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.

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.

Prevalence of Frontotemporal Dementia in Females of 5 Hispanic Families With R159H VCP Multisystem Proteinopathy.

Background and Objectives: Missense variants of the valosin-containing protein (VCP) gene cause a progressive, autosomal dominant disease termed VCP multisystem proteinopathy (MSP1). The disease is a constellation of clinical features including inclusion body myopathy (IBM), Paget disease of bone (PDB), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), typically reported at a frequency of 90%, 42%, 30%, and 9%, respectively. The Hispanic population is currently underrepresented in previous reports of VCP myopathy. We expand our genotype-phenotype studies in 5 Hispanic families with the c.476G>A, p.R159H VCP variant. Methods: We report detailed clinical findings of 11 patients in 5 Hispanic families with the c.476G > A, p.R159H VCP variant. In addition, we report frequencies of the main manifestations in 28 additional affected members of the extended family members. We also compared our findings with an existing larger cohort of patients with VCP MSP1. Results: FTD was the most prevalent feature reported, particularly frequent in females. PDB was only seen in 1 patient in contrast to the earlier reported cohorts. The overall frequency of the different manifestations: myopathy, PDB, FTD, and ALS in these 5 families was 39%, 3%, 72%, and 8%, respectively. The atypical phenotype and later onset of manifestations in these families resulted in a noticeable delay in the diagnosis of VCP disease. Discussion: Studying each VCP variant in the context of ethnic backgrounds is pivotal in increasing awareness of the variability of VCP-related diseases across different ethnicities, enabling early diagnosis, and understanding the mechanism for these genotype-phenotype variations.

Minimal change prion retinopathy: Morphometric comparison of retinal and brain prion deposits in Creutzfeldt-Jakob disease.

Sporadic Creutzfeldt-Jakob disease (sCJD) is the most commonly diagnosed human prion disease caused by the abnormal misfolding of the 'cellular' prion protein (PrPC) into the transmissible 'scrapie-type' prion form (PrPSc). Neuropathologic evaluation of brains with sCJD reveals abnormal PrPSc deposits primarily in grey matter structures, often associated with micro-vacuolar spongiform changes in neuropil, neuronal loss, and gliosis. Abnormal PrPSc deposits have also been reported in the retina of patients with sCJD, but few studies have characterized the morphology of these retinal PrPSc deposits or evaluated for any retinal neurodegenerative changes. We performed histopathologic and morphometric analyses of retinal and brain prion deposits in 14 patients with sCJD. Interestingly, we discovered that the morphology of retinal PrPSc deposits generally differs from that of brain PrPSc deposits in terms of size and shape. We found that retinal PrPSc deposits consistently localize to the outer plexiform layer of the retina. Additionally, we observed that the retinal PrPSc deposits are not associated with the spongiform change, neuronal loss, and gliosis often seen in the brain. The stereotypic morphology and location of PrPSc deposits in sCJD retinas may help guide the use of ocular imaging devices in the detection of these deposits for a clinical diagnosis.

Association of Neurofibrillary Tangle Distribution With Age at Onset-Related Clinical Heterogeneity in Alzheimer Disease: An Autopsy Study.

BACKGROUND AND OBJECTIVE: Patients with earlier age at onset of sporadic Alzheimer disease (AD) are more likely than those with later onset to present with atypical clinical and cognitive features. We sought to determine whether this age-related clinical and cognitive heterogeneity is mediated by different topographic distributions of tau-aggregate neurofibrillary tangles (NFTs) or by variable amounts of concomitant non-AD neuropathology. METHODS: The relative distribution of NFT density in hippocampus and midfrontal neocortex was calculated, and α-synuclein, TAR DNA binding protein 43 (TDP-43), and microvascular copathologies were staged, in patients with severe AD and age at onset of 51-60 (n = 40), 61-70 (n = 41), and >70 (n = 40) years. Regression, mediation, and mixed effects models examined relationships of pathologic findings with clinical features and longitudinal cognitive decline. RESULTS: Patients with later age at onset of AD were less likely to present with nonmemory complaints (odds ratio [OR] 0.46 per decade, 95% confidence interval [CI] 0.22-0.88), psychiatric symptoms (ß = -0.66, 95% CI -1.15 to -0.17), and functional impairment (ß = -1.25, 95% CI -2.34 to -0.16). TDP-43 (OR 2.00, 95% CI 1.23-3.35) and microvascular copathology (OR 2.02, 95% CI 1.24-3.40) were more common in later onset AD, and α-synuclein copathology was not related to age at onset. NFT density in midfrontal cortex (ß = -0.51, 95% CI -0.72 to -0.31) and midfrontal/hippocampal NFT ratio (ß = -0.18, 95% CI -0.26 to -0.10) were lower in those with later age at onset. Executive function (ß = 0.48, 95% CI 0.09-0.90) and visuospatial cognitive deficits (ß = 0.97, 95% CI 0.46-1.46) were less impaired in patients with later age at onset. Mediation analyses showed that the effect of age at onset on severity of executive function deficits was mediated by midfrontal/hippocampal NFT ratio (ß = 0.21, 95% CI 0.08-0.38) and not by concomitant non-AD pathologies. Midfrontal/hippocampal NFT ratio also mediated an association between earlier age at onset and faster decline on tests of global cognition, executive function, and visuospatial abilities. DISCUSSION: Worse executive dysfunction and faster cognitive decline in people with sporadic AD with earlier rather than later age at onset is mediated by greater relative midfrontal neocortical to hippocampal NFT burden and not by concomitant non-AD neuropathology.

Hydrophilic polymer embolism identified in brain tumor specimens following Wada testing: A report of 2 cases.

Hydrophilic polymers are commonly used as coatings on intravascular medical devices. As intravascular procedures continue to increase in frequency, the risk of embolization of this material throughout the body has become evident. These emboli may be discovered incidentally but can result in serious complications including death. Here, we report the first two cases of hydrophilic polymer embolism (HPE) identified on brain tumor resection following Wada testing. One patient experienced multifocal vascular complications and diffuse cerebral edema, while the other had an uneventful postoperative course. Wada testing is frequently performed during preoperative planning prior to epilepsy surgery or the resection of tumors in eloquent brain regions. These cases demonstrate the need for increased recognition of this histologic finding to enable further correlation with clinical outcomes.

CNS sites activated by renal pelvic epithelial sodium channels (ENaCs) in response to hypertonic saline in awake rats.

In some patients, renal nerve denervation has been reported to be an effective treatment for essential hypertension. Considerable evidence suggests that afferent renal nerves (ARN) and sodium balance play important roles in the development and maintenance of high blood pressure. ARN are sensitive to sodium concentrations in the renal pelvis. To better understand the role of ARN, we infused isotonic or hypertonic NaCl (308 or 500mOsm) into the left renal pelvis of conscious rats for two 2hours while recording arterial pressure and heart rate. Subsequently, brain tissue was analyzed for immunohistochemical detection of the protein Fos, a marker for neuronal activation. Fos-immunoreactive neurons were identified in numerous sites in the forebrain and brainstem. These areas included the nucleus tractus solitarius (NTS), the lateral parabrachial nucleus, the paraventricular nucleus of the hypothalamus (PVH) and the supraoptic nucleus (SON). The most effective stimulus was 500mOsm NaCl. Activation of these sites was attenuated or prevented by administration of benzamil (1µM) or amiloride (10µM) into the renal pelvis concomitantly with hypertonic saline. In anesthetized rats, infusion of hypertonic saline but not isotonic saline into the renal pelvis elevated ARN activity and this increase was attenuated by simultaneous infusion of benzamil or amiloride. We propose that renal pelvic epithelial sodium channels (ENaCs) play a role in activation of ARN and, via central visceral afferent circuits, this system modulates fluid volume and peripheral blood pressure. These pathways may contribute to the development of hypertension.

Molecular motion of the bis(maleonitriledithiolato)nickel trianion in solution.

Electron spin resonance (ESR) has been used to study the reorientational motion of the bis(maleonitriledithiolato)nickel trianion, [Ni(mnt)(2)](3-), in diethylene glycol dimethyl ether (diglyme). [Ni(mnt)(2)](3-) has one unpaired electron and was prepared by reducing the dianion, [Ni(mnt)(2)](2-), with potassium metal. The trianion and dianion are members of the redox series [Ni(mnt)(2)](n-) with n = 0, 1, 2, and 3. The monoanion, [Ni(mnt)(2)](-), also has S = 1/2 and its rotational diffusion in diglyme was the subject of previous ESR studies. This made possible the comparison of the reorientational data for two different oxidation states of the same planar complex in the same solvent. Differences were found; isotropic rotational diffusion produced agreement between the trianion's experimental and calculated spectra, whereas the monoanion's simulations required axially symmetric reorientation with diffusion about the long in-plane axis three times faster than that about the two perpendicular axes. At a given temperature, the monoanion's reorientation rates about the long in-plane axis and two perpendicular axes were faster than the trianion's isotropic rate by factors of ∼27 and ∼9, respectively. These differences suggest that [Ni(mnt)(2)](-) and [Ni(mnt)(2)](3-) have different shapes and sizes in solution; the monoanion is approximately a prolate ellipsoid, whereas the trianion is larger and more spherical. [Ni(mnt)(2)](3-) appears to be ion-paired, whereas in accord with results from other techniques, [Ni(mnt)(2)](-) is not.