TDP-43 pathology is associated with increased tau burdens and seeding.

BACKGROUND: Most Alzheimer's Disease (AD) cases also exhibit limbic predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), besides amyloid-ß plaques and neurofibrillary tangles (NFTs) containing hyperphosphorylated tau (p-tau). LATE-NC is characterized by cytoplasmic aggregates positive for pathological TDP-43 and is associated with more severe clinical outcomes in AD, compared to AD cases lacking TDP-43 pathology TDP-43: AD(LATE-NC-). Accumulating evidence suggests that TDP-43 and p-tau interact and exhibit pathological synergy during AD pathogenesis. However, it is not yet fully understood how the presence of TDP-43 affects p-tau aggregation in symptomatic AD. METHODS: In this study, we investigated the impact of TDP-43 proteinopathy on p-tau pathology with different approaches: histologically, in a human post-mortem cohort (n = 98), as well as functionally using a tau biosensor cell line and TDP-43A315T transgenic mice. RESULTS: We found that AD cases with comorbid LATE-NC, AD(LATE-NC+), have increased burdens of pretangles and/or NFTs as well as increased brain levels of p-tau199, compared to AD(LATE-NC-) cases and controls. The burden of TDP-43 pathology was also correlated with the Braak NFT stages. A tau biosensor cell line treated with sarkosyl-insoluble, brain-derived homogenates from AD(LATE-NC+) cases displayed exacerbated p-tau seeding, compared to control and AD(LATE-NC-)-treated cells. Consistently, TDP-43A315T mice injected with AD(LATE-NC+)-derived extracts also exhibited a more severe hippocampal seeding, compared to the remaining experimental groups, albeit no TDP-43 aggregation was observed. CONCLUSIONS: Our findings extend the current knowledge by supporting a functional synergy between TDP-43 and p-tau. We further demonstrate that TDP-43 pathology worsens p-tau aggregation in an indirect manner and increases its seeding potential, probably by increasing p-tau levels. This may ultimately contribute to tau-driven neurotoxicity and cell death. Because most AD cases present with comorbid LATE-NC, this study has an impact on the understanding of TDP-43 and tau pathogenesis in AD and LATE, which account for the majority of dementia cases worldwide. Moreover, it highlights the need for the development of a biomarker that detects TDP-43 during life, in order to properly stratify AD and LATE patients.

The chemicals between us-First results of the cluster analyses on anatomy embalming procedures in the German-speaking countries.

Hands-on courses utilizing preserved human tissues for educational training offer an important pathway to acquire basic anatomical knowledge. Owing to the reevaluation of formaldehyde limits by the European Commission, a joint approach was chosen by the German-speaking anatomies in Europe (Germany, Austria, Switzerland) to find commonalities among embalming protocols and infrastructure. A survey comprising 537 items was circulated to all anatomies in German-speaking Europe. Clusters were established for "ethanol"-, formaldehyde-based ("FA"), and "other" embalming procedures, depending on the chemicals considered the most relevant for each protocol. The logistical framework, volumes of chemicals, and infrastructure were found to be highly diverse between the groups and protocols. Formaldehyde quantities deployed per annum were three-fold higher in the "FA" (223 L/a) compared to the "ethanol" (71.0 L/a) group, but not for "other" (97.8 L/a), though the volumes injected per body were similar. "FA" was strongly related to table-borne air ventilation and total fixative volumes ≤1000 L. "Ethanol" was strongly related to total fixative volumes >1000 L, ceiling- and floor-borne air ventilation, and explosion-proof facilities. Air ventilation was found to be installed symmetrically in the mortuary and dissection facilities. Certain predictors exist for the interplay between the embalming used in a given infrastructure and technical measures. The here-established cluster analysis may serve as decision supportive tool when considering altering embalming protocols or establishing joint protocols between institutions, following a best practice approach to cater toward best-suited tissue characteristics for educational purposes, while simultaneously addressing future demands on exposure limits.

LATE-NC aggravates GVD-mediated necroptosis in Alzheimer's disease.

It has become evident that Alzheimer's Disease (AD) is not only linked to its hallmark lesions-amyloid plaques and neurofibrillary tangles (NFTs)-but also to other co-occurring pathologies. This may lead to synergistic effects of the respective cellular and molecular players, resulting in neuronal death. One of these co-pathologies is the accumulation of phosphorylated transactive-response DNA binding protein 43 (pTDP-43) as neuronal cytoplasmic inclusions, currently considered to represent limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), in up to 70% of symptomatic AD cases. Granulovacuolar degeneration (GVD) is another AD co-pathology, which also contains TDP-43 and other AD-related proteins. Recently, we found that all proteins required for necroptosis execution, a previously defined programmed form of neuronal cell death, are present in GVD, such as the phosphorylated necroptosis executioner mixed-lineage kinase domain-like protein (pMLKL). Accordingly, this protein is a reliable marker for GVD lesions, similar to other known GVD proteins. Importantly, it is not yet known whether the presence of LATE-NC in symptomatic AD cases is associated with necroptosis pathway activation, presumably contributing to neuron loss by cell death execution. In this study, we investigated the impact of LATE-NC on the severity of necroptosis-associated GVD lesions, phosphorylated tau (pTau) pathology and neuronal density. First, we used 230 human post-mortem cases, including 82 controls without AD neuropathological changes (non-ADNC), 81 non-demented cases with ADNC, i.e.: pathologically-defined preclinical AD (p-preAD) and 67 demented cases with ADNC. We found that Braak NFT stage and LATE-NC stage were good predictors for GVD expansion and neuronal loss in the hippocampal CA1 region. Further, we compared the impact of TDP-43 accumulation on hippocampal expression of pMLKL-positive GVD, pTau as well as on neuronal density in a subset of nine non-ADNC controls, ten symptomatic AD cases with (ADTDP+) and eight without LATE-NC (ADTDP-). Here, we observed increased levels of pMLKL-positive, GVD-exhibiting neurons in ADTDP+ cases, compared to ADTDP- and controls, which was accompanied by augmented pTau pathology. Neuronal loss in the CA1 region was increased in ADTDP+ compared to ADTDP- cases. These data suggest that co-morbid LATE-NC in AD impacts not only pTau pathology but also GVD-mediated necroptosis pathway activation, which results in an accelerated neuronal demise. This further highlights the cumulative and synergistic effects of comorbid pathologies leading to neuronal loss in AD. Accordingly, protection against necroptotic neuronal death appears to be a promising therapeutic option for AD and LATE.

Development of an interactive e-learning software "Histologie für Mediziner" for medical histology courses and its overall impact on learning outcomes and motivation.

Objective: To develop and evaluate an interactive histology learning software for medical students in the preclinical study phase. The educational design of the software was based on current learning theory models, such as the Cognitive load theory, Cognitive theory of multimedia learning, and the ARCS model, so that the acquired knowledge can be repeated using a diversified design. Moreover, the learning effects achieved by using the software shall be evaluated. Apart from the software's usability, the influence of the learning theory principles on the students' motivation shall be assessed. Methodology: The software was evaluated using an experimental wait list control group with a pre-/post-test design (n=213). Depending on the group they were assigned to, students learned the histology contents of chapter "Liver, gall bladder, pancreas" using the traditional program of the Goethe University (n=65), the new interactive software (n=56), or without any of the two software versions (n=92). The influence of the different learning aids on the acquisition of knowledge was assessed with three questionnaires comprising four different multiple choice questions each. For the evaluation of the usability and motivational factors, a second test was added to the questionnaire of both software versions. Results: The interactive software was rated significantly better with regard to usability and motivational aspects than the traditional learning program (F(7, 113)=12.48, p<.001, partial η2=.436). Moreover, use of the interactive software resulted in a significant increase of knowledge acquisition as compared to the group of students who had learned without any of the two software versions (0.77, p=.001). Conclusion: With regard to the histology contents, usability was comparable to the official learning program. Interactive elements and the educational design contributed to an increase of the factors that are essential for intrinsic motivation. Thus, our program can be valuable tool to supplement the curriculum as an additional service.

A complete situs inversus viscerum with hepatic, intestinal and renalvascular anomalies: one case report and review of the literatur

Situs inversus viscerum (SIV) is a rare congenital anomaly, which is still an intriguing phenomenon to anatomists and physicians alike. A complete SIV is characterized by a left-right transposition and mirror image of all thoraco-abdominal organs and their vasculature. The present report is based on one case with complete SIV, which was observed during the routine educational dissections of cadavers in the authors' Anatomy Department. A transposition of all truncal organs and their vasculature, and several variations of arteries and veins were present. The right branch of the proper hepatic artery was replaced by an artery that emanated from the superior mesenteric artery. The latter also released the inferior mesenteric artery. Additionally, a left accessory renal artery ran anterior to the inferior caval vein and posterior to the ureter to enter the hilum of the left kidney. There was also a variation in the anterior-posterior arrangement of the hilar structures of the left kidney. Additionally, a globally enlarged heart with coronary artery by-passes, a replaced aortic valve and an aortic arch aneurysm was observed. This case report is unique, as it presents a previously unreported co-incidence of SIV and hepatic, intestinal and renal vascular anomalies. It is important for the surgeon to be aware of such variations while planning an abdominal surgery in patients with SIV

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Modified amyloid variants in pathological subgroups of ß-amyloidosis.

OBJECTIVE: Amyloid ß (Aß) depositions in plaques and cerebral amyloid angiopathy (CAA) represent common features of Alzheimer's disease (AD). Sequential deposition of post-translationally modified Aß in plaques characterizes distinct biochemical stages of Aß maturation. However, the molecular composition of vascular Aß deposits in CAA and its relation to plaques remain enigmatic. METHODS: Vascular and parenchymal deposits were immunohistochemically analyzed for pyroglutaminated and phosphorylated Aß in the medial temporal and occipital lobe of 24 controls, 27 pathologically-defined preclinical AD, and 20 symptomatic AD cases. RESULTS: Sequential deposition of Aß in CAA resembled Aß maturation in plaques and enabled the distinction of three biochemical stages of CAA. B-CAA stage 1 was characterized by deposition of Aß in the absence of pyroglutaminated AßN3pE and phosphorylated AßpS8. B-CAA stage 2 showed additional AßN3pE and B-CAA stage 3 additional AßpS8. Based on the Aß maturation staging in CAA and plaques, three case groups for Aß pathology could be distinguished: group 1 with advanced Aß maturation in CAA; group 2 with equal Aß maturation in CAA and plaques; group 3 with advanced Aß maturation in plaques. All symptomatic AD cases presented with end-stage plaque maturation, whereas CAA could exhibit immature Aß deposits. Notably, Aß pathology group 1 was associated with arterial hypertension, and group 2 with the development of dementia. INTERPRETATION: Balance of Aß maturation in CAA and plaques defines distinct pathological subgroups of ß-amyloidosis. The association of CAA-related Aß maturation with cognitive decline, the individual contribution of CAA and plaque pathology to the development of dementia within the defined Aß pathology subgroups, and the subgroup-related association with arterial hypertension should be considered for differential diagnosis and therapeutic intervention.

Peripheral and central autonomic nervous system: does the sympathetic or parasympathetic nervous system bear the brunt of the pathology during the course of sporadic PD?

It is a well-established fact that the sympathetic, parasympathetic and enteric nervous systems are affected at early stages in Parkinson's disease (PD). However, it is not yet clarified whether the earliest pathological events preferentially occur in any of these three divisions of the autonomic nervous system (ANS). Significant involvement of the peripheral autonomic nervous system of the heart and gastrointestinal tract has been documented in PD. Accumulating evidence suggests that the PD pathology spreads centripetally from the peripheral to central nervous system through autonomic nerve fibers, implicating the ANS as a major culprit in PD pathogenesis and a potential target for therapy. This study begins with a brief overview of the structures of the central and peripheral autonomic nervous system and then outlines the major clinicopathological manifestations of cardiovascular and gastrointestinal disturbances in PD.

Hierarchical Distribution of the Tau Cytoskeletal Pathology in the Thalamus of Alzheimer's Disease Patients.

In spite of considerable progress in neuropathological research on Alzheimer's disease (AD), knowledge regarding the exact pathoanatomical distribution of the tau cytoskeletal pathology in the thalamus of AD patients in the advanced Braak and Braak AD stages V or VI of the cortical cytoskeletal pathology is still fragmentary. Investigation of serial 100 µm-thick brain tissue sections through the thalamus of clinically diagnosed AD patients with Braak and Braak AD stage V or VI cytoskeletal pathologies immunostained with the anti-tau AT8 antibody, along with the affection of the extraterritorial reticular nucleus of the thalamus, reveals a consistent and severe tau immunoreactive cytoskeletal pathology in the limbic nuclei of the thalamus (e.g., paraventricular, anterodorsal and laterodorsal nuclei, limitans-suprageniculate complex). The thalamic nuclei integrated into the associative networks of the human brain (e.g., ventral anterior and mediodorsal nuclei) are only mildly affected, while its motor precerebellar (ventral lateral nucleus) and sensory nuclei (e.g., lateral and medial geniculate bodies, ventral posterior medial and lateral nuclei, parvocellular part of the ventral posterior medial nucleus) are more or less spared. The highly stereotypical and characteristic thalamic distribution pattern of the AD-related tau cytoskeletal pathology represents an anatomical mirror of the hierarchical topographic distribution of the cytoskeletal pathology in the interconnected regions of the cerebral cortex of AD patients. These pathoanatomical parallels support the pathophysiological concept of a transneuronal spread of the disease process of AD along anatomical pathways. The AD-related tau cytoskeletal pathology in the thalamus most likely contributes substantially to the neuropsychiatric disease symptoms (e.g., dementia), attention deficits, oculomotor dysfunctions, altered non-discriminative aspects of pain experience of AD patients, and the disruption of their waking and sleeping patterns.

Precortical Phase of Alzheimer's Disease (AD)-Related Tau Cytoskeletal Pathology.

Alzheimer's disease (AD) represents the most frequent progressive neuropsychiatric disorder worldwide leading to dementia. We systematically investigated the presence and extent of the AD-related cytoskeletal pathology in serial thick tissue sections through all subcortical brain nuclei that send efferent projections to the transentorhinal and entorhinal regions in three individuals with Braak and Braak AD stage 0 cortical cytoskeletal pathology and fourteen individuals with Braak and Braak AD stage I cortical cytoskeletal pathology by means of immunostainings with the anti-tau antibody AT8. These investigations revealed consistent AT8 immunoreactive tau cytoskeletal pathology in a subset of these subcortical nuclei in the Braak and Braak AD stage 0 individuals and in all of these subcortical nuclei in the Braak and Braak AD stage I individuals. The widespread affection of the subcortical nuclei in Braak and Braak AD stage I shows that the extent of the early subcortical tau cytoskeletal pathology has been considerably underestimated previously. In addition, our novel findings support the concept that subcortical nuclei become already affected during an early 'pre-cortical' evolutional phase before the first AD-related cytoskeletal changes occur in the mediobasal temporal lobe (i.e. allocortical transentorhinal and entorhinal regions). The very early involved subcortical brain regions may represent the origin of the AD-related tau cytoskeletal pathology, from where the neuronal cytoskeletal pathology takes an ascending course toward the secondarily affected allocortex and spreads transneuronally along anatomical pathways in predictable sequences.

Determining minimal stimulus intensity for mechanomyographic analysis.

INTRODUCTION: Mechanomyography (MMG) has recently shown promise in monitoring recovery of injured muscles. However, delivering a maximal percutaneous neuromuscular stimulus (PNS) could potentially be painful on severely damaged muscles. The aim of this paper was to determine whether delivering a sub-maximal PNS could still obtain accurate MMG recordings of muscle contraction time (Tc). The effect of muscle architecture on determining the minimal level of current was also investigated. METHODS: Six muscles were investigated; 5 lower limb and the 1st dorsal interosseous. A 'current ramp' procedure was performed to determine minimal stimulus intensity required for accurate Tc recordings. A current ramp entails beginning at a low current (30mA) and increasing in increments of 10mA until a maximal muscle contraction is observed. RESULTS: For lower limb muscles, 130mA was the largest current required to obtain accurate Tc recordings in at least 95% of the population. This was up to a 50% reduction in the amount of current delivered for some muscles. Fibre type distribution showed the greatest relationship with mean minimum current. DISCUSSION: Future studies investigating injured or uninjured muscles via MMG, could use these submaximal currents to obtain accurate MMG recordings, whilst improving patient comfort and reducing experiment duration.

Age-related appearance of dendritic inclusions in catecholaminergic brainstem neurons.

We identified p62-immunoreactive inclusions in dendrites of catecholaminergic brainstem projection neurons using antibodies against p62, ubiquitin, α-synuclein, hyperphosphorylated tau, and tyrosine hydroxylase in 100-µm sections through the brainstem dorsal vagal area, locus coeruleus, and substantia nigra of 149 autopsy cases staged for intraneuronal Alzheimer's and Parkinson's disease-associated lesions. The inclusions resembled Marinesco bodies within cell nuclei of catecholaminergic neurons as well as the dot-like structures previously described by Dickson in specific neuropil areas in humans. The p62-positive inclusions were confined to dendrites of catecholaminergic neurons, lacked neuromelanin granules, and were tau- and α-synuclein-negative. Their immunoreactivity for ubiquitin varied and their prevalence significantly increased with advancing age. The presence or absence of Alzheimer's and/or Parkinson's disease-associated pathology did not influence their existence. There was a strong association between the presence of p62-positive inclusions and Marinesco bodies (p < 0.0001). Our results reveal a hitherto unknown alteration within specific neuronal types of the human brainstem that may be independent of the sequestosome-ubiquitin-proteasomal pathway and unrelated to proteinaceous aggregate-formation of neurodegenerative diseases.

The architecture and contraction time of intrinsic foot muscles.

Although critical for effective human locomotion and posture, little data exists regarding the segmentation, architecture and contraction time of the human intrinsic foot muscles. To address this issue, the Abductor Hallucis (AH), Abductor Digiti Minimi (ADM), Flexor Digitorum Brevis (FDB) and Extensor Digitorum Brevis (EDB) were investigated utilizing a cadaveric dissection and a non-invasive whole muscle mechanomyographic (wMMG) technique. The segmental structure and architecture of formaldehyde-fixed foot specimens were determined in nine cadavers aged 60-80 years. The wMMG technique was used to determine the contraction time (Tc) of individual muscle segments, within each intrinsic foot muscle, in 12 volunteers of both genders aged between 19 and 24 years. While the pattern of segmentation and segmental -architecture (e.g. fibre length) and -Tc of individual muscle segments within the same muscle were similar, they varied between muscles. Also, the average whole muscle Tc of FDB was significantly (p < 0.05) shorter (faster) (Tc = 58 ms) than in all other foot muscles investigated (ADM Tc = 72 ms, EDB Tc = 72 ms and ABH Tc = 69 ms). The results suggest that the architecture and contraction time of the FDB reflect its unique direct contribution, through toe flexion, to postural stability and the rapid development of ground reaction forces during forceful activities such as running and jumping.

Genetic variants in PSEN2 and correlation to CSF ß-amyloid42 levels in AD.

Beta-amyloid 42 (Aß42) concentrations in cerebrospinal fluid (CSF) are significantly decreased in Alzheimer's disease (AD). The aim of this study was to correlate genetic variability in presenilin 2 (PSEN2) in relation to Aß42 concentrations and to confirm association of apolipoprotein E (APOE) alleles E4/E4 genotype with lower CSF Aß42. Haplotype analysis of PSEN2 and APOE genotyping were performed in 175 Alzheimer's disease patients, as defined by clinical diagnosis and Aß42 levels. One distinct haploblock in PSEN2 was detected and the frequent haplotypes were analyzed using 4 tagging single nucleotide polymorphisms (SNPs). We found an association between haplotype 2 and higher CSF Aß42 concentrations (p = 0.021) and lower Aß42 concentrations in haplotype 5 carriers (p < 0.001). APOE E4/E4 carriers had lower Aß42 levels (p = 0.009). Additive regression analysis showed an association of Aß42 level with APOE genotype (p = 0.024), haplotype 4 (p = 0.064), and haplotype 5 (p = 0.04), whereas gender, age at onset and Mini Mental State Examination (MMSE) remained insignificant. Using CSF Aß42 as a biomarker we replicated genetic influences in APOE and observed a significant influence of a new haplotype in PSEN2. A better understanding of genetic influences on biomarkers like CSF Aß42 might help to stratify patients and develop specific treatment strategies.

Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years.

Two thousand three hundred and thirty two nonselected brains from 1- to 100-year-old individuals were examined using immunocytochemistry (AT8) and Gallyas silver staining for abnormal tau; immunocytochemistry (4G8) and Campbell-Switzer staining were used for the detection ofß-amyloid. A total of 342 cases was negative in the Gallyas stain but when restaged for AT8 only 10 were immunonegative. Fifty-eight cases had subcortical tau predominantly in the locus coeruleus, but there was no abnormal cortical tau (subcortical Stages a-c). Cortical involvement (abnormal tau in neurites) was identified first in the transentorhinal region (Stage 1a, 38 cases). Transentorhinal pyramidal cells displayed pretangle material (Stage 1b, 236 cases). Pretangles gradually became argyrophilic neurofibrillary tangles (NFTs) that progressed in parallel with NFT Stages I to VI. Pretangles restricted to subcortical sites were seen chiefly at younger ages. Of the total cases, 1,031 (44.2%) had ß-amyloid plaques. The first plaques occurred in the neocortex after the onset of tauopathy in the brainstem. Plaques generally developed in the 40s in 4% of all cases, culminating in their tenth decade (75%). ß-amyloid plaques and NFTs were significantly correlated (p < 0.0001). These data suggest that tauopathy associated with sporadic Alzheimer disease may begin earlier than previously thought and possibly in the lower brainstem rather than in the transentorhinal region.

Capillary cerebral amyloid angiopathy identifies a distinct APOE epsilon4-associated subtype of sporadic Alzheimer's disease.

The deposition of amyloid beta-protein (Abeta) in the vessel wall, i.e., cerebral amyloid angiopathy (CAA), is associated with Alzheimer's disease (AD). Two types of CAA can be differentiated by the presence or absence of capillary Abeta-deposits. In addition, as in Alzheimer's disease, risk for capillary CAA is associated with the apolipoprotein E (APOE) epsilon4-allele. Because these morphological and genetic differences between the two types of AD-related CAA exist, the question arises as to whether there exist further differences between AD cases with and without capillary CAA and, if so, whether capillary CAA can be employed to distinguish and define specific subtypes of AD. To address this question, we studied AD and control cases both with and without capillary CAA to identify the following: (1) distinguishing neuropathological features; (2) alterations in perivascular protein expression; and (3) genotype-specific associations. More widespread Abeta-plaque pathology was observed in AD cases with capillary CAA than in those without. Expression of perivascular excitatory amino acid transporter 2 (EAAT-2/GLT-1) was reduced in cortical astrocytes of AD cases with capillary CAA in contrast to those lacking capillary Abeta-deposition and controls. Genetically, AD cases with capillary CAA were strongly associated with the APOE epsilon4 allele compared to those lacking capillary CAA and to controls. To further validate the existence of distinct types of AD we analyzed polymorphisms in additional apoE- and cholesterol-related candidate genes. Our results revealed an association between AD cases without capillary CAA (i.e., AD cases with CAA but lacking capillary CAA and AD cases without CAA) and the T-allele of the alpha(2)macroglobulin receptor/low-density lipoprotein receptor-related protein-1 (LRP-1) C766T polymorphism as opposed to AD cases with capillary CAA and non-AD controls. Taken together, these results indicate that AD cases with capillary CAA differ significantly from other AD cases both genetically and morphologically, thereby pointing to a specific capillary CAA-related and APOE epsilon4-associated subtype of AD.

Inverse relationship between cerebrovascular lesions and severity of lewy body pathology in patients with lewy body diseases.

Cerebrovascular pathology is a major cause of stroke and mortality. Studies on prevalence of cerebrovascular pathologies in dementia with Lewy bodies (DLBs) and Parkinson disease (PD) patients are scarce and contradictory. We aimed to determine the prevalence and severity of cerebrovascular pathologies in DLB and PD and to analyze their relationship to LB pathology. The prevalence and severity of atherosclerosis in the circle of Willis, cerebral amyloid angiopathy, cerebral infarcts, hemorrhages, small-vessel disease, white matter lesions, including the Consortium to Establish a Registry for Alzheimer Disease (CERAD) protocol as well as Braak neurofibrillary tangle stages for AD pathology were analyzed in autopsy-verified DLB (n = 13), PD (n = 102), and control subjects (n = 53). In all patient groups, the extent of LB pathology was inversely correlated to the severity of most vascular pathologies (atherosclerosis, infarcts, and small-vessel disease; all p < 0.05). By contrast, cerebral amyloid angiopathy, CERAD, and Braak neurofibrillary tangle stages were positively correlated with LB pathology (p < 0.05). Whereas the overall prevalence and severity of small-vessel disease, infarcts, hemorrhages, and white matter lesions were comparable among both disease groups, the extents of atherosclerosis, cerebral amyloid angiopathy, CERAD, and Braak neurofibrillary tangle stages were significantly higher in DLB than in those of PD patients (p < 0.05). Microinfarcts were statistically more prevalent in each patient group than in controls, whereas gross infarcts predominated in controls (p < 0.05 each). In conclusion, DLB and PD patients with advanced LB pathology were less likely to show severe cerebrovascular disease or history of stroke.

Lewy pathology in the submandibular gland of individuals with incidental Lewy body disease and sporadic Parkinson's disease.

A retrospective autopsy-based study of the human submandibular gland, one of the three major salivary glands, together with anatomically related peripheral structures (cervical superior ganglion, cervical sympathetic trunk, vagal nerve at the level of the carotid bifurcation), was conducted on a cohort consisting of 33 individuals, including 9 patients with neuropathologically confirmed Parkinson's disease (PD), three individuals with incidental Lewy body disease (iLBD), 2 individuals with neuropathologically confirmed multiple system atrophy (MSA), and 19 controls, using alpha-synuclein immunohistochemistry in 100 mum polyethylene glycol-embedded tissue sections. Lewy pathology (LP) was present in the submandibular glands and cervical superior ganglia in PD (9/9 cases) and iLBD (2/3 cases) but not in MSA or controls. The cervical sympathetic trunk (7/9 PD cases, 2/3 iLBD cases) and peripheral vagal nerves (9/9 PD cases, 2/3 iLBD cases) also displayed LP. The results are discussed within the context of hyposmia as well as autonomic dysfunction in PD (sialorrhea, sialopenia, dysphagia). Potential disease-related changes in salivary volume, contents, and viscosity might make it possible, in combination with other tests, to employ human saliva as a biomarker.

Diminished tyrosine hydroxylase immunoreactivity in the cardiac conduction system and myocardium in Parkinson's disease: an anatomical study.

Clinical and autopsy studies have consistently reported cardiac sympathetic dysfunction in the left ventricular wall in patients with Parkinson's disease (PD). Whether the nerve fibers of the cardiac conduction system or the atrial walls are equally affected in this disease process has not yet been well documented. Therefore, the aim of this study was to investigate sympathetic nerves in the cardiac conduction system as well as in the walls of all four heart chambers in patients with PD, in incidental Lewy body disease (iLBD), and in controls. Heart tissue from five PD patients, two iLBD cases, and seven controls were investigated immunohistochemically using antibodies directed against tyrosine hydroxylase (TH) and alpha-synuclein (syn-1). A marked diminution of TH immunoreactivity (IR) within nerve fibers was observed in four PD patients and in both individuals with iLBD. In contrast, all control subjects displayed dense TH-IR nerve structures. The depletion in TH-IR involved not only the ventricles, but also the conduction system and the atrium showing a global change within cardiac TH-IR nerve fibers in the course of PD. In conclusion, the alterations in cardiac sympathetic nerves of patients with PD or in individuals with iLBD are homogeneous and global within the heart. The clinical implications related to this complete cardiac sympathetic dysfunction, including clinical correlates, diagnostic implications, and treatment, however, remain to be determined in a larger autopsy-controlled cohort of prospectively followed individuals.

Intrastromal keratotomy with femtosecond laser avoids profibrotic TGF-beta1 induction.

PURPOSE: To examine expression of the profibrotic cytokine TGF-beta1 after selective intrastromal corneal injury with the use of a femtosecond laser. METHODS: Rabbits underwent monocular intrastromal keratotomy at a preoperatively determined corneal depth of 160 to 200 mum with the use of a femtosecond laser. Femtosecond laser-induced TGF-beta1 expression was compared in nonoperated control eyes and eyes treated with photorefractive keratectomy (PRK). Follow-up examinations were performed 1, 3, 7, and 28 days after surgery. TGF-beta1 protein was identified by immunofluorescence labeling. With the use of laser-capture microdissection, epithelial, stromal, and endothelial cell layers were collected, and changes in TGF-beta1 mRNA expression were quantified with quantitative RT-PCR. RESULTS: TGF-beta1 mRNA and protein expression did not significantly increase after intrastromal femtosecond laser keratotomy. In contrast, TGF-beta1 was induced in corneal epithelial and stromal cells after PRK and showed up to 23-fold higher TGF-beta1 mRNA levels compared with control corneas. The increase of TGF-beta1 mRNA levels after PRK was accompanied by increased TGF-beta1 protein production. CONCLUSIONS: Isolated stromal injury with a femtosecond laser does not result in induction of the profibrotic cytokine TGF-beta1. Because TGF-beta1 has been implicated in a fibrotic response of the corneal stroma to injury, absence of TGF-beta1 induction argues for a favorable wound-healing response. These findings support highly selective intrastromal procedures in refractive surgery.