Regional Hypometabolism Research Articles

A longitudinal 18F‐FDG PET study in asymptomatic stage of genetic Creutzfeldt–Jakob disease

AbstractBackgroundPathogenic prion protein may start to deposit in some brain regions and cause functional alterations in the asymptomatic stages in Creutzfeldt–Jakob disease patients. However, the disease trajectory of Creutzfeldt–Jakob disease in the asymptomatic stage and when and where the degenerative process begins are still not clear.MethodsAt baseline, we enrolled five asymptomatic mutation carriers, six affected genetic Creutzfeldt–Jakob diseasepatients, and 23 healthy controls from whom 18F fluorodeoxyglucose‐positron emission tomography, clinical, and neuropsychological measures were acquired. Only five asymptomatic mutation carriers had completed longitudinal follow‐up. We set three‐time points to identify the changing trajectory in asymptomatic carriers group including baseline, 2‐year and 4‐year follow‐up.ResultsAt baseline, the cerebral glucose metabolic rate, measured as the standardized uptake value rate ratio, clinical and neuropsychological scales in all 5 asymptomatic cases were normal. In the 4‐years follow‐up, hypometabolic brain regions in asymptomatic genetic Creutzfeldt–Jakob disease group were found in the insula, frontal, parietal, and temporal lobes (false discovery rate corrected p<0.01). The standardized uptake value rate ratio changing trajectories of all asymptomatic cases were within the range between the healthy controls and affected patients. Notably, the metabolism values of one asymptomatic individual whose baseline age was older than the expected age of onset showed a rapid decline and approached the mean value of genetic Creutzfeldt–Jakob disease condition at the last follow‐up.ConclusionOur study illustrates that neurodegenerative process associated with genetic Creutzfeldt–Jakob disease may involve the insula, frontal, temporal, and parietal lobes before clinical presentation of the disease, and the decline will accelerate when close to the expected age of onset. Although there are no effective means to cure this fatal disease, the time interval before clinical disease onset may aid important trials or therapies intended to slow or halt the disease process.

“Probable 4R‐tauopathy” criteria in a Corticobasal Syndrome cohort: diagnostic accuracy, clinical, metabolic and volumetric patterns in a multimodal PET/MRI study

AbstractBackgroundCorticobasal syndrome (CBS) is a neurodegenerative disease related to multiple underlying pathologies, including four‐repeat (4R) tauopathies, namely corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), Alzheimer’s disease (AD), among others. The Movement Disorders Society‐PSP clinical criteria proposed a diagnostic category “probable 4R‐tauopathy” to include the phenotypic overlap between PSP and CBD. These criteria were specific for 4R‐tauopathies in a previous post‐mortem validation study. We aimed to investigate this proposed criteria in a cohort of patients clinically diagnosed with probable CBS, comparing the CBS‐4R tau group regarding neurological assessment, brain atrophy patterns, functional and disease‐specific imaging biomarkers. Also, we compared this group with CBS patients that matched the clinical research (cr) criteria for CBD.MethodThirty‐two patients diagnosed with probable CBS were prospectively enrolled and clinically evaluated. They were split into those who fulfilled criteria for probable 4R‐tauopathy (CBS‐4RT = 12) and probable CBD (CBS‐CBD = 28). They underwent [18F]fluorodeoxyglucose‐positron emission tomography (FDG‐PET) and [11C]Pittsburgh Compound‐B (PIB‐PET) on a hybrid PET‐MRI to assess their amyloid status. PIB‐PET images were classified individually based on visual and 3D‐SSP semi‐quantitative analysis. Quantitative group analyses were performed with SPM12, to check both brain atrophy patterns using voxel‐based morphometry (VBM), and regional brain hypometabolism patterns with FDG‐PET. A healthy control group of 30 subjects, matched by age and education, was also included.ResultOnly one patient classified as CBS‐4RT was positive at PIB‐PET (p = 0.010), compared to 12 among 28 CBS‐CBD subjects (p = 0.458). The CBS‐4RT clinical classification had 52.6% sensitivity, 92.3% specificity, and 68.7% accuracy in predicting a negative PIB‐PET result. Also, CBS‐4RT patients presented dysarthria (p = 0.017) and motor perseveration (p = 0.032) more often than the whole group. CBS‐4RT patients showed asymmetric hypometabolism in the inferior, middle, and superior frontal gyri, supplementary motor area, and caudate compared to controls. They also demonstrated brain atrophy in the superior and inferior frontal gyri and basal ganglia.ConclusionThe new proposed clinical 4R‐tauopathies criteria demonstrated high specificity to detect amyloid‐negative CBS patients. Patients fulfilling the criteria presented specific metabolic and volumetric patterns. Moreover, they presented clinical characteristics such as dysarthria and motor perseveration previously related to tauopathies.

Multifocal hypometabolic correlates to deficits of verbal memory in mesial temporal lobe epilepsy

Background and ObjectivesNeuropsychological research on mesial temporal lobe epilepsy (MTLE) often highlights material-specific memory deficits, but a lesion-focused model may not accurately reflect the underlying networks that support episodic memory in these patients. Our study evaluated the pathophysiology behind verbal learning/memory deficits as revealed by hypometabolism quantified through 18-fluorodeoxyglucose positron emission tomography (FDG-PET). MethodsThis retrospective study included thirty presurgical patients with intractable unilateral MTLE who underwent interictal FDG-PET and verbal memory assessment (12 females, mean age: 38.73 years). Fluorodeoxyglucose-positron emission tomography mapping was performed with voxel-based mapping of glucose utilization to a database of age-matched controls to derive regional Z-scores. Neuropsychological outcome variables included scores on learning and recall trials of two distinct verbal memory measures validated for use in epilepsy research. Pearson’s correlations evaluated relationships between clinical variables and verbal memory. Linear regression was used to relate regional hypometabolism and verbal memory assessment. Post hoc analyses assessed areas of FDG-PET hypometabolism (threshold Z ≤ −1.645 below mean) where verbal memory was impaired. ResultsVerbal memory deficits correlated with hypometabolism in limbic structures ipsilateral to language dominance but also correlated with hypometabolism in networks involving the ipsilateral perisylvian cortex and contralateral limbic and nonlimbic structures. DiscussionWe conclude that traditional models of verbal memory may not adequately capture cognitive deficits in a broader sample of patients with MTLE. This study has important implications for epilepsy surgery protocols that use neuropsychological data and FDG-PET to draw conclusions about surgical risks.

In situ microwave fixation provides an instantaneous snapshot of the brain metabolome

Brain glucose metabolism is highly heterogeneous among brain regions and continues postmortem. In particular, we demonstrate exhaustion of glycogen and glucose and an increase in lactate production during conventional rapid brain resection and preservation by liquid nitrogen. In contrast, we show that these postmortem changes are not observed with simultaneous animal sacrifice and in situ fixation with focused, high-power microwave. We further employ microwave fixation to define brain glucose metabolism in the mouse model of streptozotocin-induced type 1 diabetes. Using both total pool and isotope tracing analyses, we identified global glucose hypometabolism in multiple brain regions, evidenced by reduced 13C enrichment into glycogen, glycolysis, and the tricarboxylic acid (TCA) cycle. Reduced glucose metabolism correlated with a marked decrease in GLUT2 expression and several metabolic enzymes in unique brain regions. In conclusion, our study supports the incorporation of microwave fixation for more accurate studies of brain metabolism in rodent models.

Asymmetry index in anatomically symmetrized FDG-PET for improved epileptogenic focus detection in pharmacoresistant epilepsy.

Positron emission tomography (PET) imaging has assumed an essential role in the presurgical evaluation of epileptogenic foci in drug-resistant epilepsy by identifying the hypometabolic cerebral cortex. The authors herein designed a pilot study to test a novel technique of PET asymmetry after anatomical symmetrization coregistered to MRI (PASCOM), utilizing interhemispheric metabolic asymmetry on interictal fluorine 18-labeled fluorodeoxyglucose (FDG)-PET to better localize the epileptogenic zone. The authors analyzed interictal FDG-PET scans from 23 patients with drug-resistant epilepsy, mean (± SD) age 20.9 ± 13.1 years old, who had an Engel class I postsurgical outcome while followed up for > 12 months. T1-weighted and FLAIR MRI were used to create a patient-specific, structurally symmetrical template. The asymmetry index (AI) image was computed to detect the cerebral region of hypometabolism using different z-score threshold criteria to optimize sensitivity and specificity. The detected regions were compared with the resection cavity on postoperative MRI using predefined anatomical labels. PASCOM was compared with the visual analysis of FDG-PET by a nuclear medicine consultant blinded to other clinical data (VIS) and visual analysis during multidisciplinary team discussion (MDT). The efficacy of each technique was compared based on a performance score (S), sensitivity, specificity, and correct lateralization of epileptogenicity. The mean S was maximum (1.30 ± 1.23) for AI images when thresholded at z > 4 and retaining the cluster of more than 100 voxels containing the peak AI value (Z4C) with 73.03% sensitivity and 96.43% specificity. The mean S was minimum for VIS (0.27 ± 0.31). The mean sensitivity was maximum for MDT (85.04%) and minimum for Z5C (AI images thresholded at z > 5 and clustered; 59.47%), whereas the mean specificity was maximum for Z5C (97.77%) and minimum for VIS (64.60%). Z3C (AI images thresholded at z > 3 and clustered) and Z4C were able to correctly identify the side of epileptogenicity in all the patients. The PASCOM technique with a Z4C threshold had a maximum performance score with good sensitivity and specificity in localizing and lateralizing the epileptogenic zone. The described technique outperformed the conventional visual analysis of FDG-PET and hence warrants further prospective verification.

Chronic exposure to a synthetic cannabinoid alters cerebral brain metabolism and causes long-lasting behavioral deficits in adult mice.

In recent years, there has been growing evidence that cannabinoids have promising medicinal and pharmacological effects. However, the growing interest in medical cannabis highlights the need to better understand brain alterations linking phytocannabinoids or synthetic cannabinoids to clinical and behavioral phenotypes. Therefore, the aim of this study was to investigate the effects of long-term WIN 55,212-2 treatment-with and without prolonged abstinence-on cerebral metabolism and memory function in healthy wildtype mice. Adult C57BI/6J mice were divided into two treatment groups to study the acute effects of WIN 55,212-2 treatment as well the effects of WIN 55,212-2 treatment after an extended washout phase. We could demonstrate that 3mg/kg WIN 55,212-2 treatment in early adulthood leads to a hypometabolism in several brain regions including the hippocampus, cerebellum, amygdala and midbrain, even after prolonged abstinence. Furthermore, prolonged acute WIN 55,212-2 treatment in 6-months-old mice reduced the glucose metabolism in the hippocampus and midbrain. In addition, Win 55,212-2 treatment during adulthood lead to spatial memory and recognition memory deficits without affecting anxiety behavior. Overall we could demonstrate that treatment with the synthetic CB1/CB2 receptor aganist Win 55,212-2 during adulthood causes persistent memory deficits, especially when mice were treated in early adulthood. Our findings highlight the risks of prolonged WIN 55,212-2 use and provide new insights into the mechanisms underlying the effects of chronic cannabinoid exposure on the brain and behavior.

Functional Correlates of Microglial and Astrocytic Activity in Symptomatic Sporadic Alzheimer’s Disease: A CSF/18F-FDG-PET Study

Glial and microglial cells contribute to brain glucose consumption and could actively participate in shaping patterns of brain hypometabolism. Here, we aimed to investigate the association between 18F-fluorodeoxyglucose (18F-FDG) uptake and markers of microglial and astrocytic activity in a cohort of patients with Alzheimer's Disease (AD). We dosed cerebrospinal fluid (CSF) levels of soluble Triggering Receptor Expressed on Myeloid cells (sTREM2), Glial Fibrillary Acidic Protein (GFAP), a marker of reactive astrogliosis, and β-S100, a calcium-binding protein associated with a neurotoxic astrocytic profile. No associations were found between sTREM-2 and 18F-FDG uptake. Instead, 18F-FDG uptake was associated negatively with CSF β-S100 in the left supramarginal gyrus, inferior parietal lobe and middle temporal gyrus (Brodmann Areas (BA) 21 and 40). Increased β-S100 levels could negatively regulate neuronal activity in the temporo-parietal cortex to prevent damage associated with AD hyperactivity, or rather they could reflect neurotoxic astrocytic activation contributing to AD progression in key strategic areas. We also identified a trend of positive association of 18F-FDG uptake with CSF GFAP in the right fronto-medial and precentral gyri (BA 6, 9 and 11), which has been reported in early AD and could either be persisting as an epiphenomenon tied to disease progression or be specifically aimed at preserving functions in the frontal cortex. Overall, CSF markers of astrogliosis seem to correlate with cortical glucose uptake in symptomatic sporadic AD, highlighting the role of astrocytes in shaping regional hypometabolism and possibly clinical presentation.

FDG-PET shows weak correlation between focal motor weakness and brain metabolic alterations in ALS

Objective: Amyotrophic lateral sclerosis (ALS) is a clinically heterogenous disease, typically presenting with focal motor weakness that eventually generalizes. Weather there is a correlation between focal motor weakness and metabolic alterations in specific areas of the brain has not been thoroughly explored. This study aims to systematically investigate this by using fluorodeoxyglucose-positron emission tomography (FDG-PET), including longitudinal imaging. Methods: This observational imaging study included 131 ALS patients diagnosed and examined with FDG-PET at the ALS Clinical Research Center at the Karolinska University Hospital in Stockholm, Sweden. Thirteen ALS patients had a second scan and were analyzed longitudinally. The findings were compared to 39 healthy controls examined at the University Medical Center of Gröningen, the Netherlands. Results: There was a general pattern of brain metabolic alterations consistent with previously reported findings in ALS, namely hypometabolism in frontal regions and hypermetabolism in posterior regions. A higher symptom burden was associated with increased hypometabolism and decreased hypermetabolism. However, there was no clear correlation between focal motor weakness and specific metabolic alterations, neither when analyzing focal motor weakness with concomitant upper motor neuron signs or when including all focal motor weakness. Longitudinal FDG-PET imaging showed inconsistent results with little correlation between progression of motor weakness and metabolic alterations. Conclusion: Our results support the disease model of ALS as a diffuse process since no clear correlation was seen between focal motor weakness and specific metabolic alterations. However, there is need for further research on a larger number of patients, particularly including longitudinal imaging.

Thalamic pathology in frontotemporal dementia: Predilection for specific nuclei, phenotype-specific signatures, clinical correlates, and practical relevance.

Frontotemporal dementia (FTD) phenotypes are classically associated with distinctive cortical atrophy patterns and regional hypometabolism. However, the spectrum of cognitive and behavioral manifestations in FTD arises from multisynaptic network dysfunction. The thalamus is a key hub of several corticobasal and corticocortical circuits. The main circuits relayed via the thalamic nuclei include the dorsolateral prefrontal circuit, the anterior cingulate circuit, and the orbitofrontal circuit. In this paper, we have reviewed evidence for thalamic pathology in FTD based on radiological and postmortem studies. Original research papers were systematically reviewed for preferential involvement of specific thalamic regions, for phenotype-associated thalamic disease burden patterns, characteristic longitudinal changes, and genotype-associated thalamic signatures. Moreover, evidence for presymptomatic thalamic pathology was also reviewed. Identified papers were systematically scrutinized for imaging methods, cohort sizes, clinical profiles, clinicoradiological associations, and main anatomical findings. The findings of individual research papers were amalgamated for consensus observations and their study designs further evaluated for stereotyped shortcomings. Based on the limitations of existing studies and conflicting reports in low-incidence FTD variants, we sought to outline future research directions and pressing research priorities. FTD is associated with focal thalamic degeneration. Phenotype-specific thalamic traits mirror established cortical vulnerability patterns. Thalamic nuclei mediating behavioral and language functions are preferentially involved. Given the compelling evidence for considerable thalamic disease burden early in the course of most FTD subtypes, we also reflect on the practical relevance, diagnostic role, prognostic significance, and monitoring potential of thalamic metrics in FTD. Cardinal manifestations of FTD phenotypes are likely to stem from thalamocortical circuitry dysfunction and are not exclusively driven by focal cortical changes.

Multimodal imaging study of the 5-HT1A receptor biased agonist, NLX-112, in a model of L-DOPA-induced dyskinesia

IntroductionThe leading treatment for motor signs of Parkinson's disease is L-DOPA, but, upon extended use, it can lead to levodopa-induced dyskinesia (LID). Serotonergic neurons are involved in LID etiology and previous pre-clinical studies have shown that NLX-112, a 5-HT1A biased agonist, has robust antidyskinetic effects. Here, we investigated its effects in hemiparkinsonian (HPK) rats with a unilateral nigrostriatal 6-OHDA lesion. MethodsWe compared HPK rats with LID (i.e., sensitized to the dyskinetic effects of chronic L-DOPA) and without LID (HPK-non-LID), using [18F]FDG PET imaging and fMRI functional connectivity following systemic treatment with saline, L-DOPA, NLX-112 or L-DOPA + NLX-112. ResultsIn HPK-non-LID rats, [18F]FDG PET experiments showed that L-DOPA led to hypermetabolism in motor areas (cerebellum, brainstem, and mesencephalic locomotor region) and to hypometabolism in cortical regions. L-DOPA effects were also observed in HPK-LID rats, with the additional emergence of hypermetabolism in raphe nuclei and hypometabolism in hippocampus and striatum. NLX-112 attenuated L-DOPA-induced raphe hypermetabolism and cingulate cortex hypometabolism in HPK-LID rats. Moreover, in fMRI experiments NLX-112 partially corrected the altered neural circuit connectivity profile in HPK-LID rats, through activity in regions rich in 5-HT1A receptors. ConclusionThis neuroimaging study sheds light for the first time on the brain activation patterns of HPK-LID rats. The 5-HT1A receptor agonist, NLX-112, prevents occurrence of LID, likely by activating pre-synaptic autoreceptors in the raphe nuclei, resulting in a partial restoration of brain metabolic and connectivity profiles. In addition, NLX-112 also rescues L-DOPA-induced deficits in cortical activation, suggesting potential benefit against non-motor symptoms of Parkinson’s disease.

Brain glucose metabolism and nigrostriatal degeneration in isolated rapid eye movement sleep behaviour disorder.

Alterations of cerebral glucose metabolism can be detected in patients with isolated rapid eye movement sleep behaviour disorder, a prodromal feature of neurodegenerative diseases with α-synuclein pathology. However, metabolic characteristics that determine clinical progression in isolated rapid eye movement sleep behaviour disorder and their association with other biomarkers need to be elucidated. We investigated the pattern of cerebral glucose metabolism on 18F-fluorodeoxyglucose PET in patients with isolated rapid eye movement sleep behaviour disorder, differentiating between those who clinically progressed and those who remained stable over time. Second, we studied the association between 18F-fluorodeoxyglucose PET and lower dopamine transporter availability in the putamen, another hallmark of synucleinopathies. Patients with isolated rapid eye movement sleep behaviour disorder from the Mayo Clinic Alzheimer's Disease Research Center and Center for Sleep Medicine (n = 22) and age-and sex-matched clinically unimpaired controls (clinically unimpaired; n = 44) from the Mayo Clinic Study of Aging were included. All participants underwent 18F-fluorodeoxyglucose PET and dopamine transporter imaging with iodine 123-radiolabeled 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane on single-photon emission computerized tomography. A subset of patients with isolated rapid eye movement sleep behaviour disorder with follow-up evaluations (n = 17) was classified as isolated rapid eye movement sleep behaviour disorder progressors (n = 7) if they developed mild cognitive impairment or Parkinson's disease; or isolated rapid eye movement sleep behaviour disorder stables (n = 10) if they remained with a diagnosis of isolated rapid eye movement sleep behaviour disorder with no cognitive impairment. Glucose metabolic abnormalities in isolated rapid eye movement sleep behaviour disorder were determined by comparing atlas-based regional 18F-fluorodeoxyglucose PET uptake between isolated rapid eye movement sleep behaviour disorder and clinically unimpaired. Associations between 18F-fluorodeoxyglucose PET and dopamine transporter availability in the putamen were analyzed with Pearson's correlation within the nigrostriatal pathway structures and with voxel-based analysis in the cortex. Patients with isolated rapid eye movement sleep behaviour disorder had lower glucose metabolism in the substantia nigra, retrosplenial cortex, angular cortex, and thalamus, and higher metabolism in the amygdala and entorhinal cortex compared with clinically unimpaired. Patients with isolated rapid eye movement sleep behaviour disorder who clinically progressed over time were characterized by higher glucose metabolism in the amygdala and entorhinal cortex, and lower glucose metabolism in the cerebellum compared with clinically unimpaired. Lower dopamine transporter availability in the putamen was associated with higher glucose metabolism in the pallidum within the nigrostriatal pathway; and with higher 18F-fluorodeoxyglucose uptake in the amygdala, insula, and temporal pole on a voxel-based analysis, although these associations did not survive after correcting for multiple comparisons. Our findings suggest that cerebral glucose metabolism in isolated rapid eye movement sleep behaviour disorder is characterized by hypometabolism in regions frequently affected during the prodromal stage of synucleinopathies, potentially reflecting synaptic dysfunction. Hypermetabolism is also seen in isolated rapid eye movement sleep behaviour disorder, suggesting that synaptic metabolic disruptions may be leading to a lack of inhibition, compensatory mechanisms, or microglial activation, especially in regions associated with nigrostriatal degeneration.

Cerebral Metabolic Rate of Glucose and Cognitive Tests in Long COVID Patients.

Common long-term sequelae after COVID-19 include fatigue and cognitive impairment. Although symptoms interfere with daily living, the underlying pathology is largely unknown. Previous studies report relative hypometabolism in frontal, limbic and cerebellar regions suggesting focal brain involvement. We aimed to determine whether absolute hypometabolism was present and correlated to same day standardized neurocognitive testing. Fourteen patients included from a long COVID clinic had cognitive testing and quantitative dynamic [18F]FDG PET of the brain on the same day to correlate cognitive function to metabolic glucose rate. We found no hypometabolism in frontal, limbic and cerebellar regions in cognitively impaired relative to cognitive intact patients. In contrast, the cognitive impaired patients showed higher cerebellar metabolism (p = 0.03), which correlated with more severe deficits in working memory and executive function (p = 0.03). Hypermetabolism in the cerebellum may reflect inefficient brain processing and play a role in cognitive impairments after COVID-19.

18F‐fluorodeoxyglucose‐positron emission tomography Findings in Patients with Genetic Frontotemporal Dementia

AbstractBackgroundMutations in microtubule‐associated protein tau (MAPT), granulin (GRN), and hexanucleotide expansion repeat in the open reading frame of chromosome 9 (C9orf72) are found in 60% of familial frontotemporal dementia (FTD) cases. The current study aims to delineate brain regions with reduced glucose metabolism in patients with genetic FTD in comparison with cognitively normal controls.Methods(18)F‐ fluorodeoxyglucose (FDG)‐positron emission tomography (PET) images were retrospectively obtained from 17 genetic FTD patients. All patients were symptomatic at the time of imaging, and the autopsy was available for 13. Pittsburgh compound B (PiB) amyloid PET scans were done for 13 patients (Table 1). FDG‐PET was collected at Lawrence Berkeley National Laboratory on a PET or PET‐CT scanner as six 5‐min frames acquired 30 min post tracer injection. Standard Uptake Value Ratio (SUVR) images were created for each patient using pons as a reference region. W‐score (age‐adjusted Z‐score) maps were created for each patient’s FDG SUVR using a group of neurologically unimpaired controls (N=74, Mean age 65+16, 41 female) as reference.ResultOn review of single‐subject w‐maps, all patients with MAPT mutation showed hypometabolism in the anteromedial temporal lobes with 66% showing anterolateral temporal hypometabolism and 33% in the frontal and dorsolateral parietal lobes. Hypometabolism in temporal lobes was seen in all GRN patients and 75% had frontal and parietal hypometabolism in an asymmetric pattern. 80% of theC9orf72 patients had hypometabolism in anteromedial temporal and orbitofrontal regions. 60% showed hypometabolism in dorsolateral prefrontal, medial frontal, and anterolateral temporal lobes. Posterior temporal, posterior cingulate, parietal lobe, cerebellum, insula, thalamus, and caudate were hypometabolic in less than 40% of the C9orf72 patients (Figure 1).On group‐level analysis, compared to controls, patients with C9orf72 showed hypometabolism in the frontotemporal regions, cerebellum and thalamus. Hypometabolism in the frontotemporal and parietal regions was seen with GRN mutation. MAPT mutation carriers showed frontal and anteromedial temporal hypometabolism (Figure 2).ConclusionHypometabolism in the posterior regions and cerebellum is more suggestive of C9orf72 repeat expansion. An asymmetric pattern of hypometabolism was seen in all GRN mutation carriers. MAPT mutation resulted in a greater degree of hypometabolism in the anterior medial temporal lobes.

Exploration of visual hallucinations – FDG‐PET associations in DLB and MCI‐LB with and without visual hallucinations

AbstractBackgroundSeveral hypotheses exist regarding the neurologic substrate underlying visual hallucinations (VH) in Dementia with Lewy Bodies (DLB). Studies have suggested an association with regional cerebral hypometabolism in the primary visual or visual association cortices on FDG‐PET. We compared regional cerebral glucose metabolism and posterior cingulate island sign (CIS) ratios in DLB and in Mild Cognitive Impairment with Lewy Bodies (MCI‐LB) participants with (VH+) and without (VH‐) VH.MethodParticipants with clinically probable DLB or MCI‐LB and an FDG‐PET scan were identified from the Mayo ADRC database. Responses on the Visual Hallucinations and Delusions Questionnaire and Neuropsychiatric Inventory were used to assess presence or absence of VH. Standardized uptake value ratios (SUVr) were used to calculate regional cerebral glucose hypometabolism in the primary visual cortex (PVC), lateral occipital cortex (LOC), and whole occipital cortex (WOC). The CIS ratio was defined as posterior cingulate divided by the sum of the precuneus plus cuneus FDG‐PET uptake ratio.ResultTwo cohorts were identified (27 DLB and 18 MCI‐LB, 87% male). Eighteen DLB participants were VH+ and 9 were VH‐, whereas 5 MCI‐LB were VH+ and 13 were VH‐. There were no statistically significant differences in demographic (age, sex, education) and clinical features (MoCA, CDR, presence of other core DLB features, and UPDRS) between VH+ vs VH‐ in those with DLB, and between VH+ vs VH‐ in those with MCI‐LB. Similarly, there were no statistically significant differences in DLB between VH+ vs VH‐ in PVC (1.55±0.14 vs 1.58±0.15), LOC (1.22±0.16 vs 1.28±0.12), WOC (1.29±0.15 vs 1.34±0.11), or CIS ratio (1.16±0.08 vs 1.14±0.10), nor in MCI‐LB between VH+ vs VH‐ in PVC (1.68±0.19 vs 1.58±0.14), LOC (1.40±0.21 vs 1.32±0.14), WOC (1.45±0.20 vs 1.37±0.14), or CIS ratio (1.17±0.08 vs 1.19±0.10) (P>0.05 for all comparisons).ConclusionThese findings do not support a direct correlation between regional cerebral glucose metabolism and VH in DLB or MCI‐LB. Further work in DLB and MCI‐LB with larger numbers is warranted. Other neurologic substrates and mechanisms, such as REM sleep intrusions during wakefulness, neurotransmitter dysfunction, and disruption of functional connectivity across brain regions should be explored as contributors to VH in DLB.

Neurodegenerative Pathways in Alzheimer's Disease Subtypes

AbstractBackgroundBiological heterogeneity in Alzheimer’s disease (AD) has been observed and described as subtypes in measures of neurodegeneration (e.g., hypometabolism and atrophy). However, the relationship between these AD subtypes have not been studied. Thus, we aimed to compare and identify pathways associated with hypometabolism‐based and atrophy‐based subtypes.MethodCross‐sectional FDG‐PET and MRI scans from 173 amyloid‐positive AD individuals and 120 amyloid‐negative cognitively normal control individuals from the ADNI were included. Subtypes were identified in each neuroimaging modality by random forest hierarchical clustering using FDG‐PET uptake (measuring hypometabolism) and MRI volumes (measuring atrophy) in cortical and subcortical regions. We performed cross‐modal comparisons of atrophy patterns in hypometabolism‐based subtypes and hypometabolism patterns in atrophy‐based subtypes. To identify neurodegenerative pathways corresponding to each subtype, we used event‐based modelling to predict sequential progression of abnormality in hypometabolism and atrophy across brain regions (hippocampus, AD signature, frontal, posterior areas).ResultClustering revealed four hypometabolism‐based (two relatively limbic‐predominant: 25.7%, 19.8% and two relatively cortical‐predominant: 25.7%, 28.6%) and three atrophy‐based (diffuse: 18.7%, relatively limbic‐predominant: 28.6%, minimal: 52.6%) subtypes of AD with distinct spatial patterns and demographic and clinical characteristics. Cross‐modally, we found comparable AD‐typical atrophy patterns (involving the hippocampus and temporal regions) across the four hypometabolism‐based subtypes and comparable AD‐typical hypometabolism patterns (involving the retrosplenial cortex) across the three atrophy‐based subtypes. Event‐based modelling showed that each hypometabolism‐based subtype was associated with a unique sequential progression of regional hypometabolism, but not regional atrophy (sequence always initiated with frontal atrophy across all subtypes). Similarly, each atrophy‐based subtype was associated with a unique sequential progression of regional atrophy, but not regional hypometabolism (sequence always initiated with hypometabolism in AD signature areas across all subtypes).ConclusionOur findings suggest that hypometabolism‐based and atrophy‐based AD subtypes are not interchangeable. We identified unique metabolic and atrophy pathways specific to each subtype, which supports the notion that neurodegeneration manifests and progresses differentially across subtypes of AD. Despite being measures of neurodegeneration, hypometabolism and atrophy may not share the same extent of heterogeneity, bearing a complex multimodal relationship. Disentangling such relationships and combining complementary biomarkers to investigate heterogeneity could aid personalized treatment of AD.

Brain metabolism changes in middle‐aged asymptomatic APOE‐ε4 carriers. The PESA Study

AbstractBackgroundApolipoprotein E (APOE) is the major genetic risk factor for late‐onset Alzheimer’s disease (AD) and is implicated in cardiovascular disease. TheAPOE‐ε4 allele is associated with brain hypometabolism in AD, mild cognitive impairment (MCI) (Mosconi et al. Neurology 2004) and in cognitively unimpaired middle‐aged individuals (Reiman et al. NEJM 1996). Greater longitudinal decreases in brain metabolism were reported in APOE‐ε4 carriers with MCI (Paranjpe et al. Neuroimage Clin 2019), but studies on brain metabolism longitudinal changes in unimpaired middle‐aged APOE‐ε4 carriers are scarce and with relatively small sample sizes (Reiman et al. PNAS 2001). The Progression of Early Subclinical Atherosclerosis (PESA) study is a longitudinal study following >4000 asymptomatic middle‐aged subjects deeply screened for cardiovascular risk factors (CVRFs) (Fernandez‐Ortiz et al. AHJ 2013). Individuals with the highest burden of atherosclerosis underwent FDG‐PET at baseline and CVRFs were associated with hypometabolism in AD regions (Cortés‐Canteli & Gispert et al. JACC 2021). Those individuals underwent a 6‐year follow‐up FDG‐PET. Here, we investigate the effect of APOE genotype on brain metabolism progression in middle‐aged asymptomatic individuals.Method365 cognitively unimpaired adults (mean age 50 years old) were genotyped for APOE and underwent two FDG‐PET studies (Table). Baseline and follow‐up images were spatially normalized to a group template in the MNI space. FDG‐uptake was normalized to the pons and images were subtracted, yielding a measure of brain metabolic change. An ANOVA model was carried out to compare brain metabolism change between APOE‐ResultAt the global level, we observed significantly greater decreases in FDG uptake in ε4 carriers compared to the reference ε3/ε3 genotype (p=0.024). Voxelwise analysis showed greater decreases between ε4 carriers and non‐ε4 carriers in the precuneus, supramarginal gyrus, hippocampus and anterior cingulate gyrus (Figure).ConclusionAsymptomatic middle‐aged APOE‐ε4 carriers have a greater decline in brain metabolism in regions known to display hypometabolism in AD, suggesting an increased vulnerability. Further analysis will reveal the extent to which AD pathology and/or other risk factors may mediate this association.

Case of Dementia with Lewy Bodies in Young Patient with Family History

AbstractBackgroundDementia with Lewy bodies (DLB) is a neurodegenerative disorder characterized by cognitive decline, fluctuating attention, visual hallucinations, and sleep disorders, sometimes with signs of parkinsonism. Pathological evaluation reveals deposition of abnormally metabolized alpha‐synuclein, termed Lewy bodies. Clinical signs of DLB may be misdiagnosed in young patients with coexisting psychiatric disorders. A 43‐year‐old left‐handed man with a history of chronic paranoid schizophrenia, controlled with haloperidol, paroxetine, quetiapine, and clonazepam, presented with a 3‐year history of declining short‐term memory and concentration. He had a twin brother who was diagnosed with DLB and passed away at 40 years of age.MethodsThe patient was evaluated with serum laboratory tests to evaluate for metabolic abnormalities, infection, and heavy metal toxicity, including complete blood count, comprehensive metabolic panel, vitamin B12, folate, thyroid stimulating hormone, copper, and zinc. MRI Brain and subsequent PET‐FDG Brain were also conducted.ResultsThe results of the serum laboratory tests were all normal. MRI Brain was notable for bilateral parieto‐occipital atrophy and minimal chronic microvascular changes. PET‐FDG Brain revealed hypometabolism in bilateral parietal and occipital regions, with a cingulate island sign, indicative of advanced dementia with Lewy bodies.ConclusionDementia with Lewy bodies is a form of dementia that can sometimes present at an early age, and can be associated with psychological comorbidities and genetic risk factors. Further study of this case will include screening for mutations in the GBA gene, which encodes the enzyme beta‐glucocerebrosidease, which is the most frequent genetic association with dementia with Lewy bodies. Counseling on diagnosis and prognosis has been provided to the patient and his family, and he is being managed with rivastigmine 1.5mg twice daily to help slow down cognitive decline.

Biomarkers and neuropathology in posterior cortical atrophy: an international, multi‐site study

AbstractBackgroundPosterior cortical atrophy (PCA) is a clinically defined syndrome characterized by impairment in higher‐order visual processing. The underlying pathology in PCA is most commonly Alzheimer’s disease (AD), but large‐scale biomarker and neuropathological studies are lacking. In this ongoing project we aim to describe demographic, clinical, biomarker and neuropathological correlates of PCA in a large‐scale international cohort.MethodWe contacted 55 research centers conducting PCA research identified in a literature review (n=1353 papers) as well as additional sites recruited through the ISTAART Atypical AD Professional Interest Group (n=7 sites) requesting deidentified, single‐subject data from PCA patients (published and unpublished). Inclusion criteria were: 1. clinical diagnosis of PCA, 2. availability of AD biomarkers (PET or CSF) or 3. availability of autopsy diagnosis. Single‐subject demographic, clinical, fluid, neuroimaging and neuropathological data were collected.ResultAs of January 2022, we have collected individual patient data from 390 participants evaluated at 14 sites in 10 countries (Table 1). In the preliminary sample, mean age at symptom onset was 63.1 ± 8.8 years, 62.3% of participants were female, and 78.3% presented with a “PCA‐pure” clinical syndrome by Crutch 2017 diagnostic criteria. APOE4 genotype was present in 45.6% (n=125). Preliminary results show that 82.9% (n=270) display predominant MRI atrophy and 91.9% (n=185) predominant FDG hypometabolism in posterior cortical regions. CSF amyloid markers were positive in 80.2% participants (n=187), while CSF phosphorylated tau markers were positive in 61.4% (n=184). Amyloid PET was positive in 85.2% (n=129) while tau PET was only available in 65 patients (positive in all, and all were amyloid positive). At autopsy (n=36, data from 4 centers), high AD neuropathologic changes were found in all but one patient, who had primary frontotemporal lobar degeneration with TDP‐43 type A pathology. Lewy bodies, argyrophilic grains and cerebral amyloid angiopathy were common co‐pathologies (Figure 1).ConclusionIn a large international cohort, PCA is strongly associated with positive AD biomarkers and neuropathology. Data collection is ongoing, and we further aim to identify clinical features associated with non‐AD underlying causes of PCA.

A longitudinal investigation of physical and cognitive activities and the outcome of trajectories of AD neuroimaging biomarkers: The Mayo Clinic Study of Aging

AbstractBackgroundPhysical and cognitive activities are associated with decreased risk of mild cognitive impairment and dementia. However, the longitudinal associations between physical and cognitive activities with trajectories of Alzheimer’s disease (AD) neuroimaging biomarkers among older adults free of dementia remain unclear.MethodWe conducted a longitudinal study derived from the population‐based Mayo Clinic Study of Aging, including individuals aged ≥ 50 years who were free of dementia. Participants had information on physical and cognitive activity engagement in midlife (ages 30‐45 for participants aged 50‐69; ages 50‐65 for participants aged ≥ 70) and late‐life (12 months prior to baseline assessment), and AD biomarker assessments. We calculated linear mixed‐effect models to examine the association between baseline physical and cognitive activity composite scores for mid‐ and late‐life, and trajectories for individual yearly change in amyloid deposition (measured by PiB‐PET), tau burden (measured by Tau‐PET), regional glucose hypometabolism (measured by FDG‐PET), cortical thickness (measured by MRI), and white matter hyper intensities (WMH, measured by FLAIR‐MRI). The models were adjusted for age, sex, and APOE ɛ4 carrier status.ResultThe sample included 2755 persons (52% males; 2462 cognitively unimpaired, 293 with MCI). The mean [SD] age was 72.7 [9.8] years; 774 participants were APOE ɛ4 carriers. Although, overall, participants showed an increase in amyloid deposition, tau burden, WMH, and a decrease in glucose metabolism and cortical thickness over time, those with higher late‐life physical activity experienced less pronounced increase in Tau‐PET SUVR over time [estimate for late‐life physical activity with time interaction: ‐0.002; 95% CI ‐0.004, ‐0.000; p = 0.034]. In addition, participants with higher cognitive activities in midlife [est. for midlife cognitive activity with time interaction: 0.001; 95% CI 0.000, 0.003; p = 0.026] and late‐life [est. for late‐life cognitive activity with time interaction 0.002; 95% CI 0.001, 0.003; p = 0.005] had less pronounced decrease in FDG‐PET SUVR over time. There were no further significant interactions.ConclusionPreliminary findings suggest significant associations between 1) late‐life physical activity and less tauopathy, and 2) cognitive activities in mid‐ and late‐life with less synaptic dysfunction over time. Further research is needed to validate study findings.

Hypometabolic and hypermetabolic brain regions in patients with ALS-FTD show distinct patterns of grey and white matter degeneration: A pilot multimodal neuroimaging study

BackgroundUp to 50% of amyotrophic lateral sclerosis (ALS) patients develop some degree of cognitive dysfunction and a small proportion of these develop frontotemporal dementia (FTD). Non-invasive techniques of magnetic resonance imaging (MRI) and [18F]-fluoro-2-deoxy-d-glucose (18F-FDG) positron emission tomography (PET) have demonstrated structural and metabolic abnormalities, respectively, in the brains of such patients with ALS-FTD. Although initial 18F-FDG PET studies in ALS patients showed only hypometabolism of motor and extramotor brain regions, subsequent studies have demonstrated hypermetabolic changes as well. Such contrasting findings prompted us to hypothesize that hypo- and hypermetabolic brain regions in ALS-FTD patients are associated with divergent degeneration of structural grey matter (GM) and white matter (WM). MethodsCerebral glucose metabolic rate (CMRglc), cortical thickness (CT), fractal dimension (FD), and graph theory WM network analyses were performed on clinical MRI and 18F-FDG PET images from 8 ALS-FTD patients and 14 neurologic controls to explore the relationship between GM-WM degeneration and hypo- and hypermetabolic brain regions. ResultsCMRglc revealed significant hypometabolism in frontal and precentral gyrus brain regions, with hypermetabolism in temporal, occipital and cerebellar regions. Cortical thinning was noted in both hypo- and hypermetabolic brain areas. Unlike CT, FD did not reveal widespread GM degeneration in hypo- and hypermetabolic brain regions of ALS-FTD patients. Graph theory analysis showed severe WM degeneration in hypometabolic but not hypermetabolic areas, especially in the right hemisphere. ConclusionOur multimodal MRI-PET study provides insights into potentially differential pathophysiological mechanisms between hypo- and hypermetabolic brain regions of ALS-FTD patients.