Molecular abnormalities in autopsied brain tissue from the inferior horn of the lateral ventricles of nonagenarians and Alzheimer disease patients.

BACKGROUND: The ventricular system plays a vital role in blood-cerebrospinal fluid (CSF) exchange and interstitial fluid-CSF drainage pathways. CSF is formed in the specialized secretory tissue called the choroid plexus, which consists of epithelial cells, fenestrated capillaries and the highly vascularized stroma. Very little is currently known about the role played by the ventricles and the choroid plexus tissue in aging and Alzheimer's disease (AD). METHODS: In this study, we used our state-of-the-art proteomic platform, a liquid chromatography/mass spectrometry (LC-MS/MS) approach coupled with Tandem Mass Tag isobaric labeling to conduct a detailed unbiased proteomic analyses of autopsied tissue isolated from the walls of the inferior horn of the lateral ventricles in AD (77.2 ± 0.6 yrs), age-matched controls (77.0 ± 0.5 yrs), and nonagenarian cases (93.2 ± 1.1 yrs). RESULTS: Ingenuity pathway analyses identified phagosome maturation, impaired tight-junction signaling, and glucose/mannose metabolism as top significantly regulated pathways in controls vs nonagenarians. In matched-control vs AD cases we identified alterations in mitochondrial bioenergetics, oxidative stress, remodeling of epithelia adherens junction, macrophage recruitment and phagocytosis, and cytoskeletal dynamics. Nonagenarian vs AD cases demonstrated augmentation of oxidative stress, changes in gluconeogenesis-glycolysis pathways, and cellular effects of choroidal smooth muscle cell vasodilation. Amyloid plaque score uniquely correlated with remodeling of epithelial adherens junctions, Fc γ-receptor mediated phagocytosis, and alterations in RhoA signaling. Braak staging was uniquely correlated with altered iron homeostasis, superoxide radical degradation and phagosome maturation. CONCLUSIONS: These changes provide novel insights to explain the compromise to the physiological properties and function of the ventricles/choroid plexus system in nonagenarian aging and AD pathogenesis. The pathways identified could provide new targets for therapeutic strategies to mitigate the divergent path towards AD.

Artificial intelligence in neuropathology: deep learning-based assessment of tauopathy.

Accumulation of abnormal tau in neurofibrillary tangles (NFT) occurs in Alzheimer disease (AD) and a spectrum of tauopathies. These tauopathies have diverse and overlapping morphological phenotypes that obscure classification and quantitative assessments. Recently, powerful machine learning-based approaches have emerged, allowing the recognition and quantification of pathological changes from digital images. Here, we applied deep learning to the neuropathological assessment of NFT in postmortem human brain tissue to develop a classifier capable of recognizing and quantifying tau burden. The histopathological material was derived from 22 autopsy brains from patients with tauopathies. We used a custom web-based informatics platform integrated with an in-house information management system to manage whole slide images (WSI) and human expert annotations as ground truth. We utilized fully annotated regions to train a deep learning fully convolutional neural network (FCN) implemented in PyTorch against the human expert annotations. We found that the deep learning framework is capable of identifying and quantifying NFT with a range of staining intensities and diverse morphologies. With our FCN model, we achieved high precision and recall in naive WSI semantic segmentation, correctly identifying tangle objects using a SegNet model trained for 200 epochs. Our FCN is efficient and well suited for the practical application of WSIs with average processing times of 45 min per WSI per GPU, enabling reliable and reproducible large-scale detection of tangles. We measured performance on test data of 50 pre-annotated regions on eight naive WSI across various tauopathies, resulting in the recall, precision, and an F1 score of 0.92, 0.72, and 0.81, respectively. Machine learning is a useful tool for complex pathological assessment of AD and other tauopathies. Using deep learning classifiers, we have the potential to integrate cell- and region-specific annotations with clinical, genetic, and molecular data, providing unbiased data for clinicopathological correlations that will enhance our knowledge of the neurodegeneration.

Localized cortical chronic traumatic encephalopathy pathology after single, severe axonal injury in human brain.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive mild impact traumatic brain injury from contact sports. Recently, a consensus panel defined the pathognomonic lesion for CTE as accumulations of abnormally hyperphosphorylated tau (p-tau) in neurons (neurofibrillary tangles), astrocytes and cell processes distributed around small blood vessels at sulcal depths in irregular patterns within the cortex. The pathophysiological mechanism for this lesion is unknown. Moreover, a subset of CTE cases harbors cortical ß-amyloid plaques. In this study, we analyzed postmortem brain tissues from five institutionalized patients with schizophrenia and history of surgical leucotomy with subsequent survival of at least another 40 years. Because leucotomy involves severing axons bilaterally in prefrontal cortex, this surgical procedure represents a human model of single traumatic brain injury with severe axonal damage and no external impact. We examined cortical tissues at the leucotomy site and at both prefrontal cortex rostral and frontal cortex caudal to the leucotomy site. For comparison, we analyzed brain tissues at equivalent neuroanatomical sites from non-leucotomized patients with schizophrenia, matched in age and gender. All five leucotomy cases revealed severe white matter damage with dense astrogliosis at the axotomy site and also neurofibrillary tangles and p-tau immunoreactive neurites in the overlying gray matter. Four cases displayed p-tau immunoreactivity in neurons, astrocytes and cell processes encompassing blood vessels at cortical sulcal depths in irregular patterns, similar to CTE. The three cases with apolipoprotein E ε4 haplotype showed scattered ß-amyloid plaques in the overlying gray matter, but not the two cases with apolipoprotein E ε3/3 genotype. Brain tissue samples from prefrontal cortex rostral and frontal cortex caudal to the leucotomy site, and all cortical samples from the non-leucotomized patients, showed minimal p-tau and ß-amyloid pathology. These findings suggest that chronic axonal damage contributes to the unique pathology of CTE over time.

The triggering receptor expressed on myeloid cells 2 (TREM2) is associated with enhanced inflammation, neuropathological lesions and increased risk for Alzheimer's dementia.

INTRODUCTION: The objective of this study was to elucidate the relationship between the triggering receptor expressed on myeloid cells 2 (TREM2) risk variant, neuropathological lesions, alterations in gene and protein expression, and the severity of neuroinflammation. METHODS: The genetic association study of the R47 H TREM2 variant with Alzheimer's disease (AD), neuropathology, and changes in TREM2 and TYRO protein tyrosine kinase-binding protein (TYROBP) gene and protein expression, and neuroinflammatory markers. RESULTS: The TREM2 variant is associated with: (i) AD (odds ratio: 4.76; P = .014); (ii) increased density of amyloid plaques and neurofibrillary tangles in multiple brain regions; (iii) increased TREM2 (P = .041) and TYROBP (P = .006) gene expression; (iv) decreased TREM2 protein levels (P = .016); and (v) upregulation of proinflammatory cytokines (regulated on activation, normal T cell expressed and secreted [RANTES] and interferon [IFN] gamma) (P = .003) and nominal downregulation of protective markers (α2-macroglobulin, interleukin 4 or IL-4, and ApoA1) (P = .018). DISCUSSION: These findings link the TREM2 missense mutation with specific molecular abnormalities and increases in neuropathological lesions in the human brain.

Synthesis and antimicrobial activity of some new 1,3,4-thiadiazoles and 1,3,4-thiadiazines containing 1,2,4-Triazolo nucleus.

The desired fused ring system 3-(3-chlorophenyl)-6-aryl-5,6-dihydro[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 5a-j were synthesized by the reaction of 4-amino-5-(3-chlorophenyl)-4H-1,2,4-triazole-3-thiol and different aryl aldehydes in the presence of catalytic amount of p-TsOH in dry DMF, while 3-(3-chlorophenyl)-6-aryl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines 7a-j were synthesized by using 4-amino-5-(3-chlorophenyl)-4H-1,2,4-triazole-3-thiol and different phenacyl bromides in dry methanol. Their IR, 1H NMR, mass spectral data and elemental analyses were in accord with assigned structures. All the newly synthesized compounds were screened for their antimicrobial activity. Some of the compounds exhibited significant inhibition on bacterial and fungal growth as compared to standard drugs.

Progressive Multifocal Leukoencephalopathy in a Patient With Progressive Multiple Sclerosis Treated With Ocrelizumab Monotherapy.

Importance: Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection caused by the JC virus that has no proven effective treatment. Although rare cases of PML have occurred with other anti-CD20 therapies, there had been no prior cases associated with ocrelizumab. Objective: To report the first ever case of PML occurring with ocrelizumab monotherapy in a patient with progressive multiple sclerosis without prior immunomodulation. Design, Setting, and Participant: This case was reported from an academic medical center. The patient had multiple sclerosis while receiving ocrelizumab monotherapy. Exposures: Ocrelizumab monotherapy. Results: A 78-year-old man with progressive multiple sclerosis treated with ocrelizumab monotherapy for 2 years presented with 2 weeks of progressive visual disturbance and confusion. Examination demonstrated a right homonymous hemianopia, and magnetic resonance imaging revealed an enlarging nonenhancing left parietal lesion without mass effect. Cerebrospinal fluid revealed 1000 copies/mL of JC virus, confirming the diagnosis of PML. Blood work on diagnosis revealed grade 2 lymphopenia, with absolute lymphocyte count of 710/µL, CD4 of 294/µL (reference range, 325-1251/µL), CD8 of 85/µL (reference range, 90-775/µL), CD19 of 1/µL, preserved CD4/CD8 ratio (3.45), and negative HIV serology. Retrospective absolute lymphocyte count revealed intermittent grade 1 lymphopenia that preceded ocrelizumab (absolute lymphocyte count range, 800-1200/µL). The patient's symptoms progressed over weeks to involve bilateral visual loss, right-sided facial droop, and dysphasia. Ocrelizumab was discontinued and off-label pembrolizumab treatment was initiated. The patient nevertheless declined rapidly and ultimately died. PML was confirmed at autopsy. Conclusions and Relevance: In this case report, PML occurrence was likely a result of the immunomodulatory function of ocrelizumab as well as age-related immunosenescence. This case report emphasizes the importance of a thorough discussion of the risks and benefits of ocrelizumab, especially in patients at higher risk for infections such as elderly patients.

Single-nucleus transcriptome analysis of human brain immune response in patients with severe COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has been associated with neurological and neuropsychiatric illness in many individuals. We sought to further our understanding of the relationship between brain tropism, neuro-inflammation, and host immune response in acute COVID-19 cases. METHODS: Three brain regions (dorsolateral prefrontal cortex, medulla oblongata, and choroid plexus) from 5 patients with severe COVID-19 and 4 controls were examined. The presence of the virus was assessed by western blot against viral spike protein, as well as viral transcriptome analysis covering > 99% of SARS-CoV-2 genome and all potential serotypes. Droplet-based single-nucleus RNA sequencing (snRNA-seq) was performed in the same samples to examine the impact of COVID-19 on transcription in individual cells of the brain. RESULTS: Quantification of viral spike S1 protein and viral transcripts did not detect SARS-CoV-2 in the postmortem brain tissue. However, analysis of 68,557 single-nucleus transcriptomes from three distinct regions of the brain identified an increased proportion of stromal cells, monocytes, and macrophages in the choroid plexus of COVID-19 patients. Furthermore, differential gene expression, pseudo-temporal trajectory, and gene regulatory network analyses revealed transcriptional changes in the cortical microglia associated with a range of biological processes, including cellular activation, mobility, and phagocytosis. CONCLUSIONS: Despite the absence of detectable SARS-CoV-2 in the brain at the time of death, the findings suggest significant and persistent neuroinflammation in patients with acute COVID-19.

Predictors of cognitive impairment in primary age-related tauopathy: an autopsy study.

Primary age-related tauopathy (PART) is a form of Alzheimer-type neurofibrillary degeneration occurring in the absence of amyloid-beta (Aß) plaques. While PART shares some features with Alzheimer disease (AD), such as progressive accumulation of neurofibrillary tangle pathology in the medial temporal lobe and other brain regions, it does not progress extensively to neocortical regions. Given this restricted pathoanatomical pattern and variable symptomatology, there is a need to reexamine and improve upon how PART is neuropathologically assessed and staged. We performed a retrospective autopsy study in a collection (n = 174) of post-mortem PART brains and used logistic regression to determine the extent to which a set of clinical and neuropathological features predict cognitive impairment. We compared Braak staging, which focuses on hierarchical neuroanatomical progression of AD tau and Aß pathology, with quantitative assessments of neurofibrillary burden using computer-derived positive pixel counts on digitized whole slide images of sections stained immunohistochemically with antibodies targeting abnormal hyperphosphorylated tau (p-tau) in the entorhinal region and hippocampus. We also assessed other factors affecting cognition, including aging-related tau astrogliopathy (ARTAG) and atrophy. We found no association between Braak stage and cognitive impairment when controlling for age (p = 0.76). In contrast, p-tau burden was significantly correlated with cognitive impairment even when adjusting for age (p = 0.03). The strongest correlate of cognitive impairment was cerebrovascular disease, a well-known risk factor (p < 0.0001), but other features including ARTAG (p = 0.03) and hippocampal atrophy (p = 0.04) were also associated. In contrast, sex, APOE, psychiatric illness, education, argyrophilic grains, and incidental Lewy bodies were not. These findings support the hypothesis that comorbid pathologies contribute to cognitive impairment in subjects with PART. Quantitative approaches beyond Braak staging are critical for advancing our understanding of the extent to which age-related tauopathy changes impact cognitive function.

Early Selective Vulnerability of the CA2 Hippocampal Subfield in Primary Age-Related Tauopathy.

Primary age-related tauopathy (PART) is a neurodegenerative entity defined as Alzheimer-type neurofibrillary degeneration primarily affecting the medial temporal lobe with minimal to absent amyloid-ß (Aß) plaque deposition. The extent to which PART can be differentiated pathoanatomically from Alzheimer disease (AD) is unclear. Here, we examined the regional distribution of tau pathology in a large cohort of postmortem brains (n = 914). We found an early vulnerability of the CA2 subregion of the hippocampus to neurofibrillary degeneration in PART, and semiquantitative assessment of neurofibrillary degeneration in CA2 was significantly greater than in CA1 in PART. In contrast, subjects harboring intermediate-to-high AD neuropathologic change (ADNC) displayed relative sparing of CA2 until later stages of their disease course. In addition, the CA2/CA1 ratio of neurofibrillary degeneration in PART was significantly higher than in subjects with intermediate-to-high ADNC burden. Furthermore, the distribution of tau pathology in PART diverges from the Braak NFT staging system and Braak stage does not correlate with cognitive function in PART as it does in individuals with intermediate-to-high ADNC. These findings highlight the need for a better understanding of the contribution of PART to cognitive impairment and how neurofibrillary degeneration interacts with Aß pathology in AD and PART.

Serum lipids are related to Alzheimer's pathology in nursing home residents.

BACKGROUND: Studies of associations between serum lipids and Alzheimer's disease (AD) or other dementias in the elderly show conflicting results, perhaps due to misclassification of the various dementias. METHODS: For 358 nursing home residents, serum lipids were studied at admission and diagnoses established at autopsy. We used defined neuropathological criteria to distinguish the presence of AD and to avoid errors of clinical dementia assessment. RESULTS: Residents with any AD pathology, as compared to those without AD pathology, had higher mean serum total cholesterol (TC; 200.4 vs. 185.9 mg/dl; p = 0.02) and higher mean low-density lipoprotein cholesterol (LDL; 124.5 vs. 111.5 mg/dl; p = 0.03). Further, mean TC, LDL and high-density lipoprotein cholesterol levels all increased progressively with increasing pathological certainty of AD (p for trend = 0.001, 0.02 and 0.02). CONCLUSIONS: TC and LDL were significantly related to pathologically defined AD. If serum lipids have a role in the pathogenesis of AD, interventions may modify the course of disease.

Clinical dementia rating performed several years prior to death predicts regional Alzheimer's neuropathology.

AIMS: To assess the relationships between early and late antemortem measures of dementia severity and Alzheimer disease (AD) neuropathology severity. METHODS: 40 residents of a nursing home, average age at death 82.0, participated in this longitudinal cohort study with postmortem assessment. Severity of dementia was measured by Clinical Dementia Rating (CDR) at two time points, averaging 4.5 and 1.0 years before death. Densities of postmortem neuritic plaques (NPs) and neurofibrillary tangles (NFTs) were measured in the cerebral cortex, hippocampus, and entorhinal cortex. RESULTS: For most brain areas, both early and late CDRs were significantly associated with NPs and NFTs. CDRs assessed proximal to death predicted NFTs beyond the contribution of early CDRs. NPs were predicted by both early and late CDRs. NPs were predictive of both early and late CDRs after controlling for NFTs. NFTs were only associated significantly with late CDR in the cerebral cortex after controlling for NPs. CONCLUSIONS: Even if assessed several years before death, dementia severity is associated with AD neuropathology. NPs are more strongly associated with dementia severity than NFTs. NFTs consistently associate better with late than early CDR, suggesting that these neuropathological changes may occur relatively later in the course of the disease.

Increased hippocampal plaques and tangles in patients with Alzheimer disease with a lifetime history of major depression.

CONTEXT: The hallmark pathological changes in Alzheimer disease (AD) are abundant plaque and tangle formation, especially in the temporal lobes and hippocampus. Although there is increasing evidence that major depression may interact with neuropathological processes in AD, there have been no studies of neuropathological changes in AD as a function of history of major depression. OBJECTIVE: To test the hypothesis that neuritic plaques and neurofibrillary tangles are more pronounced in the hippocampus of patients with AD with a lifetime history of major depressive disorder, as compared with patients with AD without depression history. DESIGN: Postmortem study. SETTING: Nursing home. PARTICIPANTS: The brains of 52 patients with AD without a lifetime history of major depression were compared with the brains of 50 patients with AD with a lifetime history of major depression. MAIN OUTCOME MEASURES: Neuropathological ratings from the Consortium to Establish a Registry in Alzheimer Disease battery. RESULTS: Brains of patients with AD with a lifetime history of depression showed higher levels of both plaque (P<.005) and tangle (P<.002) formation within the hippocampus than brains of patients with AD without a history of depression. Post hoc analyses showed that patients with AD who had a history of depression exhibited more rapid cognitive decline than patients without a history of depression (P<.004). Furthermore, within the group of patients with AD with a history of depression, patients who exhibited concurrent depression at the time of first diagnosis of AD exhibited more pronounced neuropathological changes in the hippocampus (P<.006). CONCLUSIONS: In AD, the presence of a lifetime history of depression corresponds to increases in AD-related neuropathological changes within the hippocampus. These changes go along with more rapid cognitive decline in patients with AD with a history of depression, and are more pronounced in patients with AD suffering from depression early on in the disease process, suggesting an interaction between major depression and AD neuropathology.

Type 2 diabetes is negatively associated with Alzheimer's disease neuropathology.

BACKGROUND: In cross-sectional and longitudinal studies, type 2 diabetes has been positively associated with the risk of Alzheimer's disease (AD). The present descriptive study compared diabetic and nondiabetic subjects on the severity of neuritic plaques and neurofibrillary tangles (NFTs) in the cerebral cortex and in the hippocampus. METHODS: The study included specimens from 385 consecutive autopsies of residents of a nursing home (15.8% diabetics). Mean age at death = 84 years [standard deviation (SD) = 10], 66% were female, Clinical Dementia Rating mean = 3.0 (SD = 1.6), and 32.5% had an APOE4 allele. Additional analyses limited the sample to 268 subjects (14.1% diabetics) without neuropathology other than AD. RESULTS: Analyses of covariance controlling for age at death, dementia severity (Clinical Dementia Rating score), and APOE4 allele indicated that diabetics had significantly fewer neuritic plaques (p =.008) and NFTs (p =.047) in the cerebral cortex than did nondiabetics. In the hippocampus, diabetics had significantly lower plaque ratings than did nondiabetics (p =.019), but the lower ratings of NFTs did not achieve statistical significance (p =.082). In the entire sample, diabetics had significantly less AD-associated neuropathology in all four analyses. CONCLUSIONS: These results raise the possibility that the varied associations observed between diabetes and AD may be specific to as yet ill-defined subgroups of dementia and diabetic patients or may be more characteristic of younger patients than of those who survive to a mean age of 84 years. Future studies are encouraged to examine a variety of other characteristics such as age that may interact with diabetes affecting the incidence of AD.

Hippocampal and entorhinal cortex neurofibrillary tangle formation in Guamanian Chamorros free of overt neurologic dysfunction.

Since first described, amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of Guam has represented an important model of age-related neurodegenerative disease. ALS/PDC is characterized neuropathologically by severe widespread involvement by neurofibrillary tangles (NFTs). Over the past 30 years there has been a dramatic decrease in the incidence of ALS and a 10-year increase in the age of onset of ALS and PDC. In 1979, Anderson et al reported evidence of significant NFT involvement in Guam natives who had been free of evidence of neurologic dysfunction. Using the slides from this study, we re-examined the extent of hippocampus and entorhinal NFT involvement and compared it to brains recently obtained from neurologically intact Guam natives and age-matched controls from New York. The tendency towards hippocampal and entorhinal NFT formation continues to be encountered among the inhabitants of Guam, particularly among those over age 50. although severe involvement was less commonly noted in relatively young individuals (< 50 years). As noted by Anderson et al, the pattern of neuropathologic lesions seen in those with extensive NFT involvement suggests that such cases represent preclinical examples of ALS/PDC in individuals who have yet to accumulate a sufficient burden of pathology to attract clinical attention and diagnostic evaluation.

Postmortem assessment of thalamic nuclear volumes in subjects with schizophrenia.

OBJECTIVE: The authors assessed schizophrenia-associated changes in volume and neuronal number in the mediodorsal nucleus and the pulvinar regions of the thalamus. METHOD: Right-hemisphere thalami obtained at autopsy from 14 schizophrenic and eight comparison subjects were examined. Computer-assisted morphometric techniques were used to determine volumes for the mediodorsal nucleus, pulvinar, and the anterior and centromedian nuclei as well as the parvocellular, magnocellular, and caudodorsal subdivisions of the mediodorsal nucleus. Neurons in the mediodorsal nucleus and pulvinar were counted and measured by using a stereology-based sampling strategy. RESULTS: Four schizophrenic and three comparison subjects had Alzheimer's type pathology, leaving 10 schizophrenic and five comparison subjects without other documented neuropathological changes. In analyses that included either the full cohort or only the subjects without Alzheimer's type pathology, volumes of the mediodorsal nucleus and pulvinar, but not the anterior or centromedian nuclei, were significantly smaller in the schizophrenic subjects. For the schizophrenic subjects, neuronal number in the mediodorsal nucleus, parvocellular subdivision, and pulvinar was significantly lower, and neuronal size in the mediodorsal nucleus, caudodorsal subdivision, and pulvinar was significantly smaller. CONCLUSIONS: Schizophrenia is associated with volume and neuronal changes in the mediodorsal nucleus and pulvinar, the major association nuclei of the thalamus, whereas total thalamic volume and the volumes of anterior and centromedian nuclei were not significantly altered.

Caspase gene expression in the brain as a function of the clinical progression of Alzheimer disease.

BACKGROUND: Caspase gene expression has previously been reported in terminal Alzheimer disease (AD) brain, but, currently, little is known about the temporal pattern of caspase gene expression relative to the onset and clinical progression of AD. OBJECTIVE: To derive a profile of caspase gene expression and proapoptotic indexes as a function of the clinical and neuropathologic progression of AD dementia. SETTING AND PATIENTS: Postmortem survey of nursing home patients characterized clinically by Clinical Dementia Rating (CDR) and neuropathologically by Consortium to Establish a Registry for Alzheimer's Disease criteria. DESIGN AND OUTCOME MEASURES: To assess messenger RNA expression of caspase-1, -2L, -2S, -3, -5, -6, -7, -8, and -9; apoptotic cell death by TUNEL assay; and poly (ADP-ribose) polymerase cleavage in postmortem brain tissue samples from cognitively normal (CDR 0), high risk of developing AD dementia (CDR 0.5), and severe dementia (CDR 5) cases. RESULTS: Compared with CDR 0 cases, elevated messenger RNA expression of caspase-1 and caspase-7 in the entorhinal cortex of CDR 0.5 cases coincided with increased poly (ADP-ribose) polymerase cleavage but not apoptotic cell injury. In the entorhinal cortex of CDR 5 cases, we found elevation of caspase-1, -2L, -3, -5, -6, -7, -8, and -9 and a greater than 4-fold increase in TUNEL-positive cells. Caspase messenger RNA expression was closely associated with neurofibrillary tangle and, to a lesser extent, neuritic plaque density. CONCLUSIONS: Proapoptotic mechanisms may be at play early in the onset of AD (before overt signs of apoptosis) and may be a conditional factor for later apoptotic cell injury or death. These data have relevance to potential therapeutic interventions for AD using selective caspase inhibitors.

Depression in autopsy-confirmed dementia with Lewy bodies and Alzheimer's disease.

Depression has frequently been cited as a manifestation of dementia with Lewy bodies (DLB). Previous studies have suggested an increase of depression in patients with DLB, compared to those with Alzheimer's disease (AD). The purpose of this study was to examine depressive symptomatology in nursing home residents, from a consecutive series of DLB (n=16) and AD (n=39) autopsy-confirmed cases. Subjects received standard neuropathological analysis and postmortem chart review for clinical assessment of depression. Depressive symptomatology did not differ between the AD and DLB groups, and there was no significant relationship between depression and cortical or subcortical Lewy body (LB) count in the locus ceruleus or substantia nigra. This study suggests that the presence or absence of depression cannot be used to distinguish between AD and DLB. Furthermore, depressive symptomatology in DLB does not appear to be related to severity of cortical or subcortical LB pathology.

Palliative and aggressive end-of-life care for patients with dementia.

OBJECTIVES: The goals of this study were to establish the frequency of palliative and aggressive treatment measures among patients with and without dementia during the last six months of life, to identify relationships between the severity of dementia and aggressive and palliative care, and to determine whether treatment patterns have changed over time. METHODS: Antemortem data for 279 patients with dementia and 24 control patients who were brought for autopsy in chronic care facilities between 1985 and 2000 were reviewed. The severity of dementia was defined by scores on the Clinical Dementia Rating scale. Data on use of systemic antibiotics (designated as an aggressive treatment measure) and on use of narcotic and nonnarcotic pain medications and nasal oxygen (defined as palliative measures) were collected from medical charts. RESULTS: Fifty-three percent of the patients with dementia and 46 percent of those without dementia had received systemic antibiotics. Fourteen percent of the patients with dementia and 38 percent of those without dementia had received narcotic pain medications. The prevalence of aggressive and palliative measures did not vary significantly with the severity of dementia. Eleven percent of the patients with dementia who died between 1991 and 1995 and 18 percent of those who died between 1996 and 2000 had received narcotic pain medications in the last six months of their lives. CONCLUSIONS: Use of systemic antibiotics is prevalent in the treatment of patients with end-stage dementia, despite the limited utility and discomfort associated with the use of these agents. That patients with severe dementia and those with milder cognitive impairment received similar treatment may be contrary to good clinical practice, given the poor prognosis of patients with severe dementia.

Parkinson's disease without expected neuropathologic abnormality.

A case is reported of an initially 78-year-old man whose presentation and course, closely followed over 10 years by an academic neurologist, were consistent with classic idiopathic Parkinson's disease (PD), including unilateral onset, obvious cogwheeling, and a very good prolonged response to levodopa/carbidopa (LD/CD). Yet at autopsy, there was no neuronal loss in the substantia nigra nor were there any Lewy bodies or immunochemical evidence of alpha synuclein in the multiple brain structures studied. This case does not support the hypothesis that the use of LD/CD is toxic to the substantia nigra in people. This patient had been on traditional doses of LD/CD for approximately 10 years, yet the number of cells in the substantia nigra was well within the normal range at autopsy. These findings are not unique, but point out the need to explain the occurrence of typical PD symptoms and course in the absence of any PD-related neuropathologic changes.

Cell cycle checkpoint abnormalities during dementia: A plausible association with the loss of protection against oxidative stress in Alzheimer's disease [corrected].

BACKGROUND: Increasing evidence suggests an association between neuronal cell cycle (CCL) events and the processes that underlie neurodegeneration in Alzheimer's disease (AD). Elevated levels of oxidative stress markers and mitochondrial dysfunction are also among early events in AD. Recent studies have reported the role of CCL checkpoint proteins and tumor suppressors, such as ATM and p53 in the control of glycolysis and oxidative metabolism in cancer, but their involvement in AD remains uncertain. METHODS AND FINDINGS: In this postmortem study, we measured gene expression levels of eight CCL checkpoint proteins in the superior temporal cortex (STC) of persons with varying severities of AD dementia and compare them to those of cognitively normal controls. To assess whether the CCL changes associated with cognitive impairment in AD are specific to dementia, gene expression of the same proteins was also measured in STC of persons with schizophrenia (SZ), which is also characterized by mitochondrial dysfunction. The expression of CCL-checkpoint and DNA damage response genes: MDM4, ATM and ATR was strongly upregulated and associated with progression of dementia (cognitive dementia rating, CDR), appearing as early as questionable or mild dementia (CDRs 0.5-1). In addition to gene expression changes, the downstream target of ATM-p53 signaling - TIGAR, a p53-inducible protein, the activation of which can regulate energy metabolism and protect against oxidative stress was progressively decreased as severity of dementia evolved, but it was unaffected in subjects with SZ. In contrast to AD, different CCL checkpoint proteins, which include p53, CHEK1 and BRCA1 were significantly downregulated in SZ. CONCLUSIONS: These results support the activation of an ATM signaling and DNA damage response network during the progression of AD dementia, while the progressive decrease in the levels of TIGAR suggests loss of protection initiated by ATM-p53 signaling against intensifying oxidative stress in AD.