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Introduction: Dementia prediction models are necessary to inform the development of dementia risk reduction strategies. Here, we examine the utility of neuropathological-based risk scores to predict clinical dementia., Methods: Models were developed for predicting Alzheimer's disease (AD) and non-AD neuropathologies using the Honolulu Asia Aging neuropathological sub-study (HAAS; n = 852). Model accuracy for predicting clinical dementia, over 30 years, was tested in the non-autopsied HAAS sample (n = 2960) and the Age, Gene/Environment Susceptibility-Reykjavik Study (n = 4614)., Results: Different models were identified for predicting neurodegenerative and vascular neuropathology (c-statistic range: 0.62 to 0.72). These typically included age, APOE, and a blood pressure-related measure. The neurofibrillary tangle and micro-vascular lesion models showed good accuracy for predicting clinical vascular dementia., Discussion: There may be shared risk factors across dementia-related lesions, suggesting common pathways. Strategies targeting these models may reduce risk or postpone clinical symptoms of dementia as well as reduce neuropathological burden associated with AD and vascular lesions., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Cerebral pericytes are an integral component of the neurovascular unit, which governs the blood-brain barrier. There is paucity of knowledge on cortical pericytes across different dementias. We quantified cortical pericytes in capillaries in 124 post-mortem brains from subjects with post-stroke dementia (PSD), vascular dementia (VaD), Alzheimer's disease (AD) and AD-VaD (Mixed) and, post-stroke non-demented (PSND) stroke survivors as well as normal ageing controls. Collagen 4 (COL4)-positive nucleated pericyte soma were identified as protrusions on capillaries of the frontal cortex. The COL4-positive somata or nodule-like cell bodies were also verified by platelet derived growth factor receptor-β (PDGFR-β) immunohistochemistry. The mean (± SEM) pericyte somata in frontal cortical capillaries in normal young controls (46-65 years of age) was estimated as 5.2 ± 0.2 per mm capillary length. This number was reduced by 45% in older controls (> 78 years) to 2.9 ± 0.1 per mm capillary length (P < 0.001). We further found that the numbers of pericyte cell bodies per COL4 mm 2 area or per mm capillary length were not decreased but rather preserved or increased in PSD, AD and Mixed dementia groups compared to similar age older controls (P < 0.01). Consistent with this, we noted that capillary length densities identified by the endothelial marker glucose transporter 1 or COL4 were not different across the dementias compared to older controls. There was a negative correlation with age (P < 0.001) suggesting fewer pericyte somata in older age, although the % COL4 immunoreactive capillary area was increased in older controls compared to young controls. Using a proven reliable method to quantify COL4-positive nucleated pericytes, our observations demonstrate ageing related loss but mostly preserved pericytes in the frontal cortex of vascular and AD dementias. We suggest there is differential regulation of capillary pericytes in the frontal lobe between the cortex and white matter in ageing-related dementias., (© 2021. The Author(s).)

Background: Comprehensive clinicopathological studies of neuropsychiatric symptoms (NPS) in dementia are lacking., Objective: To describe the pathological correlations of NPS in a sample of institutionalized people with dementia., Methods: We studied 59 people who were consecutively admitted to a nursing home and donated their brain. Correlations between pathological variables and NPS upon admission (n = 59) and at one-year follow-up assessment (n = 46) were explored and confirmed using bivariate and multivariate statistical methods., Results: Mean (SD) age at admission was 83.2 (6.4) years and mean (SD) age at demise was 85.4 (6.6); 73% of the subjects were female and 98% presented advanced dementia. The most frequent etiological diagnosis was Alzheimer's disease (AD; 74.6% clinical diagnosis, 67.8% pathological diagnosis). The pathological diagnosis of AD was associated with aggression (β est 0.31), depression (β est 0.31), anxiety (β est 0.38), and irritability (β est 0.28). Tau stage correlated with aggressive symptoms (β est 0.32) and anxiety (βest 0.33). Coexistence of AD and Lewy body pathology was associated with depression (β est 0.32), while argyrophilic grains were associated with eating symptoms (β est 0.29). Predictive models were achieved for apathy, including cognitive performance, basal ganglia ischemic lesions, and sex as predictors (R2 0.38) and for sleep disorders, including pathological diagnosis of AD and age at demise (R2 0.18) (all p-values <0.05, unadjusted)., Conclusion: AD was the main pathological substrate of NPS in our sample of very elderly people with advanced dementia. However, correlations were mild, supporting a model of focal/asymmetric rather than diffuse brain damage, along with relevance of environmental and other personal factors, in the genesis of those symptoms.

As brain networks break down in neurodegenerative disorders such as Alzheimer's disease, language and executive function frequently decline. We aimed to quantify the relationship between fluency (both categorical and phonemic) and cortical thickness using data from a large cohort of patients who were undergoing assessment at a memory disorders clinic. In addition, we defined the pattern of these relationships across the four major lobes of the brain. A total of 590 patients underwent extensive psychometric testing, including categorical (animal-naming) and phonemic (FAS) tests of fluency. All patients also underwent structural MRI featuring a volumetric T1-weighted sequence that served as the input for postprocessing calculations using FreeSurfer, yielding cortical parcellations and thicknesses. The fluency-thickness relationships were summarized using Pearson's correlation coefficient. In a univariable analysis over all lobes, there were significant correlations using categorical fluency with both cortical thickness and age, with education less correlated; using phonemic fluency there were similar correlations with cortical thickness and age, but education was more correlated. Neither handedness nor sex was significantly correlated with either categorical or phonemic score. At a lobar level, for both fluency tests, scores were positively correlated with cortical thickness in all lobes; these relationships were strongest in the temporal lobe (p < 0.01). The correlations for categorical testing were generally stronger than the correlations for phonemic testing and were again strongest in the temporal lobe (r = 0.38 for categorical testing vs 0.22 for phonemic testing). The bilateral parietal lobes were more important for categorical testing than for phonemic testing, and the left frontal lobe was more important for phonemic testing than for categorical testing. Comparison of the homologous lobes between the two hemispheres demonstrated that only the frontal lobes were significantly different for both scores, with the left side having a stronger relationship with the scores (categorical: r = 0.21 for left; r = 0.14 for right; p < 0.01. phonemic: r = 0.13 for left; r = 0.08 for right; p < 0.01). In conclusion, these results demonstrated that structural MRI and fluency tests reveal a significant spatial pattern of correlations between cortical thickness and fluency, which varies with the type of fluency test., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Dementia is a state of cognitive dysfunction which leads to functional decline. It is a syndrome caused by several medical and neurological causes, but most cases of dementia are due to "primary dementias." Primary dementias are neurological diseases whose manifestations are predominantly cognitive. Most primary dementias are caused by neurodegenerative proteinopathies where an accumulation of misfolded proteins leads to neuronal loss, neuroinflammation and glial reaction. Each proteinopathy is characterized by the type of protein implicated in its pathophysiology. Neurodegenerative dementias include the most prevalent cause of dementia-Alzheimer's disease-as well as Lewy body dementia, Parkinson's disease dementia, frontotemporal dementias, and prion diseases. Vascular dementia, especially small vessel disease, though not a neurodegenerative condition, is often grouped together with primary dementias. Each type of proteinopathy, characterized by the location and nature of misfolded protein accumulation, may correspond to a particular clinical phenotype. The correspondence between pathologies and clinical phenotypes is not exclusive, and there is a large degree of overlap. Although in the research setting the clinicopathological construct is on the wane, in the clinic it is the most practical way of approaching primary dementias. In this article, we introduce the clinicopathological construct, the understanding of which will form the basis of the other articles in this volume., Competing Interests: Dr. Salardini has nothing to disclose., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Advances in neuroimaging have enabled greater understanding of the progression of cerebral degenerative processes associated with ageing-related dementias. Leukoaraiosis or rarefied white matter (WM) originally described on computed tomography is one of the most prominent changes which occurs in older age. White matter hyperintensities (WMH) evident on magnetic resonance imaging have become commonplace to describe WM changes in relation to cognitive dysfunction, types of stroke injury, cerebral small vessel disease and neurodegenerative disorders including Alzheimer's disease. Substrates of WM degeneration collectively include myelin loss, axonal abnormalities, arteriolosclerosis and parenchymal changes resulting from lacunar infarcts, microinfarcts, microbleeds and perivascular spacing. WM cells incorporating astrocytes, oligodendrocytes, pericytes and microglia are recognized as key cellular components of the gliovascular unit. They respond to ongoing pathological processes in different ways leading to disruption of the gliovascular unit. The most robust alterations involve oligodendrocyte loss and astrocytic clasmatodendrosis with displacement of the water channel protein, aquaporin 4. These modifications likely precede arteriolosclerosis and capillary degeneration and involve tissue oedema, breach of the blood-brain barrier and induction of a chronic hypoxic state in the deep WM. Several pathophysiological mechanisms are proposed to explain how WM changes commencing with haemodynamic changes within the vascular system impact on cognitive dysfunction. Animal models simulating cerebral hypoperfusion in man have paved the way for several translational opportunities. Various compounds with variable efficacies have been tested to reduce oxidative stress, inflammation and blood-brain barrier damage in the WM. Our review demonstrates that WM degeneration encompasses multiple substrates and therefore more than one pharmacological approach is necessary to preserve axonal function and prevent cognitive impairment. This article is part of the Special Issue "Vascular Dementia"., (© 2017 International Society for Neurochemistry.)

Background: Clinicopathological studies are important in determining the brain lesions underlying dementia. Although almost 60% of individuals with dementia live in developing countries, few clinicopathological studies focus on these individuals. We investigated the frequency of neurodegenerative and vascular-related neuropathological lesions in 1,092 Brazilian admixed older adults, their correlation with cognitive and neuropsychiatric symptoms, and the accuracy of dementia subtype diagnosis., Methods and Findings: In this cross-sectional study, we describe clinical and neuropathological variables related to cognitive impairment in 1,092 participants (mean age = 74 y, 49% male, 69% white, and mean education = 4 y). Cognitive function was investigated using the Clinical Dementia Rating (CDR) and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE); neuropsychiatric symptoms were evaluated using the Neuropsychiatric Inventory (NPI). Associations between neuropathological lesions and cognitive impairment were investigated using ordinal logistic regression. We developed a neuropathological comorbidity (NPC) score and compared it to CDR, IQCODE, and NPI scores. We also described and compared the frequency of neuropathological diagnosis to clinical diagnosis of dementia subtype. Forty-four percent of the sample met criteria for neuropathological diagnosis. Among these participants, 50% had neuropathological diagnoses of Alzheimer disease (AD), and 35% of vascular dementia (VaD). Neurofibrillary tangles (NFTs), hippocampal sclerosis, lacunar infarcts, hyaline atherosclerosis, siderocalcinosis, and Lewy body disease were independently associated with cognitive impairment. Higher NPC scores were associated with worse scores in the CDR sum of boxes (β = 1.33, 95% CI 1.20-1.46), IQCODE (β = 0.14, 95% CI 0.13-0.16), and NPI (β = 1.74, 95% CI = 1.33-2.16). Compared to neuropathological diagnoses, clinical diagnosis had high sensitivity to AD and high specificity to dementia with Lewy body/Parkinson dementia. The major limitation of our study is the lack of clinical follow-up of participants during life., Conclusions: NFT deposition, vascular lesions, and high NPC scorewere associated with cognitive impairment in a unique Brazilian sample with low education. Our results confirm the high prevalence of neuropathological diagnosis in older adults and the mismatch between clinical and neuropathological diagnoses.

Although a large number of studies have examined possible differences in cognitive performance between Alzheimer's disease (AD) and vascular dementia (VaD), the data in the literature are conflicting. The aims of this study were to analyze the neuropsychological pattern of subjects affected by degenerative dementia without evidence of small vessel pathology (DD) and small vessel VaD subjects in the early stages and to investigate differences in the progression of cognitive impairment. Seventy-five patients with probable VaD and 75 patients with probable DD were included. All the subjects underwent a standard neuropsychological evaluation, including the following test: Visual Search, Attentional matrices, Story Recall, Raven's Coloured Progressive Matrices, Phonological and Semantic Verbal Fluency, Token, and Copying Drawings. The severity of cognitive impairment was stratified according to the MMSE score. Fifteen subjects with probable DD and 10 subjects with probable VaD underwent a 12-month cognitive re-evaluation. No significant difference was found between DD and VaD subjects in any of the neuropsychological tests except Story Recall in the mild cognitive impairment (P < 0.001). The re-test value was significantly worse than the baseline value in the MMSE (P = 0.037), Corsi (P = 0.041), Story Recall (P = 0.032), Phonological Verbal Fluency (P = 0.02), and Copying Drawings (P = 0.043) in DD patients and in the Visual Search test (P = 0.036) in VaD subjects. These results suggest that a neuropsychological evaluation might help to differentiate degenerative dementia without evidence of small vessel pathology from small vessel VaD in the early stages of these diseases.

Background: Postsynaptic cholinergic deficits, including reduced cortical muscarinic M1 receptor coupling to G-proteins, are neurochemical findings postulated to underlie the limited efficacy of presynaptically-targeted cholinergic replacement therapies in Alzheimer's disease (AD). While the loss of M1-G-protein coupling has been associated with β-amyloid (Aβ) burden in AD, the status of M1 coupling to G-proteins in Parkinson's disease-related or mixed dementias is unclear., Objective: To test the hypothesis that M1 receptor uncoupling is correlated with Aβ burden, we aimed to study muscarinic M1 neurochemical parameters in neurodegenerative dementias characterized by low and high Aβ loads., Methods: M1 receptors, M1 coupling to G-proteins as well as Aβ were measured in postmortem frontal cortex of a cohort of longitudinally assessed patients with Parkinson's Disease Dementia (PDD, low Aβ load) and AD with significant subcortical cerebrovascular disease (AD + CVD, high Aβ load)., Results: We found unchanged levels of M1 receptors in both dementia groups, while M1 coupling was reduced only in AD + CVD (p < 0.01). Furthermore, Aβ concentration was significantly increased only in AD + CVD, and correlated negatively with M1-G-protein coupling in the dementia groups., Conclusions: Our study suggests that loss of M1 coupling to G-proteins may be a neurochemical feature of neurodegenerative dementias with high cortical Aβ burden, and that cholinergic replacement therapies may be more efficacious for PDD due to low Aβ burden.

Aims: Deposition of amyloid beta (Aβ) in the brain is one of the defining abnormalities of Alzheimer's disease (AD). Phosphorylation of Aβ at serine 8 (pAβ) has been implicated in its aggregation in vitro and pAβ level has been shown to be significantly elevated in AD. We aimed to assess the specificity of pAβ for AD and have investigated associations of pAβ with parenchymal and cerebrovascular accumulation of Aβ, disease progression, angiotensin-converting enzyme activity and APOE genotype., Methods: The distribution of pAβ was studied by immunohistochemistry in sporadic and familial AD, pure dementia with Lewy bodies (DLB), pure vascular dementia (VaD) and age-matched controls. Soluble and insoluble (guanidine-extractable) pAβ level was measured by enzyme-linked immunosorbent assay (ELISA) in the midfrontal and parahippocampal cortex in sporadic AD (n = 20, 10 with Braak tangle stages of III-IV and 10 of stages V-VI), DLB (n = 10), VaD (n = 10) and age-matched controls (n = 20)., Results: We found pAβ to be associated with only a subset of Aβ plaques and vascular deposits in sporadic and familial AD, with absent or minimal immunohistochemically detectable pAβ in control, DLB and VaD brains. In both brain regions, insoluble pAβ level was significantly elevated only in advanced AD (Braak tangle stage of V or VI) and in the parahippocampus soluble and insoluble pAβ level increased with the number of APOE ε4 alleles., Conclusions: These results indicate that pAβ accumulation in the parenchyma and vasculature is largely restricted to late-stage AD (Braak tangle stage V-VI)., (© 2014 British Neuropathological Society.)

Subcortical white matter (WM) is a frequent target of ischemic injury and extensive WM lesions are important substrates of vascular cognitive impairment (VCI) in humans. However, ischemic stroke rodent models have been shown to mainly induce cerebral infarcts in the gray matter, while cerebral hypoperfusion models show only WM rarefaction without infarcts. The lack of animal models consistently replicating WM infarct damage may partially explain why many neuroprotective drugs for ischemic stroke or VCI have failed clinically, despite earlier success in preclinical experiments. Here, we report a novel animal model of WM infarct damage with cognitive impairment can be generated by surgical implantation of different devices to the right and left common carotid artery (CCA) in C57BL/6J mice. Implantation of an ameroid constrictor to the right CCA resulted in gradual occlusion of the vessel over 28 d, whereas placement of a microcoil to the left CCA induced ∼50% arterial stenosis. Arterial spin labeling showed a gradual reduction of cerebral blood flow over 28 d post operation. Such reductions were more marked in the right, compared with the left, hemisphere and in subcortical, rather than the cortical, areas. Histopathological analysis showed multiple infarct damage in right subcortical regions, including the corpus callosum, internal capsule, hippocampal fimbria, and caudoputamen, in 81% of mice. Mice displaying such damage performed significantly poorer in locomotor and cognitive tests. The current mouse model replicates the phenotypes of human subcortical VCI, including multiple WM infarcts with motor and cognitive impairment., (Copyright © 2015 the authors 0270-6474/15/353915-14$15.00/0.)

Background and Purpose: The progression pattern of brain structural changes in patients with isolated cerebrovascular disease (CVD) remains unclear. To investigate the role of isolated CVD in cognitive impairment patients, patterns of cortical thinning and hippocampal atrophy in pure subcortical vascular mild cognitive impairment (svMCI) and pure subcortical vascular dementia (SVaD) patients were characterized., Methods: Forty-five patients with svMCI and 46 patients with SVaD who were negative on Pittsburgh compound B (PiB) positron emission tomography imaging and 75 individuals with normal cognition (NC) were recruited., Results: Compared with NC, patients with PiB(-) svMCI exhibited frontal, language and retrieval type memory dysfunctions, which in patients with PiB(-) SVaD were further impaired and accompanied by visuospatial and recognition memory dysfunctions. Compared with NC, patients with PiB(-) svMCI exhibited cortical thinning in the frontal, perisylvian, basal temporal and posterior cingulate regions. This atrophy was more prominent and extended further toward the lateral parietal and medial temporal regions in patients with PiB(-) SVaD. Compared with NC subjects, patients with PiB(-) svMCI exhibited hippocampal shape deformities in the lateral body, whilst patients with PiB(-) SVaD exhibited additional deformities within the lateral head and inferior body., Conclusions: Our findings suggest that patients with CVD in the absence of Alzheimer's disease pathology can be demented, showing cognitive impairment in multiple domains, which is consistent with the topography of cortical thinning and hippocampal shape deformity., (© 2014 The Author(s) European Journal of Neurology © 2014 EFNS.)

The structural and functional neuroimaging of dementia have substantially evolved over the last few years. The most common forms of dementia, Alzheimer disease (AD), Lewy body dementia (LBD) and fronto-temporal lobar degeneration (FTLD), have distinct patterns of cortical atrophy and hypometabolism that evolve over time, as reviewed in the first part of this article. The second part discusses unspecific white matter alterations on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images as well as cerebral microbleeds, which often occur during normal aging and may affect cognition. The third part summarises molecular neuroimaging biomarkers recently developed to visualise amyloid deposits, tau protein deposits and neurotransmitter systems. The fourth section reviews the utility of advanced image analysis techniques as predictive biomarkers of cognitive decline in individuals with early symptoms compatible with mild cognitive impairment (MCI). As only about half of MCI cases will progress to clinically overt dementia, whereas the other half remain stable or might even improve, the discrimination of stable versus progressive MCI is of paramount importance for both individual patient treatment and patient selection for clinical trials. The fifth and final part discusses the inter-individual variation in the neurocognitive reserve, which is a potential constraint for all proposed methods.

Imaging plays an important role in the diagnosis and management of dementia. This review covers the imaging features of the most common dementing illnesses: Alzheimer's disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB) and frontotemporal lobar degeneration (FTLD). It describes typical findings on structural neuroimaging and discusses functional and molecular imaging techniques such as FDG PET, amyloid PET, magnetic resonance (MR) perfusion imaging, diffusion tensor imaging (DTI) and functional MR imaging (fMRI).

Subcortical vascular dementia (SVaD), one of common causes of dementia, has concomitant Alzheimer's disease (AD) pathology in over 30%, termed "mixed dementia". Identifying mixed dementia from SVaD is important because potential amyloid-targeted therapies may be effective for treatment in mixed dementia. The purpose of this study was to discriminate mixed dementia from pure SVaD using magnetic resonance imaging (MRI). We measured brain amyloid deposition using the 11C-Pittsburgh compound B positron emission tomography (PiB-PET) in 68 patients with SVaD. A PiB retention ratio greater than 1.5 was considered PiB(+). Hippocampal and amygdalar shape were used in the incremental learning method to discriminate mixed dementia from pure SVaD because these structures are known to be prominently involved by AD pathologies. Among 68 patients, 23 (33.8%) patients were positive for PiB binding. With use of hippocampal shape analysis alone, PiB(+) SVaD could be discriminated from PiB(-) SVaD with 77.9% accuracy (95.7% sensitivity and 68.9% specificity). With use of amygdalar shape, the discrimination accuracy was 75.0% (87.0% sensitivity and 68.9% specificity). When hippocampal and amygdalar shape were analyzed together, accuracy increased to 82.4% (95.7% sensitivity and 75.6% specificity). An incremental learning method using hippocampal and amygdalar shape distinguishes mixed dementia from pure SVaD. Furthermore, our results suggest that amyloid pathology and vascular pathology have different effects on the shape of the hippocampus and amygdala.

Aim: Histamine H(3) receptor antagonists have been proposed as a novel therapeutic approach for the symptomatic treatment of Alzheimer's disease (AD). However, it is unclear whether there is a neurochemical basis for extending their potential use in vascular and mixed dementias. In this study, we measured cortical H(3) receptors in patients with subcortical ischemic vascular dementia (SIVD) and mixed SIVD/AD (MIX)., Materials and Methods: Radioligand binding assays using [(3)H]GSK189254 were used to measure H(3) receptors in the postmortem frontal cortex, anterior cingulate gyrus and hippocampus of a cohort of longitudinally assessed SIVD, MIX and age-matched controls., Results: H(3) receptor levels were unchanged in SIVD and MIX in all areas studied. Furthermore, frontal H(3) receptor densities negatively correlated with predeath assessment of cognition using Mini-Mental State Examination (MMSE) scores., Conclusion: Our data suggest that H(3) receptors are preserved in SIVD and MIX, thus supporting further assessments of H(3) antagonists as potential therapeutics in these dementias., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Clinical neuroimaging is increasingly being used in the diagnosis of neurodegenerative diseases and has become one of the most important paraclinical tools in the diagnosis of dementia. According to current guidelines, neuroimaging, preferably magnetic resonance imaging (MRI), should be performed at least once during the diagnostic work-up of patients with suspected or definite dementia. MRI is helpful in identifying or excluding potentially treatable causes of dementia; however, these account only for a small proportion of dementias. In addition, MRI is able to support the clinical diagnosis in a memory clinic setting by identifying certain patterns of atrophy and vascular damage. Visual rating scales are well-established methods in the clinical routine for the assessment and quantification of regional/global cortical atrophy, hippocampal atrophy and vascular damage. In addition, MRI is able to detect certain aspects of pathology associated with dementia, such as cerebral microbleeds which are related to cerebral amyloid angiopathy and Alzheimer pathology. This review paper aims to give an overview of the application of structural MRI in the diagnostic procedure for memory clinic patients in terms of excluding and supporting the diagnosis of various diseases associated with dementia.

Objective: Neuronal loss in the locus coeruleus (LC) is common in Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). The aims of the present study were to investigate LC degeneration in different dementia disorders including vascular dementia (VaD) and frontotemporal lobar degeneration (FTLD), to compare LC degeneration with severity of pathology in AD and DLB/PDD, to further evaluate the usefulness of a previously presented scoring system and to examine the predictive value of macroscopic assessment of the LC., Methods: A horizontal mid-level section of the pons was examined in 200 neuropathologically examined cases with clinical dementia. A previous macroscopic assessment of the LC was performed in 149 of the cases., Results: Cases with DLB/ PDD and AD presented with the highest microscopic LC degeneration scores, with significant differences compared to combined AD + VaD, in turn with a higher score than VaD, FTLD and other dementia disorders. Interrater agreement (weighted kappa;) for LC degeneration scoring was 0.83 - 0.91. DLB/ PDD, AD and AD + VaD were the diagnoses for 85% of the cases with macroscopic LC depigmentation., Conclusion: LC degeneration, which may be macroscopically noted, often indicates synuclein and/or Alzheimer pathology among demented. When clinical information is scarce or inconsistent, a macroscopic assessment of the LC may facilitate focusing of the subsequent neuropathological investigation. Also, the semiquantitative scoring system is a reliable tool for histological assessment of LC degeneration.

Background: While the prevalence of Alzheimer disease (AD) increases with age, little is known about the frequency of dementia with Lewy bodies (DLB) in the oldest old. A retrospective hospital-based study compared the relative prevalence of DLB among very old individuals., Methods: 1,100 consecutive autopsy cases of demented patients aged over 70 years (mean age: 83.9 ± 5.4 years) were examined using standardized neuropathological methods and current diagnostic consensus criteria., Results: Evaluation of three age groups (8th-10th decade) showed a significant increase in the relative prevalence of AD with cerebrovascular lesions including mixed dementia, while AD with Lewy body (LB) pathology showed a mild but insignificant age-related increase. Both 'pure' AD and vascular dementia showed a mild but insignificant decline, while DLB (without severe AD pathology) decreased progressively. While the severity of Lewy pathology in DLB slightly decreased with age, concomitant Alzheimer-like pathology increased progressively., Conclusion: Whether DLB in the oldest old represents a distinct group is a matter of discussion, but the relative prevalence of AD with LB in our sample remained fairly stable., (Copyright © 2011 S. Karger AG, Basel.)

While animal data suggest a protective effect of caffeine on cognition, studies in humans remain inconsistent. We examined associations of coffee and caffeine intake in midlife with risk of dementia, its neuropathologic correlates, and cognitive impairment among 3494 men in the Honolulu-Asia Aging Study (mean age 52 at cohort entry, 1965-1968) examined for dementia in 1991-1993, including 418 decedents (1992-2004) who underwent brain autopsy. Caffeine intake was determined according to self-reported coffee, tea, and cola consumption at baseline. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for overall dementia, Alzheimer's disease (AD), vascular dementia (VaD), cognitive impairment (Cognitive Abilities Screening Instrument score <74), and neuropathologic lesions at death (Alzheimer lesions, microvascular ischemic lesions, cortical Lewy bodies, hippocampal sclerosis, generalized atrophy), according to coffee and caffeine intake. Dementia was diagnosed in 226 men (including 118 AD, 80 VaD), and cognitive impairment in 347. There were no significant associations between coffee or caffeine intake and risk of cognitive impairment, overall dementia, AD, VaD, or moderate/high levels of the individual neuropathologic lesion types. However, men in the highest quartile of caffeine intake (>/=411.0 mg/d) [corrected] were less likely than men in the lowest quartile (

Epidemiological studies have indicated that excessive alcohol consumption leads to cognitive impairment, but the specific pathological mechanism involved remains unknown. The present study evaluated the association between heavy alcohol intake and the neuropathological hallmark lesions of the three most common neurodegenerative disorders, i.e., Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and vascular cognitive impairment (VCI), in post-mortem human brains. The study cohort was sampled from the subjects who underwent a medicolegal autopsy during a 6-month period in 1999 and it included 54 heavy alcohol consumers and 54 age- and gender-matched control subjects. Immunohistochemical methodology was used to visualize the aggregation of beta-amyloid, hyperphosphorylated tau, and alpha-synuclein and the extent of infarcts. In the present study, no statistically significant influence was observed for alcohol consumption on the extent of neuropathological lesions encountered in the three most common degenerative disorders. Our results indicate that alcohol-related dementia differs from VCI, AD, and DLB; i.e., it has a different etiology and pathogenesis.

Background and Aim: Changes of arterial stiffness indicate alteration in arterial mechanics predisposing to the evolution of stroke or vascular dementia. The aim of this pilot study was to investigate whether ultrasound parameters, particularly beta stiffness index (BSI), should be further explored as independent markers or risk factors for dementia., Patients and Methods: There were 38 demented patients included in this study (72.53+/-7.87 yrs) and 33 clinically healthy controls (68.85+/-3.52 yrs). Risk factors were noted and ultrasound measurements performed on common carotid artery (CCA) using eTracking software on Aloka ProSound ALPHA 10 with 13 MHz linear probe. Level of significance was p<0.05., Results: Arterial hypertension was present in 24 patients, atrial fibrillation in 9, diabetes in 3, and hypercholesterolemia in 18. Hypertension was present as a single risk factor in 15 controls with average diastolic blood pressure significantly lower in patients. Significantly higher in patients were mean intima-media thickness, systolic and diastolic CCA diameters (CD), and mean BSI in CCA bilaterally. Linear regression analysis for groups of Alzheimer's dementia and vascular dementia proved that MMSE of the two groups relates to CCA diameter change (CDc) and BSI change explaining up to 5% of variability., Conclusions: CD, CDc and BSI should be monitored in patients with cognitive decline and further explored as possible independent markers or risk factors; in future studies groups of demented and non-demented patients should be age, sex and risk factor matched.

Our studies of the brain microvascular system have focused on some aspects not commonly studied by other research groups because we use some techniques not often used by others. Our observations tend to add new details to the pathological picture rather than contradict the mainstream findings. We use large, thick celloidin sections which provide a three dimensional view of vascular networks, and alkaline phosphatase (AP) staining which allows one to differentiate between afferent and efferent vessels. We found millions of lipid microemboli in the brains of patients after cardiac surgery, and concluded that they caused vascular dementia in many patients. We previously proposed an animal model of vascular dementia using brain irradiation, which induces capillary loss. Lipid emboli might also be used to create an animal model of vascular dementia. The deep white matter is vulnerable to chronic hypoperfusion because the blood vessels supplying this region arise from the border-zone and have the longest course of all vessels penetrating the cerebrum. In cases with leukoaraiosis (LA), we found periventricular venous collagenosis (PVC), resulting in stenosis. Thirteen of 20 subjects older than 60 years had PVC, and 10 of 13 subjects with severe PVC had LA. Vascular stenosis might induce chronic ischemia and/or edema in the deep white matter, leading to LA. We suggest three mechanisms for a possible genetic predisposition to PVC: i) a predisposition to excessive venous collagenosis; ii) an indirect effect that causes chronic periventricular ischemia with a reactive over-production of collagen; and iii) mechanical damage to small vessels due to increased pulsatile motion. We found tortuous arterioles supplying the deep white matter beginning at about age 50. We also found a trend toward an increase in tortuosity in LA. If tortuosity is a factor in LA, it is probably significant in only a subset of cases. String vessels, remnants of capillaries, occur commonly in the brain, and are increased in ischemia, AD, and irradiation. Capillary injury or shutdown of blood flow can lead to capillary loss and string vessel formation. We found string vessels in brains from preterm babies to the very old. They seem to disappear after some months or years. We found an early loss of capillaries in LA, followed in a few years by the disappearance of string vessels. LA lesions do not progress to cortical cavitating lesions. Our findings raise three questions. 1. Why is the capillary loss arrested before infarction? 2. Why is there a floor below which the vascular density will not fall? 3. Why does the process which initiates string vessels shut down? We explain the vascular changes in LA as follows. LA induces apoptosis with loss of oligodendrocytes. Capillaries and neuropil are lost. Increased oxygen extraction from the blood in the deep white matter in LA implies that there are too many cells for the remaining capillaries. Thus, the capillaries appear to die first. But why do they stop dying? Perhaps a minimum number of capillaries are needed to transport the arterial blood to the venous system. Once the capillaries stop dying, no more string vessels are formed, and the string vessels gradually disappear.

Background: The clinical presentations in dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD) overlap considerably with that of Alzheimer's disease (AD) despite different pathological processes. Autopsy studies have also shown that multiple brain pathology occurs frequently, even in cases with a single clinical diagnosis. We aimed to determine the frequency of clinical diagnosis of FTD and DLB and the underlying pathology in a well-characterized cohort of patients with a clinical diagnosis of probable or possible AD., Methods: We conducted a retrospective analysis of 170 AD patients (probable AD = 83; possible AD = 87) originally enrolled in a case-control study, 27 with postmortem examination, to establish the number of cases meeting probable diagnosis for FTD and DLB, using a checklist of features compiled from their consensus criteria., Results: 23/83 probable AD cases and 32/87 possible AD cases met probable criteria for another dementia, more commonly DLB than FTD. AD pathology was present in 8/15 probable AD and 8/12 possible AD cases coming to autopsy. DLB pathology was seen in four cases and FTD pathology in eight cases. In the AD cases reaching clinical diagnosis for a second dementia syndrome and coming to autopsy, a minority showed non-AD pathology only., Conclusions: Presence of core clinical features of non-AD dementia syndromes is common in AD. Concordance between clinical and pathological diagnoses of dementia remains variable. We propose that repeat clinical examinations and structural neuroimaging will improve diagnostic accuracy. In addition, clinical diagnostic criteria for the main dementia syndromes require refinement.

Objective: Accurate distinction between dementia subtypes is important for patient care and pharmacological treatment. Continuing systematic comparisons of clinical and neuropathological dementia diagnoses may provide a basis for further improvement of the diagnostic procedure. The purpose of this study was to investigate concordance between clinical dementia diagnosis and neuropathological findings in the specialized dementia care., Methods: Inclusion required 1) a clinical dementia disorder diagnosed at a hospital-based memory clinic and 2) a neuropathological examination within the Department of Pathology at the University Hospital in Lund, Sweden, during the years 1996-2006. A total of 176 consecutive patients fulfilled the criteria and were thus included. Clinical dementia diagnoses were obtained from the medical records and compared with the neuropathological findings., Results: The clinical and pathological dementia diagnoses were in full accordance in 86 (49%) of the patients (kappa 0.37). In an additional 24 (14%) cases, the clinical diagnosis corresponded with some but not all pathological components judged to contribute to the dementia disorder. Of the patients with clinical Alzheimer disease, 84% (46/55) had a significant Alzheimer component with or without other significant pathology at neuropathological examination. The corresponding figure for vascular dementia (VaD) was 59% (24/41), for frontotemporal dementia 74% (20/27), for combined Alzheimer and VaD 25% (4/16), and for dementia with Lewy bodies 67% (6/9)., Conclusions: This study shows that clinical dementia diagnoses do not always correspond with neuropathological changes. It stresses the importance of neuropathological examination in research and in daily clinical practice.

White matter damage and its contribution to clinical manifestations in patients with dementia have been increasingly recognized. To explore white matter changes in different types of dementia, we examined brain water diffusivity with diffusion tensor imaging (DTI). We measured fractional anisotropy and mean diffusivity of multiple white matter regions in patients with amnesic mild cognitive impairment (MCI, n=10), Alzheimer's disease (AD, n=30), subcortical ischemic vascular dementia (SIVD, n=18), frontotemporal dementia (FTD, n=7), and control subjects (n=20). We performed pairwise comparisons in each region of interest between patients and controls. MCI patients showed diffusion tensor change (DTC) in the left anterior periventricular (PV) area, possibly in the right posterior PV area, and the genu of the corpus callosum. AD patients showed DTC in the corpus callosum, and in frontal and parieto-occipital subcortical and anterior PV areas. In SIVD patients, DTC occurred in the genu of the corpus callosum, and in bilateral frontal subcortical and PV areas. FTD patients differed from controls in showing DTC in the temporal and frontal subcortical areas, the genu of the corpus callosum and PV areas. The degree of DTC correlated with the clinical severity of dementia as assessed by the clinical dementia rating (CDR). Mean diffusivity was diffusely and positively associated with the CDR scores. Fractional anisotropy of the PV areas was negatively associated with the CDR scores, suggesting a critical role of the lateral cholinergic pathways.

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and familial pigmentary orthochromatic leukodystrophy (POLD) present as adult-onset dementia with motor impairment and epilepsy. They are regarded as distinct diseases. We review data from the literature that support their being a single entity. Apart from a slightly older age at onset, a more rapid course, and more prominent pyramidal tract involvement, familial POLD is clinically similar to HDLS. Moreover, the pathologic hallmarks of the two diseases, axonal spheroids in HDLS and pigmented macrophages in POLD, can be identified in both conditions. This supports HDLS and POLD being referred collectively as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).

Objective: To study the reliability of white matter rating scale on magnetic resonance imaging (MRI) of elderly patients in the urban community of Bangkok., Material and Method: One hundred elderly with clinical diagnosis of cognitive impairment in the urban community around Siriraj Hospital underwent cranial MRI according to the Dementia and Disability in Thai Elderly Project. The axial T1wi, T2wi, and fluid attenuated inversion recovery (FLAIR) were separately assessed by two neuroradiologists. The assessment included white matter change by using Scheltens' rating scale, atrophy, and evidence of infarction. The inter-rater agreements were analyzed., Results: The inter-rater agreement of periventricular hyperintensities, white matter, basal ganglion and infratentorial foci of hyperintensities were very good (ICC = 0.89-0.98). The agreement was good for central atrophy (Kw = 0.66) and moderate for cortical atrophy (Kw = 0.49). The silent infarction was found in the study population and divided into cortical (15%), subcortical (26%), brainstem (3%), and infratentorial infarction (8%)., Conclusion: White matter hyperintensities was an important radiological criteria for diagnosis of vascular dementia. Appropriate rating scale is necessary especially in research study. The authors found that Scheltens rating scale needed some training and slightly time consuming at the beginning but was a good reliable tool.

Background and Purpose: MRI biomarkers play an important role in the diagnostic work-up of dementia, but their prognostic value is less well-understood. We investigated if simple MRI rating scales predict mortality in a memory clinic population., Methods: We included 1138 consecutive patients attending our memory clinic. Diagnostic categories were: subjective complaints (n=220), mild cognitive impairment (n=160), Alzheimer disease (n=357), vascular dementia (n=46), other dementia (n=136), and other diagnosis (n=219). Baseline MRIs were assessed using visual rating scales for medial temporal lobe atrophy (range, 0-4), global cortical atrophy (range, 0-3), and white matter hyperintensities (range, 0-3). Number of microbleeds and presence of infarcts were recorded. Cox-regression models were used to calculate the risk of mortality., Results: Mean follow-up duration was 2.6 (+/-1.9) years. In unadjusted models, all MRI markers except infarcts predicted mortality. After adjustment for age, sex, and diagnosis, white matter hyperintensities, and microbleeds predicted mortality (white matter hyperintensities: hazard ratio [HR], 1.2; 95% CI, 1.0-1.4; microbleeds: HR, 1.02 95% CI, 1.00-1.03; categorized: HR, 1.5; 95% CI, 1.1-2.0). The predictive effect of global cortical atrophy was restricted to younger subjects (HR, 1.7; 95% CI, 1.2-2.6). An interaction between microbleeds and global cortical atrophy indicated that mortality was especially high in patients with both microbleeds and global cortical atrophy., Conclusions: Simple MRI biomarkers, in addition to their diagnostic use, have a prognostic value with respect to mortality in a memory clinic population. Microbleeds were the strongest predictor of mortality.

Investigations of alterations in brain asymmetry often focus on the planum temporale of patients with schizophrenia. Data also suggest changes in laterality of demented patients associated with a more marked impairment of the left hemisphere. Our study was performed on autoptic brain tissue of 84 patients, out of which there were 25 non-demented non-psychotic controls, 50 demented patients (34 Alzheimer disease, 9 multi - infarct dementia and 7 mixed-type dementia patients) and 9 people with schizophrenia. The plana temporalia were evaluated via a new volumetric method using dental resin matter. Areas, cortical thickness and volumes of the right and left planum temporale were evaluated without normalization to brain weight in 60 patients and with normalization in 24 people. In controls, a mild right/left laterality of areas, cortical thickness and volumes was found. Moreover, in control women the areas of the left planum temporale were smaller than those observed in control men. The shifts to left/right laterality of areas and volumes were found in all demented groups. In the more numerous Alzheimer group, the change in laterality of an area was associated with a mild decrease on the right and a mild increase on the left side. In contrast, marked but only bilateral area shrinkage as well as reduced cortical thickness and brain volumes were observed in schizophrenic patients.

The concept of vascular dementia (VaD) has greatly evolved in the past decades. Advances in neuroimaging techniques have led to a better identification of cases with small vessel disease and chronic ischemic changes. Autopsy data from population-based studies have revealed the frequent occurrence of both vascular and degenerative lesions in aged brains. However, the clinical significance of vascular pathology has been difficult to establish. This chapter will review data from clinicoradiological and clinicopathological studies that have attempted to define the cognitive impact of macroscopic and microscopic ischemic pathology in pure VaD and in cases with associated degenerative pathology. Magnetic resonance imaging studies have focused on lacunes and white matter lesions, whereas autopsy series have provide important insights into the clinical correlates of macroinfarcts,lacunes, diffuse and periventricular demyelination, microinfarcts and focal and diffuse gliosis.Results from these studies have led to a better understanding of the influence of lesion type,location and severity on cognitive function. Vascular scores have been proposed that can be combined with well-established classifications of Alzheimer's disease (AD) pathology to distinguish mixed dementias from pure AD and pure VaD., (Copyright (c) 2009 S. Karger AG, Basel.)

We describe a fully automated method for hippocampal segmentation. The method uses SPM5 (http://www.fil.ion.ucl.ac.uk/spm/) software to segment the brain into grey/white matter, and spatially normalize the images to standard space. Grey matter pixels within a predefined hippocampal region in standard space are identified to segment the hippocampi. The method was validated on 36 subjects (9 each of Alzheimer's disease, dementia with Lewy bodies, vascular dementia, and healthy controls). The mean absolute difference in volume compared with manual segmentation was 11% (SD 9%). Linear regression between manual and automated volume gave V(auto) = V(manual) x 0.83 + 401 ml. The method provides an acceptable automated alternative to manual segmentation which may be of value in large studies., (Copyright 2007 Wiley-Liss, Inc.)

Background: Epidemiological studies show that up to 10% of individuals aged 65 years and older suffer from dementia, most commonly from dementia of the Alzheimer Type (DAT) (1). Clinicopathological studies are critical to our understanding of this disease and improving the accuracy of clinical diagnoses., Objectives: Our objectives were to examine the validity of clinical diagnoses of DAT, to determine the prevalence of different forms of dementia in this sample, and to investigate the relationship between age at death and polymorbidity., Subjects and Method: Clinical data were available from 221 patients who had been examined at the Basel Memory Clinic between 1986 and 1996. From this population, 34% (75 patients) were autopsied in the Department of Pathology, University Hospital Basel, and neuropathological examinations were additionally performed on 62 (83%) of these patients. Clinical and neuropathological data were retrospectively compared., Results: 67.8% of the neuropathologically examined patients received a definitive diagnosis of AD (Alzheimer's disease), vascular dementia (VaD) or mixed dementia (AD and VaD). AD alone or with other histopathological hallmarks of dementia was the most prevalent neuropathological diagnosis (63%). VaD was deemed the only cause of dementia in only 4.8% of patients. The sensitivity for DAT was 75.9%, the specificity 60.6%. Increasing age was associated with an increasing number of clinical and neuropathological diagnoses., Conclusion: The sensitivity and specificity of the clinical diagnoses of DAT found in our study are similar to previous reports (2-5). Older patients had more etiologies of their dementia than younger patients. This study reaffirms the need for internationally accepted criteria for clinical and neuropathological diagnoses, as well as further clinical-neuropathological investigations to further refine the clinical diagnostic process.

Background: Dementia is an increasing problem in society. The underlying cause of dementia may be difficult to diagnose during life. Only neuropathologic examination gives definite diagnosis. Differences in the reported frequency may be related to factors such as the age or gender of subjects with dementia., Materials and Methods: In our neuropathology-based study we examined 156 consecutive subjects clinically diagnosed with dementia during a 3-year period. Using histopathological criteria we calculated the frequencies of various disorders causing dementia. We studied the effect of age and gender on these frequencies., Results: Alzheimer's disease was the most frequent pathologic finding (57.7%) followed by vascular dementia (43%); diffuse Lewy body disease (15.4%); argyrophilic grain dementia (12.1%), various forms of frontotemporal dementia (5.7%); and other (4.5%). The latter comprise prion disease, alcoholic encephalopathy, and hippocampal sclerosis. Mixed pathology was common: concomitant Alzheimer's disease was present in 41.6% of diffuse Lewy body disease cases and in 49.2% of vascular dementia patients. Pure disease forms are rare: Alzheimer's disease: 26.3%, vascular dementia: 17.3%, diffuse Lewy body disease: 5.1%, argyrophilic grain dementia: 2.5%. Females were overrepresented among those with Alzheimer's disease with age at death above 75 years (p < 0.02), while males were overrepresented in patients below 75 years with vascular dementia (p < 0.05)., Conclusions: Our study indicates that the frequency of neurodegenerative dementias is high in the examined patients, but vascular pathology frequently influences the clinical course.

Alzheimer's disease (AD) is thought to be the most common cause of late-life dementia. But pure AD is infrequent whereas AD pathology is often insufficient to explain dementia in the elderly. Conversely, cerebrovascular disease is omnipresent and the crucial role of microvascular alterations increasingly recognized in late dementia or "Alzheimer syndrome". Pathomechanisms of vascular cognitive impairment are still debated but recent data indicate that the initial concept of chronic low grade cerebral hypoxia should not have been abandoned. Thus, it is proposed that windkessel dysfunction is the missing link between vascular and craniospinal senescence on the one hand, and chronic low grade cerebral hypoxia, "senile brain degeneration" and "Alzheimer syndrome" on the other hand. An age-related decrease in the buffering capacity of both the vessels and the craniospinal cavity favours cerebral hypoxia; due to increased capillary pulsatility with disturbances in capillary exchanges or due to a marked reduction in craniospinal compliance with a mechanical reduction in cerebral arterial inflow. "Invisible" windkessel dysfunction, most often related to "hardening of the arteries" may be the most frequent pathomechanism of late-onset dementia whereas associated mild or moderate AD may be merely a toxic manifestation of a primarily hypoxic disease. Structural patterns of arteriosclerotic dementia fit well with an underlying arterial windkessel dysfunction: with secondary mechanical damage to the cerebral small vessels and the brain and predominantly deep hypoxia. The clinical significance of leukoaraïosis, small foci of necrosis, ventricular dilatation, hippocampal and cortical atrophy is in good agreement with their value as indirect markers of windkessel dysfunction. An age-related "invisible" reduction in craniospinal compliance may also contribute to the associations between heart failure, arterial hypotension and cognitive impairment in the elderly and to the high percentage of dementia of unknown origin in the very old. Both neuropathological and clinical overlap between AD and windkessel dysfunction can explain that cerebrovascular dysfunction remains misdiagnosed for AD in the elderly. Evidence of the key role of cerebrovascular dysfunction should markedly facilitate and widen therapeutic research in late-life dementia. Routine MRI including direct assessment of intracranial dynamics should be increasingly used to define etiological subtypes of the "Alzheimer syndrome" and develop a well-targeted therapeutic strategy.

Background: Adult leg length is influenced by nutritional intake in childhood. Shorter leg length has been found to be associated with adverse health outcomes in late life, including dementia. Smaller head circumference has also been found to be associated with dementia. The independence of these two potential markers of risk for dementia has not been investigated., Methods: Community residents aged 65 or over (n = 916) within a defined geographic area of South Korea were screened clinically for dementia and dementia subtypes. Data on anthropometric measures (head circumference and leg length), demographics (age, gender), apolipoprotein E, and early life environment (birth order, number of siblings, parental occupation, area of residence, education) were gathered. Reproductive history was also ascertained in women., Results: Both smaller head circumference and shorter leg length were associated with increased age, rural residence in childhood and lower education. After adjustment for these factors, they were both independently associated with Alzheimer's disease but only in women., Conclusions: Smaller head size and shorter limb length were associated with lower early-life socio-economic status. Both factors were apparently independent markers of risk for dementia which may indicate risk factors occurring in childhood affecting both brain and skeletal development. Associations were principally present in women. Reasons for gender differences in associations require clarification but, for this population and age group, may include preferential treatment of male children.

We aim to investigate the pathological background of mild cognitive impairment (MCI). The most recent 545 cases from the Brain Bank for Aging Research (BBAR) were studied, with a mean age of 80.7 years and male : female ratio of 324 : 221. Cases with clinical dementia rating scale (CDR) 0.5 were retrieved as the best substitute of MCI. CDR was retrospectively determined from clinical charts. Pathological examinations followed the BBAR protocol (JNEN 2004). Post mortem assessment of CDR was possible for 486 cases, and was 0 in 201 cases, 0.5 in 57 cases and 1-3 in 228 cases. CDR 0.5 group was clinicopathologically classified into 33 cases with degenerative changes, nine cases with vascular changes, four cases with combined degenerative and vascular changes, two with hippocampal sclerosis, two with trauma, one with metabolic disease and six with unremarkable changes. The degenerative group was further subclassified into groups with pure and combined pathology. The former consisted of six cases each with Alzheimer change (AC), argyrophilic grain change (AGC) and neurofibrillary tangle predominant change (NFTC), three each with Lewy body disease change without parkinsonism (DLBC) or Parkinson's disease (PDMCI) and one case with progressive supranuclear palsy. The latter consisted of three cases with AC plus AGC, two with AGC plus NFTC and one each with AC plus DLBC, DLBC plus amyotrophic lateral sclerosis and AGC plus DLBC. The pathological backgrounds of patients of class CDR 0.5 were varied and not restricted to AC.

Objective: Several studies suggest that depression is a risk factor for development of dementia in the elderly. In a study of older depressed individuals, the authors examined both neuroimaging and genetic factors in development of dementia. The authors hypothesized that change in subcortical gray matter and white matter hyperintensity volumes would be associated with development of dementia, as would presence of an apolipoprotein E (APOE) epsilon 4 allele., Methods: The sample consisted of 161 older depressed subjects without dementia who had magnetic resonance imaging scans at baseline and at two years. Blood samples were also taken to determine APOE genotype. All participants were treated with antidepressants using a guideline-based treatment algorithm. Their cognitive status was evaluated annually. A consensus panel of experts evaluated each case to determine cognitive status and assign a diagnosis., Results: Twenty subjects became demented over the follow-up period (5.4 years on average). Change in white matter hyperintensity volume was significantly associated with development of dementia, especially among non-Alzheimer dementias. There was a trend for change in subcortical gray matter hyperintensity volume to be associated with incident dementia. APOE genotype was not associated with onset of dementia., Conclusion: Worsening cerebrovascular disease in older depressed adults is associated with cognitive decline and dementia, particularly of the non-Alzheimer disease type. The association of change in white matter lesion volume and incident dementia among depressed elders extends the vascular depression hypothesis of geriatric depression to include cognitive outcomes of depression in the elderly.

Cardiovascular risk factors (CRF) such as hypertension and diabetes mellitus favour the development of both vascular dementia (VaD) and Alzheimer's disease (AD). The resulting deafferentation may increase the experience of pain in VaD and in AD. The goal of the present study was to examine the relationship between CRF and pain in a sample of 107 cognitively impaired nursing home patients who had also a chronic pain condition. The prevalence of pain in patients with hypertension or diabetes mellitus was higher (25/41=61% of them had pain) than those without diabetes or hypertension (of whom 24/66=36.4% had pain, p=0.017). In a multivariate logistic regression model (adjusted for gender, age and depression) the presence of diabetes or hypertension was a risk indicator for pain: odds ratio: 3.48, p=0.005, 95% CI: 1.45-8.38. This finding supports the hypothesis that as a result of CRF, disruptions of cortico-cortico and cortico-subcortical pathways occur, and consequently, enhances pain in this group of patients.

We report two patients with dural arteriovenous fistulas (DAVFs) who presented with pure progressive dementia. Both patients showed only slowly progressive dementia, without headache, papilledema and other neurologic signs associated with diffuse white matter changes in MRI. MR cerebral angiography showed sigmoid sinus DAVFs that were mainly supplied by the occipital artery, together with retrograde filling of the superior sagittal and straight sinus and dilated cortical veins. SPECT studies showed extensive blood flow reduction in the occipital and parieto-occipital areas and right temporal lobe in one patient. Selective embolization for treatment of the DAVF improved cognitive function associated with the abnormal white matter MRI signal. MRI and SPECT showed that severity of dementia correlated with diffuse white matter changes and regional cerebral blood flow. Our cases suggest that gradually impaired cerebral circulation due to venous hypertensive encephalopathy could be involved in slowly progressive dementia with leukoencephalopathy resulting from a DAVF. DAVFs may be particularly important for differential diagnosis in elderly patients with pure progressive dementia. Thus, early diagnosis of DAVFs and treatment by endovascular surgery is important as treatable or reversible dementia.

Background: Differential patterns of brain lesions in patients with Alzheimer's disease (AD) or vascular dementia (VaD) can result in differing clinical courses and presentations., Method: Thirty patients with AD were compared with 29 patients with VaD for differences in behavioral symptoms using the Behavioral Pathology in Alzheimer's Disease (BEHAV-AD) rating scale., Results: Patients with AD had significantly more delusions, hallucinations, anxieties and phobias and caregiver distress than patients with VaD., Conclusions: Behavioral symptoms in both AD and VaD exhibit specific longitudinal patterns. An understanding of the pattern can aid the treating physician in giving appropriate advice to caregivers regarding the course of the illness and also help them in planning appropriate interventions.

Objective: The aim of the present study was to investigate if depressive symptoms in demented patients are associated with white matter changes (WMCs) in the brain., Background: WMCs are frequently found in patients with dementia, as well as among elderly nondemented patients with depressive symptoms. However, it is less established whether or not WMCs are related to depressive symptoms in demented patients., Methods: 67 (26 men, 41 women) patients with primary degenerative dementia (Alzheimer's disease, frontotemporal dementia), vascular dementia (VaD), or mixed Alzheimer/VaD dementia were included in the study. The patients were young-old (mean 68.1, SD 7.3). All patients underwent a standardized examination procedure and MRI of the brain. The degree of WMCs was visually rated, blindly. Depressive symptoms were rated according to the Gottfries-Bråne-Steen scale (anxiety, fear-panic, depressed mood)., Results: No significant relationship was found between WMCs and depressive symptoms in the demented patients., Conclusion: The possible involvement of WMCs in the pathogenesis of depressive symptoms in dementia is unclear. A link between disruptions of frontal-subcortical pathways, due to WMCs, and depressive symptomatology in dementia has been hypothesised from earlier findings, which would imply common elements of pathogenesis for depressive symptomatology and cognitive impairment in dementia. However, the results of the present study do not add further support to this hypothesis., (Copyright (c) 2006 John Wiley & Sons, Ltd.)

Background: Prospective population-based neuropathological studies have a special place in dementia research which is under emphasised., Methods: A systematic review of the methods of population-based neuropathological studies of dementia was carried out. These studies were assessed in relation to their representativeness of underlying populations and the clinical, neuropsychological and neuropathological approaches adopted., Results: Six studies were found to be true population-based neuropathological studies of dementia in the older people: the Hisayama study (Japan); Vantaa 85+ study (Finland); CC75C study (Cambridge, UK); CFAS (multicentre, UK); Cache County study (Utah, USA); HAAS (Hawaï, USA). These differ in the core characteristics of their populations. The studies used standardised neuropathological methods which facilitate analyses on: clinicopathological associations and confirmation of diagnosis, assessing the validity of hierarchical models of neuropathological lesion burden; investigating the associations between neuropathological burden and risk factors including genetic factors. Examples of findings are given although there is too little overlap in the areas investigated amongst these studies to form the basis of a systematic review of the results., Conclusion: Clinicopathological studies based on true population samples can provide unique insights in dementia. Individually they are limited in power and scope; together they represent a powerful source to translate findings from laboratory to populations.

Background and Purpose: Previous studies have shown that midlife systolic blood pressure (SBP) predicts late-life cognitive decline and incident dementia. This study explores whether this association is attributable to the pulsatile, ie, pulse pressure (PP), or the nonpulsatile component of blood pressure (BP)., Methods: Data are from the Honolulu-Asia Aging Study, a community-based study of Japanese American men. Midlife BP was measured in 1971 to 1974 and dementia assessment was conducted in late-life. The 2505 men who were dementia free in 1991 and had complete follow-up data were re-examined for incident dementia in 1994 to 1996 and 1997 to 1999. Their age ranged from 71 to 93 years. Survival analysis with age as the time scale was performed to estimate the risk (hazard ratio [HR] and 95% CI) for incident dementia associated with mid- and late-life tertiles of PP and mean arterial BP, as well as SBP and diastolic BP categories., Results: Over a mean of 5.1 years of follow-up, 189 cases (7.5%) of incident Alzheimer disease or vascular dementia were identified. After adjustment for cerebrovascular risk factors, dementia was significantly associated with SBP (HR 1.77; 95% CI, 1.10 to 2.84, for SBP > or =140 mm Hg compared with SBP <120 mm Hg), but not with PP tertiles. Limiting the analysis to those never treated with antihypertensives, high levels of all 4 BP components were significantly associated with dementia. In models with 2 BP components, only SBP remained significant in both the total sample and the never-treated subgroup (HR 2.29; 95% CI, 1.23 to 4.25, for SBP > or =140 mm Hg in total sample), whereas PP was not significantly associated with the risk for dementia., Conclusions: Midlife PP is not independently associated with dementia incidence. Midlife SBP is the strongest BP component predicting incident dementia.