Regional Atrophy Research Articles

Sex differences in dementia risk and gray matter volume associated with hearing impairment

AbstractBackgroundHearing impairment is highly prevalent in older adults and was recently recognized as a modifiable risk factor for dementia. However, it is unknown if risk differs by sex and whether other issues associated with hearing, like social engagement or depression, impact these associations.MethodUK Biobank data was used to identify 165,471 participants (57±8 years, 55% female) without dementia who had a hearing assessment at baseline. Hearing was assessed using a speech reception threshold task, with scores grouped into good, insufficient, and poor severity levels based on previously derived cut‐offs (Dawes et al., 2014). Cox proportional‐hazard models were used to investigate sex differences in the association between hearing impairment and dementia risk. Sensitivity analyses were conducted to determine if social engagement or depressive symptoms mediated these associations. In a subset of participants with MRI data (n=2,322, 62±7 years, 52% female), linear mixed models stratified by sex were conducted to examine if development of impaired hearing from baseline was associated with gray matter atrophy in auditory and limbic regions.ResultInsufficient and poor hearing were associated with increased risk for dementia compared to good hearing (HR=1.76, 95%CI 1.43‐2.18 and HR=2.13, 95%CI 1.46‐3.11, respectively), but differed by sex. Women with insufficient (HR=1.73, 95% CI 1.25‐2.40) and poor (HR=3.08, 95%CI 1.80‐5.28) hearing had the greatest risk of dementia, whereas only men with insufficient hearing had increased risk (HR=1.78, 95%CI 1.34‐2.35; poor HR=1.60 95%CI 0.94‐2.73). These relationships were not mediated by social engagement or depression. In the MRI subset, women who developed or maintained impaired hearing had greater atrophy over 2.29 years in auditory pathway (e.g., primary auditory cortex, thalamus) and limbic (e.g., hippocampus, parahippocampus, amygdala) regions compared to women with good hearing. Men who developed impairment exhibited decreases over 2.30 years in a secondary auditory region only.ConclusionWomen with impaired hearing have greater risk of dementia compared to men. These sex differences are not mediated by social engagement or depression. Women with impaired hearing exhibit greater atrophy in auditory and limbic regions, while men do not. Sex differences in gray matter atrophy may explain why women with impaired hearing are at greater risk of dementia.

Volumetry of the Olfactory‐Related Structure as a New Biomarker of Individuals at Risk of Alzheimer Disease? Results From the CIMA‐Q Cohort

AbstractBackgroundHippocampal and entorhinal atrophies are used as gold‐standard biomarkers of the prodromal stage of Alzheimer's disease (AD). These atrophies are related to episodic memory deficits found in individuals with mild cognitive impairment (MCI). Olfactory deficits have been identified as clinical biomarkers of AD and found in individuals with MCI. Olfactory‐related structures such as the primary olfactory cortex (POC) were found to be atrophied in patients with AD. The aim of this study was to evaluate if the atrophy of hippocampal and entorhinal regions in individuals with MCI was accompanied with the atrophy of the POC regions.MethodUsing voxel‐based morphometry (VBM), we compared hippocampal, entorhinal and POC’s grey matter volume between a group of 93 participants with memory complaint (mean age: 72.15, SD: 4.74) and a group of 40 patients with MCI (mean age: 72.08, SD: 5.51) from the Consortium for the early identification of Alzheimer's disease–Quebec (CIMA‐Q). VBM analyses were done using the region of interest (ROI) approach with a specific mask combining masks for the hippocampus and the entorhinal cortex from the Neuromorphometrics atlas and a mask for POC structures from Northwestern University (Zhou et al., 2019).ResultVBM analysis reveals smaller bilateral grey matter volume within bilateral hippocampus (left peak: MNI ‐32 −10 ‐22, k = 24, T = 3.78, pFWE corr. = 0.033) (right peak: MNI 30 −8 ‐26, k = 111, T = 4.11, pFWE corr. = 0.016) and right POC (peak: MNI 27 0 ‐14, kE = 20, T = 3.71, pFWE corr. = 0.035) in MCI patients compared to the older participants with memory complaints.ConclusionThe neurodegeneration of olfactory‐related structures seems to occur in the prodromal stage of AD and atrophy of these structures might represent a way to improve the specificity of preclinical AD if combined with hippocampal atrophy.

Constructional Impairments and Their Neural Correlates in Nondemented Adults With Cerebral Autosomal-dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic small-vessel disease that is characterized by a wide range of neurologic and neuropsychological impairments. Constructional impairments have been reported in some cases but have never been assessed systematically. To evaluate constructional abilities and their cognitive and neural correlates in nondemented individuals with CADASIL. Thirty individuals with CADASIL who were not affected by clinically relevant cognitive deterioration and 30 healthy controls (HC) underwent an extensive cognitive assessment and paper-and-pencil visuoconstructional tasks in order to detect constructional impairments. Performance on the visuoconstructional tasks was correlated with the cognitive assessment scores and with quantitative indices of regional gray matter atrophy (obtained via FreeSurfer image analysis) and white matter involvement. The individuals with CADASIL achieved significantly lower scores on the cognitive assessment compared with the HC. Poor visuoconstructional abilities were observed in seven (23.3%) of the individuals with CADASIL when performing the copy drawing task and in nine (30%) when performing the Rey Complex Figure Test. Logistic regression revealed that visuoconstructional impairments were significantly associated with scores on the Frontal Assessment Battery and the Attentional Matrices Test. Morphometric results revealed that scores on the visuoconstructional tasks were related to gray matter atrophy of the left frontal lobe and right parietal lobe. Impairments on visuoconstructional tasks are quite common in individuals with CADASIL, even in the lack of clinically relevant cognitive deterioration, and are critically related to frontal and parietal atrophy.

Associations Between Mild Behavioral Impairment (MBI‐C) Affective Domains and Alzheimer’s Disease Neuroimaging Biomarkers in Older Adults

AbstractBackgroundPrevious work has shown that neuropsychiatric symptoms (NPS) such as depression in older adults are associated with cognitive decline and brain pathology related to Alzheimer’s disease (AD), but the constellation of NPS driving these associations is unclear. Traditionally, depressive symptoms have been assessed with the Geriatric Depression Scale (GDS), but newer NPS assessments, such as the Mild Behavioral Impairment‐Checklist (MBI‐C), have shown promise for identification of specific early features of symptomology. Here we examined the two affective domains of the MBI‐C in cognitively unimpaired older adults with moderate‐to‐severe depressive symptoms and non‐depressed older adults, and the association between these domains and neuroimaging biomarkers of AD.Method21 clinically normal (CN) older adults who met DSM5 criteria for major depression (MDD) (73.0±4.3 y.o., 62% female) and 25 non‐depressed older adults from related observational studies at our site (70.8±3.7 y.o., 64% female) underwent a clinical battery that included the GDS and MBI‐C self‐report domains focused on decreased interest‐motivation‐drive and increased dysphoria‐anhedonia‐anxiety (Range for each domain: 0–18). Participants completed neuroimaging consisting of MRI, amyloid‐(C11‐PiB)‐PET, and tau‐(F18‐FTP)‐PET. We focused analyses on neocortical amyloid and regional tau and atrophy in the amygdala and hippocampus. A Pearson correlation was used to assess the association between GDS total score and MBI‐C component scores. Linear regressions adjusted for age were used to investigate relationships between MBI‐C domains and ATN biomarkers.ResultGDS total score was correlated with both MBI‐C domains across all participants (Fig.1, p<0.01). In participants with MDD, the MBI‐C decreased interest‐motivation‐drive domain was associated with elevated FTP in the amygdala and hippocampus, while the increased dysphoria‐anhedonia‐anxiety domain was not significantly related to PET signal (Table 2, Fig.2). MBI‐C domains were not related to PET signal or atrophy in non‐depressed control participants.ConclusionPreliminary findings with the MBI‐C suggest that the decreased interest‐motivation‐drive domain may be associated with tau pathology in older adults with moderate‐to‐severe depression. Additional work needs to be done in a larger depressed cohort to further understand the associations between specific depressive phenotypes and AD pathology.

Regional cortical hypoperfusion and atrophy correlate with striatal dopaminergic loss in Parkinson's disease: a study using arterial spin labeling MR perfusion.

To investigate the relationship of the striatal dopamine transporter density to changes in the gray matter (GM) volume and cerebral perfusion in patients with Parkinson's disease (PD). We evaluated the regional cerebral blood flow (CBF) and GM volume, concurrently measured using arterial spin labeling and T1-weighted magnetic resonance imaging, respectively, as well as the striatal specific binding ratio (SBR) in 123I-N-ω-fluoropropyl-2β-carboxymethoxy-3β-(4-iodophenyl)nortropane (123I-FP-CIT) single-photon emission computed tomography in 30 non-demented patients with PD (15 men and 15 women; mean age, 67.2 ± 8.8years; mean Hoehn-Yahr stage, 2.2 ± 0.9). Voxel-wise regression analyses using statistical parametric mapping (SPM) were performed to explore the brain regions that showed correlations of the striatal SBR to the GM volume and CBF, respectively, with a height threshold of p < 0.0005 at the voxel level and p < 0.05 family-wise error-corrected at the cluster level. SPM analysis showed a significant positive correlation between the SBR and GM volume in the inferior frontal gyrus (IFG). Whereas, a positive correlation between the SBR and CBF was widely found in the frontotemporal and parietotemporal regions, including the IFG. Notably, the opercular part of the IFG showed significant correlations in both SPM analyses of the GM volume (r2 = 0.90, p < 0.0001) and CBF (r2 = 0.88, p < 0.0001). The voxel-wise analyses revealed the brain regions, mainly the IFG, that showed hypoperfusion and atrophy related to dopaminergic loss, which suggests that the progression of dopaminergic neurodegeneration leads to regional cortical dysfunction in PD.

Can hippocampal subfield measures supply information that could be used to improve the diagnosis of Alzheimer's disease?

The diagnosis of Alzheimer's disease (AD) needs to be improved. We investigated if hippocampal subfield volume measured by structural imaging, could supply information, so that the diagnosis of AD could be improved. In this study, subjects were classified based on clinical, neuropsychological, and amyloid positivity or negativity using PET scans. Data from 478 elderly Korean subjects grouped as cognitively unimpaired β-amyloid-negative (NC), cognitively unimpaired β-amyloid-positive (aAD), mild cognitively impaired β-amyloid-positive (pAD), mild cognitively impaired-specific variations not due to dementia β-amyloid-negative (CIND), severe cognitive impairment β-amyloid-positive (ADD+) and severe cognitive impairment β-amyloid-negative (ADD-) were used. NC and aAD groups did not show significant volume differences in any subfields. The CIND did not show significant volume differences when compared with either the NC or the aAD (except L-HATA). However, pAD showed significant volume differences in Sub, PrS, ML, Tail, GCMLDG, CA1, CA4, HATA, and CA3 when compared with the NC and aAD. The pAD group also showed significant differences in the hippocampal tail, CA1, CA4, molecular layer, granule cells/molecular layer/dentate gyrus, and CA3 when compared with the CIND group. The ADD- group had significantly larger volumes than the ADD+ group in the bilateral tail, SUB, PrS, and left ML. The results suggest that early amyloid depositions in cognitive normal stages are not accompanied by significant bilateral subfield volume atrophy. There might be intense and accelerated subfield volume atrophy in the later stages associated with the cognitive impairment in the pAD stage, which subsequently could drive the progression to AD dementia. Early subfield volume atrophy associated with the β-amyloid burden may be characterized by more symmetrical atrophy in CA regions than in other subfields. We conclude that the hippocampal subfield volumetric differences from structural imaging show promise for improving the diagnosis of Alzheimer's disease.

Intellectual enrichment and genetic modifiers of cognition and brain volume in Huntington's disease.

An important step towards the development of treatments for cognitive impairment in ageing and neurodegenerative diseases is to identify genetic and environmental modifiers of cognitive function and understand the mechanism by which they exert an effect. In Huntington's disease, the most common autosomal dominant dementia, a small number of studies have identified intellectual enrichment, i.e. a cognitively stimulating lifestyle and genetic polymorphisms as potential modifiers of cognitive function. The aim of our study was to further investigate the relationship and interaction between genetic factors and intellectual enrichment on cognitive function and brain atrophy in Huntington's disease. For this purpose, we analysed data from Track-HD, a multi-centre longitudinal study in Huntington's disease gene carriers and focused on the role of intellectual enrichment (estimated at baseline) and the genes FAN1, MSH3, BDNF, COMT and MAPT in predicting cognitive decline and brain atrophy. We found that carrying the 3a allele in the MSH3 gene had a positive effect on global cognitive function and brain atrophy in multiple cortical regions, such that 3a allele carriers had a slower rate of cognitive decline and atrophy compared with non-carriers, in agreement with its role in somatic instability. No other genetic predictor had a significant effect on cognitive function and the effect of MSH3 was independent of intellectual enrichment. Intellectual enrichment also had a positive effect on cognitive function; participants with higher intellectual enrichment, i.e. those who were better educated, had higher verbal intelligence and performed an occupation that was intellectually engaging, had better cognitive function overall, in agreement with previous studies in Huntington's disease and other dementias. We also found that intellectual enrichment interacted with the BDNF gene, such that the positive effect of intellectual enrichment was greater in Met66 allele carriers than non-carriers. A similar relationship was also identified for changes in whole brain and caudate volume; the positive effect of intellectual enrichment was greater for Met66 allele carriers, rather than for non-carriers. In summary, our study provides additional evidence for the beneficial role of intellectual enrichment and carrying the 3a allele in MSH3 in cognitive function in Huntington's disease and their effect on brain structure.

Identifying brain hierarchical structures associated with Alzheimer's disease using a regularized regression method with tree predictors.

Brain segmentation at different levels is generally represented as hierarchical trees. Brain regional atrophy at specific levels was found to be marginally associated with Alzheimer's disease outcomes. In this study, we propose an ℓ1 -type regularization for predictors that follow a hierarchical tree structure. Considering a tree as a directed acyclic graph, we interpret the model parameters from a path analysis perspective. Under this concept, the proposed penalty regulates the total effect of each predictor on the outcome. With regularity conditions, it is shown that under the proposed regularization, the estimator of the model coefficient is consistent in ℓ2 -norm and the model selection is also consistent. When applied to a brain sMRI dataset acquired from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the proposed approach identifies brain regions where atrophy in these regions demonstrates the declination in memory. With regularization on the total effects, the findings suggest that the impact of atrophy on memory deficits is localized from small brain regions, but at various levels of brain segmentation. Data used in preparation of this paper were obtained from the ADNIdatabase.

B Vitamin Supplementation Slows Cognitive Decline in Mild Cognitive Impairment Patients with Frontal Lobe Atrophy.

The effects of B vitamins on mild cognitive impairment (MCI) patients' cognition have been mixed, suggesting the existence of moderating factors. A post hoc analysis of a negative B vitamin trial was performed to examine the potential modulating effect of regional brain atrophy on the cognitive response to B vitamins in MCI patients. In the 24-month randomized trial, 279 MCI outpatients took 500μ#x03BC;g methylcobalamin and 400μ#x03BC;g folic acid once per day or placebo tablets once per day. Sixty-four aspirin users were excluded from analysis as aspirin use has been found to have significant negative interaction effects. Subjects were followed up at months 12 and 24. The primary cognitive outcome was clinical dementia rating scale sum of boxes (CDR_SOB). In a subgroup of 83 subjects, MRI brain scans were performed at baseline to estimate regional brain atrophy ratios. Among the trial subjects who had MRI data, B vitamin supplementation had no significant effect on CDR_SOB, despite having significant homocysteine lowering effects. The atrophy ratio of the left frontal lobe significantly moderated the effect of B vitamin supplementation on CDR_SOB, after adjusting for confounders, in that B vitamin supplementation was associated with lower CDR_SOB scores (i.e., better cognitive function) at the 24th month among those patients with above median atrophy ratios, but not among those with lower atrophy ratios, in the left frontal lobe. B vitamins may be more effective in slowing down cognitive decline in MCI patients with atrophy in the left frontal lobe.

Brain atrophy pattern in patients with mild cognitive impairment: MRI study.

We evaluated the accuracy of the quantitative and semiquantitative analysis in detecting regional atrophy patterns and differentiating mild cognitive impairment patients who remain stable (aMCI-S) from patients who develop Alzheimer’s disease (aMCI-AD) at clinical follow-up. Baseline magnetic resonance imaging was used for quantitative and semiquantitative analysis using visual rating scales. Visual rating scores were related to gray matter thicknesses or volume measures of some structures belonging to the same brain regions. Receiver operating characteristic (ROC) analysis was performed to assess measures’ accuracy in differentiating aMCI-S from aMCI-AD. Comparing aMCI-S and aMCI-AD patients, significant differences were found for specific rating scales, for cortical thickness belonging to the middle temporal lobe (MTL), anterior temporal (AT), and fronto-insular (FI) regions, for gray matter volumes belonging to MTL and AT regions. ROC curve analysis showed that middle temporal atrophy, AT, and FI visual scales showed better diagnostic accuracy than quantitative measures also when thickness measures were combined with hippocampal volumes. Semiquantitative evaluation, performed by trained observers, is a fast and reliable tool in differentiating, at the early stage of disease, aMCI patients that remain stable from those patients that may progress to AD since visual rating scales may be informative both about early hippocampal volume loss and cortical thickness reduction.

Effects of apolipoprotein E4 genotype on cerebro-cerebellar connectivity, brain atrophy, and cognition in patients with Alzheimer's disease

IntroductionWhile several studies have substantially revealed the influence of the apolipoprotein E4 genotype (APOE4) on the vulnerability of Alzheimer's disease (AD), there are still far fewer studies investigating whether and how APOE4, in the absence of the amyloid-β (Aβ), alters regional brain atrophy, cerebro-cerebellar connectivity and cognitive performance in AD patients. MethodsWe employed MRI and neuropsychological data from 234 old adults with AD dementia, including 143 APOE4-positive (with ε2/ε4, ε3/ε4, or ε4/ε4 alleles) and 91 APOE4-negative (with ε2/ε2, ε2/ε3 or ε3/ε3), to investigate the cerebro-cerebellar connectivity in three cerebro-cerebellar brain networks: default mode network, motor network and affective-limbic network. Amyloid PET images were used to evaluate individual Aβ burdens, later used as covariates. Regional volumetric and cortical thickness measures were quantified in both the cerebellum and the cerebrum using the cerebellum segmentation algorithm and Freesurfer5.3, respectively. ResultsOur corrected functional connectivity (FC) results showed that APOE4 carriers (APOE4+) had lower FC within the cerebro-cerebellar motor network. In addition, significant group differences in regional cortical thickness were observed in the left Crus I, the right VIIB, left superior frontal, and right middle temporal gyri. Group differences in regional brain volumes were observed in the left lobule V and right parstriangularis. Furthermore, multiple linear regression analysis indicated that APOE4+ AD patients show greater episodic memory impairment. ConclusionSince amyloid-β, age, education, and gender were included as confounds in the statistical models, our findings suggest that APOE4 independently contributes to brain atrophy, disrupted FC, and associated memory declines in AD patients.

Presenilin 1 gene mutations: a potential marker to help diagnose early onset Alzheimer’s disease

Alzheimer’s disease is a prevalent neurodegenerative disorder that affects millions of people worldwide with a substantial healthcare expenditure of almost $500 billion dollars. Alzheimer’s is primarily considered a disease of the aging population, with 95% of cases being diagnosed in patients over 65. Alzheimer’s in patients under 65 years of age are termed early onset Alzheimer’s disease (EOAD). The clinical presentation and disease mechanism of EOAD are quite distinct from typical Alzheimer’s. For example, EOAD patients often experience more rapid cognitive decline and have cortical region atrophy as opposed to temporal region atrophy. The atypical nature of EOAD frequently leads to delayed diagnosis and treatment. This delay is especially problematic for EOAD patients because they are at a stage of life with significant responsibilities such as maintaining their careers and families. This case study examines a previously healthy 32-year-old man that was mistakenly suspected of having frontotemporal dementia. Alzheimer’s was not considered as a correct diagnosis due to the atypical symptoms and weak family history for the disease. For these reasons, genetic analysis was not used to help make a diagnosis. The patient died at the age of 36 and autopsy revealed markers of Alzheimer’s including neuritic plaques and tau neurofibrillary tangles. Genetic analysis revealed no presenilin 1 (PSEN1) mutations which has been associated with EOAD. However, this patient may have had deletion mutations that could not be investigated due to the lack of frozen tissue for RNA analysis. This case illustrates the importance of genetic testing for EOAD diagnosis.

Linking the phenotype of SNCA Triplication with PET-MRI imaging pattern and alpha-synuclein CSF seeding

Lewy-body pathology with aggregation of abnormal conformations of the protein alpha-synuclein (α-Syn) represent the histopathological hallmarks of Parkinson’s disease (PD). Genetic prototypes such as PD due to mutations in the alpha-synuclein gene (SNCA) offer the opportunity to evaluate α-Syn-related profiles in patient-derived biomaterial. We identified a family with a SNCA triplication and assessed the index patient for CSF α-Syn seeding capacity and levels of total α-Syn along with other neurodegenerative CSF markers (Aβ1-42, total-Tau, phospho-Tau, NFL). As no published CSF data in patients with SNCA triplication are available, we descriptively compared his CSF profiles to those of sporadic PD patients and PD patients with GBA mutations as these are also specifically associated with prominent α-Syn pathology. Additionally, skin biopsies with staining for phospho-α-Syn were done. To assess cerebral glucose metabolism and brain atrophy combined positron emission tomography and magnetic resonance imaging ([18F]FDG-PET/MRI) was performed. Age at onset was 24 years and motor impairment was accompanied by prominent non-motor symptoms with early development of dementia, depression, REM sleep behavior disorder, hyposmia, and dysautonomia. Correspondingly, PET-MRI showed hypometabolism and atrophy in frontal, temporoparietal and occipital regions. CSF levels of total α-Syn were threefold higher and RT-QuIC showed remarkable α-Syn seeding activity in all kinetic categories in the SNCATriplication patient compared to patients with GBA mutations. Our results are consistent with findings that not only mutant forms but also overexpression of the wild-type α-Syn protein lead to PD and PD dementia and show a striking CSF α-Syn seeding profile, thus substantiating the role of RT-QuIC as a specific in vivo biomarker of α-Syn brain pathology.

Retraction Note: analysis of regional atrophy and prolong adaptive exclusive atlas to detect the alzheimers neuro disorder using medical images

Retraction Note: analysis of regional atrophy and prolong adaptive exclusive atlas to detect the alzheimers neuro disorder using medical images

Periventricular remyelination failure in multiple sclerosis: a substrate for neurodegeneration.

In multiple sclerosis, spontaneous remyelination is generally incomplete and heterogeneous across patients. A high heterogeneity in remyelination may also exist across lesions within the same individual, suggesting the presence of local factors interfering with myelin regeneration. In this study we explored in vivo the regional distribution of myelin repair and investigated its relationship with neurodegeneration. We first took advantage of the myelin binding property of the amyloid radiotracer 11C-PiB to conduct a longitudinal 11C-PiB PET study in an original cohort of 19 participants with a relapsing-remitting form of multiple sclerosis, followed-up over a period of 1-4 months. We then replicated our results on an independent cohort of 40 people with multiple sclerosis followed-up over 1 year with magnetization transfer imaging, an MRI metrics sensitive to myelin content. For each imaging method, voxel-wise maps of myelin content changes were generated according to modality-specific thresholds. We demonstrated a selective failure of remyelination in periventricular white matter lesions of people with multiple sclerosis in both cohorts. In both the original and the replication cohort, we estimated that the probability of demyelinated voxels to remyelinate over the follow-up increased significantly as a function of the distance from ventricular CSF. Enlarged choroid plexus, a recently discovered biomarker linked to neuroinflammation, was found to be associated with the periventricular failure of remyelination in the two cohorts (r = -0.79, P = 0.0018; r = -0.40, P = 0.045, respectively), suggesting a role of the brain-CSF barrier in affecting myelin repair in surrounding tissues. In both cohorts, the failure of remyelination in periventricular white matter lesions was associated with lower thalamic volume (r = 0.86, P < 0.0001; r = 0.33; P = 0.069, respectively), an imaging marker of neurodegeneration. Interestingly, we also showed an association between the periventricular failure of remyelination and regional cortical atrophy that was mediated by the number of cortex-derived tracts passing through periventricular white matter lesions, especially in patients at the relapsing-remitting stage. Our findings demonstrate that lesion proximity to ventricles is associated with a failure of myelin repair and support the hypothesis that a selective periventricular remyelination failure in combination with the large number of tracts connecting periventricular lesions with cortical areas is a key mechanism contributing to cortical damage in multiple sclerosis.

Neural correlates of episodic memory in adults with Down syndrome and Alzheimer’s disease

BackgroundAdults with Down syndrome are at an ultra-high risk of developing early-onset Alzheimer’s disease. Episodic memory deficits are one of the earliest signs of the disease, but their association with regional brain atrophy in the population with Down syndrome has not been explored. We aimed to investigate the neuroanatomical correlates of episodic memory in adults with Down syndrome and symptomatic Alzheimer’s disease.MethodsSingle-center, cross-sectional study. A total of 139 adults with Down syndrome (85 asymptomatic and 54 with symptomatic Alzheimer’s disease) were included in the study (mean age 43.6 ± 10.9 years, 46% female). Episodic memory was assessed using the modified Cued Recall Test. Immediate (trial 1 free immediate recall, trial 3 free immediate recall, total free immediate recall score, and total immediate score) and delayed scores (free delayed recall score and total delayed score) were examined. Cortical thickness from magnetic resonance imaging was determined with surface-based morphometry using the FreeSurfer 6.0 software package. The clusters of reduced cortical thickness were compared between symptomatic and asymptomatic participants to create a cortical atrophy map. Then, the correlation between cortical thickness and the modified Cued Recall Test subscores were separately assessed in symptomatic and asymptomatic subjects, controlling for age, sex, and severity of intellectual disability.ResultsCompared with asymptomatic participants, those with symptomatic Alzheimer’s disease showed a pattern of cortical atrophy in posterior parieto-temporo-occipital cortices. In symptomatic subjects, trial 1 immediate free recall significantly correlated with cortical atrophy in lateral prefrontal regions. Trial 3 free immediate recall and total free immediate recall were associated with the most widespread cortical atrophy. Total immediate score was related to posterior cortical atrophy, including lateral parietal and temporal cortex, posterior cingulate cortex, precuneus, and medial temporal lobe areas. Delayed memory scores were associated with cortical atrophy in temporoparietal and medial temporal lobe regions. No significant relationships were observed between episodic memory measures and cortical atrophy in asymptomatic subjects.ConclusionsDifferent episodic memory measures were associated with cortical atrophy in specific brain regions in adults with Down syndrome and Alzheimer’s disease. These results overlap with those described in sporadic Alzheimer’s disease and further support the similarities between Down syndrome-associated Alzheimer’s disease and that in the general population.

Considering hearing loss as a modifiable risk factor for dementia

ABSTRACT Introduction Accumulating evidence links hearing loss to impaired cognitive performance and increased risk for dementia. Hearing loss can lead to deafferentation-induced atrophy of frontotemporal brain regions and dysregulation of cognitive control networks from increased listening effort. Hearing loss is also associated with reduced social engagement, loneliness, and depression, which are independently associated with poor cognitive function. Areas Covered We summarize the evidence and postulated mechanisms linking hearing loss to dementia in older adults and synthesize the available literature demonstrating beneficial effects of hearing remediation on brain structure and function. Expert Opinion : Further research is needed to evaluate whether treatment of hearing loss may reduce risk of cognitive decline and improve neural consequences of hearing loss. Studies may investigate the pathologic mechanisms linking these late-life disorders and identify individuals vulnerable to dementia, and future clinical trials may evaluate whether hearing treatment may reduce the risk for dementia.

I'm looking through you: Mentalizing in frontotemporal dementia and progressive supranuclear palsy

Mentalizing and emotion recognition are impaired in behavioral variant frontotemporal dementia (bvFTD). It is not clear whether these abilities are also disturbed in other conditions with prominent frontal lobe involvement, such as progressive supranuclear palsy (PSP). Our aim was to investigate social cognition (facial emotion recognition, recognition of social norms violation and mentalizing) in bvFTD and PSP. The neural basis of these functions in PSP and bvFTD groups, by analysis of structural neuroimaging, were also investigated. Twenty-three bvFTD patients, 21 PSP patients and 23 healthy controls were included. All participants underwent 3T brain MRI and a full cognitive exam including the short version of Social and Emotional Assessment (Mini-SEA), which is composed of a facial emotion recognition test (FERT) and the faux pas test. Two components of the faux pas test were distinguished: a score assessing the recognition of social norms violation and a score assessing mentalizing. Compared to controls, bvFTD and PSP patients had significantly reduced scores in all tests of social cognition but did not differ on these measures. PSP and bvFTD had cerebral atrophy in critical regions for social cognition processes, when compared to controls. The cortical correlates of emotion recognition partially overlapped in bvFTD and PSP, with correlations retrieved within the frontal medial cortex, cingulate, insula and limbic structures. PSP and bvFTD patients also displayed similar patterns of brain correlations for the composite score of social norms, with a significant cluster in anterior temporal lobes. Mentalizing scores were associated with frontal and temporal poles bilaterally, in both bvFTD and PSP. These findings support previous observations that PSP patients exhibit impairment in complex cognitive abilities, such as mentalizing. Moreover, these data extend previous findings showing that PSP and bvFTD share key clinical, cognitive and neuroimaging features.

Distinct disease trajectories in frontotemporal dementia-motor neuron disease and behavioural variant frontotemporal dementia: A longitudinal study.

The heterogeneity of cognitive and behavioural disturbances in frontotemporal dementia-motor neuron disease (FTD-MND), and clinical differences between FTD-MND and FTD subtypes, have been illustrated cross-sectionally. This study aimed to examine the FTD-MND disease trajectory by comparing clinical features of FTD-MND and the behavioural variant FTD (bvFTD) longitudinally. Neuropsychological and disease severity assessments were conducted in a cohort of FTD-MND (baseline, n= 42; follow-up, n= 18) and bvFTD (baseline, n= 116; follow-up, n= 111) using a longitudinal, case-control design. Age-, sex-, and education-matched controls (n= 52) were recruited. Predictors of clinical progression were analyzed. Voxel-based morphometry analysis was undertaken to investigate the progression of brain atrophy. At baseline, FTD-MND was characterized by semantic and general cognition deficits, whereas bvFTD had greater behavioural disturbances. General cognition and language deteriorated in FTD-MND when followed longitudinally. Language deficits at baseline predicted cognitive deterioration and disease progression and correlated with progressive atrophy of language regions. Further deterioration in behaviour was evident in bvFTD over time. The rate of disease progression (i.e., general cognition, semantic association, and disease severity) was significantly faster in FTD-MND than in bvFTD. FTD-MND and bvFTD appear to have distinct disease trajectories, with more rapid progression in FTD-MND. Language impairments should be closely monitored in FTD-MND as potential predictors of cognitive deterioration and disease progression.

Detecting Primary Progressive Aphasia Atrophy Patterns: A Comparison of Visual Assessment and Quantitative Neuroimaging Techniques.

Background:There are now clinically available automated MRI analysis software programs that compare brain volumes of patients to a normative sample and provide z-score data for various brain regions. These programs have yet to be validated in primary progressive aphasia (PPA).Objective:To address this gap in the literature, we examined Neuroreader™ z-scores in PPA, relative to visual MRI assessment. We predicted that Neuroreader™ 1) would be more sensitive for detecting left > right atrophy in the cortical lobar regions in logopenic variant PPA clinical phenotype (lvPPA), and 2) would distinguish lvPPA (n = 11) from amnestic mild cognitive impairment (aMCI; n = 12).Methods:lvPPA or aMCI patients who underwent MRI with Neuroreader™ were included in this study. Two neuroradiologists rated 10 regions. Neuroreader™ lobar z-scores for those 10 regions, as well as a hippocampal asymmetry metric, were included in analyses.Results:Cohen’s Kappa coefficients were significant in 10 of the 28 computations (k = 0.351 to 0.593, p≤0.029). Neuroradiologists agreed 0% of the time that left asymmetry was present across regions. No significant differences emerged between aMCI and lvPPA in Neuroreader™ z-scores across left or right frontal, temporal, or parietal regions (ps > 0.10). There were significantly lower z-scores in the left compared to right for the hippocampus, as well as parietal, occipital, and temporal cortices in lvPPA.Conclusion:Overall, our results indicated moderate to low interrater reliability, and raters never agreed that left asymmetry was present. While lower z-scores in the left hemisphere regions emerged in lvPPA, Neuroreader™ failed to differentiate lvPPA from aMCI.