly controls. For each phenotype, the frequency of atrophy in 116 brain regions was used to infer the anatomical origin of disease and its progression across 4 phases of atrophy. Results from the amnestic cohort were used to determine appropriate parameter settings for the phase assignment algorithm, based on correspondence to Braak pathology staging. Phase 1 regions, which represent the origin of disease, included the hippocampus for the amnestic group (comprising 33 scans); left lateral temporal lobe for logopenic-variant primary progressive aphasia (88 scans); occipitoparietal cortex for posterior cortical atrophy (51 scans); temporoparietal cortex for corticobasal syndrome (31 scans); and frontotemporal cortex for behavioral/dysexecutive variant AD (37 scans). In nonamnestic patients, atrophy spread to other neocortical areas in later phases, but the hippocampus exhibited only late-phase atrophy in posterior cortical atrophy and corticobasal syndrome. Region-specific phase values were also associated with regional measures of tau, beta amyloid, neuronal loss, and gliosis for the subset of patients (n = 17) with neuropathology findings; this comparison represented a first validation of the phase assignment algorithm. We subsequently assigned a phase to each patient scan based on the similarity of regional atrophy patterns with atrophy predicted for the corresponding phenotype at each phase. Scan-specific phases were correlated with disease duration as well as global and domain-specific cognition, supporting these phase values as global estimates of patients' disease progression. Logistic regression models based on spatial overlap with model-predicted atrophy patterns reliably discriminated nonamnestic phenotypes from each other and from amnestic AD. The frequency-based phase assignment algorithm used in the present study thus represents a promising approach for studying the neocortical origin and spread of disease in nonamnestic AD.

Progression of gray matter atrophy in seizure-free patients with temporal lobe epilepsy.

To investigate the presence and progression of gray matter (GM) reduction in seizure-free patients with temporal lobe epilepsy (TLE). We enrolled 39 consecutive TLE patients, seizure-free for at least 2 years--20 with magnetic resonance imaging (MRI) signs of hippocampal sclerosis (TLE-HS), 19 with normal MRI (TLE-NL), and 74 healthy controls. For longitudinal analysis, we included individuals who had a second MRI with minimum interval of 18 months: 21 patients (10 TLE-HS, 11 TLE-NL) and 11 controls. Three-dimensional (3D) T1 -weighted images acquired in 3 Tesla MRI were analyzed with voxel-based morphometry (VBM). The images of patients with right-sided interictal epileptogenic zone (EZ) were right-left flipped, as well as a comparable proportion of controls. Cross-sectional analysis: The patients' images from each group were compared to controls to investigate differences in GM volumes. Longitudinal analysis: The first and second images were compared in each group to look for decreased GM volume. Cross-sectional analysis: Patients with TLE-HS had diffuse GM atrophy, including hippocampus and parahippocampal gyrus, insula, frontal, and occipital lobes ipsilateral to EZ, bilateral thalamus and contralateral orbitofrontal gyrus, and caudate. In contrast, TLE-NL group did not present significant differences compared to controls. Longitudinal analysis: TLE-HS presented progressive GM reduction in ipsilateral insula and occipital lobe, contralateral motor area, and bilateral temporal and frontal lobes. TLE-NL had GM progression in ipsilateral hypothalamus and parietal lobe, contralateral cerebellum, and bilateral temporal lobe. Controls did not show changes in GM volume between MRIs. Diffuse extrahippocampal GM atrophy is present in seizure-free patients with TLE-HS. In addition, there is progressive GM atrophy in patients with and without HS. These results demonstrate that not only ongoing seizures are involved in the progression of GM atrophy. An underlying pathologic mechanism could be responsible for progressive brain volume loss in TLE patients even in seizure-free periods.

Following the Spreading of Brain Structural Changes in Alzheimer's Disease: A Longitudinal, Multimodal MRI Study.

Longitudinal MRI studies in Alzheimer's disease (AD) are one of the most reliable way to track brain changes along the course of the disease. To investigate the evolution of grey matter (GM) atrophy and white matter (WM) damage in AD patients, and to assess the relationships of MRI changes with baseline clinical and cognitive variables and their evolution over time. Clinical, neuropsychological, and MRI assessments (T1-weighted and diffusion tensor [DT]-MRI) were obtained from 14 patients with AD at baseline and after a 16 ± 3 month period. Lumbar puncture was obtained at study entry. At baseline, AD patients were compared to 37 controls. GM atrophy progression was assessed with tensor-based morphometry and GM volumes of interest, and WM damage progression using tract-based spatial statistics and tractography. At baseline, patients showed cortical atrophy in the medial temporal and parietal regions and a widespread pattern of WM damage involving the corpus callosum, cingulum, and temporo-occipital, parietal, and frontal WM tracts. During follow up, AD patients showed total GM atrophy, while total WM volume did not change. GM tissue loss was found in frontal, temporal, and parietal regions. In addition, AD patients showed a progression of WM microstructural damage to the corpus callosum, cingulum, fronto-parietal and temporo-occipital connections bilaterally. Patients with higher baseline cerebrospinal fluid total tau showed greater WM integrity loss at follow up. GM and WM changes over time did not correlate with each other nor with cognitive evolution. In AD, GM atrophy and WM tract damage are likely to progress, at least partially, independently. This study suggests that a multimodal imaging approach, which includes both T1-weighted and DT MR imaging, may provide additional markers to monitor disease progression.

Mapping the Progression of Atrophy in Early- and Late-Onset Alzheimer's Disease.

The term early-onset Alzheimer's disease (EOAD) identifies patients who meet criteria for AD, but show onset of symptoms before the age of 65. We map progression of gray matter atrophy in EOAD patients compared to late-onset AD (LOAD). T1-weighted MRI scans were obtained at diagnosis and one-year follow-up from 15 EOAD, 10 LOAD, and 38 age-matched controls. Voxel-based and tensor-based morphometry were used, respectively, to assess the baseline and progression of atrophy. At baseline, EOAD patients already showed a widespread atrophy in temporal, parietal, occipital, and frontal cortices. After one year, EOAD had atrophy progression in medial temporal and medial parietal cortices. At baseline, LOAD patients showed atrophy in the medial temporal regions only, and, after one year, an extensive pattern of atrophy progression in the same neocortical cortices of EOAD. Although atrophy mainly involved different lateral neocortical or medial temporal hubs at baseline, it eventually progressed along the same brain default-network regions in both groups. The cortical region showing a significant progression in both groups was the medial precuneus/posterior cingulate.

Ascending Progression of Grey Matter Atrophy in Parkinson’s Disease (P2.010)

Ascending Progression of Grey Matter Atrophy in Parkinson’s Disease (P2.010)

Temporal and spatial evolution of grey matter atrophy in primary progressive multiple sclerosis

Grey matter (GM) atrophy occurs early in primary progressive MS (PPMS), but it is unknown whether its progression involves different brain regions at different rates, as is seen in other neurodegenerative diseases. We aimed to investigate the temporal and regional evolution of GM volume loss over 5years and its relationship with disability progression in early PPMS.We studied 36 patients with PPMS within five years from onset and 19 age and gender-matched healthy controls with clinical and imaging assessments at study entry and yearly for 3years and then at 5years. Patients were scored on the expanded disability status scale (EDSS) and MS Functional Composite (MSFC) at each time-point. An unbiased longitudinal voxel-based morphometry approach, based on high-dimensional spatial alignment within-subject, was applied to the serial imaging data. The rate of local (voxel-wise) volume change per year was compared between groups and its relationship with clinical outcomes was assessed.Patients deteriorated significantly during the five years follow-up. Patients showed a greater decline of GM volume (p<0.05, FWE-corrected) bilaterally in the cingulate cortex, thalamus, putamen, precentral gyrus, insula and cerebellum when compared to healthy controls over five years, although the rate of volume loss varied across the brain, and was the fastest in the cingulate cortex. Significant (p<0.05, FWE-corrected) volume loss was detected in the left insula, left precuneus, and right cingulate cortex in patients at three years, as compared to baseline, whilst the bilateral putamen and the left superior temporal gyrus showed volume loss at five years. In patients, there was a relationship between a higher rate of volume loss in the bilateral cingulate cortex and greater clinical disability, as measured by the MSFC, at five years (Pearson's r=0.49, p=0.003).Longitudinal VBM demonstrated that the progression of GM atrophy in PPMS occurs at different rates in different regions across the brain. The involvement of the cingulate cortex occurs early in the disease course, continues at a steady rate throughout the follow-up period and is associated with patient outcome. These findings provide new insights into the characteristics of GM atrophy across the brain in MS, and have potential consequences for the selection of brain atrophy as an outcome measure in neuroprotective clinical trials.

Cued Recall Measure Predicts the Progression of Gray Matter Atrophy in Patients with Amnesic Mild Cognitive Impairment

Amnesic mild cognitive impairment (aMCI) is a heterogeneous syndrome that could be subdivided into distinct neuropsychological variants. To investigate relationships between the neuropsychological profile of memory impairment at baseline and the neuroimaging pattern of grey matter (GM) loss over 18 months, we performed a prospective volumetric brain study on 31 aMCI patients and 29 matched controls. All subjects were tested at baseline using a standardized neuropsychological battery, which included the Free and Cued Selective Recall Reminding Test (FCSRT) for the assessment of verbal declarative memory. Over 18 months, patients with impaired free recall but normal total recall (high index of cueing) on the FCSRT developed subcortical and frontal GM loss, while patients with impaired free and total recall (low index of cueing) developed GM atrophy within the left anterior and lateral temporal lobe. In summary, cued recall deficits are associated with a progression of atrophy that closely parallels the spatiotemporal distribution of neurofibrillary degeneration in early Alzheimer's disease (AD), indicating possible AD pathological changes.

CSF Biomarker and PIB-PET-Derived Beta-Amyloid Signature Predicts Metabolic, Gray Matter, and Cognitive Changes in Nondemented Subjects

Beta-amyloid (Aβ) is a histopathological hallmark of Alzheimer's disease dementia, but high levels of Aβ in the brain can also be found in a substantial proportion of nondemented subjects. Here we investigated which 2-year rate of brain and cognitive changes are present in nondemented subjects with high and low Aβ levels, as assessed with cerebrospinal fluid and molecular positron emission tomography (PET)-based biomarkers of Aβ. In subjects with mild cognitive impairment, increased brain Aβ levels were associated with significantly faster cognitive decline, progression of gray matter atrophy within temporal and parietal brain regions, and a trend for a faster decline in parietal Fludeoxyglucose (FDG)-PET metabolism. Changes in gray matter and FDG-PET mediated the association between Aβ and cognitive decline. In contrast, elderly cognitively healthy controls (HC) with high Aβ levels showed only a faster medial temporal lobe and precuneus volume decline compared with HC with low Aβ. In conclusion, the current results suggest not only that both functional and volumetric brain changes are associated with high Aβ years before the onset of dementia but also that HC with substantial Aβ levels show higher Aβ pathology resistance, lack other pathologies that condition neurotoxic effects of Aβ, or accumulated Aβ for a shorter time period.

CSF biomarker and PIB-PET–derived beta-amyloid signature predicts metabolic, grey matter and cognitive changes in nondemented subjects

Beta-amyloid (Ab) is a histopathological hallmark of Alzheimer’s disease dementia, but high levels of Ab in the brain can also be found in a substantial proportion of nondemented subjects. Here we investigated which 2-year rate of brain and cognitive changes are present in nondemented subjects with high and low Ab levels, as assessed with cerebrospinal fluid and molecular positron emission tomography (PET)--based biomarkers of Ab. In subjects with mild cognitive impairment, increased brain Ab levels were associated with significantly faster cognitive decline, progression of gray matter atrophy within temporal and parietal brain regions, and a trend for a faster decline in parietal Fludeoxyglucose (FDG)PET metabolism. Changes in gray matter and FDG-PET mediated the association between Ab and cognitive decline. In contrast, elderly cognitively healthy controls (HC) with high Ab levels showed only a faster medial temporal lobe and precuneus volume decline compared with HC with low Ab. In conclusion, the current results suggest not only that both functional and volumetric brain changes are associated with high Ab years before the onset of dementia but also that HC with substantial Ab levels show higher Ab pathology resistance, lack other pathologies that condition neurotoxic effects of Ab, or accumulated Ab for a shorter time period.

Longitudinal assessment of grey matter contraction in amyotrophic lateral sclerosis: A tensor based morphometry study

Our objective was to investigate grey matter (GM) contraction in patients with amyotrophic lateral sclerosis (ALS) using tensor based morphometry (TBM). Using a 1.5 Tesla scanner, T1-weighted MRI scans were obtained at baseline and at follow-up (mean interval, 9 months) from 16 ALS and 10 controls. Standard TBM procedures in Statistical Parametric Mapping (SPM2) were used for image processing and statistical analyses. The frontotemporal cortex and basal ganglia were considered areas of interest, based on pathological studies. Eight patients showed rapid clinical progression of ALS during the follow-up period. Compared to controls, all ALS patients showed progression of GM atrophy in left premotor cortex and right basal ganglia. Patients with rapidly progressing ALS showed GM atrophy changes in a larger motor cortical-subcortical area and in extramotor frontal regions compared to both controls and to non-rapidly progressing cases. Thus, TBM detected longitudinal atrophy changes in the motor network in ALS occurring over less than one year. The faster the clinical progression, the greater was the GM loss in motor and prefrontal areas. Further advances in tracking longitudinal changes in cortical and subcortical regions in ALS may provide an objective marker for monitoring disease progression, and the disease-modifying effect of potential treatments.