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.

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.

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.

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.

Corticosteroids, but not NSAIDs, are associated with less Alzheimer neuropathology.

The objective of this study was to test the hypothesis that corticosteroid and nonsteroidal anti-inflammatory drug (NSAID) medications are associated with less global and regional Alzheimer's disease (AD) neuropathology. This postmortem study was based on 694 brains of subjects from the Mount Sinai School of Medicine Brain Bank who did not have neuropathologies other than neuritic plaques (NPs), neurofibrillary tangles (NFTs), or cerebrovascular disease. Densities of NPs and of NFTs were assessed in several neocortical regions and in the hippocampus, entorhinal cortex, and amygdala. Counts of NPs in several neocortical regions were also assessed. For each neuropathology measure, analyses of covariance controlling for age at death and sex compared subjects who received only corticosteroids (n = 54) or those who received only NSAIDs (n = 56) to the same comparison group, subjects who received neither (n = 576). Subjects receiving corticosteroids had significantly lower ratings and counts of NPs for all neuropathological measures, and NFTs overall and in the cerebral cortex and amygdala. In contrast, no measures were significant for subjects who received NSAIDs. Use of corticosteroids was associated with approximately 50% fewer NPs and NFTs in most brain regions examined, compared with nonmedicated subjects. In contrast, use of NSAIDs was not substantially associated with the reductions in hallmark lesions of AD. Because corticosteroids have anti-inflammatory as well as a myriad of other neurobiological effects, more direct studies in model systems could reveal novel therapeutic targets and mechanisms for AD lesion reduction.

Profiles of Alzheimer's disease-related pathology in an aging urban population sample in India.

Systematic studies on Alzheimer's disease (AD)-related pathology that complement clinical and epidemiological data on dementia from low and middle income countries are rare. We report the first large study on AD-related pathology in autopsy service-derived brains from an urban center in India, a low/middle income country, and compare findings with a similar sample from New York. Amyloid-ß plaques and neurofibrillary tangles were assessed in 91 brain specimens derived from hospital autopsy cases from Mumbai, India (age 60+ years; mean age 71.1 years, ± 8.3 SD; range 60-107 years) and compared with identically examined age-matched sample obtained in New York. These cases had no known clinical history of dementia. Our study showed that in comparison with the New York sample, the mean brain weight of the Mumbai sample was lower (p = 0.013) and mean diffuse plaque density was higher (p = 0.019), while differences in mean density and counts of neurofibrillary tangles and neuritic plaques were not statistically significant (p > 0.05). Our findings indicate that the burden of AD-related pathology was approximately equivalent in Mumbai and New York samples, which is at variance with expected lower AD-related lesion burden based on the clinical/epidemiological studies suggesting lower prevalence of AD in India.

Cortical neuritic plaques and hippocampal neurofibrillary tangles are related to dementia severity in elderly schizophrenia patients.

Cognitive decline has been described in elderly patients with schizophrenia, but the underlying pathology remains unknown. Some studies report increases in plaques and neurofibrillary tangles, but there is no evidence for an increased risk for Alzheimer's disease (AD) in elderly schizophrenics. Models of a decreased cerebral reserve suggest that increases in AD-related neuropathology below the threshold for a neuropathological diagnosis could be related to dementia severity in elderly schizophrenia patients. We tested this hypothesis in 110 autopsy specimens of schizophrenia patients, without a neuropathological diagnosis of AD or other neurodegenerative disorders. Furthermore, we assessed the effects of apolipoprotein E (ApoE) status, a known genetic risk factor for AD. Measures of density of neuritic plaques were obtained in five cortical regions, and the degree of hippocampal neurofibrillary tangles was rated. Dementia severity was measured prior to postmortem using the Clinical Dementia Rating (CDR) scale. multivariate analyses of variance were conducted with the factors dementia severity, by ApoE4 carrier status. Hippocampal neurofibrillary tangles correlated with increased dementia severity (p<.05). Neuritic plaque density increased with greater dementia severity (p<.005), and ApoE4 carrier status (p<.005), and these differences were magnified by the ApoE4 carrier status (p<.01). Even below the threshold for a neuropathological diagnosis of AD, neuritic plaques and hippocampal neurofibrillary tangles are associated with dementia severity in schizophrenia patients, even more so in the presence of genetic risk factors, suggesting that a decreased cerebral reserve in elderly schizophrenics may increase susceptibility for dementia.

Parkinson's disease dementia: a diminished role for the Lewy body.

The literature currently views Lewy bodies as central in the pathogenesis of Parkinson's disease dementia (PDD) when Alzheimer's disease (AD) or vascular pathology is not present. Because the neuropathology of PDD is not well understood, the pathological features of PDD were characterized in eighteen PD brain specimens using published criteria for AD, Diffuse Lewy Body Disease (DLBD), and Vascular Disease as a framework. Among the PD dementia (n=16) subjects, 3 (19%) did not have LBs outside of the brain stem, nor AD or vascular pathology. In two additional cases, one did have rare LBs in the neocortex and cingulate gyrus. However, these two cases did not meet the diagnostic criteria for DLBD. Beyond these 5 cases, the remaining PD dementia subjects fitted a classical pathological profile consistent with AD (38%), vascular disease (12.5%), DLBD (6%), or a combination of these pathologies (12.5%). The findings from this study do not support the hypothesis that LBs are the main substrate for dementia in PD. More research with a larger sample size is needed to determine whether the LB may be a secondary phenomenon and/or an "innocent-bystander". The entire role of the LB in PD dementia is again brought into question.

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.

Number of children is associated with neuropathology of Alzheimer's disease in women.

OBJECTIVE: To examine the association between number of born children and neuropathology of Alzheimer's disease (AD). METHODS: The brains of 86 subjects with data on the number of biological children born, were studied postmortem. Primary analyses included 73 subjects (average age at death=80; 42 women) devoid of cerebrovascular disease associated lesions (i.e., infarcts) or of non-AD related neuropathology. Women were significantly older at death than men (85.6 vs. 73.4; p<.0005) but did not differ significantly from men in number of children or dementia severity. Secondary analyses included 13 additional subjects who had concomitant cerebrovascular disease. Density of neuritic plaques (NPs) and neurofibrillary tangles (NFTs) in the hippocampus, entorhinal cortex, amygdala and multiple regions of the cerebral cortex, as well as composites of these indices reflecting overall neuropathology, were analyzed. For men and women separately, partial correlations, controlling for age at death and dementia severity, were used to assess the associations of number of children with these neuropathological variables. RESULTS: Among women, all the partial correlations were positive, with statistical significance for overall neuropathology (r=.37; p=.02), overall NPs (r=.36; p=.02), and for NPs in the amygdala (r=.47; p=.002). Among men, none of the partial correlations were statistically significant. Results of the secondary analyses were similar. CONCLUSIONS: Since the associations between number of children and neuropathology of AD were found for women only, they might reflect sex-specific mechanisms (such as variations in estrogen or luteinizing hormone levels) rather than social, economic, biological or other mechanisms common to both men and women.

Role of the neuropathology of Alzheimer disease in dementia in the oldest-old.

BACKGROUND: Neuritic plaques (NPs) and neurofibrillary tangles (NFTs) in the brain, especially in the hippocampus, entorhinal cortex, and isocortex, are hallmark lesions of Alzheimer disease and dementia in the elderly. However, this association has not been extensively studied in the rapidly growing population of the very old. OBJECTIVE: To assess the relationship between estimates of cognitive function and NP and NFT pathologic conditions in 317 autopsied persons aged 60 to 107 years. DESIGN: We studied the relationship between severity of dementia and the density of these characteristic lesions of Alzheimer disease in young-old, middle-old, and oldest-old persons. The relationship of the severity of dementia as measured by the Clinical Dementia Rating scale to the density of NPs and NFTs was then assessed in each age group. PARTICIPANTS: Three hundred seventeen brains of persons aged 60 years and older were selected to have either no remarkable neuropathological lesions or only NP and NFT lesions. Brains with any other neuropathological conditions, either alone or in addition to Alzheimer disease findings, were excluded. The study cohort was then stratified into the youngest quartile (aged 60-80 years), middle 2 quartiles (aged 81-89 years), and oldest quartile (aged 90-107 years). RESULTS: While the density of NPs and NFTs rose significantly by more than 10-fold as a function of the severity of dementia in the youngest-old group, significant increases in the densities of NPs and NFTs were absent in the brains of the oldest-old. This lack of difference in the densities of NPs and NFTs was due to reduced lesion densities in the brains of oldest-old persons with dementia rather than to increased density of these lesions in the brains of nondemented oldest-old persons. CONCLUSIONS: These findings suggest that the neuropathological features of dementia in the oldest-old are not the same as those of cognitively impaired younger-old persons and compel a vigorous search for neuropathological indices of dementia in this most rapidly growing segment of the elderly population.

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 neurofibrillary tangles in patients with Alzheimer disease with comorbid depression.

OBJECTIVE: Recent evidence suggests that a history of major depression may lead to increases in hippocampal neuropathology in Alzheimer disease (AD). The authors tested the hypothesis that neuritic plaques and neurofibrillary tangles are more pronounced in the brains of patients with AD with comorbid depression as compared with patients with AD without depression. METHODS: Brain samples from patients were selected from the U.S. National Alzheimer's Coordinating Center database. The primary analysis included 7164 individuals: 6468 had AD as the primary neuropathologic diagnosis and 696 were considered neuropathologically normal. Depression at study inclusion was rated as present or absent in consensus conferences. Neuropathologic ratings from the Consortium to Establish a Registry in Alzheimer's Disease rating of neuritic plaques and Braak staging of neurofibrillary tangles were used for between-group analyses. RESULTS: Brains of patients with AD with comorbid depression showed higher levels of cortical tangle formation than brains of patients with AD without comorbid depression. Results remained stable when controlling for age, gender, level of education, and cognitive status. Within patients with AD, comorbid depression increased the odds for advanced neuropathologic disease stage (odds ratio: 1.47; 95% confidence interval: 1.03-2.08). CONCLUSION: In AD, the presence of depression comorbidity corresponds to increases in AD-related neuropathologic changes beyond age, gender, level of education, and cognitive status, suggesting an interaction between depression and the neuropathologic processes in AD.

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.

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.

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.

Cognitive burden and excess Lewy-body pathology in the Lewy-body variant of Alzheimer disease.

OBJECTIVES: Authors compared the degrees of cognitive deficit among individuals with Alzheimer disease (AD), the Lewy-body variant of AD (LBV), and "pure" dementia with Lewy bodies (DLB); and compared cortical Lewy body (LB) counts in LBV versus DLB and neuritic plaque and neurofibrillary tangle severity in LBV versus AD. METHODS: Authors examined brain specimens from consecutive autopsies of elderly nursing home subjects. Numbers and densities of plaques, Lewy bodies, and tangle severity were determined in multiple cortical regions, and demographic and clinical variables were compared among the three groups. RESULTS: The three groups did not differ in demographic or clinical variables. The LBV group was significantly more impaired than the other groups. Cortical LB counts were significantly higher in LBV than in DLB. There was no evidence of increased plaque or tangle severity in LBV than in AD. CONCLUSION: The co-occurrence of AD and LB pathology is associated with higher numbers of LBs and more severe dementia than when classical AD or LB lesions occur alone.

Severe generalized dystonia due to primary putaminal degeneration: case report and review of the literature.

Putaminal lesions of a variety of etiologies may cause secondary dystonia. We report on a case of primary putaminal degeneration as a cause of severe childhood-onset generalized dystonia and review the literature of the pathology of dystonia. A 44-year-old patient with severe generalized childhood-onset dystonia and macrocephaly underwent neurological evaluation and neuropathological examination. Neurological examination was normal apart from dystonia and signs referable to prior cryothalamotomy. Workup for metabolic and genetic causes of dystonia was negative. Neuroimaging showed severe bilateral putaminal degeneration, which subsequently correlated with the neuropathological findings of gliosis, spongiform degeneration, and cavitation. The substantia nigra pars compacta contained a normal number of neurons but decreased tyrosine hydroxylase immunoreactivity. There were no histopathological markers of other metabolic or degenerative diseases.