Left Temporal Lobe Research Articles

Extensive Shrinkage and Long-term Stable Disease in a Teenage Female Patient With High-grade Glioma Treated With Temozolomide and Radiation in Combination With Oral Recombinant Methioninase and a Low-methionine Diet.

Gliomas are the most common and recalcitrant malignant primary brain tumors. All cancer types are addicted to methionine, which is a fundamental and general hallmark of cancer known as the Hoffman effect. Particularly glioma cells exhibit methionine addiction. Because of methionine addiction, [11C]-methionine positron emission tomography (MET-PET) is widely used for glioma imaging in clinical practice, which can monitor the extent of methionine addiction. Methionine restriction including recombinant methioninase (rMETase) and a low-methionine diet, has shown high efficacy in preclinical models of gliomas, especially in combination with chemotherapy. The aim of the present study was to determine the efficacy of methionine restriction with oral rMETase (o-rMETase) and a low-methionine diet, combined with radiation and temozolomide (TMZ), on a teenage female patient with high-grade glioma. A 16-year-old girl was diagnosed with high-grade glioma. Magnetic resonance imaging (MRI) showed a left temporal-lobe tumor with compression to the left lateral ventricle and narrowing of sulci in the left temporal lobe. After the start of methionine restriction with o-rMETase and a low-methionine diet, along with TMZ combined with radiotherapy, the tumor size shrunk at least 60%, with improvement in the left lateral ventricle and sulci. The patient's condition remains stable for 19 months without severe adverse effects. Methionine restriction consisting of o-rMETase and a low-methionine diet, in combination with radiation and TMZ as first-line chemotherapy, were highly effective in a patient with high-grade glioma.

Speech and lexico-semantic errors during direct cortical stimulation mapping of the language-dominant hemisphere: effects of object and action naming.

In this retrospective study, the authors aimed to establish the stereotactically defined probability distribution for speech (i.e., anarthria, speech arrest) and lexico-semantic errors (i.e., anomia) through direct cortical stimulation (DCS) by using two tasks: action naming and object naming. They also analyzed the patterns of interindividual variability in the localization of the language sites involved, and investigated whether any patient or lesion location factors were associated with greater variability. Eighty-one Italian-speaking patients who underwent awake surgery between 2010 and 2021 for low- and high-grade gliomas in eloquent areas of the language-dominant hemisphere were entered in the analyses. The intraoperative DCS protocol included automatic speech tasks, object naming, and action naming. The position of the tags, as depicted on the intraoperative video or photograph, was transposed into Montreal Neurological Institute space. Subsequently, a 2D scatterplot and cluster analysis were performed. Associations between various clinical and radiological characteristics and the quantity of positive stimulated sites were determined by univariate analyses using binary logistic regression. Associated variables (p < 0.2) were included in stepwise multivariate logistic regression with backward elimination (p < 0.05). A total of 1380 cortical sites were stimulated, with a positive response in 511 cases (37%). Most anarthric errors were triggered when stimulating the left precentral gyrus, and most speech arrest errors were elicited when stimulating the left posterior inferior frontal gyrus. Anomias were found in the left inferior frontal gyrus and in the posterior part of the left temporal lobe for object naming. DCS to the left dorsal premotor cortex elicited anomic errors for action naming. Anomias were also elicited during DCS to the left posterior temporal lobe, with both object and action naming. The distribution of speech and lexico-semantic errors is in line with the current literature. The action-naming results are new and mostly involve the dorsal premotor cortex. These findings stress the importance of maximizing the use of different language tasks during surgery, because even when looking for the same type of errors, different tasks may be better suited to map specific brain regions. DCS with action and object naming identifies more positive sites than object naming alone.

Examining the relationship between anxiety and regional brain volumes in the National Alzheimer's Coordinating Center uniform, imaging, and biomarker datasets

Anxiety has been associated with a greater risk of Alzheimer's disease (AD). Existing research has identified structural differences in regional brain tissue in participants with anxiety, but results have been inconsistent. We sought to determine the association between anxiety and regional brain volumes, and the moderation effect of APOE ε4. Using data from participants in the National Alzheimer's Coordinating Center (NACC) Uniform Data Set, with complete imaging (MRI) and biomarker data (n = 1533), multiple linear regression estimated the adjusted effect of anxiety on 30 structural MRI regions. The moderation effect of APOE ε4 on the relation between structural MRI regions and anxiety was assessed as was the moderation effect of cognitive status. False discovery rate was used to adjust for multiple comparisons. After controlling for intracranial volume, age, sex, years of education, race, Hispanic ethnicity, and cognitive status, seven MRI regions demonstrated lower volumes among participants with anxiety: total cerebrum gray matter volume, right hippocampus volume, hippocampal volume (total), right and left frontal lobe cortical gray matter volume, and right and total temporal lobe cortical gray matter volume. Findings suggest that anxiety is associated with significant atrophy in multiple brain regions, with corresponding ventricular enlargement. Future research should investigate if anxiety-related changes to brain morphology contribute to greater AD risk.

Distinct parallel activation and interaction between dorsal and ventral pathways during phonological and semantic processing: A cTBS-fMRI study.

Successful visual word recognition requires the integration of phonological and semantic information, which is supported by the dorsal and ventral pathways in the brain. However, the functional specialization or interaction of these pathways during phonological and semantic processing remains unclear. Previous research has been limited by its dependence on correlational functional magnetic resonance imaging (fMRI) results or causal validation using patient populations, which are susceptible to confounds such as plasticity and lesion characteristics. To address this, the present study employed continuous theta-burst stimulation combined with fMRI in a within-subject design to assess rapid adaptation in regional activity and functional connectivity of the dorsal and ventral pathways during phonological and semantic tasks. This assessment followed the precise inhibition of the left inferior parietal lobule and anterior temporal lobe in the dorsal and ventral pathways, respectively. Our results reveal that both the dorsal and ventral pathways were activated during phonological and semantic processing, while the adaptation activation and interactive network were modulated by the task type and inhibited region. The two pathways exhibited interconnectivity in phonological processing, and disruption of either pathway led to rapid adaptation across both pathways. In contrast, only the ventral pathway exhibited connectivity in semantic processing, and disruption of this pathway alone resulted in adaptive effects primarily in the ventral pathway. These findings provide essential evidence supporting the interactive theory, phonological information processing in particular, potentially providing meaningful implications for clinical populations.

A case of autoimmune encephalitis in a patient with a solitary intracranial plasmacytoma.

A 65-year-old woman presented with fever and abnormal behavior. Magnetic resonance imaging showed swelling of the left medial temporal lobe and an intracranial extra-axial occipital tumor. While her neurological symptoms improved after the administration of corticosteroid therapy under the suspicion of autoimmune encephalitis, the occipital tumor unexpectedly shrank, and the diagnosis of a solitary plasmacytoma was confirmed by biopsy. Additional examinations revealed elevated anti-glutamate receptor antibodies in the cerebrospinal fluid. The patient was diagnosed with autoimmune encephalitis concurrent with an intracranial solitary plasmacytoma. Central nervous system involvement can be considered a neurological complication in patients with a solitary plasmacytoma.

An exploration of anomia rehabilitation in drug-resistant temporal lobe epilepsy

Around 40% of patients who undergo a left temporal lobe epilepsy (LTLE) surgery suffer from anomia (word-finding difficulties), a condition that negatively impacts quality of life. Despite these observations, language rehabilitation is still understudied in LTLE. We assessed the effect of a four-week rehabilitation on four drug-resistant LTLE patients after their surgery. The anomia rehabilitation was based on cognitive descriptions of word finding deficits in LTLE. Its primary ingredients were psycholinguistic tasks and a psychoeducation approach to help patients cope with daily communication issues. We repeatedly assessed naming skills for trained and untrained words, before and during the therapy using an A-B design with follow-up and replication. Subjective anomia complaint and standardized language assessments were also collected. We demonstrated the effectiveness of the rehabilitation program for trained words despite the persistence of seizures. Furthermore, encouraging results were observed for untrained items. Variable changes in anomia complaint were observed. One patient who conducted the protocol as self-rehabilitation responded similarly to the others, despite the different manner of intervention. These results open promising avenues for helping epileptic patients suffering from anomia. For example, this post-operative program could easily be adapted to be conducted preoperatively.

Verbal episodic memory in children undergoing temporal lobe epilepsy surgery: a one-year follow-up study.

Verbal episodic memory (VEM) is often unimpaired in children with focal epilepsy undergoing left temporal lobe resections, unlike what we might expect in the adult brain. The latter findings suggest that epileptiform activity in early life disrupts memory system lateralization, leading to the development of bilateral memory representation. The present study aims to analyze whether the laterality of epilepsy is a major predictor for post-operative VEM prognosis in pediatric temporal lobe epilepsy (TLE) surgery. This research also pretends to provide evidence about the relationship of VEM performance with other relevant demographical and clinical factors such as sex, age at onset of seizures, age at surgery and duration of epilepsy, as well as to study the impact of presurgical VEM performance on postsurgical outcomes. Pre-operative and one-year follow-up post-operative word-list recall scores from 25 children who underwent TLE surgery (left-sided, n = 11; right-sided, n = 14) were extracted from the Hospital Sant Joan de Deu database and were retrospectively analyzed. No significant presurgical intergroup differences were found when comparing VEM scores by laterality of epilepsy (p > 0.5). Looking at the left TLE group, a high negative correlation was found between the onset age and the pre-operative long-term free recall score (rho = -0.72, p = 0.01). No significant pre- to post-operative intragroup changes were found regarding VEM performance, regardless of epilepsy laterality (left TLE group, p > 0.56; right TLE group, p > 0.12). The laterality of epilepsy does not show to be a significant factor in and of itself regarding presurgical VEM outcome and its prognosis one year after surgery, thus supporting the bilateral memory representation hypothesis. Furthermore, a younger age at onset of seizures seems to be related with a better pre-operative VEM performance, likely due to a more efficient reorganization of memory system induced by a greater brain plasticity at lower ages; however, this relationship has been only reported for the left-sided epilepsies in our sample.

The Diagnostic Challenge of Distinguishing Temporal Lobe Encephaloceles from Sphenoid Sinus Mucoceles

Introduction: Temporal lobe encephaloceles are rare malformations defined as brain parenchyma herniation through a skull base structural defect into adjacent structure such as sphenoid sinus, while sphenoid sinus mucoceles are expansive cystic lesions caused by mucus buildup and thinning of the sinus wall, mostly involving the frontal and ethmoid sinus. Both illnesses may present similar clinical symptoms, such as neurological symptoms, nasal and ophthalmologic symptoms. However, misdiagnosis of temporal lobe encephaloceles can have significant clinical implications, as the best treatment plans vary depending on the disease. Case report: A 27-year-old healthy man who presented with seizure and loss of consciousness in public gave a history of head trauma 13 years back. Upon physical examination, the patient had normal cranial nerve function, and no cerebellar or meningitis signs. Rigid nasoendoscopy showed unremarkable findings. A computed tomography scan revealed an expanded left sphenoid sinus likely mucocele with a left temporal lobe encephalomalacia. Further investigations with brain magnetic resonance imaging (MRI) discovered temporal lobe encephalocele and transcranial repair of sphenoid encephalocele was arranged. Conclusion: Imaging results interpreted incorrectly may result in significant clinical ramifications. Distinguishing between both diseases with a complete investigation including MRI scan is crucial for appropriate management and treatment planning.

Prosopagnosia: face blindness and its association with neurological disorders.

Loss of facial recognition or prosopagnosia has been well-recognized for over a century. It has been categorized as developmental or acquired depending on whether the onset is in early childhood or beyond, and acquired cases can have degenerative or non-degenerative aetiologies. Prosopagnosia has been linked to involvement of the fusiform gyri, mainly in the right hemisphere. The literature on prosopagnosia comprises case reports and small case series. We aim to assess demographic, clinical and imaging characteristics and neurological and neuropathological disorders associated with a diagnosis of prosopagnosia in a large cohort. Patients were categorized as developmental versus acquired; those with acquired prosopagnosia were further subdivided into degenerative versus non-degenerative, based on neurological aetiology. We assessed regional involvement on [18F] fluorodeoxyglucose-PET and MRI of the right and left frontal, temporal, parietal and occipital lobes. The Intake and Referral Center at the Mayo Clinic identified 487 patients with possible prosopagnosia, of which 336 met study criteria for probable or definite prosopagnosia. Ten patients, 80.0% male, had developmental prosopagnosia including one with Niemann-Pick type C and another with a forkhead box G1 gene mutation. Of the 326 with acquired prosopagnosia, 235 (72.1%) were categorized as degenerative, 91 (27.9%) as non-degenerative. The most common degenerative diagnoses were posterior cortical atrophy, primary prosopagnosia syndrome, Alzheimer's disease dementia and semantic dementia, with each diagnosis accounting for >10% of this group. The most common non-degenerative diagnoses were infarcts (ischaemic and haemorrhagic), epilepsy-related and primary brain tumours, each accounting for >10%. We identified a group of patients with non-degenerative transient prosopagnosia in which facial recognition loss improved or resolved over time. These patients had migraine-related prosopagnosia, posterior reversible encephalopathy syndrome, delirium, hypoxic encephalopathy and ischaemic infarcts. On [18F] fluorodeoxyglucose-PET, the temporal lobes proved to be the most frequently affected regions in 117 patients with degenerative prosopagnosia, while in 82 patients with non-degenerative prosopagnosia, MRI revealed the right temporal and right occipital lobes as most affected by a focal lesion. The most common pathological findings in those with degenerative prosopagnosia were frontotemporal lobar degeneration with hippocampal sclerosis and mixed Alzheimer's and Lewy body disease pathology. In this large case series of patients diagnosed with prosopagnosia, we observed that facial recognition loss occurs across a wide range of acquired degenerative and non-degenerative neurological disorders, most commonly in males with developmental prosopagnosia. The right temporal and occipital lobes, and connecting fusiform gyrus, are key areas. Multiple different pathologies cause degenerative prosopagnosia.

KRM–II–81 suppresses epileptifom activity across the neural network of cortical tissue from a patient with pharmacoresistant epilepsy

A clinical case of a 19-year-old male patient with pharmacoresistant seizures occurring following parieto-occipital tumor-resection at age 6 is described. Seizure surgery work-up included prolonged video EEG monitoring and head CT without contrast. Seizure focus was localized to the left temporal lobe, and we felt that the patient was an excellent candidate for seizure surgery. The patient underwent a left frontotemporal craniotomy for removal of the seizure focus with intraoperative electrocorticography (ECoG) conducted pre and post resection. ECoG recordings pre- and post-resection confirmed resolution of seizure generation. Imaging obtained immediately postoperatively showed complete resection of the residual tumor with no evidence of recurrence in follow-ups. A year after the surgery the patient is seizure-free but remains on seizure medication. With the patient's consent the excised epileptogenic tissue was used for ex-vivo research studies. The microelectrode recordings confirmed epileptiform activity in the excised tissue incubated in excitatory artificial cerebrospinal fluid. The epileptiform activity in the epileptogenic tissue was suppressed by addition of KRM–II–81, a novel α2/3 subtype preferring GABAA receptor (GABAAR) potentiator with previously demonstrated antiepileptic efficacy in multiple animal models of epilepsy and with reduced potential for CNS side-effects compared to classical benzodiazepine GABAAR potentiators. These findings support the proposition that KRM–II–81 might reduce seizure burden in pharmacoresistant patients.

10018-COT-4 COMPARATIVE VOLUMETRIC ANALYSES FOLLOWING BEVACIZUMAB THERAPY FOR A PATIENT WITH CO- INCIDENCE OF GLIOBLASTOMA, MENINGIOM

Abstract BACKGROUND Given that glioblastoma, meningioma and dural arteriovenous fistura (dAVF) represent angiogenic disease mainly caused by high expression of vascular endothelial growth factor (VEGF), bevacizumab is expected to be effective for these diseases. We experienced a patient with co-incidence of these 3 diseases was given neoadjuvant bevacizumab which provided a volume reduction of glioblastoma with improvement of clinical symptoms. CASE REPORT An eighty five year-old man has suffered from aphasia and dementia. Brain MRI showed a ring enhanced intraaxial tumor with perifocal edema in left temporal lobe, a dural-attached extraaxial tumor in the left sphenoid ridge and dAVF at left transverse-sigmoid sinus. Due to elderly with poor general condition, he was treated by administrate bevacizumab rather than the resection to confirm histological diagnosis. Three days after the administration, he began to walk and speech. RESULTS For comparison of the reactivity to bevacizumab among these three diseases, we calculated the volumetric quantitative assessment of glioblastoma and meningioma by the contrast-enhanced MRI and made a qualitative assesment for the dAVF by digital subtraction angiography (DSA) and MRA with comparison between before and afterbevacizumab administration. The volume reduction rates 1 and 5 months later after bevacizumab administration in glioblastoma and in meningioma were 0.34% and 94.5%, 13.7%, 6.8%, respectively. The volume reduction rate of glioblastoma was significantly larger than of Mg. The DSA showed the dAVF did not change even though bevacizumab therapy. DISCUSSION As previously reported, the VEGF concentration in the glioblastoma was significantly higher than that in other types of tumors including meningioma. In dAVF, other angiogenic factors would be produced in addition to VEGF. CONCLUSIONS Based on these evidences and the current rare case with co-incidence of glioblastoma, meningioma, and dAVF, it suggested that the effectiveness of bevacizumab therapy would be depend on the expression level of the VEGF concentration.

10037-SPE-3 APPROACH TO SAFE AND RELIABLE BRAIN TUMOR SURGERY APPLYING INTRAOPERATIVE GAMMA OSCILLATION REGULARITY ANALYSIS

Abstract In primary brain tumors, the complexity of Electroencephalogram (EEG) has been reported to be higher compared to healthy individuals. In gliomas, a significant decrease in gamma oscillation regularity in the tumor-surrounding brain cortex has been demonstrated. It is considered acceptable to remove the areas with significantly decreased gamma oscillation regularity as non-functional regions with deteriorated normal brain function. This article introduces the practical application of safe and reliable brain tumor surgery using an approach from non-functional regions through intraoperative analysis of gamma oscillation regularity. The patient had undergone a partial resection surgery for a left temporal lobe tumor at another hospital and was diagnosed with a glioblastoma. Upon transfer to our hospital, the patient exhibited mild motor aphasia but had good comprehension. Language dominance was determined to be on the left side through the WADA test. Approximately 50% of the tumor, which was enhanced near the Broca's area and Wernicke's area, remained after the first surgery. We performed a non-awake extraction surgery for the residual tumor using intraoperative analysis of gamma oscillation regularity. By depicting a non-functional field during the operation, almost all of the tumors to be contrasted were removed without exacerbation of symptoms. Since the non-functional field can be depicted intraoperatively, surgery can be performed safely even in patients who cannot tolerate awake surgery. Brain tumor surgery using intraoperative analysis of gamma oscillation regularity is considered highly beneficial.

Cardiorespiratory fitness is associated with cortical thickness of medial temporal brain areas associated with spatial cognition in young but not older adults.

Cardiorespiratory fitness has a potent effect on neurocognitive health, especially regarding the hippocampal memory system. However, less is known about the impact of cardiorespiratory fitness on medial temporal lobe extrahippocampal neocortical regions. Specifically, it is unclear how cardiorespiratory fitness modulates these brain regions in young adulthood and if these regions are differentially related to cardiorespiratory fitness in young versus older adults. The primary goal of this study was to investigate if cardiorespiratory fitness predicted medial temporal lobe cortical thickness which, with the hippocampus, are critical for spatial learning and memory. Additionally, given the established role of these cortices in spatial navigation, we sought to determine if cardiorespiratory fitness and medial temporal lobe cortical thickness would predict greater subjective sense of direction in both young and older adults. Cross-sectional data from 56 young adults (20-35 years) and 44 older adults (55-85 years) were included. FreeSurfer 6.0 was used to automatically segment participants' 3T T1-weighted images. Using hierarchical multiple regression analyses, we confirmed significant associations between greater cardiorespiratory fitness and greater left entorhinal, left parahippocampal, and left perirhinal cortical thickness in young, but not older, adults. Left parahippocampal cortical thickness interacted with age group to differentially predict subjective sense of direction in young and older adults. Young adults displayed a positive, and older adults a negative, correlation between left parahippocampal cortical thickness and sense of direction. Our findings extend previous work on the association between cardiorespiratory fitness and hippocampal subfield structure in young adults to left medial temporal lobe neocortical regions.

Data‐driven neuroanatomical subtype trajectories of primary progressive aphasia

AbstractBackgroundPrimary progressive aphasia (PPA) is an atypical neurodegenerative dementia with three main clinical variants: semantic (svPPA), non‐fluent/agrammatic (nfvPPA) and logopenic (lvPPA). While svPPA is typically associated with left anterior temporal lobe atrophy, neuroimaging findings in nfvPPA, lvPPA and PPA not otherwise specified (PPA‐nos) are more variable. We therefore applied unsupervised machine learning to one of the largest databases of PPA magnetic resonance imaging (MRI) scans ever acquired.MethodBaseline MRI scans were collected from 273 people with PPA participating in the longitudinal research programme in the Queen Square Dementia Research Centre (svPPA n = 97; nfvPPA n = 109; lvPPA n = 51; PPA‐nos n = 16). Longitudinal scans were collected from 138 participants. We used Subtype and Stage Inference (SuStaIn), a model that combines disease progression modelling with unsupervised machine learning to identify subgroups of patients following a similar trajectory. We standardised the data with respect to cognitively normal controls (n = 360). Based on clinicians’ input we chose 19 brain regions of interest to model from those generated by GIF (Cardoso et al. 2012). The model was fit using baseline data, selecting the appropriate number of subtypes using cross‐validation (Young et al. 2018).ResultCross‐validation supported four subtypes of spatiotemporal atrophy (Figure 1). Clinical variant representation per subtype assignment (1/2/3/4) was: svPPA (n = 74/15/4/4), nfvPPA (n = 3/35/21/44), lvPPA (n = 1/18/30/2) and PPA‐nos (n = 7/4/3/2) (Figure 2). Subtype 1 showed early decline in the left anterior temporal lobe and sparing of the left frontal lobe. Subtype 2 showed early decline of the left insula and sparing of the temporal pole. Subtype 3 showed initial atrophy of the left temporoparietal junction; Subtype 4 showed early atrophy in the left precentral gyrus. Statistical analysis of posterior distributions found low similarity between subtypes (Hellinger distance &gt; 0.66) (Figure 3), validating the presence of four distinct subtypes.ConclusionWhile the data‐driven atrophy subtypes did not align perfectly with clinical variants, we found a correspondence between Subtype 1 and svPPA, the most coherent PPA variant. Subtypes 2,3 and 4 were associated with nfvPPA and lvPPA, corroborating work suggesting these diagnostic terms encompass multiple clinical phenotypes. Future work will investigate the association between clinical diagnosis, longitudinal subtype, and clinical measures.

Data‐driven neuroanatomical subtype trajectories of primary progressive aphasia

AbstractBackgroundPrimary progressive aphasia (PPA) is an atypical neurodegenerative dementia with three main clinical variants: semantic (svPPA), non‐fluent/agrammatic (nfvPPA) and logopenic (lvPPA). While svPPA is typically associated with left anterior temporal lobe atrophy, neuroimaging findings in nfvPPA, lvPPA and PPA not otherwise specified (PPA‐nos) are more variable. We therefore applied unsupervised machine learning to one of the largest databases of PPA magnetic resonance imaging (MRI) scans ever acquired.MethodBaseline MRI scans were collected from 273 people with PPA participating in the longitudinal research programme in the Queen Square Dementia Research Centre (svPPA n = 97; nfvPPA n = 109; lvPPA n = 51; PPA‐nos n = 16). Longitudinal scans were collected from 138 participants. We used Subtype and Stage Inference (SuStaIn), a model that combines disease progression modelling with unsupervised machine learning to identify subgroups of patients following a similar trajectory. We standardised the data with respect to cognitively normal controls (n = 360). Based on clinicians’ input we chose 19 brain regions of interest to model from those generated by GIF (Cardoso et al. 2012). The model was fit using baseline data, selecting the appropriate number of subtypes using cross‐validation (Young et al. 2018).ResultCross‐validation supported four subtypes of spatiotemporal atrophy (Figure 1). Clinical variant representation per subtype assignment (1/2/3/4) was: svPPA (n = 74/15/4/4), nfvPPA (n = 3/35/21/44), lvPPA (n = 1/18/30/2) and PPA‐nos (n = 7/4/3/2) (Figure 2). Subtype 1 showed early decline in the left anterior temporal lobe and sparing of the left frontal lobe. Subtype 2 showed early decline of the left insula and sparing of the temporal pole. Subtype 3 showed initial atrophy of the left temporoparietal junction; Subtype 4 showed early atrophy in the left precentral gyrus. Statistical analysis of posterior distributions found low similarity between subtypes (Hellinger distance &gt; 0.66) (Figure 3), validating the presence of four distinct subtypes.ConclusionWhile the data‐driven atrophy subtypes did not align perfectly with clinical variants, we found a correspondence between Subtype 1 and svPPA, the most coherent PPA variant. Subtypes 2,3 and 4 were associated with nfvPPA and lvPPA, corroborating work suggesting these diagnostic terms encompass multiple clinical phenotypes. Future work will investigate the association between clinical diagnosis, longitudinal subtype, and clinical measures.

Subcortical deformation is uniquely related to cortical thickness among FTLD mutation carriers

AbstractBackgroundFrontotemporal lobar degeneration (FTLD) due to familial mutations results in heterogenous clinical phenotypes for which there are no specific biomarkers. Here, we test whether subcortical deformation differs in FTLD genetic mutation carriers, and if deformation was uniquely related to cortical thickness.Method317 participants from ALLFTD with familial FTLD (C9orf72 (n = 139), GRN (n = 77), and MAPT (n = 101)) and 27 controls without mutations (NCC) were evaluated. MRI data underwent FreeSurfer processing to estimate cortical thickness (CT). High‐dimensional, large‐deformation diffeomorphic metric mapping was used to model surfaces of the caudate and putamen. Regression analyses investigated the effect of mutation on CT and subcortical surface deformation, after controlling for age, sex, and education. Finally, linear models were constructed in each mutation group to explore the association between areas of significant surface deformity and CT, corrected for age and multiple comparisons.ResultFigure 1 shows significant (corrected p&lt;.05) T‐scores where mutation carrier groups differ in CT from NCC (red = greater atrophy in mutation). Figure 2 shows greater outward local deformation in the caudate body among C9 and MAPT compared to NCC. Significant relationships between deformation and CT (corrected p&lt;.05) were observed in bilateral temporoparietal, frontal and cingulate cortex in both C9 and MAPT carriers. C9 and MAPT mutation carriers have greater outward deformation in postero‐lateral putamen. Deformation was associated with CT in C9 within the left temporal and prefrontal lobes, and in the right temporoparietal, occipital and cingulate cortices for MAPT (Figure 3). No significant deformation was observed in GRN compared to NCC.ConclusionFamilial FTLD mutations are associated with subtle subcortical shape variations that show unique relationships to cortical atrophy.

Lower Endogenous Estrogens in APOE4‐Positive Postmenopausal Women Associated with Lower Regional Brain Volumes

AbstractBackgroundDuring the menopause transition, levels of estradiol (E2) ecline. Although these changes are likely key determinants of cognition and brain structure during the menopause transition, how they are related to brain volume in women at elevated risk of Alzheimer’s disease (AD) is not known. We predict associations of endogenous E1 and E2 levels to regional brain volumes will depend on APOE4 carrier status, such that the associations between lower levels of E1 and E2 and lower regional brain volumes will be more positive among APOE4 carriers.MethodsParticipants were enrolled in MsBrain, a cohort study of postmenopausal women (n = 191, mean age 59.4 +/‐ 3.4 years, 45 APOE4 carriers, 84.3% white). Serum E1 and E2 were assessed using liquid chromatography‐tandem mass spectrometry. Cortical volume was measured and segmented by FreeSurfer software using individual T1w MPRAGE images. Cross‐sectional associations of interest were analyzed with APOE4 genotype (carrier versus noncarrier; excluding APOE2)ormone levels, and their interaction, as predictors and regional brain volumes (33 regions per hemisphere) as outcome measures using lme4 Package in R. Models controlled for, years of education, and body mass index.ResultsNeither APOE4 carrier status nor hormone levels were associated with brain volumes . However, significant interactions were observed between APOE4 carrier status and E2 levels in relation to volume of the right (p&lt;.05) and left isthmus cingulate (p&lt;.01), right and left middle temporal lobe (p&lt;.05), and the left posterior cingulate (p&lt;.05), such that the positive association between E2 and regional brain volumes was more positive among APOE4 carriers (Figure 1). Further, there was a significant interaction between APOE4 carrier status and E1 levels in relation to volumes of the right and left inferior parietal lobe (p&lt;.05), right (p&lt;.05) and left isthmus cingulate (p&lt;.05), left cuneus (p&lt;.05), left precuneus (p&lt;.05), and left lingual gyrus (p&lt;.05)(Figure 2).ConclusionAlthough some of these findings would be expected by chance, results suggest that lower levels of endogenous estrogens may be a risk factor for regional brain volume loss in female APOE4 carriers compared to non‐carriers.Supported by NIH RF1AG053504 and R01AG053504 (Thurston &amp; Maki)

Subcortical deformation is uniquely related to cortical thickness among FTLD mutation carriers

AbstractBackgroundFrontotemporal lobar degeneration (FTLD) due to familial mutations results in heterogenous clinical phenotypes for which there are no specific biomarkers. Here, we test whether subcortical deformation differs in FTLD genetic mutation carriers, and if deformation was uniquely related to cortical thickness.Method317 participants from ALLFTD with familial FTLD (C9orf72 (n = 139), GRN (n = 77), and MAPT (n = 101)) and 27 controls without mutations (NCC) were evaluated. MRI data underwent FreeSurfer processing to estimate cortical thickness (CT). High‐dimensional, large‐deformation diffeomorphic metric mapping was used to model surfaces of the caudate and putamen. Regression analyses investigated the effect of mutation on CT and subcortical surface deformation, after controlling for age, sex, and education. Finally, linear models were constructed in each mutation group to explore the association between areas of significant surface deformity and CT, corrected for age and multiple comparisons.ResultFigure 1 shows significant (corrected p&lt;.05) T‐scores where mutation carrier groups differ in CT from NCC (red = greater atrophy in mutation). Figure 2 shows greater outward local deformation in the caudate body among C9 and MAPT compared to NCC. Significant relationships between deformation and CT (corrected p&lt;.05) were observed in bilateral temporoparietal, frontal and cingulate cortex in both C9 and MAPT carriers. C9 and MAPT mutation carriers have greater outward deformation in postero‐lateral putamen. Deformation was associated with CT in C9 within the left temporal and prefrontal lobes, and in the right temporoparietal, occipital and cingulate cortices for MAPT (Figure 3). No significant deformation was observed in GRN compared to NCC.ConclusionFamilial FTLD mutations are associated with subtle subcortical shape variations that show unique relationships to cortical atrophy.

Data‐driven analysis of most common neurodegenerative dementias reveals atrophy patterns associated with overlapping cognitive symptoms

AbstractBackgroundA precise understanding of the neuroanatomical basis of clinical manifestation of dementia is an important step for timely diagnosis. Dementia due to proteinopathies, such as Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and Frontotemporal dementia (FTD), have different yet overlapping atrophy patterns which could account for their overlapping clinical presentations. To disentangle these relationships and facilitate timely differential diagnosis, we estimated distinct and overlapping atrophy patterns and associated them with cognitive deficits.MethodWe included 1702 AD (age = 66.1±8.3), 319 FTD (age = 63.3±7.7), 213 DLB (age = 69.7±7.0), and 1330 subjective cognitive decline (SCD) (age = 59.8±9.0) participants from the Amsterdam Dementia Cohort. MRIs were processed with Freesurfer and outputs were manually checked. Scanner‐related bias in outputs was corrected using NeuroHarmony pipeline. Participants’ cognition was evaluated using standardized neuropsychological tests. Z‐scores for cognitive domains of memory, executive functioning, attention, language, and visuospatial functioning were derived using SCD group as reference. We estimated distinct and overlapping atrophy patterns in each disease by computing odds ratio in each region, using SCD group as reference. Furthermore, we computed group‐wise Pearson partial correlation between the (sub‐)cortical measures and cognition while correcting for confounding effects of age, sex, and education level.ResultAtrophy in bilateral inferior temporal, and right hippocampus was more prevalent in AD and FTD patients than in DLB patients (Figures 1‐3). Temporal pole atrophy was more prevalent in FTD than in AD or DLB patients. Superior parietal and supra marginal atrophy was more prevalent in AD than in FTD or DLB patients. Bilateral hippocampus and amygdala atrophy associated with memory impairment in AD, whereas left hemisphere atrophy associated with memory impairment in FTD. Frontal atrophy associated with worse executive functioning and attention in FTD, but not in AD. Language deficit associated with left temporal lobe atrophy in both FTD and AD. Visuospatial dysfunction associated with parietal lobe atrophy in both AD and FTD. In DLB, we observed no significant correlation between atrophy and cognitive deficits.ConclusionWe identified distinct and overlapping atrophy patterns and associations of atrophy patterns with cognitive deficits in AD, FTD, and DLB. These data‐driven insights are crucial for accurate diagnosis and prognosis.

Sleep disturbance associated with temporal lobe degeneration in frontotemporal dementia

AbstractBackgroundSleep abnormalities are increasingly recognized as markers and potential drivers of neurodegenerative proteinopathies. However, the sleep phenotype of less common dementias remains poorly characterised. In particular, clinical experience suggests that patients with focal temporal lobe degeneration in the frontotemporal dementia spectrum can experience sometimes striking sleep disruption. We recently had the opportunity to corroborate this clinical impression in a small series of representative patients participating in a larger cohort study.MethodsTo date, we have studied seven patients and three healthy age‐matched controls. The patients’ diagnoses comprise behavioural variant frontotemporal dementia associated with focal right temporal lobe atrophy (n = 3), semantic dementia associated with focal left temporal lobe atrophy (n = 2), young onset Alzheimer’s disease and logopenic aphasia (each n = 1). No participant had a past history of a clinical sleep disorder. Detailed data on sleep patterns, adapted standard sleep questionnaires (Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale), overnight oximetry and neuropsychological test scores (covering domains of executive function, emotion processing, memory, and auditory perceptual learning) pre‐/post‐overnight sleep were collected with the assistance of patients’ caregivers.ResultsTwo patients with right temporal lobe atrophy and one with left temporal lobe atrophy had marked sleep fragmentation, in one right temporal case accompanied by frequent sleep attacks, with increased overall time in bed and/or attempting to sleep. Epworth and Pittsburgh indices in these patients indicated significant daytime sleepiness and reduced sleep quality; none had evidence of significant sleep apnoea on overnight oximetry. Comparatively mild clinical sleep disturbances were reported in patients with other dementia diagnoses. However, there was evidence for reduced auditory perceptual learning benefit from overnight sleep relative to healthy older controls, particularly in the patients with underlying Alzheimer pathology.ConclusionsThese preliminary findings suggest that focal temporal lobe degeneration may be associated with clinically relevant sleep disruption, as part of the more pervasive derangement of homeostasis in these syndromes. Further work is indicated to define the hypnic phenotype in detail, with sleep electrophysiology and correlative behavioural, neuroimaging and laboratory data in larger patient cohorts.