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Ten percent to 15% of glucose used by the brain is metabolized nonoxidatively despite adequate tissue oxygenation, a process termed aerobic glycolysis (AG). Because of the known role of glycolysis in biosynthesis, we tested whether learning-induced synaptic plasticity would lead to regionally appropriate, learningdependent changes in AG. Functional MRI (fMRI) before, during, and after performance of a visual–motor adaptation task demonstrated that left Brodmann area 44 (BA44) played a key role in adaptation, with learning-related changes to activity during the task and altered resting-state, functional connectivity after the task. PET scans before and after task performance indicated a sustained increase inAG in left BA 44 accompanied by decreased oxygen consumption. Intersubject variability in behavioral adaptation rate correlated strongly with changes in AG in this region, as well as functional connectivity, which is consistent with a role for AG in synaptic plasticity. [ABSTRACT FROM AUTHOR]

Motor features of Parkinson's disease (PD) are heterogeneous and well-studied; non-tremor features of postural instability and gait dysfunction (PIGD) have been linked to worse outcomes and Alzheimer's disease (AD) co-pathology. However, these features are understudied in Lewy body dementias (LBD). Here we perform retrospective analysis of a unique cohort of LBD (n = 30) with Unified Parkinson's Disease Rating Scale (UPDRS) data collected at baseline in proximity to cerebrospinal fluid collection to test the hypothesis that LBD patients with a positive AD biomarker profile (LBD + AD = 13) would have higher PIGD burden compared with LBD patients without AD biomarker positivity (LBD-AD = 17). We find novel evidence for selective impairment of PIGD burden in LBD + AD vs LBD-AD (OR = 1.95, 95%CI = 1.02-3.70, p = 0.04) and a direct association of increasing CSF tau/Aβ1-42 ratio with increasing PIGD disability in the total cohort (β = 0.23, SE = 0.08, p = 0.01). This unique biomarker stratification approach suggests AD co-pathology may contribute to PIGD motor signs in LBD. [ABSTRACT FROM AUTHOR]

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neuropathologic subtypes of frontotemporal lobar degeneration with tau inclusions (FTLD-tau), primary tauopathies in which intracellular tau aggregation contributes to neurodegeneration. Gosuranemab (BIIB092) is a humanized monoclonal antibody that binds to N-terminal tau. While Gosuranemab passive immunotherapy trials for PSP failed to demonstrate clinical benefit, Gosuranemab reduced N-terminal tau in the cerebrospinal fluid of transgenic mouse models and PSP patients. However, the neuropathologic sequelae of Gosuranemab have not been described. In this present study, we examined the brain tissue of three individuals who received Gosuranemab. Post-mortem human brain tissues were studied using immunohistochemistry to identify astrocytic and microglial differences between immunized cases and a cohort of unimmunized PSP, CBD and aging controls. Gosuranemab immunotherapy was not associated with clearance of neuropathologic FTLD-tau inclusions. However, treatment-associated changes were observed including the presence of perivascular vesicular astrocytes (PVA) with tau accumulation within lysosomes. PVAs were morphologically and immunophenotypically distinct from the tufted astrocytes seen in PSP, granular fuzzy astrocytes (GFA) seen in aging, and astrocytic plaques seen in CBD. Additional glial responses included increased reactive gliosis consisting of bushy astrocytosis and accumulation of rod microglia. Together, these neuropathologic findings suggest that Gosuranemab may be associated with a glial response including accumulation of tau within astrocytic lysosomes. [ABSTRACT FROM AUTHOR]

We compared regional retention of 18F-flortaucipir between 20 patients with Lewy body disorders (LBD), 12 Alzheimer's disease patients with positive amyloid positron emission tomography (PET) scans (AD+Aβ) and 15 healthy controls with negative amyloid PET scans (HC−Aβ). In LBD subjects, we compared the relationship between 18F-flortaucipir retention and cerebrospinal fluid (CSF) tau, cognitive performance, and neuropathological tau at autopsy. The LBD cohort was stratified using an Aβ42 cut-off of 192 pg/mL to enrich for groups likely harboring tau pathology (LBD+Aβ = 11, LBD−Aβ = 9). 18F-flortaucipir retention was higher in LBD+AB than HC−Aβ in five, largely temporal-parietal regions with sparing of medial temporal regions. Higher retention was associated with higher CSF total-tau levels (p = 0.04), poorer domain-specific cognitive performance (p = 0.02–0.04), and greater severity of neuropathological tau in corresponding regions. While 18F-flortaucipir retention in LBD is intermediate between healthy controls and AD, retention relates to cognitive impairment, CSF total-tau, and neuropathological tau. Future work in larger autopsy-validated cohorts is needed to define LBD-specific tau biomarker profiles. • LBD has moderate intensity 18F-Flortaucipir retention in temporo-parietal regions. • LBD with low CSF Aβ42 has more regions of elevated 18F-Flortaucipir retention. • In LBD, 18F-Flortaucipir retention relates to CSF total-tau. • In LBD, regional 18F-Flortaucipir retention relates to cognitive dysfunction. • In LBD, neuropathologic tau is higher in regions with greater retention. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the impact of Alzheimer's disease (AD) co‐pathology on an in vivo structural measure of neurodegeneration in Lewy body disorders (LBD). Methods: We studied 72 LBD patients (Parkinson disease (PD) = 2, PD‐MCI = 25, PD with dementia = 10, dementia with Lewy bodies = 35) with either CSF analysis or neuropathological examination and structural MRI during life. The cohort was divided into those harboring significant AD co‐pathology, either at autopsy (intermediate/high AD neuropathologic change) or with CSF signature indicating AD co‐pathology (t‐tau/Aβ1‐42 > 0.3) (LBD+AD, N = 19), and those without AD co‐pathology (LBD−AD, N = 53). We also included a reference group of 25 patients with CSF biomarker‐confirmed amnestic AD. We investigated differences in MRI cortical thickness estimates between groups, and in the 21 autopsied LBD patients (LBD−AD = 14, LBD+AD = 7), directly tested the association between antemortem MRI and post‐mortem burdens of tau, Aβ, and alpha‐synuclein using digital histopathology in five representative neocortical regions. Results: The LBD+AD group was characterized by cortical thinning in anterior/medial and lateral temporal regions (P < 0.05 FWE‐corrected) relative to LBD−AD. In LBD+AD, cortical thinning was most pronounced in temporal neocortex, whereas the AD reference group showed atrophy that equally encompassed temporal, parietal and frontal neocortex. In autopsied LBD, we found an inverse correlation with cortical thickness and post‐mortem tau pathology, while cortical thickness was not significantly associated with Aβ or alpha‐synuclein pathology. Interpretation: LBD+AD is characterized by temporal neocortical thinning on MRI, and cortical thinning directly correlated with post‐mortem histopathologic burden of tau, suggesting that tau pathology influences the pattern of neurodegeneration in LBD. [ABSTRACT FROM AUTHOR]

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

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

We aim to better characterize mild cognitive impairment (MCI) patients with suspected non-Alzheimer's disease (AD) pathology (SNAP) based on their longitudinal outcome, cognition, biofluid, and neuroimaging profile. MCI participants (n = 361) from ADNI-GO/2 were designated “amyloid positive” with abnormal amyloid-beta 42 levels (AMY+) and “neurodegeneration positive” (NEU+) with abnormal hippocampal volume or hypometabolism using fluorodeoxyglucose–positron emission tomography. SNAP was compared with the other MCI groups and with AMY− controls. AMY−NEU+/SNAP, 16.6%, were older than the NEU− groups but not AMY− controls. They had a lower conversion rate to AD after 24 months than AMY+NEU+ MCI participants. SNAP-MCI participants had similar amyloid-beta 42 levels, florbetapir and tau levels, but larger white matter hyperintensity volumes than AMY− controls and AMY−NEU− MCI participants. SNAP participants performed worse on all memory domains and on other cognitive domains, than AMY−NEU− participants but less so than AMY+NEU+ participants. Subthreshold levels of cerebral amyloidosis are unlikely to play a role in SNAP-MCI, but pathologies involving the hippocampus and cerebrovascular disease may underlie the neurodegeneration and cognitive impairment in this group. [ABSTRACT FROM AUTHOR]