Gray Matter Volume Loss Research Articles

Disability in cerebellar ataxia syndromes is linked to cortical degeneration

ObjectiveWe aimed to relate clinical measures of disability in chronic cerebellar degeneration to structural whole-brain changes using voxel-based and surface-based morphometry (vbm and sbm). We were particularly interested in remote effects of cerebellar degeneration in the cerebral cortex.MethodsWe recruited 30 patients with cerebellar degeneration of different aetiologies (downbeat nystagmus syndrome, DBN n = 14, spinocerebellar ataxia, SCA n = 9, sporadic adult late-onset ataxia, SAOA n = 7). All patients were thoroughly characterised in the motor, cognitive, vestibular and ocular–motor domains. Vbm and sbm were used to evaluate structural differences between cerebellar degeneration patients and a group of healthy age- and gender-matched volunteers. Linear regression models were used to correlate functional measures of disease progression and postural stability with whole brain volumetry.ResultsPatients with SCA and SAOA showed widespread volume loss in the cerebellar hemispheres and less prominently in the vermis. Patients with DBN showed a distinct pattern of grey matter volume (GMV) loss that was restricted to the vestibular and ocular–motor representations in lobules IX, X and V–VII. Falls were associated with brainstem white matter volume. VBM and SBM linear regression models revealed associations between severity of ataxic symptoms, cognitive performance and preferred gait velocity. This included extra-cerebellar (sub-)cortical hubs of the motor and locomotion network (putamen, caudate, thalamus, primary motor cortex, prefrontal cortex) and multisensory areas involved in spatial navigation and cognition.ConclusionFunctional disability in multiple domains was associated with structural changes in the cerebral cortex.

Longitudinal changes in qualitative aspects of semantic fluency in presymptomatic and prodromal genetic frontotemporal dementia.

The semantic fluency test is one of the most widely used neuropsychological tests in dementia diagnosis. Research utilizing the qualitative, psycholinguistic information embedded in its output is currently underexplored in presymptomatic and prodromal genetic FTD. Presymptomatic MAPT (n = 20) and GRN (n = 43) mutation carriers, and controls (n = 55) underwent up to 6years of neuropsychological assessment, including the semantic fluency test. Ten mutation carriers became symptomatic (phenoconverters). Total score and five qualitative fluency measures (lexical frequency, age of acquisition, number of clusters, cluster size, number of switches) were calculated. We used multilevel linear regression modeling to investigate longitudinal decline. We assessed the co-correlation of the qualitative measures at each time point with principal component analysis. We explored associations with cognitive decline and grey matter atrophy using partial correlations, and investigated classification abilities using binary logistic regression. The interrater reliability of the qualitative measures was good (ICC = 0.75-0.90). There was strong co-correlation between lexical frequency and age of acquisition, and between clustering and switching. At least 4years pre-phenoconversion, GRN phenoconverters had fewer but larger clusters (p < 0.001), and fewer switches (p = 0.004), correlating with lower executive function (r = 0.87-0.98). Fewer switches was predictive of phenoconversion, correctly classifying 90.3%. Starting at least 4years pre-phenoconversion, MAPT phenoconverters demonstrated an increase in lexical frequency (p = 0.009) and a decline in age of acquisition (p = 0.034), correlating with lower semantic processing (r = 0.90). Smaller cluster size was predictive of phenoconversion, correctly classifying 89.3%. Increase in lexical frequency and decline in age of acquisition were associated with grey matter volume loss of predominantly temporal areas, while decline in the number of clusters, cluster size, and switches correlated with grey matter volume loss of predominantly frontal areas. Qualitative aspects of semantic fluency could give insight into the underlying mechanisms as to why the "traditional" total score declines in the different FTD mutations. However, the qualitative measures currently demonstrate more fluctuation than the total score, the measure that seems to most reliably deteriorate with time. Replication in a larger sample of FTD phenoconverters is warranted to identify if qualitative measures could be sensitive cognitive biomarkers to identify and track mutation carriers converting to the symptomatic stage of FTD.

Consensus Paper: Cerebellum and Ageing.

Given the key roles of the cerebellum in motor, cognitive, and affective operations and given the decline of brain functions with aging, cerebellar circuitry is attracting the attention of the scientific community. The cerebellum plays a key role in timing aspects of both motor and cognitive operations, including for complex tasks such as spatial navigation. Anatomically, the cerebellum is connected with the basal ganglia via disynaptic loops, and it receives inputs from nearly every region in the cerebral cortex. The current leading hypothesis is that the cerebellum builds internal models and facilitates automatic behaviors through multiple interactions with the cerebral cortex, basal ganglia and spinal cord. The cerebellum undergoes structural and functional changes with aging, being involved in mobility frailty and related cognitive impairment as observed in the physio-cognitive decline syndrome (PCDS) affecting older, functionally-preserved adults who show slowness and/or weakness. Reductions in cerebellar volume accompany aging and are at least correlated with cognitive decline. There is a strongly negative correlation between cerebellar volume and age in cross-sectional studies, often mirrored by a reduced performance in motor tasks. Still, predictive motor timing scores remain stable over various age groups despite marked cerebellar atrophy. The cerebello-frontal network could play a significant role in processing speed and impaired cerebellar function due to aging might be compensated by increasing frontal activity to optimize processing speed in the elderly. For cognitive operations, decreased functional connectivity of the default mode network (DMN) is correlated with lower performances. Neuroimaging studies highlight that the cerebellum might be involved in the cognitive decline occurring in Alzheimer's disease (AD), independently of contributions of the cerebral cortex. Grey matter volume loss in AD is distinct from that seen in normal aging, occurring initially in cerebellar posterior lobe regions, and is associated with neuronal, synaptic and beta-amyloid neuropathology. Regarding depression, structural imaging studies have identified a relationship between depressive symptoms and cerebellar gray matter volume. In particular, major depressive disorder (MDD) and higher depressive symptom burden are associated with smaller gray matter volumes in the total cerebellum as well as the posterior cerebellum, vermis, and posterior Crus I. From the genetic/epigenetic standpoint, prominent DNA methylation changes in the cerebellum with aging are both in the form of hypo- and hyper-methylation, and the presumably increased/decreased expression of certain genes might impact on motor coordination. Training influences motor skills and lifelong practice might contribute to structural maintenance of the cerebellum in old age, reducing loss of grey matter volume and therefore contributing to the maintenance of cerebellar reserve. Non-invasive cerebellar stimulation techniques are increasingly being applied to enhance cerebellar functions related to motor, cognitive, and affective operations. They might enhance cerebellar reserve in the elderly. In conclusion, macroscopic and microscopic changes occur in the cerebellum during the lifespan, with changes in structural and functional connectivity with both the cerebral cortex and basal ganglia. With the aging of the population and the impact of aging on quality of life, the panel of experts considers that there is a huge need to clarify how the effects of aging on the cerebellar circuitry modify specific motor, cognitive, and affective operations both in normal subjects and in brain disorders such as AD or MDD, with the goal of preventing symptoms or improving the motor, cognitive, and affective symptoms.

Depression in dementia with Lewy bodies: a critical update.

Depression with an estimated prevalence of 35% is a frequent manifestation of dementia with Lewy bodies (DLB), having negative effects on cognitive performance and life expectancy, yet the underlying neurobiology is poorly understood and most likely heterogeneous. Depressive symptoms in DLB can occur during the clinical course and, together with apathy, is a common prodromal neuropsychiatric symptom of this neurocognitive disorder in the group of Lewy body synucleinopathies. There are no essential differences in the frequency of depression in DLB and Parkinson disease-dementia (PDD), while its severity is up to twice as high as in Alzheimer disease (AD). Depression in DLB that is frequently underdiagnosed and undertreated, has been related to a variety of pathogenic mechanisms associated with the basic neurodegenerative process, in particular dysfunctions of neurotransmitter systems (decreased monoaminergic/serotonergic, noradrenergic and dopaminergic metabolism), α-synuclein pathology, synaptic zinc dysregulation, proteasome inhibition, gray matter volume loss in prefrontal and temporal areas as well as dysfunction of neuronal circuits with decreased functional connectivity of specific brain networks. Pharmacotherapy should avoid tricyclic antidepressants (anticholinergic adverse effects), second-generation antidepressants being a better choice, while modified electroconvulsive therapy, transcranial magnetic stimulation therapy and deep brain stimulation may be effective for pharmacotherapy-resistant cases. Since compared to depression in other dementias like Alzheimer disease and other parkinsonian syndromes, our knowledge of its molecular basis is limited, and further studies to elucidate the heterogeneous pathogenesis of depression in DLB are warranted.

Biomarkers for predicting disease course in Sanfilippo syndrome: An urgent unmet need in childhood-onset dementia.

Sanfilippo syndrome (MPS III) is an autosomal recessive inherited disorder causing dementia in children, following an essentially normal early developmental period. First symptoms typically include delayed language development, hyperactivity and/or insomnia from 2 years of age, followed by unremitting and overt loss of previously acquired skills. There are no approved treatments, and the median age of death is 18 years. Treatments under clinical trial demonstrate therapeutic benefit when applied pre-symptomatically in children diagnosed early through known familial inheritance risk. Newborn screening for Sanfilippo syndrome would enable pre-symptomatic diagnosis and optimal therapeutic benefit, however, many fold more patients with Sanfilippo syndrome are expected to be identified in the population than present with childhood dementia. Therefore, the capacity to stratify which Sanfilippo infants will need treatment in toddlerhood is necessary. While diagnostic methods have been developed, and continue to be refined, currently there are no tools or laboratory-based biomarkers available to provide pre-symptomatic prognosis. There is also a lack of progression and neurocognitive response-to-treatment biomarkers; disease stage and rate of progression are currently determined by age at symptom onset, loss of cerebral grey matter volume by magnetic resonance imaging and developmental quotient score for age. Robust blood-based biomarkers are an urgent unmet need. In this review, we discuss the development of biomarker assays for Sanfilippo based on the neuropathological pathways known to change leading into symptom onset and progression, and their performance as biomarkers in other neurodegenerative diseases. We propose that neural-derived exosomes extracted from blood may provide an ideal liquid biopsy to detect reductions in synaptic protein availability, and mitochondrial function. Furthermore, given the prominent role of neuroinflammation in symptom expression, glial fibrillary acidic protein detection in plasma/serum, alongside measurement of active brain atrophy by neurofilament light chain, warrant increased investigation for prognostic, progression and neurocognitive response-to-treatment biomarker potential in Sanfilippo syndrome and potentially other childhood dementias.

Measuring olfactory‐related brain region volume loss in MCI and AD using structural MRI

AbstractBackgroundAlzheimer disease (AD) is a chronic disorder that affects millions of individuals worldwide. Olfactory dysfunction is a common symptom of several neurological disorders including AD. Olfactory dysfunction can be an early alteration heralding the presence of AD. Studying the pattern of alterations in olfaction‐related brain regions might help detection of neurodegenerative diseases at an earlier stage. Objectives of this study are to assess the volume of olfactory areas associated with odour processing in healthy elderly, MCI and AD populations using structural MRI scans. To test whether there are any differences in the volume of olfactory related regions between patients and healthy controls. To determine whether there is an effect of sex on olfactory‐related brain regions’ volume loss.MethodNeurologically healthy participants aged 66‐85 (n = 95), MCI aged 58‐86 (n = 81) and mild probable AD aged 55‐88 (n = 37) participants were recruited. T1‐ weighted MRI scans acquired at 1.5T were processed using SPM12. Smoothed images were used to extract the volume of olfactory cortex, hippocampus, parahippocampus, amygdala, orbitofrontal cortex and entorhinal cortex.ResultOne‐way ANOVA analyses showed a significant reduction in all olfaction‐related brain regions (p≤0.0001). Post‐hoc multiple comparison tests showed a significant reduction in volume in the AD group in all olfaction‐related brain regions. In the MCI group, a significantly smaller volume than the healthy controls was found in four of the selected olfactory‐related brain regions (namely, hippocampus, parahippocampus, amygdala and entorhinal cortex) for the total and left volume in the female group only. Additionally in the female MCI, the volume of the right entorhinal cortex however, was also significantly smaller than that of the control group. When adjusting for MMSE, however, between group differences in all olfaction‐related brain regions were no longer significant.ConclusionThese preliminary data show a significant reduction in grey matter volume in all olfaction‐related brain regions. Grey matter volume loss in these regions appears to be a good proxy of disease severity.

Dietary pattern and brain structure among young adults

AbstractBackgroundEnvironmental factors, such as nutrition, influence brain physiology and health throughout the life course. While research has focused on the extremes of the age spectrum, less is known about early adulthood, yet a critical period for the consolidation of brain maturation and the building of adult behaviors. Nutrition may impact late maturational changes in the post‐adolescent brain and contribute to the degree of brain reserve that minimizes the risk to develop dementia. We took advantage of a large sample of young adults to evaluate the association of dietary behavior with brain structure characteristics.MethodThis cross‐sectional study included 1721 university students (18‐35 years‐old) from the French i‐Share cohort, who underwent brain MRI. A 12‐item online Food Frequency Questionnaire was used to evaluate consumption in major food groups and to determine dietary patterns from Principal Component Analysis (PCA). Multivariable‐adjusted linear regressions were used to estimate the association of PCA scores with brain structure (cortical thickness and surface area, grey matter and white matter volumes, diffusion parameters).ResultThe first PCA component (explained variance, 17%) contrasted a healthy diet (higher fruit and vegetable intakes) to a poor diet (higher fast food, sugary drink and snack consumptions). In models adjusted for total intracranial volume, age, sex, physical activity, body mass index, alcohol and tobacco consumptions, a higher PCA score (reflecting healthier diet) was associated with lower total gray matter volume (β for 1 point score = –0.17 [95%CI, –0.31; –0.03] cm3), in various brain areas (Figure). Healthy diet was also associated with lower global white matter volume (β = –0.18 [–0.32; –0.03] cm3). No association was found with diffusion tensor imaging, and neurite orientation dispersion and density imaging metrics in the white matter.ConclusionIn this large sample of young adults, healthier diet was associated with lower brain volumes, independent of multiple potential confounders. Gray matter volume loss during post‐adolescence is a marker of brain maturation; thus, environmental factors emphasizing this loss may benefit maturation. Our results raise the hypothesis that a healthy diet may favor and a poor diet may hamper brain maturation; an assumption which deserves further investigation in other populations.

Voxel-Based and Surface-Based Morphometry Analysis in Patients with Pathologically Confirmed Argyrophilic Grain Disease and Alzheimer's Disease.

Due to clinicoradiological similarities, including amnestic cognitive impairment and limbic atrophy, differentiation of argyrophilic grain disease (AGD) from Alzheimer's disease (AD) is often challenging. Minimally invasive biomarkers, especially magnetic resonance imaging (MRI), are valuable in routine clinical practice. Although it is necessary to explore radiological clues, morphometry analyses using new automated analytical methods, including whole-brain voxel-based morphometry (VBM) and surface-based morphometry (SBM), have not been sufficiently investigated in patients with pathologically confirmed AGD and AD. This study aimed to determine the volumetric differences in VBM and SBM analyses between patients with pathologically confirmed AGD and AD. Eight patients with pathologically confirmed AGD with a lower Braak neurofibrillary tangle stage (<III), 11 patients with pathologically confirmed AD without comorbid AGD, and 10 healthy controls (HC) were investigated. Gray matter volumetric changes in VBM and cortical thickness changes in SBM were compared between the two patient groups (i.e., AGD and AD) and the HC group. In contrast to widespread gray matter volume or cortical thickness loss in the bilateral limbic, temporoparietal, and frontal lobes of the AD group, these were limited, especially in the limbic lobes, in the AGD group, compared with that of the HC group. Although bilateral posterior dominant gray matter volume loss was identified in the AD group compared with the AGD group on VBM, there was no significant cluster between these patient groups on SBM. VBM and SBM analyses both showed a different distribution of atrophic changes between AGD and AD.

Ocrelizumab-treated patients with relapsing multiple sclerosis show volume loss rates similar to healthy aging

Background: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by two major and interconnected hallmarks: inflammation and progressive neurodegeneration. Objective: The aim of this work was to compare neurodegenerative processes, in the form of global and regional brain volume loss rates, in healthy controls (HCs) and in patients with relapsing MS (RMS) treated with ocrelizumab, which suppresses acute inflammation. Methods: Whole brain, white matter, cortical gray matter, thalamic, and cerebellar volume loss rates were assessed in 44 HCs that were part of a substudy in the OPERA II randomized controlled trial (NCT01412333) and 59 patients with RMS enrolled in the same substudy as well as age- and sex-matched patients in OPERA I (NCT01247324) and II. Volume loss rates were computed using random coefficients models over a period of 2 years. Results: Ocrelizumab-treated patients showed global and regional brain volume loss rates that were approaching that of HCs. Conclusion: These findings are consistent with an important role of inflammation on overall tissue loss and the role of ocrelizumab in reducing this phenomenon.

Protective Effect of APOE-ɛ2 on Cortical Thickness and Volume in a Cerebrovascular Registry (S36.010)

<h3>Objective:</h3> To compare cortical thickness across APOE genotypes, and to assess the potential protective effect of APOE2 on brain cortical thinning and grey matter volume. <h3>Background:</h3> Studies have shown a negative association of APOE-ɛ4 allele with regional cortical thickness and volume. The role of the APOE-ɛ3 allele has been considered neutral in several studies. The protective role of APOE-ɛ2 against cortical thinning has not been well established. <h3>Design/Methods:</h3> From a biomarker cerebrovascular registry, 187 individuals with APOE testing and MRI brain from 2010 to 2020 were included. APOE genotype tested were ɛ2ɛ2, ɛ2ɛ3, ɛ2ɛ4, ɛ3ɛ3, ɛ3ɛ4, ɛ4ɛ4, stratified to APOE-ɛ2 carrier or APOE-ɛ2 non-carrier. Cortical thickness, cortical volume and gray matter volume were estimated on T1-weighted images using FreeSurfer. Measures of brain atrophy were compared across APOE genotypes, and between ɛ2 vs non-ɛ2 allele carriers. Mini-Mental Status Examination (MMSE) were compared between groups. <h3>Results:</h3> In our cohort (n=187), mean age was 60±16 years and 55.4% were female. Of the APOE genotypes, 18.5% were APOE-ɛ2 carriers (ɛ2ɛ2 3, ɛ2ɛ3 33), 81.5% were APOE-ɛ2 non-carriers (ɛ3ɛ3 114, ɛ3ɛ4 43, ɛ4ɛ4 2). Compared to ɛ2 non-carriers, ɛ2 carriers were less likely to have hypertension, diabetes, coronary artery disease, and had higher LDL (p&lt;0.05). Across APOE genotypes, cortex was thickest in ɛ2ɛ2 (2.35 mm) and thinnest in ɛ4ɛ4 (1.92 mm) (p = 0.0137). APOE-ɛ2 carriers had significantly thicker cortex (2.13 mm vs 1.96 mm, p=0.001), larger cortical volume (313.26 cm3 vs 266.09 cm3, p=&lt;0.001) and grey matter volumes (459.93 cm3 vs 411.01 cm3, p=0.001), compared to ɛ2 non-carriers. There was no difference in MMSE between ɛ2carriers vs non-carriers (24.4 vs 25.6, p=0.316). <h3>Conclusions:</h3> Our study suggested a protective effect of APOE-ɛ2 allele against cortical thinning and grey matter volume loss. Future study may examine the effect of APOE-ɛ2 on brain resilience after brain injury such as stroke. <b>Disclosure:</b> Mr. Youssef has nothing to disclose. Mr. Mateti has nothing to disclose. Erik Middlebrooks has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Varian Medical Systems Inc. Erik Middlebrooks has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Boston Scientific Corp. The institution of Erik Middlebrooks has received research support from Varian Medical Systems Inc. The institution of Dr. Taner has received research support from NIH. The institution of Dr. Meschia has received research support from NINDS. The institution of Dr. Meschia has received research support from NINDS. Dr. Lin has nothing to disclose.

Altered nucleus accumbens functional connectivity precedes apathy in Parkinson's disease.

Work in animal and human neuroscience has identified neural regions forming a network involved in the production of motivated, goal-directed behaviour. In particular, the nucleus accumbens and anterior cingulate cortex are recognized as key network nodes underlying decisions of whether to exert effort for reward, to drive behaviour. Previous work has convincingly shown that this cognitive mechanism, known as effort-based decision making, is altered in people with Parkinson's disease with a syndrome of reduced goal-directed behaviour-apathy. Building on this work, we investigated whether the neural regions implementing effort-based decision-making were associated with apathy in Parkinson's disease, and more importantly, whether changes to these regions were evident prior to apathy development. We performed a large, multimodal neuroimaging analysis in a cohort of people with Parkinson's disease (n = 199) with and without apathy at baseline. All participants had ∼2-year follow-up apathy scores, enabling examination of brain structure and function specifically in those with normal motivation who converted to apathy by ∼2-year follow-up. In addition, of the people with normal motivation, a subset (n = 56) had follow-up neuroimaging data, allowing for examination of the 'rate of change' in key nodes over time in those who did, and did not, convert to apathy. Healthy control (n = 54) data were also included to aid interpretation of findings. Functional connectivity between the nucleus accumbens and dorsal anterior cingulate cortex was higher in people with normal motivation who later converted to apathy compared to those who did not, whereas no structural differences were evident between these groups. In contrast, grey matter volume in these regions was reduced in the group with existing apathy. Furthermore, of those with normal motivation who had undergone longitudinal neuroimaging, converters to apathy showed a higher rate of change in grey matter volume within the nucleus accumbens. Overall, we show that changes in functional connectivity between nucleus accumbens and anterior cingulate cortex precedes apathy in people with Parkinson's disease, with conversion to apathy associated with higher rate of grey matter volume loss in nucleus accumbens, despite no baseline differences. These findings significantly add to an accumulating body of transdiagnostic evidence that apathy arises from disruption to key nodes within a network in which normal goal-directed behaviour is instantiated, and raise the possibility of identifying those at risk for developing apathy before overt motivational deficits have arisen.

Associative memory is more strongly predicted by age-related differences in the prefrontal cortex than medial temporal lobes

It is well established that episodic memory declines with age and one of the primary explanations for this decline is an age-related impairment in the ability to form new associations. At a neural level, both the medial temporal lobe (MTL) and lateral prefrontal cortex (PFC) are thought to be critical for associative memory, and grey matter volume loss in these regions has been associated with age-related declines in episodic memory. While some recent work has compared the relative contributions of grey matter volume in MTL and PFC regions to item and associative memory, studies investigating the unique and shared contributions of age-related differences in the MTL and PFC to memory differences are still rare. In this study, we use a lifespan approach to examine the relationship between grey matter volume within substructures of the MTL and PFC on the one hand and item and associative memory on the other. To this end, we used data from over 300 healthy individuals uniformly spread across the adult lifespan from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) and tested the multivariate relationship between grey matter volumes and item/associative memory scores using canonical correlation analysis. We show that structures of the PFC alone predict memory performance better than either structures of the MTL alone or PFC and MTL combined. Moreover, our results also indicate that grey matter volume in the inferior frontal gyrus - pars opercularis, superior frontal gyrus, and middle frontal gyrus relates most strongly to memory (particularly associative memory, which loaded higher than item memory) and this effect persists when controlling for age and education. Finally, we also show that the relationship between frontal grey matter volume and memory is not moderated by age or sex. Taken together, these findings emphasize the critical role of the frontal lobes, and the control processes they subserve, in determining the effects of age on associative memory.

Significant Acceleration of Regional Brain Aging and Atrophy After Mild Traumatic Brain Injury.

Brain regions' rates of age-related volumetric change after traumatic brain injury (TBI) are unknown. Here, we quantify these rates cross-sectionally in 113 persons with recent mild TBI (mTBI), whom we compare against 3 418 healthy controls (HCs). Regional gray matter (GM) volumes were extracted from magnetic resonance images. Linear regression yielded regional brain ages and the annualized average rates of regional GM volume loss. These results were compared across groups after accounting for sex and intracranial volume. In HCs, the steepest rates of volume loss were recorded in the nucleus accumbens, amygdala, and lateral orbital sulcus. In mTBI, approximately 80% of GM structures had significantly steeper rates of annual volume loss than in HCs. The largest group differences involved the short gyri of the insula and both the long gyrus and central sulcus of the insula. No significant sex differences were found in the mTBI group, regional brain ages being the oldest in prefrontal and temporal structures. Thus, mTBI involves significantly steeper regional GM loss rates than in HCs, reflecting older-than-expected regional brain ages.

Perturbed iron biology in the prefrontal cortex of people with schizophrenia

Despite loss of grey matter volume and emergence of distinct cognitive deficits in young adults diagnosed with schizophrenia, current treatments for schizophrenia do not target disruptions in late maturational reshaping of the prefrontal cortex. Iron, the most abundant transition metal in the brain, is essential to brain development and function, but in excess, it can impair major neurotransmission systems and lead to lipid peroxidation, neuroinflammation and accelerated aging. However, analysis of cortical iron biology in schizophrenia has not been reported in modern literature. Using a combination of inductively coupled plasma-mass spectrometry and western blots, we quantified iron and its major-storage protein, ferritin, in post-mortem prefrontal cortex specimens obtained from three independent, well-characterised brain tissue resources. Compared to matched controls (n = 85), among schizophrenia cases (n = 86) we found elevated tissue iron, unlikely to be confounded by demographic and lifestyle variables, by duration, dose and type of antipsychotic medications used or by copper and zinc levels. We further observed a loss of physiologic age-dependent iron accumulation among people with schizophrenia, in that the iron level among cases was already high in young adulthood. Ferritin, which stores iron in a redox-inactive form, was paradoxically decreased in individuals with the disorder. Such iron-ferritin uncoupling could alter free, chemically reactive, tissue iron in key reasoning and planning areas of the young-adult schizophrenia cortex. Using a prediction model based on iron and ferritin, our data provide a pathophysiologic link between perturbed cortical iron biology and schizophrenia and indicate that achievement of optimal cortical iron homeostasis could offer a new therapeutic target.

Visceral and Subcutaneous Abdominal Fat Predict Brain Volume Loss at Midlife in 10,001 Individuals.

Abdominal fat is increasingly linked to brain health. A total of 10,001 healthy participants were scanned on 1.5T MRI with a short whole-body MR imaging protocol. Deep learning with FastSurfer segmented 96 brain regions. Separate models segmented visceral and subcutaneous abdominal fat. Regression analyses of abdominal fat types and normalized brain volumes were evaluated, controlling for age and sex. Logistic regression models determined the risk of brain total gray and white matter volume loss from the highest quartile of visceral fat and lowest quartile of these brain volumes. This cohort had an average age of 52.9 ± 13.1 years with 52.8% men and 47.2% women. Segmented visceral abdominal fat predicted lower volumes in multiple regions including: total gray matter volume (r = -.44, p<.001), total white matter volume (r =-.41, p<.001), hippocampus (r = -.39, p< .001), frontal cortex (r = -.42, p<.001), temporal lobes (r = -.44, p<.001), parietal lobes (r = -.39, p<.001), occipital lobes (r =-.37, p<.001). Women showed lower brain volumes than men related to increased visceral fat. Visceral fat predicted increased risk for lower total gray matter (age 20-39: OR = 5.9; age 40-59, OR = 5.4; 60-80, OR = 5.1) and low white matter volume: (age 20-39: OR = 3.78; age 40-59, OR = 4.4; 60-80, OR = 5.1). Higher subcutaneous fat is related to brain volume loss. Elevated visceral and subcutaneous fat predicted lower brain volumes and may represent novel modifiable factors in determining brain health.

Postoperative delirium is associated with grey matter brain volume loss.

Delirium is associated with long-term cognitive dysfunction and with increased brain atrophy. However, it is unclear whether these problems result from or predisposes to delirium. We aimed to investigate preoperative to postoperative brain changes, as well as the role of delirium in these changes over time. We investigated the effects of surgery and postoperative delirium with brain MRIs made before and 3 months after major elective surgery in 299 elderly patients, and an MRI with a 3 months follow-up MRI in 48 non-surgical control participants. To study the effects of surgery and delirium, we compared brain volumes, white matter hyperintensities and brain infarcts between baseline and follow-up MRIs, using multiple regression analyses adjusting for possible confounders. Within the patients group, 37 persons (12%) developed postoperative delirium. Surgical patients showed a greater decrease in grey matter volume than non-surgical control participants [linear regression: B (95% confidence interval) = -0.65% of intracranial volume (-1.01 to -0.29, P < 0.005)]. Within the surgery group, delirium was associated with a greater decrease in grey matter volume [B (95% confidence interval): -0.44% of intracranial volume (-0.82 to -0.06, P = 0.02)]. Furthermore, within the patients, delirium was associated with a non-significantly increased risk of a new postoperative brain infarct [logistic regression: odds ratio (95% confidence interval): 2.8 (0.7-11.1), P = 0.14]. Our study was the first to investigate the association between delirium and preoperative to postoperative brain volume changes, suggesting that delirium is associated with increased progression of grey matter volume loss.

The APOE4 effect: structural brain differences in Alzheimer's disease according to the age at symptom onset.

How the APOE genotype can differentially affect cortical and subcortical memory structures in biomarker-confirmed early-onset (EOAD) and late-onset (LOAD) Alzheimer's disease (AD) was assessed. Eighty-seven cerebrospinal fluid (CSF) biomarker-confirmed AD patients were classified according to their APOE genotype and age at onset. 28 were EOAD APOE4 carriers (+EOAD), 21 EOAD APOE4 non-carriers (-EOAD), 23 LOAD APOE4 carriers (+LOAD) and 15 LOAD APOE4 non-carriers (-LOAD). Grey matter (GM) volume differences were analyzed using voxel-based morphometry in Papez circuit regions. Multiple regression analyses were performed to determine the relation between GM volume loss and cognition. Significantly more mammillary body atrophy in +EOAD compared to -EOAD is reported. The medial temporal and posterior cingulate cortex showed less GM in +LOAD compared to -LOAD. Medial temporal GM volume loss was also found in +EOAD compared to -LOAD. With an exception for +EOAD, medial temporal GM was strongly associated with episodic memory in the three groups, whilst posterior cingulate cortex GM volume was more related with visuospatial abilities. Visuospatial abilities and episodic memory were also associated with the anterior thalamic nucleus in -LOAD. Our results show that the APOE genotype has a significant effect on GM integrity as a function of age of disease onset. Specifically, whilst LOAD APOE4 genotype is mostly associated with increased medial temporal and parietal atrophy compared to -LOAD, for EOAD APOE4 might have a more specific effect on subcortical (mammillary body) structures. The findings suggest that APOE genotype needs to be taken into account when classifying patients by age at onset.

The fluid biomarker landscape in genetic FTD

AbstractBackgroundThere is an increasing need for the use of fluid biomarkers in clinical management and future therapeutic trials of patients with genetic FTD.MethodSeveral fluid biomarkers have been investigated in the largest longitudinal cohort of patients with genetic FTD (GENFI; n &gt; 1000) associated with mutations in the progranulin (GRN), MAPtau and C9orf72 gene. Concentration changes in neurofilament light and neurofilament high protein (NfL and pNfH), neuronal pentraxin (NPTX2), glial fibrillary acidic protein (GFAP), dipeptides, complement factors and miRNAs have been correlated with disease onset and progression, disease severity and grey matter volume loss in pre‐ and symptomatic carriers. Sequences of biomarker abnormalities were analyzed using discriminative event‐based modelling (DEBM).ResultA number of promising fluid biomarkers have been identified in all or in specific genetic subtypes of FTD, with a specific sequence of biomarker changes over time from pre‐ to symptomatic stage. The next step will bet he development of a multi‐modal prediction tool at individual level, which may improve patient stratification and track the efficacy of therapeutic interventions.ConclusionMajor scientific achievements have been made in fluid biomarker studies of the largest cohort of genetic FTD (GENFI).

Tau accumulation and degeneration differ across functional networks in atypical Alzheimer's disease phenotypes

AbstractBackgroundRecent models of Alzheimer's disease (AD) posit that pathogenic tau propagates through interconnected structural networks, suggesting amnestic and non‐amnestic AD (aAD &amp; naAD) phenotypes could reflect differential involvement of functional networks. We tested this hypothesis by contrasting longitudinal grey matter (GM) atrophy and tau accumulation across AD clinical phenotypes in 7 canonical functional networks.MethodsWe analyzed longitudinal 3‐Tesla T1‐weighted MRI from 122 patients [aAD=49; logopenic primary progressive aphasia (lvPPA)=31; posterior cortical atrophy (PCA)=23; behavioral/dysexecutive AD (bvAD)=6; corticobasal syndrome (CBS)=6; mixed naAD=4] with autopsy or CSF evidence of AD pathology and 91 cognitively normal controls (Table 1). Thirty‐one patients (aAD=9; lvPPA=7; PCA=9; bvAD=2; CBS=3; naAD=1) had longitudinal flortaucipir PET (FTP‐PET) data. We computed baseline values and annualized change for GM volume and FTP‐PET standardized uptake value ratios (SUVRs) in the 100‐label, 7‐network parcellation of Schaefer et al. (2018). Linear mixed effects models (α=0.05, corrected) adjusting for MMSE assessed group differences in atrophy and tau accumulation.ResultsAll groups exhibited significant baseline and longitudinal atrophy vs. controls in multiple networks (Figs. 1‐2). Differences in longitudinal atrophy rate (Fig. 2) were observed in the dorsal attention network [PCA&gt;lvPPA, t(371)=3.1, p&lt;0.04], salience network [PCA&gt;aAD, t(371)=3.1, p&lt;0.04], and limbic network [CBS&gt;aAD, t(371)=3.3, p&lt;0.02; CBS&gt;bvAD, t(371)=3.7, p&lt;0.006]. PCA patients exhibited FTP‐PET SUVR increases in all networks (all p&lt;0.02), while aAD patients displayed increases in all networks except visual and limbic (all others p&lt;0.0001). LvPPA patients exhibited net SUVR increases only in the somatomotor network [t(97)=3.5, p&lt;0.001]. At baseline, lvPPA patients had left &gt; right atrophy in all networks [all t&gt;3.7, p&lt;0.0002]; right &gt; left atrophy was observed in the visual network for PCA and CBS; the salience network for PCA and bvAD; and in the dorsal attention, frontoparietal control, and default mode networks for bvAD [all t&gt;3.0, p&lt;0.03]. In longitudinal analyses, no hemispheric differences were found in rates of GM volume loss or FTP‐PET change.ConclusionAD clinical variants exhibited GM atrophy and tau accumulation in partially overlapping networks. Investigating early‐stage disease will be crucial for assessing whether disease spread through canonical functional networks can explain anatomic differences in aAD and naAD phenotypes.

Structural Cerebellar Abnormalities and Parkinsonism in Patients with 22q11.2 Deletion Syndrome.

Background: The phenotypic expression of 22q11.2 deletion syndrome (22q11.2DS) is variable and may include cognitive, psychiatric, and neurological manifestations, e.g., parkinsonism. We investigated brain structural alterations in patients with 22q11.2DS with and without parkinsonism (Park+ and Park-) in comparison with healthy controls (HCs). Methods: Voxel-based morphometry was performed on 3D T1-weighted MR images to explore gray matter volume (GMV) differences between 29 patients (15 Park+, 14 Park-), selected from a consecutive series of 56 adults diagnosed with 22q11.2DS, and 24 HCs. One-way ANOVA and multiple linear regression analyses were performed to explore group differences in GMV and correlations between clinical scores (MDS-UPDR-III and MoCA scores) and structural alterations. Results: Significant between-group differences in GMV were found in the cerebellum, specifically in bilateral lobes VIII and left Crus II, as well as in the left superior occipital gyrus. Although both Park+ and Park- patients showed GMV decrements in these regions with respect to HCs, GMV loss in the right lobe VIII and left Crus II was greater in Park+ than in Park- patients. GMV loss did not correlate with clinical scores. Conclusions: Patients with 22q11.2DS and parkinsonism manifest specific cerebellar volume alterations, supporting the hypothesis of neurodegenerative processes in specific cerebellar regions as a putative pathophysiological mechanism responsible for parkinsonism in patients with 22q11.2DS.