Intermittent swimming and muscle power output in brook trout, Salvelinus fontinalis.

Slow and sustainable intermittent swimming has recently been described in several Centrarchid fishes, such as bluegill and largemouth bass. This swimming behavior involves short periods of body-caudal fin undulation alternating with variable periods of coasting. This aerobic muscle powered swimming appears to reduce energetic costs for slow, sustainable swimming, with fish employing a "fixed-gear" or constant tailbeat frequency and modulating swimming speed by altering the length of the coasting period. We asked if this swimming behavior was found in other fish species by examining volitional swimming by brook trout in a static swimming tank. Further, we employed muscle mechanics experiments to explore how intermittent swimming affects muscle power output in comparison to steady swimming behavior. Brook trout regularly employ an intermittent swimming form when allowed to swim volitionally, and consistently showed a tailbeat frequency of ~2 Hz. Coasting duration had a significant, inverse relationship to swimming speed. Across a range of slow, sustainable swimming speeds, tailbeat frequency increased modestly with speed. The duration of periods of coasting decreased significantly with increasing speed. Workloop experiments suggest that intermittent swimming reduces fatigue, allowing fish to maintain high power output for longer compared to continuous activity. This study expands the list of species that employ intermittent swimming, suggesting this behavior is a general feature of fishes.

Sex differences for clinical correlates of substantia nigra neuron loss in people with Lewy body pathology.

BACKGROUND: Lewy body dementia (LBD) phenotype is associated with the presence and degree of Lewy body, Alzheimer's pathologies, and substantia nigra neuron loss. Nigral neuron loss is associated with parkinsonism in LBD, and females with LBD are less likely than males to have parkinsonism. As sex differences were reported for clinical correlates of Lewy body and Alzheimer's pathologies, we aimed to investigate whether there are also sex differences for correlates of nigral neuron loss. METHODS: Data were obtained from the National Alzheimer's Coordinating Center for females (n = 159) and males (n = 263) with brainstem, limbic, and neocortical Lewy body pathology. Sex differences for the nigral neuron loss' association with Lewy body pathology staging and core clinical LBD features (cognitive fluctuations, visual hallucinations, rapid eye movement sleep behavior disorder, parkinsonism) during follow-up were analyzed with generalized linear models adjusting for age and Alzheimer's pathology staging. Whether any of the core clinical features at the time of dementia onset can predict underlying nigral neuron loss for females and males were also analyzed with generalized linear models. RESULTS: Compared to males, females died older and had higher levels of Braak tau staging, but had similar levels of Lewy body pathology staging and nigral neuron loss. Females were less likely than males to have a clinical Lewy body disease diagnosis during follow-up. More advanced Lewy body pathology staging was associated with more nigral neuron loss, more so for males than females. More nigral neuron loss was associated with parkinsonism and clinical LBD diagnosis during follow-up, more so for males than females. Across the subgroup with dementia (40 females, 58 males), core LBD features at first visit with dementia were not associated with nigral neuron loss. CONCLUSIONS: Nigral neuron loss' association with Lewy body pathology staging and core LBD features can differ by sex. Compared to males, females with Lewy body pathology have a higher risk of underdiagnosis. There is a need to elucidate the mechanisms underlying sex differences for pathology and clinicopathological correlations to advance diagnostic and therapeutic efforts in LBD.

Lewy body dementia (LBD) is the third most common dementia associated with Lewy body pathology, Alzheimer's pathology, and substantia nigra loss. It is often less recognized in females compared to males, because the typical symptoms are less evident in females. In this study, we investigated whether substantia nigra neuron loss plays a role in the atypical presentation of LBD in females, contributing to the underdiagnosis compared to males. We analyzed data from 159 females and 263 males with pathological Lewy body disease obtained from the National Alzheimer's Coordinating Center. Females tended to be older at the time of death and had more tau buildup, but similar levels of Lewy body pathology and substantia nigra neuron loss compared to males. When we compared males and females of similar age with similar levels of Alzheimer's pathology, we observed that females had less substantia nigra neuron loss at less advanced Lewy body pathology stages. Greater nigral neuron loss was associated with parkinsonism and the typical LBD symptoms in males, but not as strongly in females. The extent of nigral loss could not be predicted based on the clinical features at the time of dementia diagnosis. Thus, the relationship between nigral neuron loss and the LBD symptoms seems to vary by sex. Females with underlying Lewy body disease are more likely to be underdiagnosed compared to males. We need further work to understand why these sex differences exist and how we can better identify and treat LBD.

TDP43 pathology in chronic traumatic encephalopathy retinas.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive head trauma. Brain pathology in CTE is characterized by neuronal loss, gliosis, and a distinctive pattern of neuronal accumulation of hyper-phosphorylated tau (p-tau) and phospho-TDP43 (p-TDP43). Visual anomalies have been reported by patients with CTE, but the ocular pathology underlying these symptoms is unknown. We evaluated retinal pathology in post-mortem eyes collected from 8 contact sport athletes with brain autopsy-confirmed stage IV CTE and compared their findings to retinas from 8 control patients without CTE and with no known history of head injury. Pupil-optic nerve cross sections were prepared and stained with hematoxylin and eosin (H&E), p-tau, p-TDP43, and total TDP43 by immunohistochemistry. No significant retinal degeneration was observed in CTE eyes compared to control eyes by H&E. Strong cytoplasmic p-TDP43 and total TDP43 staining was found in 6/8 CTE eyes in a subset of inner nuclear layer interneurons (INL) of the retina, while only 1/8 control eyes showed similar p-TDP43 pathology. The morphology and location of these inner nuclear layer interneurons were most compatible with retinal horizontal cells, although other retinal cell types present in INL could not be ruled out. No p-tau pathology was observed in CTE or control retinas. These findings identify novel retinal TDP43 pathology in CTE retinas and support further investigation into the role of p-TDP43 in producing visual deficits in patients with CTE.

Muscle power production during intermittent swimming in bluegill sunfish.

Locomotion is essential for the survival and fitness of animals. Fishes have evolved a variety of mechanisms to minimize the cost of transport. For instance, bluegill sunfish have recently been shown to employ intermittent swimming in nature and in laboratory conditions. We focused on the functional properties of the power-producing muscles that generate propulsive forces in bluegill to understand the implications of intermittent activity. We used in vivo aerobic or red muscle activity parameters (e.g., oscillation frequency and onset time and duration of activation) in muscle physiology experiments to examine muscle power output during intermittent versus steady swimming in these fish. Intermittent propulsion involves swimming at relatively slow speeds with short propulsive bursts alternating with gliding episodes. The propulsive bursts are at higher oscillation frequencies than would be predicted for a given average swimming speed with constant propulsion. The work-loop muscle physiology experiments with red muscle demonstrated that intermittent activity allows muscle to produce sufficient power for swimming compared with imposed steady swimming conditions. Further, the intermittent muscle activity in vitro reduces fatigue relative to steady or continuous activity. This work supports the fixed-gear hypothesis that suggests that there are preferred oscillation frequencies that optimize efficiency in muscle use and minimize cost of transport.

Case report: Neuronal intranuclear inclusion disease presenting with acute encephalopathy.

Neuronal intranuclear inclusion disease (NIID), a neurodegenerative disease previously thought to be rare, is increasingly recognized despite heterogeneous clinical presentations. NIID is pathologically characterized by ubiquitin and p-62 positive intranuclear eosinophilic inclusions that affect multiple organ systems, including the brain, skin, and other tissues. Although the diagnosis of NIID is challenging due to phenotypic heterogeneity, a greater understanding of the clinical and imaging presentations can improve accurate and early diagnosis. Here, we present three cases of pathologically proven adult-onset NIID, all presenting with episodes of acute encephalopathy with protracted workups and lengthy time between symptom onset and diagnosis. Case 1 highlights challenges in the diagnosis of NIID when MRI does not reveal classic abnormalities and provides a striking example of hyperperfusion in the setting of acute encephalopathy, as well as unique pathology with neuronal central chromatolysis, which has not been previously described. Case 2 highlights the progression of MRI findings associated with multiple NIID-related encephalopathic episodes over an extended time period, as well as the utility of skin biopsy for antemortem diagnosis.

Fluid and Biopsy Based Biomarkers in Parkinson's Disease.

Several advances in fluid and tissue-based biomarkers for use in Parkinson's disease (PD) and other synucleinopathies have been made in the last several years. While work continues on species of alpha-synuclein (aSyn) and other proteins which can be measured from spinal fluid and plasma samples, immunohistochemistry and immunofluorescence from peripheral tissue biopsies and alpha-synuclein seeding amplification assays (aSyn-SAA: including real-time quaking induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA)) now offer a crucial advancement in their ability to identify aSyn species in PD patients in a categorical fashion (i.e., of aSyn + vs aSyn -); to augment clinical diagnosis however, aSyn-specific assays that have quantitative relevance to pathological burden remain an unmet need. Alzheimer's disease (AD) co-pathology is commonly found postmortem in PD, especially in those who develop dementia, and dementia with Lewy bodies (DLB). Biofluid biomarkers for tau and amyloid beta species can detect AD co-pathology in PD and DLB, which does have relevance for prognosis, but further work is needed to understand the interplay of aSyn tau, amyloid beta, and other pathological changes to generate comprehensive biomarker profiles for patients in a manner translatable to clinical trial design and individualized therapies.

Tau seeds occur before earliest Alzheimer's changes and are prevalent across neurodegenerative diseases.

Tau neurofibrillary tangles are a hallmark of Alzheimer's disease neuropathological change. However, it remains largely unclear how distinctive Alzheimer's disease tau seeds (i.e. 3R/4R) correlate with histological indicators of tau accumulation. Furthermore, AD tau co-pathology is thought to influence features and progression of other neurodegenerative diseases including Lewy body disease; yet measurements of different types of tau seeds in the setting of such diseases is an unmet need. Here, we use tau real-time quaking-induced conversion (RT-QuIC) assays to selectively quantitate 3R/4R tau seeds in the frontal lobe which accumulates histologically identifiable tau pathology at late disease stages of AD neuropathologic change. Seed quantitation across a spectrum of neurodegenerative disease cases and controls indicated tau seeding activity can be detected well before accompanying histopathological indication of tau deposits, and even prior to the earliest evidence of Alzheimer's-related tau accumulation anywhere in the brain. In later stages of AD, 3R/4R tau RT-QuIC measures correlated with immunohistochemical tau burden. In addition, Alzheimer's tau seeds occur in the vast majority of cases evaluated here inclusive of primary synucleinopathies, frontotemporal lobar degeneration and even controls albeit at multi-log lower levels than Alzheimer's cases. α-synuclein seeding activity confirmed synucleinopathy cases and further indicated the co-occurrence of α-synuclein seeds in some Alzheimer's disease and primary tauopathy cases. Our analysis indicates that 3R/4R tau seeds in the mid-frontal lobe correlate with the overall Braak stage and Alzheimer's disease neuropathologic change, supporting the quantitative predictive value of tau RT-QuIC assays. Our data also indicate 3R/4R tau seeds are elevated in females compared to males at high (≥ IV) Braak stages. This study suggests 3R/4R tau seeds are widespread even prior to the earliest stages of Alzheimer's disease changes, including in normal, and even young individuals, with prevalence across multiple neurodegenerative diseases to further define disease subtypes.

Impacts of thermal acclimatization on fish skeletal muscle.

Thermal acclimation allows ectotherms to maintain physiological homeostasis while occupying habitats with constantly changing temperatures. This process is especially important in skeletal muscle which powers most movements necessary for life. We aimed to understand how fish skeletal muscle is impacted by acclimatization in the laboratory. To accomplish this, we compared muscle contraction kinetics of four-week lab acclimatized fish (at 20 °C) to fish taken directly from the field when sea surface temperatures were similar to lab treatment temperature (ocean temperature ranged from 17.7 to 19.9 °C in the four weeks prior to collection at 20 °C). To examine these effects, we chose to study tautog (Tautoga onitis) and cunner (Tautogolabrus adspersus) from Long Island Sound. We found that timing of contraction kinetics in cunner and tautog did not differ from the lab acclimatized and field acclimatized groups. However, lab acclimatized cunner produced greater contraction force than fish taken directly from the field. This increased force production allowed lab acclimatized cunner to produce greater power when compared to cunner from the field treatment. Furthermore, laboratory acclimatized cunner did not express any slow myosin heavy chain, suggesting that their muscle had transitioned to mostly fast twitch fibers after being held at a constant temperature in the lab. None of these effects were seen in tautog. In this work we highlight the importance of considering the impacts laboratory conditions have on experimental conditions.

Metabolic reprogramming underlies cavefish muscular endurance despite loss of muscle mass and contractility.

Physical inactivity is a scourge to human health, promoting metabolic disease and muscle wasting. Interestingly, multiple ecological niches have relaxed investment into physical activity, providing an evolutionary perspective into the effect of adaptive physical inactivity on tissue homeostasis. One such example, the Mexican cavefish Astyanax mexicanus, has lost moderate-to-vigorous activity following cave colonization, reaching basal swim speeds ~3.7-fold slower than their river-dwelling counterpart. This change in behavior is accompanied by a marked shift in body composition, decreasing total muscle mass and increasing fat mass. This shift persisted at the single muscle fiber level via increased lipid and sugar accumulation at the expense of myofibrillar volume. Transcriptomic analysis of laboratory-reared and wild-caught cavefish indicated that this shift is driven by increased expression of pparγ-the master regulator of adipogenesis-with a simultaneous decrease in fast myosin heavy chain expression. Ex vivo and in vivo analysis confirmed that these investment strategies come with a functional trade-off, decreasing cavefish muscle fiber shortening velocity, time to maximal force, and ultimately maximal swimming speed. Despite this, cavefish displayed a striking degree of muscular endurance, reaching maximal swim speeds ~3.5-fold faster than their basal swim speeds. Multi-omic analysis suggested metabolic reprogramming, specifically phosphorylation of Pgm1-Threonine 19, as a key component enhancing cavefish glycogen metabolism and sustained muscle contraction. Collectively, we reveal broad skeletal muscle changes following cave colonization, displaying an adaptive skeletal muscle phenotype reminiscent to mammalian disuse and high-fat models while simultaneously maintaining a unique capacity for sustained muscle contraction via enhanced glycogen metabolism.

Morphological and histochemical characterization of the pectoral fin muscle of batoids.

Batoids differ from other elasmobranch fishes in that they possess dorsoventrally flattened bodies with enlarged muscled pectoral fins. Most batoids also swim using either of two modes of locomotion: undulation or oscillation of the pectoral fins. In other elasmobranchs (e.g., sharks), the main locomotory muscle is located in the axial myotome; in contrast, the main locomotory muscle in batoids is found in the enlarged pectoral fins. The pectoral fin muscles of sharks have a simple structure, confined to the base of the fin; however, little to no data are available on the more complex musculature within the pectoral fins of batoids. Understanding the types of fibers and their arrangement within the pectoral fins may elucidate how batoid fishes are able to utilize such unique swimming modes. In the present study, histochemical methods including succinate dehydrogenase (SDH) and immunofluoresence were used to determine the different fiber types comprising these muscles in three batoid species: Atlantic stingray (Dasyatis sabina), ocellate river stingray (Potamotrygon motoro) and cownose ray (Rhinoptera bonasus). All three species had muscles comprised of two muscle fiber types (slow-red and fast-white). The undulatory species, D. sabina and P. motoro, had a larger proportion of fast-white muscle fibers compared to the oscillatory species, R. bonasus. The muscle fiber sizes were similar between each species, though generally smaller compared to the axial musculature in other elasmobranch fishes. These results suggest that batoid locomotion can be distinguished using muscle fiber type proportions. Undulatory species are more benthic with fast-white fibers allowing them to contract their muscles quickly, as a possible means of escape from potential predators. Oscillatory species are pelagic and are known to migrate long distances with muscles using slow-red fibers to aid in sustained swimming.

Thermal acclimation in brook trout myotomal muscle varies with fiber type and age.

As climate change alters the thermal environment of the planet, interest has grown in how animals may mitigate the impact of a changing environment on physiological function. Thermal acclimation to a warm environment may, for instance, blunt the impact of a warming environment on metabolism by allowing a fish to shift to slower isoforms of functionally significant proteins such as myosin heavy chain. The thermal acclimation of brook trout (Salvelinus fontinalis) was examined by comparing swimming performance, myotomal muscle contraction kinetics and muscle histology in groups of fish acclimated to 4, 10 and 20 °C. Brook trout show a significant acclimation response in their maximum aerobic swimming performance (Ucrit), with acclimation to warm water leading to lower Ucrit values. Maximum muscle shortening velocity (Vmax) decreased significantly with warm acclimation for both red or slow-twitch and white or fast-twitch muscle. Immunohistochemical analysis of myotomal muscle suggests changes in myosin expression underly the thermal acclimation of swimming performance and contraction kinetics. Physiological and histological data suggest a robust acclimation response to a warming environment, one that would reduce the added metabolic costs incurred by an ectotherm when environmental temperature rises for sustained periods of time.

Digital Histological Study of Neocortical Grey and White Matter Tau Burden Across Tauopathies.

3R/4R-tau species are found in Alzheimer disease (AD) and ∼50% of Lewy body dementias at autopsy (LBD+tau); 4R-tau accumulations are found in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Digital image analysis techniques can elucidate patterns of tau pathology more precisely than traditional methods but repeatability across centers is unclear. We calculated regional percentage areas occupied by tau pathological inclusions from the middle frontal cortex (MFC), superior temporal cortex (STC), and angular gyrus (ANG) from cases from the University of Pennsylvania and the University of California San Diego with AD, LBD+tau, PSP, or CBD (n = 150) using QuPath. In both cohorts, AD and LBD+tau had the highest grey and white matter tau burden in the STC (p ≤ 0.04). White matter tau burden was relatively higher in 4R-tauopathies than 3R/4R-tauopathies (p < 0.003). Grey and white matter tau were correlated in all diseases (R2=0.43-0.79, p < 0.04) with the greatest increase of white matter per unit grey matter tau observed in PSP (p < 0.02 both cohorts). Grey matter tau negatively correlated with MMSE in AD and LBD+tau (r = -4.4 to -5.4, p ≤ 0.02). These data demonstrate the feasibility of cross-institutional digital histology studies that generate finely grained measurements of pathology which can be used to support biomarker development and models of disease progression.

Perception of Fragmented Letters by Patients With Pathologically Confirmed Dementia With Lewy Bodies or Alzheimer Disease.

BACKGROUND AND OBJECTIVE: Patients with dementia with Lewy bodies perform worse than those with Alzheimer disease (AD) on tests of visual perception, but the clinical utility of these tests remains unknown because studies often had clinically diagnosed groups that may inadvertently cross-contaminate Lewy body disease (LBD) with pure AD pathology, used experimental tests not easily adaptable for clinical use, and had no way to examine relationships between the severity of LBD pathology and degree of cognitive impairment. Therefore, we sought to determine whether performance on a widely used clinical test of visuoperceptual ability effectively differentiates between patients with autopsy-confirmed LBD or AD and correlates with the severity of LBD pathology. METHODS: Patients with mild to moderate dementia (n = 42) and cognitively healthy controls (n = 22) performed a Fragmented Letters Test in which they identified letters of the alphabet that were randomly visually degraded by 70% and additional visuospatial and episodic memory tests. At autopsy, dementia cases were confirmed to have LBD (n = 19), all with concomitant AD, or only AD (n = 23). Severity of α-synuclein pathology in the hippocampus and neocortex was rated on an ordinal scale. RESULTS: Patients with LBD performed worse than those with AD (B = -2.80 ± 0.91, p = 0.009) and healthy controls (B = -3.34 ± 1.09, p = 0.01) on the Fragmented Letters Test after adjustment for age, sex, education, Mini-Mental State Examination score, and ability to name intact letters. Patients with AD did not differ from controls (B = -0.55 ± 1.08, p = 0.87). The test effectively distinguished between patients with LBD or AD with 73% sensitivity and 87% specificity, and the area under the curve in receiver operating characteristic analyses was 0.85 (95% CI 0.72-0.95), higher than for standard tests of visuospatial ability (Block Design; 0.72; CI 0.35-0.75) or memory (California Verbal Learning Test, trials 1-5; 0.55; CI 0.57-0.88). Fragmented Letters Test scores were negatively correlated with LBD pathology density ratings in hippocampus and neocortical regions (Spearman rs = -0.53 to -0.69). DISCUSSION: Fragmented Letters Test performance can effectively differentiate patients with LBD pathology from those with only AD pathology at a mild to moderate stage of dementia, even when LBD occurs with significant concomitant AD pathology, and may also be useful for gauging the severity of cortical α-synuclein pathology in those with LBD.

α-Synuclein Seed Amplification in CSF and Brain from Patients with Different Brain Distributions of Pathological α-Synuclein in the Context of Co-Pathology and Non-LBD Diagnoses.

OBJECTIVE: The purpose of this study was to determine the sensitivity and specificity of α-synuclein seed amplification assay (αSyn-SAA) in antemortem and postmortem cerebrospinal fluid (CSF) of autopsy-confirmed patients with different distributions of pathological αSyn, co-pathologies, and clinical diagnoses. METHODS: The αSyn-SAA was used to test antemortem CSF samples from 119 subjects with a variety of clinical syndromes and standardized neuropathological examinations from Oregon Health and Science University (OHSU) and University of California San Diego (UCSD; 56 additional postmortem CSF samples available). The αSyn-SAA was also applied to frontal cortex and amygdala homogenates. Sensitivity and specificity were compared across distributions of αSyn pathology. Clinical data and co-pathologies were compared across αSyn-SAA positive and negative groups. RESULTS: Fifty-three individuals without and 66 with αSyn-pathology (neocortical [n = 38], limbic [n = 7], and amygdala-predominant [n = 21]) were included. There was a sensitivity of 97.8% and specificity of 98.1% of the αSyn-SAA to identify patients with limbic/neocortical pathology from antemortem CSF. Sensitivity to detect amygdala-predominant pathology was only 14.3%. Postmortem CSF and brain tissue αSyn-SAA analyses also showed higher assay positivity in samples from limbic/neocortical cases. INTERPRETATION: CSF αSyn-SAA reliably identifies αSyn seeds in patients with diffuse αSyn pathology in the context of co-pathology and non-Lewy body disease (LBD) diagnoses. The analysis of brain homogenates suggests that pathological αSyn in the amygdala might differ from pathological αSyn in the frontal cortex. The αSyn-SAA might facilitate the differential diagnosis of dementias with mixed pathologies. ANN NEUROL 2022;92:650-662.

Investigational therapeutics for the treatment of progressive supranuclear palsy.

INTRODUCTION: Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disease marked by a variety of movement, ocular, and cognitive symptoms. Currently, treatment is symptomatic, and there are no disease-modulating therapies. While clinical presentations can be variable, at autopsy, PSP shows 4-repeat (4 R) tau species that accumulate in brainstem, subcortical, and neocortical areas. Thus, several tau-directed therapies have been trialed in PSP but with disappointing results to date. AREAS COVERED: We review PSP clinicopathological correlates and biomarkers and searched clinicaltrials.gov and pubmed.ncbi.nlm.nih.gov for disease-modulating trials in PSP from the preclinical stage to clinical stage 3 and reviewed their rationale and results in human trials. EXPERT OPINION: Factors that may have hampered tau-directed therapies in PSP include patient selection, intervening in an advanced disease stage, lack of biomarkers for prodromal diagnosis, outcome measurements, target engagement measures, selection of specific tau epitopes, and brain penetration of trialed therapies. Coupled with early intervention, targets upstream of tau accumulation and corresponding cell death may need to be identified to modulate the disease course. PSP remains a promising disease to study tau-directed therapies, and several possible targets are being tackled using novel approaches bringing hope for future success.

Sex Differences for Clinical Correlates of Alzheimer's Pathology in People with Lewy Body Pathology.

BACKGROUND: Lewy body (LB) dementias have limited clinical diagnostic accuracy because of frequent copathologies contributing to clinical heterogeneity. Although sex differences in clinical prevalence and frequency of pure LB pathology were shown, differences for clinicopathological correlations are less known. OBJECTIVE: The aim of this study was to determine sex differences for clinical associations of Alzheimer's disease (AD) copathology in those with LB pathology. METHODS: Data were from National Alzheimer's Coordinating Center for 223 women and 468 men with limbic or neocortical LB, separated into two groups as those with high likelihood and low/intermediate likelihood for LB clinical phenotype based on pathology. Clinical associations of sex and interaction of sex and pathology for the clinical phenotype were analyzed. RESULTS: More severe AD copathology was associated with worse cognitive decline and lower likelihood of LB disease clinical phenotype. Women with more severe AD copathology and tau had worse cognitive decline and higher likelihood of AD clinical phenotype than men. Men with more severe AD copathology had lower likelihood of LB clinical phenotype than women. Interaction of sex and pathology was more pronounced in those aged between 70 and 80 years. CONCLUSIONS: AD copathology reduces the likelihood of LB clinical phenotype for both women and men; however, men may be at higher risk for LB disease underdiagnosis and women at higher risk for dementia. The use of both LB and AD biomarkers, even when LB or AD pathology is not clinically expected, is necessary for the accurate clinical diagnosis of both LB diseases and AD. © 2022 International Parkinson and Movement Disorder Society.

Lateralized ante mortem and post mortem pathology in a case of Lewy body disease with corticobasal syndrome.

Introduction: Lewy body diseases are pathologically characterized by α-synuclein pathology. Alzheimer's disease (AD) co-pathology can influence phenotypes. In vivo AD biomarkers can suggest the presence of this co-pathology in unusual cases, but pathological validation remains essential. Methods: This patient originally presented with corticobasal syndrome and later developed visual hallucinations and parkinsonism consistent with a synucleinopathy. The patient underwent CSF sampling, 18F-flortaucipir PET scanning, and brain donation with bilateral regions available for digital histological analysis. Results: CSF Aß42 and t-tau were in the AD range. 18F-flortaucipir scanning showed right-lateralized retention in all lobes (t = 4.3-10.0, P < .006). Neocortical stage Lewy body pathology and high levels of AD neuropathological changes were present at autopsy. There was right lateralization of α-synuclein and tau pathology (T value = 3.1, P value = .007 and T value = 3.3, P value = .004 respectively). Discussion: This case with overlapping tauopathy and synucleinopathy clinical features had in-depth biomarker characterization and rare bilateral post-mortem sampling showing lateralized tau and α-synuclein pathology suggesting possible synergistic relationships.

Neuropathological substrates of cognition in Parkinson's disease.

Autopsy validation is still required for a definitive diagnosis of Parkinson's disease (Postuma et al., 2015), where the presence of Lewy bodies and Lewy neurites, composed primarily of alpha-synuclein, are observed in stereotyped patterns throughout regions of the brainstem, limbic, and neocortical regions of the brain (Braak et al., 2003). In spite of these relatively reliable observed patterns of alpha-synuclein pathology, there is a large degree of heterogeneity in the timing and features of neuropsychiatric and cognitive dysfunction in Parkinson's disease (Fereshtehnejad et al., 2015; Selikhova et al., 2009; Williams-Gray et al., 2013). Detailed studies of their neuropathological substrates of cognitive dysfunction and their associations with a variety of in vivo biomarkers have begun to disentangle this complex relationship, but ongoing multicentered, longitudinal studies of well-characterized and autopsy validated cases are still required.