Observations on the relationship between verbal explicit and implicit memory and neuronal density in the left and right hippocampus in temporal lobectomy patients.

The relationship between neuronal density and verbal memory in left and right hippocampal subfields was investigated in patients who underwent surgery for alleviation of temporal lobe epilepsy. The surgery consisted of unilateral partial removal of the hippocampus along with the anterior temporal lobe and amygdala. Study 1 looked at post-surgical explicit versus implicit verbal memory for lists of words while Study 2 looked at pre- and post-surgical explicit memory for word pairs. Left subfield CA1 appeared to be the most consistently involved in explicit and implicit memory. The results of the two studies confirm presence of hemispheric asymmetry in verbal memory. The notion that hippocampal control of memory is most apparent in post-surgical performance is discussed

Pro: Can neuropathology really confirm the exact diagnosis?

Recent advances in the clinical diagnostic instruments for diagnosing Alzheimer's disease (AD) and in neuroimaging may cast doubt in the minds of some practitioners about the continued need for neuropathology to provide the ultimate diagnosis. Certainly the majority of cases of AD can be clinically correctly diagnosed by experienced clinicians but many cases are given this label by less experienced practitioners. Even after the most thorough work-up, a few cases of confidently diagnosed AD turn out to be something else when microscopy of the brain is undertaken. Even for neuropathologists, however, it can be difficult to correctly assign cognitive decline to the various pathological processes that can be found together in an older brain. We need further clinicopathogical study to enlighten us about, for example, the contribution of commonly found cerebrovascular disease to dementia. Human studies are also needed to explore the changes in pathology that new treatments for AD may produce

Complement and humoral adaptive immunity in the human choroid plexus: roles for stromal concretions, basement membranes, and epithelium

The choroid plexus (CP) provides a barrier to entry of toxic molecules from the blood into the brain and transports vital molecules into the cerebrospinal fluid. While a great deal is known about CP physiology, relatively little is known about its immunology. Here, we show immunohistochemical data that help define the role of the CP in innate and adaptive humoral immunity. The results show that complement, in the form of C1q, C3d, C9, or C9neo, is preferentially deposited in stromal concretions. In contrast, immunoglobulin (Ig) G (IgG) and IgA are more often found in CP epithelial cells, and IgM is found in either locale. C4d, IgD, and IgE are rarely, if ever, seen in the CP. In multiple sclerosis CP, basement membrane C9 or stromal IgA patterns were common but were not specific for the disease. These findings indicate that the CP may orchestrate the clearance of complement, particularly by deposition in its concretions, IgA and IgG preferentially via its epithelium, and IgM by either mechanism

IL-21 and IL-21 Receptor Expression in Lymphocytes and Neurons in Multiple Sclerosis Brain

IL-17–producing CD4+ T cells (Th-17) contribute to the pathogenesis of experimental autoimmune encephalomyelitis and are associated with active disease in multiple sclerosis (MS). In addition to IL-17, Th-17 cells can also express IL-21, IL-22, and IL-6 under Th-17–polarizing conditions (IL-6 and transforming growth factor-β). In this study we investigated IL-21 and IL-21 receptor (IL-21R) expression in MS lesions by in situ hybridization and immunohistochemistry. We detected strongly IL-21+ infiltrating cells predominantly in acute but also in chronic active white matter MS lesions in which IL-21 expression was restricted to CD4+ cells. In contrast, IL-21R was much more broadly distributed on CD4+, CD19+, and CD8+ lymphocytes but not major histocompatibility complex class-II+ macrophages/microglia. Interestingly, in cortical areas we detected both IL-21 and IL-21R expression by neurons. These findings suggest role(s) for IL-21 in both the acute and chronic stages of MS via direct effects on T and B lymphocytes and, demonstrated for the first time, also on neurons

Cases, Regulations, and Statutes

With the exception of ApoE4, genome-wide association studies have failed to identify strong genetic risk factors for late-onset Alzheimer's disease, despite strong evidence of heritability, suggesting that many low penetrance genes may be involved. Additionally, the nature of the identified genetic risk factors and their relation to disease pathology is also largely obscure. Previous studies have found that a cancer-associated variant of the cell cycle inhibitor gene p21cip1 is associated with increased risk of Alzheimer's disease. The aim of this study was to confirm this association and to elucidate the effects of the variant on protein function and Alzheimer-type pathology. We examined the association of the p21cip1 variant with Alzheimer's disease and Parkinson's disease with dementia. The genotyping studies were performed on 719 participants of the Oxford Project to Investigate Memory and Ageing, 225 participants of a Parkinson's disease DNA bank, and 477 participants of the Human Random Control collection available from the European Collection of Cell Cultures. The post mortem studies were carried out on 190 participants. In the in-vitro study, human embryonic kidney cells were transfected with either the common or rare p21cip1 variant; and cytometry was used to assess cell cycle kinetics, p21cip1 protein expression and sub-cellular localisation. The variant was associated with an increased risk of Alzheimer's disease, and Parkinson's disease with dementia, relative to age matched controls. Furthermore, the variant was associated with an earlier age of onset of Alzheimer's disease, and a more severe phenotype, with a primary influence on the accumulation of tangle pathology. In the in-vitro study, we found that the SNPs reduced the cell cycle inhibitory and anti-apoptotic activity of p21cip1. The results suggest that the cancer-associated variant of p21cip1 may contribute to the loss of cell cycle control in neurons that may lead to Alzheimer-type neurodegeneration

Vascular Cognitive Impairment Neuropathology Guidelines (VCING): the contribution of cerebrovascular pathology to cognitive impairment

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Age-dependent expression of VEGFR2 in deep brain arteries in small vessel disease, CADASIL, and healthy brains

Vascular myocytes are central to brain aging. Small vessel disease (SVD; arteriolosclerosis) is a widespread cause of lacunar stroke and vascular dementia, and is characterised by fibrosis and depletion of vascular myocytes in small penetrating arteries. Vascular endothelial growth factor (VEGF) is associated with brain aging, and VEGFR2 is a potent determinant of cell fate. Here, we tested whether VEGFR2 in vascular myocytes is associated with older age and SVD in human brain. VEGFR2 immunolabelling in deep grey matter was assessed in older people with or without moderate-severe SVD, or in younger people without brain pathology or with a monogenic form of SVD (CADASIL). All cases were without Alzheimer’s disease pathology. Myocyte VEGFR2 was associated with increasing age (p=0.0026) but not with SVD pathology or with sclerotic index or blood vessel density. We conclude that VEGFR2 is consistently expressed in small artery myocytes of older people, and may mediate effects of VEGF on brain vascular aging

Alpha-synuclein RT-QuIC in the CSF of patients with alpha-synucleinopathies

We have developed a novel real-time quaking-induced conversion RT-QuICbased assay to detect alpha-synuclein aggregation in brain and cerebrospinal fluid from dementia with Lewy bodies and Parkinson’s disease patients. This assay can detect alpha-synuclein aggregation in Dementia with Lewy bodies and Parkinson’s disease cerebrospinal fluid with sensitivities of 92% and 95%, respectively, and with an overall specificity of 100% when compared to Alzheimer and control cerebrospinal fluid. Patients with neuropathologically confirmed tauopathies (progressive supranuclear palsy; corticobasal degeneration) gave negative results. These results suggest that RT-QuiC analysis of cerebrospinal fluid is potentially useful for the early clinical assessment of patients with alpha-synucleinopathies

Concurrent multiple sclerosis and amyotrophic lateral sclerosis: where inflammation and neurodegeneration meet?

The concurrence of multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) is exceedingly rare and the pathological features have not been examined extensively. Here we describe the key pathological features of a 40 year old man with pathologically confirmed concurrent MS and ALS