Objective: The glymphatic system cleans amyloid and tau proteins from the brain in animal studies of Alzheimer disease (AD). However, there is no direct evidence showing this in humans.Methods: Participants (n = 50, 62.6 ± 5.4 years old, 36 women) with AD and normal controls underwent amyloid positron emission tomography (PET), tau PET, structural T1‐weighted magnetic resonance imaging, and neuropsychological evaluation. Whole‐brain glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI‐ALPS).Results: ALPS‐indexes showed negative correlations with deposition of amyloid and tau on PET images and positive correlations with cognitive scores even after adjusting for age, sex, years of education, andAPOE4genotype covariates in multiple AD‐related brain regions (allp < 0.05). Mediation analysis showed that ALPS‐index acted as a significant mediator between regional standardized uptake value ratios of amyloid and tau images and cognitive dysfunction even after correcting for multiple covariates in AD‐related brain regions. These regions are responsible for attention, memory, and executive function, which are vulnerable to sleep deprivation.Interpretation: Glymphatic system activity may act as a significant mediator in AD‐related cognitive dysfunction even after adjusting for multiple covariates and gray matter volumes. ALPS‐index may provide useful disease progression or treatment biomarkers for patients with AD as an indicator of modulation of glymphatic activity. ANN NEUROL 2023;93:164–174

Neuropathic pain indicates pain caused by damage to the somatosensory system and is difficult to manage and treat. A new treatment strategy urgently needs to be developed. Both autophagy and apoptosis are critical adaptive mechanisms when neurons encounter stress or damage. Recent studies have shown that, after nerve damage, both autophagic and apoptotic activities in the injured nerve, dorsal root ganglia, and spinal dorsal horn change over time. Many studies have shown that upregulated autophagic activities may help myelin clearance, promote nerve regeneration, and attenuate pain behavior. On the other hand, there is no direct evidence that the inhibition of apoptotic activities in the injured neurons can attenuate pain behavior. Most studies have only shown that agents can simultaneously attenuate pain behavior and inhibit apoptotic activities in the injured dorsal root ganglia. Autophagy and apoptosis can crosstalk with each other through various proteins and proinflammatory cytokine expressions. Proinflammatory cytokines can promote both autophagic/apoptotic activities and neuropathic pain formation, whereas autophagy can inhibit proinflammatory cytokine activities and further attenuate pain behaviors. Thus, agents that can enhance autophagic activities but suppress apoptotic activities on the injured nerve and dorsal root ganglia can treat neuropathic pain. Here, we summarized the evolving changes in apoptotic and autophagic activities in the injured nerve, dorsal root ganglia, spinal cord, and brain after nerve damage. This review may help in further understanding the treatment strategy for neuropathic pain during nerve injury by modulating apoptotic/autophagic activities and proinflammatory cytokines in the nervous system.

The pathophysiology of insulin resistance-induced hypertension and hyperlipidemia might entail differences in dementia risk in cases with hypertension and hyperlipidemia without prior diabetes mellitus (DM). This study investigated whether incident hypertension, incident hyperlipidemia, or both, increased the dementia risk in patients with and without DM. A nationwide retrospective cohort study was conducted. The study sample was obtained from the National Health Insurance Research Database. We enrolled 10,316 patients with a new diagnosis of DM between 2000 and 2002 in the DM cohort. For the same period, we randomly selected 41,264 patients without DM in the non-DM cohort (matched by age and sex at a 1:4 ratio with the DM cohort). Both cohorts were then separately divided into four groups on the basis of incident hypertension or incident hyperlipidemia status. In total, 51,580 patients aged between 20 and 99 years were enrolled. The dementia risk was higher in the DM cohort than in the non-DM cohort (adjusted hazard ratio (HR) = 1.47, 95% confidence interval (CI) = 1.30–1.67, p < 0.001). In the DM cohort, the dementia risk in patients with both hypertension and hyperlipidemia did not significantly increase compared with that in those without hypertension and hyperlipidemia (p = 0.529). Similar results were observed in those with either hypertension (p = 0.341) or hyperlipidemia (p = 0.189). In the non-DM cohort, patients with both hypertension and hyperlipidemia had a higher dementia risk (adjusted HR = 1.33, 95% CI = 1.09–1.63, p = 0.006). The results remained largely unchanged in patients with only hypertension (adjusted HR = 1.22, 95% CI = 1.05–1.40, p = 0.008). However, the dementia risk did not increase significantly in patients with only hyperlipidemia (p = 0.187). The development of hypertension, hyperlipidemia, or both, following a diagnosis of incident diabetes is secondary to diabetes onset and likely mediated through insulin resistance associated with diabetes, which does not further accentuate dementia risk. DM itself (i.e., the systemic influence of hyperglycemia) might be the main driver of increased dementia risk.

Varicella-zoster virus (VZV) infection can cause chickenpox and herpes zoster. It sometimes involves cranial nerves, and rarely, it can involve multiple cranial nerves. We aimed to study clinical presentations of cranial nerve involvement in herpes zoster infection. We included patients who had the diagnosis of herpes zoster infection and cranial nerve involvement. The diagnosis was confirmed by typical vesicles and a rash. We excluded patients who had cranial neuralgias or neuropathies but without typical skin lesions (zoster sine herpete or post-herpetic neuralgia). We included 330 patients (mean age, 55.0 ± 17.0 years) who had herpes zoster with cranial nerve involvement, including 155 men and 175 women. Most frequently involved cranial nerves were the trigeminal nerve (57.9%), facial nerve (52.1%), and vestibulocochlear nerve (20.0%). Other involved cranial nerves included the glossopharyngeal nerve (0.9%), vagus nerve (0.9%), oculomotor nerve, trochlear nerve, and abducens nerve (each 0.3%, respectively). One hundred and seventy patients (51.5%) had only sensory symptoms/signs; in contrast, 160 patients (48.5%) had both sensory and motor symptoms/signs. Of those 160 patients, sensory preceded motor symptoms/signs in 64 patients (40.0%), sensory and motor symptoms/signs occurred simultaneously in 38 patients (23.8%), and motor preceded sensory symptoms/signs in 20 patients (12.5%). At one month after herpes zoster infection, vesicles and rash disappeared in 92.6% of patients; meanwhile facial palsy showed a significant improvement in 81.4% of patients (p < 0.05). Cranial motor neuropathies are not infrequent in herpes zoster infections. Multiple cranial nerve involvement frequently occurred in Ramsay Hunt syndrome. We found a significantly increased seasonal occurrence of cranial nerve zoster in spring rather than summer. Cranial motor nerves were affected while the hosts sometimes had a compromised immune system.

Vascular parkinsonism (VP) is a parkinsonian syndrome characterized by lower body parkinsonism, marked gait difficulty, less tremor, less rigidity, better hand dexterity, relatively symmetrical symptomatic distribution, association with pyramidal tract signs, more frequent dementia, and poor response to levodopa treatment compared with Parkinson disease (PD).^1,2 The syndrome was first described by Critchley³ in 1929 and is now generally accepted as a clinical entity^4,5 for which proper diagnostic criteria have been proposed.^6,7 Vascular parkinsonism is typically associated with multiple cerebral infarctions in basal ganglia or extensive white matter (WM) changes, or a combination of both, as shown on magnetic resonance imaging (MRI) and computed tomographic (CT) scans. The brain imaging changes have been shown to correlate with postmortem pathological changes.^2,8,9 Unfortunately, little is known about associations between the clinical status of VP and WM microstructural properties derived from imaging data for specific fiber bundles. Existing reports on VP are based on more conventional imaging protocols (eg, T2-weighted MRI) and can therefore only reveal nonspecific global structural WM abnormalities in these patients.^8-11 In addition, apparently similar vascular lesions noted on brain imaging data may be associated with parkinsonism in some patients, but not in others.^2,10,12 Recent developments of diffusion tensor imaging (DTI)^13-15 permit us to study directly the involvement of anatomically well-defined fiber tracts in VP patients. With DTI, the directionality and magnitude of random water movement in tissue can be estimated yielding several quantitative measures, such as the 3 principle diffusivities (ie, the eigenvalues of the diffusion tensor λ1 > λ2 > λ3), mean diffusivity ([λ1 + λ2 + λ3]/3 [MD]), transverse diffusivity ([λ2 + λ3]/2), axial diffusivity (λ1), and the degree of diffusion anisotropy (eg, the fractional anisotropy [FA]).¹⁴ Without barriers, water molecules move uniformly in all directions, which results in isotropic diffusion. By contrast, in the presence of barriers, such as cell membranes, nerve fibers, or myelin sheets, the diffusion rate is typically larger in one direction than in another, which is then referred to as anisotropic diffusion.¹⁶ Being quantitative in nature, these DTI-based measures are more sensitive to tissue abnormalities than the typical visual evaluation of WM hyperintensities observed in conventional MRI data.^17,18 To date, DTI studies have revealed WM alterations through measurements of decreased FA and/or increased MD in a variety of conditions, including aging,^18-20 multiple sclerosis,²¹ schizophrenia,²² traumatic brain injury,^23,24 amyotrophic lateral sclerosis,²⁵ and Alzheimer disease.²⁶ For an in-depth discussion of DTI and a more detailed description of several diffusion metrics (eg, FA and MD), we refer the interested reader to a recent review by Tournier et al.¹⁵ In the present work, we investigated WM microstructural properties with DTI and associated the observed abnormalities in VP patients with the status or score of their clinical symptoms or signs. To this end, we applied (1) a global analysis (highly sensitive but not specific); (2) a voxel-based analysis (regionally specific but with relatively low sensitivity); and (3) a tract-based analysis (fiber bundle specific with relatively high sensitivity).²⁷ By combining these 3 complementary approaches to analyze the same data sets, we can provide a robust and more complete picture of the observed findings.