There is a preliminary record suggesting that β2-adrenergic agonists may have therapeutic value in Parkinson\'s disease; recent studies have proposed a possible role of these agents in suppressing the formation of α-synuclein protein, a component of Lewy bodies. The present study focuses on the importance of the prototypical β2-adrenergic agonist epinephrine in relation to the incidence of Parkinson\'s disease in humans, and its further investigation via synthetic selective β2-receptor agonists, such as levalbuterol. Levalbuterol exerts significant anti-inflammatory activity, a property that may suppress cytokine-mediated degeneration of dopaminergic neurons and progression of Parkinsonism. In a completely novel finding, epinephrine and certain other adrenergic agents modeled in the Harvard/MIT Broad Institute genomic database, CLUE, demonstrated strong associations with the gene-expression signatures of anti-inflammatory glucocorticoids. This prompted in vivo confirmation in mice engrafted with human peripheral blood mononuclear cells (PBMCs). Upon toxic activation with mononuclear antibodies, levalbuterol inhibited (1) the release of the eosinophil attractant chemokine eotaxin-1, which is implicated in CNS and peripheral inflammatory disorders, (2) elaboration of the tumor-promoting angiogenic factor VEGFa, and (3) release of the pro-inflammatory cytokine IL-13 from activated PBMCs. These observations suggest possible translation to Parkinson\'s disease, other neurodegenerative syndromes, and malignancies, via several mechanisms.

Lewy body disorders are heterogeneous neurological conditions defined by intracellular inclusions composed of misshapen α-synuclein protein aggregates. Although α-synuclein aggregates are only one component of inclusions and not strictly coupled to neurodegeneration, evidence suggests they seed the propagation of Lewy pathology within and across cells. Genetic mutations, genomic multiplications, and sequence polymorphisms of the gene encoding α-synuclein are also causally linked to Lewy body disease. In nonfamilial cases of Lewy body disease, the disease trigger remains unidentified but may range from industrial/agricultural toxicants and natural sources of poisons to microbial pathogens. Perhaps due to these peripheral exposures, Lewy inclusions appear at early disease stages in brain regions connected with cranial nerves I and X, which interface with inhaled and ingested environmental elements in the nasal or gastrointestinal cavities. Irrespective of its identity, a stealthy disease trigger most likely shifts soluble α-synuclein (directly or indirectly) into insoluble, cross-β-sheet aggregates. Indeed, β-sheet-rich self-replicating α-synuclein multimers reside in patient plasma, cerebrospinal fluid, and other tissues, and can be subjected to α-synuclein seed amplification assays. Thus, clinicians should be able to capitalize on α-synuclein seed amplification assays to stratify patients into potential responders versus non-responders in future clinical trials of α-synuclein targeted therapies. Here, we briefly review the current understanding of α-synuclein in Lewy body disease and speculate on pathophysiological processes underlying the potential transmission of α-synucleinopathy across the neuraxis.

BACKGROUND: Alzheimer\'s disease (AD) is a heterogeneous proteinopathy. Co-pathology with Lewy bodies (LB) is frequent and known to contribute to a differential pattern of executive cognitive impairment compared to typical AD. While primary age-related tauopathy (PART) presents with neurofibrillary tangles, mainly restricted to the temporal lobe and in the absence of amyloid-beta plaques, LB co-pathology is also present. However, it is still unknown how the combination of these proteinopathies affects patterns of brain atrophy, which might help clarify the clinical importance and pathophysiology of combined pathology within these groups. Here we investigated the influence of LB on patterns of brain atrophy in AD and PART.
METHODS: We selected 214 patients with AD neuropathological change (ADNC) with no LB (n = 102), ADNC with LB (ADNC+LB) (n = 77), PART with no LB (n = 22) and PART with LB (PART+LB) (n = 13) with ante-mortem volumetric MRI from the National Alzheimer\'s Coordinating Center, after exclusion of other neurodegenerative pathologies. Dementia severity was compared using Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). Cortical and subcortical MRI volume residuals were compared between groups after correction for age. Statistical significance was considered at p-value < 0.05 after false discovery rate correction for multiple comparisons.
RESULTS: We found that ADNC, ADNC+LB and PART+LB presented similar levels of dementia severity, whereas PART with no LB was the least affected group. MRI revealed higher atrophy of the right frontal operculum and amygdala in ADNC+LB compared to ADNC. ADNC and ADNC+LB showed increased atrophy in regions across all cortical lobes, hippocampus, amygdala and putamen compared to PART, but did not reveal significant differences compared to PART+LB. Interestingly, PART+LB showed higher atrophy of the frontal poles bilaterally, right superior frontal gyrus, left frontal operculum and right putamen compared to PART.
CONCLUSIONS: Altogether, these results suggest that LB co-pathology contributes to frontal lobe regional atrophy in ADNC and likely drives it in PART. Particularly in PART+LB, it suggests that cognitive impairment might derive from alpha-synuclein pathology rather than tauopathy. These findings indicate that LB pathology determines disease severity within the PART- and AD-continuums.

BACKGROUND: Multiple lines of evidence support peripheral organs in the initiation or progression of Lewy body disease (LBD), a spectrum of neurodegenerative diagnoses that include Parkinson\'s Disease (PD) without or with dementia (PDD) and dementia with Lewy bodies (DLB). However, the potential contribution of the peripheral immune response to LBD remains unclear. This study aims to characterize peripheral immune responses unique to participants with LBD at single-cell resolution to highlight potential biomarkers and increase mechanistic understanding of LBD pathogenesis in humans.
METHODS: In a case-control study, peripheral mononuclear cell (PBMC) samples from research participants were randomly sampled from multiple sites across the United States. The diagnosis groups comprise healthy controls (HC, n = 159), LBD (n = 110), Alzheimer\'s disease dementia (ADD, n = 97), other neurodegenerative disease controls (NDC, n = 19), and immune disease controls (IDC, n = 14). PBMCs were activated with three stimulants (LPS, IL-6, and IFNa) or remained at basal state, stained by 13 surface markers and 7 intracellular signal markers, and analyzed by flow cytometry, which generated 1,184 immune features after gating.
RESULTS: The model classified LBD from HC with an AUROC of 0.87 ± 0.06 and AUPRC of 0.80 ± 0.06. Without retraining, the same model was able to distinguish LBD from ADD, NDC, and IDC. Model predictions were driven by pPLCγ2, p38, and pSTAT5 signals from specific cell populations under specific activation. The immune responses characteristic for LBD were not associated with other common medical conditions related to the risk of LBD or dementia, such as sleep disorders, hypertension, or diabetes.
CONCLUSIONS: Quantification of PBMC immune response from multisite research participants yielded a unique pattern for LBD compared to HC, multiple related neurodegenerative diseases, and autoimmune diseases thereby highlighting potential biomarkers and mechanisms of disease.

The patient was an 85-year-old man with a one-year history of difficulty reading kana. Neuropsychological evaluation revealed kana (phonogram)-selective reading impairment and kanji (ideogram)-dominant writing impairment. MRI revealed significant cerebral atrophy in the left occipital cortex, leading to the clinical diagnosis of posterior cortical atrophy (PCA). Cerebrospinal fluid amyloid β1-42 levels were reduced, and amyloid PET showed accumulation in the posterior cingulate cortex, precuneus, and frontal lobe. In contrast, tau PET showed no accumulation in the atrophied brain areas. Episodes of REM sleep behavior disorder and decreased uptake on meta-iodobenzylguanidine (MIBG) myocardial scintigraphy suggested the involvement of Lewy body pathology. PCA with distinct laterality has been rarely reported, and ‍this is the first case to present Kana-selective reading impairment and Kanji-dominant writing impairment with neurodegenerative background.

Numerous studies have demonstrated that dementia is associated with increased utilization of health care services, which in turn results in increased costs of care. Dementia with Lewy bodies (DLB) is associated with greater costs of care relative to other forms of dementia due to higher rates of hospitalization and nursing home placement directly related to neuropsychiatric symptoms, parkinsonism, increased susceptibility to delirium, and elevated rates of caregiver burden. There is a critical need for researchers to identify potentially modifiable factors contributing to increased costs of care and poor clinical outcomes for patients with DLB, which may include comorbidities, polypharmacy/contraindicated medications, and access to specialty care. Previous research has utilized Medicare claims data, limiting the ability to study patients with early-onset (ie, prior to age 65) DLB. Integrated health systems offer the ability to combine electronic medical record data with Medicare, Medicaid, and commercial claims data and may therefore be ideal for utilization research in this population. The goals of this narrative review are to 1) synthesize and describe the current literature on health care utilization studies for patients with DLB, 2) highlight the current gaps in the literature, and 3) provide recommendations for stakeholders, including researchers, health systems, and policymakers. It is important to improve current understanding of potentially modifiable factors associated with increased costs of care among patients with DLB to inform public health policies and clinical decision-making, as this will ultimately improve the quality of patient care.

Parkinson\'s disease (PD) is a widespread neurodegenerative disorder occurs due to the degradation of dopaminergic neurons present in the substantia nigra pars compacta (SNpc). Millions of people are affected by this devastating disorder globally, and the frequency of the condition increases with the increase in the elderly population. A significant amount of progress has been made in acquiring more knowledge about the etiology and the pathogenesis of PD over the past decades. Animal models have been regarded to be a vital tool for the exploration of complex molecular mechanisms involved in PD. Various animals used as models for disease monitoring include vertebrates (zebrafish, rats, mice, guinea pigs, rabbits and monkeys) and invertebrate models (Drosophila, Caenorhabditis elegans). The animal models most relevant for study of PD are neurotoxin induction-based models (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-Hydroxydopamine (6-OHDA) and agricultural pesticides (rotenone, paraquat), pharmacological models (reserpine or haloperidol treated rats), genetic models (α-synuclein, Leucine-rich repeat kinase 2 (LRRK2), DJ-1, PINK-1 and Parkin). Several non-mammalian genetic models such as zebrafish, Drosophila and Caenorhabditis elegance have also gained popularity in recent years due to easy genetic manipulation, presence of genes homologous to human PD, and rapid screening of novel therapeutic molecules. In addition, in vitro models (SH-SY5Y, PC12, Lund human mesencephalic (LUHMES) cells, Human induced pluripotent stem cell (iPSC), Neural organoids, organ-on-chip) are also currently in trend providing edge in investigating molecular mechanisms involved in PD as they are derived from PD patients. In this review, we explain the current situation and merits and demerits of the various animal models.

UNASSIGNED: Parkinsonism is associated with traumatic brain injury and chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repetitive head impact (RHI) exposure, but the neuropathologic substrates that underlie parkinsonism in individuals with CTE are yet to be defined.
UNASSIGNED: To evaluate the frequency of parkinsonism in individuals with CTE and the association of RHI and neuropathologic substrates with parkinsonism in these individuals.
UNASSIGNED: This cross-sectional study included brain donors with neuropathologically diagnosed CTE without other significant neurodegenerative disease and with information on parkinsonism from the Understanding Neurologic Injury and Traumatic Encephalopathy brain bank between July 2015 and May 2022.
UNASSIGNED: Years of contact sports participation as a proxy for RHI.
UNASSIGNED: The main outcomes were frequency of parkinsonism in individuals with CTE and associations between (1) RHI with substantia nigra (SN) Lewy bodies (LBs) and neurofibrillary tangles (NFTs); (2) LBs, NFTs, and arteriolosclerosis with SN neuronal loss; and (3) SN neuronal loss, LBs, NFTs, and arteriolosclerosis with parkinsonism, tested by age-adjusted logistic regressions.
UNASSIGNED: Of 481 male brain donors with neuropathologically diagnosed CTE, parkinsonism occurred frequently in individuals with CTE (119 [24.7%]; 362 [75.3%] did not have parkinsonism). Participants with parkinsonism had a higher mean (SD) age at death (71.5 [13.0] years) than participants without parkinsonism (54.1 [19.3] years) (P < .001) and higher rates of dementia (104 [87.4%] vs 105 [29.0%]), visual hallucinations (45 [37.8%] vs 51 [14.1%]), and probable rapid eye movement sleep behavior disorder (52 [43.7%] vs 58 [16.0%]) (P < .001 for all). Participants with parkinsonism had a more severe CTE stage (eg, stage IV: 35 [29.4%] vs 39 [10.8%]) and nigral pathology than those without parkinsonism (NFTs: 50 of 117 [42.7%] vs 103 of 344 [29.9%]; P = .01; neuronal loss: 61 of 117 [52.1%] vs 59 of 344 [17.1%]; P < .001; and LBs: 28 of 116 [24.1%] vs 20 of 342 [5.8%]; P < .001). Years of contact sports participation were associated with SN NFTs (adjusted odds ratio [AOR], 1.04; 95% CI, 1.00-1.07; P = .03) and neuronal loss (AOR, 1.05; 95% CI, 1.01-1.08; P = .02). Nigral neuronal loss (AOR, 2.61; 95% CI, 1.52-4.47; P < .001) and LBs (AOR, 2.29; 95% CI, 1.15-4.57; P = .02) were associated with parkinsonism. However, SN neuronal loss was associated with SN LBs (AOR, 4.48; 95% CI, 2.25-8.92; P < .001), SN NFTs (AOR, 2.51; 95% CI, 1.52-4.15; P < .001), and arteriolosclerosis (AOR, 2.27; 95% CI, 1.33-3.85; P = .002). In American football players, regression analysis demonstrated that SN NFTs and neuronal loss mediated the association between years of play and parkinsonism in the context of CTE (β, 0.012; 95% CI, 0.001-0.038).
UNASSIGNED: In this cross-sectional study of contact sports athletes with CTE, years of contact sports participation were associated with SN tau pathology and neuronal loss, and these pathologies were associated with parkinsonism. Repetitive head impacts may incite neuropathologic processes that lead to symptoms of parkinsonism in individuals with CTE.

The first postmortem neuropathological findings of a hemiparkinsonism and hemiatrophy (HPHA) patient are presented. A 50-year-old man developed resting tremors affecting the right hand and leg, followed by mild clumsiness of the right hand. On examination, he exhibited muscle atrophy of the right leg extremity, accompanied by right-sided parkinsonism. Brain magnetic resonance imaging was normal. Based on the clinical and radiological findings, HPHA syndrome was diagnosed, showing a good response to L-DOPA. He gradually developed muscular atrophy of the right distal upper extremity. Thirteen years after the onset of the disease, left-sided parkinsonism appeared. The patient died of Trousseau\'s syndrome associated with a rapidly emerging pancreatic tumor. The total duration of the disease was 14 years. Neuropathologically, the substantia nigra showed markedly left-predominant neuronal loss, along with almost symmetrical Lewy body (LB) pathology. These findings indicated that the patient originally had fewer neurons in the left substantia nigra than in the right, probably caused by congenital or childhood cerebral injury, followed by the development of unilateral parkinsonism due to the progression of LB pathology. Despite our extensive neuropathological analysis, we could not specify the etiology or anatomical substrate responsible for the development of right upper and lower extremity atrophy. Further clinicopathological studies are needed to elucidate the pathoanatomical areas causing hemiparkinsonism and hemiatrophy.

Parkinson\'s disease (PD) is diagnosed by its cardinal motor symptoms that are associated with the loss of dopamine neurons in the substantia nigra pars compacta (SNc). However, PD patients suffer from various non-motor symptoms years before diagnosis. These prodromal symptoms are thought to be associated with the appearance of Lewy body pathologies (LBP) in brainstem regions such as the dorsal motor nucleus of the vagus (DMV), the locus coeruleus (LC) and others. The neurons in these regions that are vulnerable to LBP are all slow autonomous pacemaker neurons that exhibit elevated oxidative stress due to their perpetual influx of Ca2+ ions. Aggregation of toxic α-Synuclein (aSyn) - the main constituent of LBP - during the long prodromal period challenges these vulnerable neurons, presumably altering their biophysics and physiology. In contrast to pathophysiology of late stage parkinsonism which is well-documented, little is known about the pathophysiology of the brainstem during prodromal PD. In this review, we discuss ion channel dysregulation associated with aSyn aggregation in brainstem pacemaker neurons and their cellular responses to them. While toxic aSyn elevates oxidative stress in SNc and LC pacemaker neurons and exacerbates their phenotype, DMV neurons mount an adaptive response that mitigates the oxidative stress. Ion channel dysregulation and cellular adaptations may be the drivers of the prodromal symptoms of PD. For example, selective targeting of toxic aSyn to DMV pacemakers, elevates the surface density of K+ channels, which slows their firing rate, resulting in reduced parasympathetic tone to the gastrointestinal tract, which resembles the prodromal PD symptoms of dysphagia and constipation. The divergent responses of SNc & LC vs. DMV pacemaker neurons may explain why the latter outlive the former despite presenting LBPs earlier. Elucidation the brainstem pathophysiology of prodromal PD could pave the way for physiological biomarkers, earlier diagnosis and novel neuroprotective therapies for PD.