Nelson et al. describe a recently recognized brain disorder that mimics the clinical features of Alzheimer’s disease: L imbic-predominant A ge-related T DP-43 E ncephalopathy (LATE). They review the literature and present consensus-based recommendations of an international, multidisciplinary working group, providing guidelines for diagnosis and staging of LATE neuropathological changes.

Objective To investigate the association of hippocampal sclerosis (HS) with TAR-DNA binding protein of 43 kDa (TDP-43) and other common age-related pathologies, dementia, probable Alzheimer’s disease (AD), mild cognitive impairment (MCI) and cognitive domains in community-dwelling older subjects. Methods Diagnoses of dementia, probable AD and MCI in 636 autopsied subjects from the Religious Order Study and the Rush Memory and Aging Project were based on clinical evaluation and cognitive performance tests. HS was defined as severe neuronal loss and gliosis in the hippocampal CA1and/or subiculum. The severity and distribution of TDP-43 was assessed and other age-related pathologies were also documented. Results HS was more common in those aged > 90 years (18.0%) compared to younger subjects (9.2%). HS cases commonly coexisted with TDP-43 pathology (86%), which was more severe (p < 0.001) in HS cases. Although, HS also commonly coexisted with AD and Lewy body (LB) pathology; only TDP-43 pathology increased the odds of HS (OR=2.63; 95% CI 2.07-3.34). In logistic regression models accounting for age, TDP-43 and other common age-related pathologies; HS cases had higher odds of dementia (OR=3.71; 95% CI=1.93-7.16), MCI and probable AD (OR=3.75; 95% CI=2.01-7.02). In linear regression models, including an interaction term for HS and TDP-43 pathology; HS with coexisting TDP-43 was associated with lower function in multiple cognitive domains while HS without TDP-43 did not have statistically significant associations. TDP-43 without HS was separately related to lower episodic memory. Interpretation The combined role of hippocampal sclerosis and TDP-43 pathology are significant factors underlying global cognitive impairment and probable AD in older subjects.

Objective: We tested the hypothesis that cerebral amyloid angiopathy (CAA) is related to Alzheimer disease (AD) dementia and decline in multiple cognitive systems in old age, independent of AD plaque and tangle pathology and other common age-related neuropathologies.Methods: Participants (n 5 1,113) came from 2 longitudinal clinical-pathologic studies of aging, the Rush Memory and Aging Project and the Religious Orders Study. All underwent annual clinical evaluations including detailed cognitive testing for a mean of 7.1 years before death. Clinical diagnoses of AD were established after reviewing all clinical data, blinded to neuropathologic information. Neuropathologic examinations provided measures of CAA, AD pathology, macroscopic infarcts, microinfarcts, and neocortical Lewy bodies. The association of CAA with AD dementia was examined using logistic regression models, and its association with cognitive decline was examined using linear mixed models.Results: CAA was common, present in 78.9% of participants, and moderately related to AD pathology (r 5 0.401, p , 0.0001). In analyses adjusted for plaques, tangles, and other common age-related neuropathologies, CAA was associated with an increased odds of AD dementia (odds ratio 5 1.237, 95% confidence interval 1.082-1.414) and an increased rate of decline in global cognition, perceptual speed, episodic memory, and semantic memory. The associations of CAA with cognitive outcomes were not driven by the presence of capillary involvement.Conclusions: CAA is an important determinant of AD dementia and decline in multiple cognitive systems in old age. Cerebral amyloid angiopathy (CAA) is frequently observed in the brains of older persons and cooccurs with Alzheimer disease (AD) pathology.1,2 However, the independent relation of CAA with late-life cognitive outcomes is unclear. Although several studies suggest a link between CAA and dementia, 3-7 findings come mainly from highly selected samples, and AD and other common age-related neuropathologies have infrequently been considered. [8][9][10][11] Furthermore, little is known about the relation of CAA with cognitive decline. We previously reported associations between CAA, perceptual speed, and episodic memory proximate to death in a sample a third the size of that in this study, 12 but studies examining the relation of CAA with the rate of change in multiple cognitive systems over time are rare.We tested the hypothesis that CAA is related to cognitive outcomes over and above other common age-related neuropathologies, particularly AD. Participants and data came from 2 longitudinal clinical-pathologic studies of aging. 13 We first examined the independent relation of CAA with likelihood of AD dementia, and then examined the association of CAA with cognitive decline using data collected annually for up to 19 years before death.METHODS Standard protocol approvals, registrations, and patient consents. Data for this study came from 2 ongoing longitudinal cohort studies of aging. 13,14 These studies were approved b...

Background Motor symptoms such as mild parkinsonian signs are common in older persons, but little is known about their underlying neuropathology. We tested the hypothesis that nigral pathology is related to parkinsonism in older persons without Parkinson’s disease (PD). Methods More than 2,500 persons participating in the Religious Orders Study or the Memory and Aging Project agreed to annual assessment of parkinsonism with a modified version of the Unified Parkinson’s Disease Rating Scale(mUPDRS) and brain donation. Brains from744 deceased participants without PD were assessed for nigral neuronal loss and α-synuclein immunopositive Lewy bodies. Results Mean age at death was 88.5. Mean global parkinsonism was 18.6(SD, 11.90). About of cases had mild or more severe nigral neuronal loss and about 17% had Lewy bodies. In separate regression models which adjusted for age, sex and education, nigral neuronal loss and Lewy bodies were both related to global parkinsonism[(Neuronal loss, Estimate, 0.231, S.E, 0.068, p<0.001); (Lewy bodies, Estimate, 0.291, S.E, 0.133, p=0.029)]. Employing a similar regression model which included both measures, neuronal loss remained associated with global parkinsonism(Neuronal loss, Estimate, 0.206, S.E, 0.075,p=0.006). By contrast, the association between Lewy bodies and global parkinsonism was attenuated by more than 60%and was no longer significant(Lewy bodies, Estimate, 0.112, S.E, 0.148, p=0.447), suggesting that neuronal loss may mediate the association of Lewy bodies with global parkinsonism. Interpretation Nigral pathology is common in persons without PD and may contribute to loss of motor function in old age.

Objective: To test the hypothesis that higher neuronal density in brainstem aminergic nuclei contributes to neural reserve.Methods: Participants are 165 individuals from the Rush Memory and Aging Project, a longitudinal clinical-pathologic cohort study. They completed a mean of 5.8 years of annual evaluations that included a battery of 19 cognitive tests from which a previously established composite measure of global cognition was derived. Upon death, they had a brain autopsy and uniform neuropathologic examination that provided estimates of the density of aminergic neurons in the locus ceruleus, dorsal raphe nucleus, substantia nigra, and ventral tegmental area plus summary measures of neuronal neurofibrillary tangles and Lewy bodies from these nuclei and medial temporal lobe and neocortex.Results: Neuronal densities in each nucleus were approximately normally distributed. In separate analyses, higher neuronal density in each nucleus except the ventral tegmental area was associated with slower rate of cognitive decline, but when modeled together only locus ceruleus neuronal density was related to cognitive decline (estimate 5 0.003, SE 5 0.001, p , 0.001). Higher densities of tangles and Lewy bodies in these brainstem nuclei were associated with faster cognitive decline even after controlling for pathologic burden elsewhere in the brain. Locus ceruleus neuronal density, brainstem tangles, and brainstem Lewy bodies had independent associations with rate of cognitive decline. In addition, at higher levels of locus ceruleus neuronal density, the association of Lewy bodies with cognitive decline was diminished. ) or their components (synapses 8,9 ) in key locations. This approach allows collection of neuronal and pathologic data from the same brain regions, facilitating examination of their conjoint correlations with cognition. ConclusionThe present study examines the associations among neuronal density, neurodegenerative lesions, and change in cognitive function. We assessed neuronal density in brainstem aminergic nuclei (i.e., locus ceruleus, dorsal raphe nucleus, substantia nigra, and ventral tegmental area) because these nuclei support multiple cognitive processes, synthesize important monoamines that function as neurotransmitters and neuromodulators, are therapeutic targets for cognitive enhancement, 10 and bear a disproportionate burden of age-related neurodegeneration. 11,12 Participants from the Rush Memory and Aging Project had annual cognitive testing for a mean of 5.8 years, died, and underwent a neuropathologic examination that yielded neuronal counts for each brainstem nucleus From the Rush Alzheimer's Disease

Brain edema continues to be a major cause of mortality after diverse types of brain pathologies such as major cerebral infarcts, hemorrhages, trauma, infections and tumors. The classification of edema into vasogenic, cytotoxic, hydrocephalic and osmotic has stood the test of time although it is recognized that in most clinical situations there is a combination of different types of edema during the course of the disease. Basic information about the types of edema is provided for better understanding of the expression pattern of some of the newer molecules implicated in the pathogenesis of brain edema. These molecules include the aquaporins, matrix metalloproteinases and growth factors such as vascular endothelial growth factors A and B and the angiopoietins. The potential of these agents in the treatment of edema is discussed. Since many molecules are involved in the pathogenesis of brain edema, effective treatment cannot be achieved by a single agent but will require the administration of a "magic bullet" containing a variety of agents released at different times during the course of edema in order to be successful.

The significance of caveolin-1, a major constituent of caveolae, and the tight junction proteins occludin and claudin-5 in early blood-brain barrier (BBB) breakdown was assessed by sequential demonstration of the expression of these proteins over a period of 12 h to 6 days post-lesion in the rat cortical cold injury model. Pial and intracerebral vessels of control rats showed punctuate endothelial immunoreactivity for caveolin-1 and caveolin-2, while claudin-5 and occludin were localized as longitudinal strands in endothelium. During the early phase of BBB breakdown following injury at 12 h and on day 2, western blot analyses detected a significant increase in caveolin-1 expression at the lesion site while immunohistochemistry showed that the caveolin-1 increase was localized to the endothelium of lesion vessels. Decreased expression of occludin occurred at the lesion site only on days 2 and 4 post-lesion while claudin-5 expression was decreased only on day 2. Dual labeling for fibronectin, a marker of BBB breakdown, and caveolin-1 or the tight junction proteins demonstrated that only lesion vessels with BBB breakdown showed a marked increase of caveolin-1, loss of occludin and reduced localization of claudin-5. The issue whether these alterations precede or follow BBB breakdown is uncertain; however, increased expression of caveolin-1 preceded the decreased expression of occludin and claudin-5. Thus caveolae and caveolin-1 have an important role in early BBB breakdown and could be potential therapeutic targets in the control of early brain edema.

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