Clinical Evidence Of Dementia Research Articles

18F‐Florbetaben PET/CT to Assess Alzheimer's Disease: A new Analysis Method for Regional Amyloid Quantification

While AD can be definitively confirmed by postmortem histopathologic examination, in vivo imaging may improve the clinician's ability to identify AD at the earliest stage. The aim of the study was to test the performance of amyloid PET using new processing imaging algorithm for more precise diagnosis of AD. Amyloid PET results using a new processing imaging algorithm (MRI-Less and AAL Atlas) were correlated with clinical, cognitive status, CSF analysis, and other imaging. The regional SUVR using the white matter of cerebellum as reference region and scores from clinical and cognitive tests were used to create ROC curves. Leave-one-out cross-validation was carried out to validate the results. Forty-four consecutive patients with clinical evidence of dementia, were retrospectively evaluated. Amyloid PET scan was positive in 26/44 patients with dementia. After integration with 18F-FDG PET, clinical data and CSF protein levels, 22 of them were classified as AD, the remaining 4 as vascular or frontotemporal dementia. Amyloid and FDG PET, CDR 1, CSF Tau, and p-tau levels showed the best true positive and true negative rates (amyloid PET: AUC = .85, sensitivity .91, specificity .79). A SUVR value of 1.006 in the inferior frontal cortex and of 1.03 in the precuneus region was the best cutoff SUVR value and showed a good correlation with the diagnosis of AD. Thirteen of 44 amyloid PET positive patients have been enrolled in clinical trials using antiamyloid approaches. Amyloid PET using SPM-normalized SUVR analysis showed high predictive power for the differential diagnosis of AD.

79. Amyloid-PET analysis based on tissue probability maps

Purpose The regional quantification of amyloid burden is crucial for the clinical diagnosis of Alzheimer’s disease [1]. The best method to evaluate regional amyloid deposition in PET is through the use MR imaging for brain space normalization. However, since MR imaging is not always available in the clinical practice, a MR-less methodology is needed in order to compute semi-quantitative and analyze regional amyloid burden. Methods Forty-four patients with clinical evidence of dementia, underwent 18F-Florbetaben PET (FBB-PET), FDG-PET, neuropsychological assessment and cerebrospinal fluid analysis. We implemented a methodology that uses SPM12 to import and normalize the FBB-PET images in Montreal Neurological Institute (MNI) space without MRI, and the Automated Anatomical Labeling (AAL) atlas [2] in order to extract regional uptake from normalized FBB-PET. SUVR has been computed by using cerebellum as control region (‘ Cerebelum _ 4 _ 5 ’ of AAL atlas). We then computed Receiver Operating Characteristic (ROC) curve in order to find best thresholds for identifying clinical subgroups in our patients. Results Semi-quantitative evaluation of FBB-PET images and ROC analysis stated that SUVR value of 1,006 in the bilateral inferior frontal cortex and a SUVR of 1.03 in the precuneus region were the best cutoff (AUC 0.883 and 0.826, respectively). Box-Plot analysis showed a trend distribution of elevated SUVR levels in bilateral frontal cortex, angular girus, occipital, parietal, precuneus and paracentral lobule, among AD patients. Conclusion MR-less methodology based on Tissue Probability Map and AAL atlas provide regional quantification of amyloid burden. The ROC analysis is able to retrieve useful thresholds for the classification of AD versus non-AD thus providing a tool in clinical practice. We will perform the study on a larger sample in order to confirm the results.

A proteomic network approach across the ALS-FTD disease spectrum resolves clinical phenotypes and genetic vulnerability in human brain.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlap in clinical presentation, neuropathology, and genetic underpinnings. The molecular basis for the overlap of these disorders is not well established. We performed a comparative unbiased mass spectrometry‐based proteomic analysis of frontal cortical tissues from postmortem cases clinically defined as ALS, FTD, ALS and FTD (ALS/FTD), and controls. We also included a subset of patients with the C9orf72 expansion mutation, the most common genetic cause of both ALS and FTD. Our systems‐level analysis of the brain proteome integrated both differential expression and co‐expression approaches to assess the relationship of these differences to clinical and pathological phenotypes. Weighted co‐expression network analysis revealed 15 modules of co‐expressed proteins, eight of which were significantly different across the ALS‐FTD disease spectrum. These included modules associated with RNA binding proteins, synaptic transmission, and inflammation with cell‐type specificity that showed correlation with TDP‐43 pathology and cognitive dysfunction. Modules were also examined for their overlap with TDP‐43 protein–protein interactions, revealing one module enriched with RNA‐binding proteins and other causal ALS genes that increased in FTD/ALS and FTD cases. A module enriched with astrocyte and microglia proteins was significantly increased in ALS cases carrying the C9orf72 mutation compared to sporadic ALS cases, suggesting that the genetic expansion is associated with inflammation in the brain even without clinical evidence of dementia. Together, these findings highlight the utility of integrative systems‐level proteomic approaches to resolve clinical phenotypes and genetic mechanisms underlying the ALS‐FTD disease spectrum in human brain.

3D printing of beta-amyloid protein deposits along capillary walls

Abnormally high levels of neocortical beta-amyloid protein (A+) reflect Alzheimer’s disease (AD) pathology in persons with clinical evidence of dementia or mild cognitive impairment (MCI). The abnormal aggregation of beta-amyloid protein in the brain neuropil may lead to either diffuse plaques and/or concentrated neuritic plaques, with the latter form of deposits often present in the vicinity of the cerebral microvasculature. The A protein, with its crystalline molecular structure, infiltrates the vessel walls and compromises the blood-brain barrier (BBB). The physical basis for this was elegantly shown by Meyer and colleagues, in a 2008 publication showing two-dimensional (2D) confocal laser scanning microscopic imaging of vascular A protein deposits in APP23 transgenic mice. These investigators showed accumulations of “tuft-life structures”, also referred to as “pompons” with protruding spikes on – and embedded within – microvessels. These pompons of beta-amyloid protein “consist of fibrillar structures, [and] can encircle and constrict capillaries, and are often associated with distortion of capillaries”.We were struck by both the heuristic value of the imaging of Meyer and colleagues, in explaining the root cause of both the amyloid-related alterations in the vascular bed, and depicting minute protein deposits that are both geometrically complex, seemingly delicate and fragile, and yet tenacious in their embedding within small vessel walls. We re-created these images with standard 3D printing technology (extruded plastic) for both educational/teaching and artistic purposes.

Differential pathways for the interleukin-1β production activated by chromogranin A and Aβ in microglia

Materials and methods MG6 microglia and primary cultured microglia were used in this study. Microglia isolated from young and aged mouse brains by magnetic cell sorting using CD11b-conjugated microbeads were also used. Processings of pro-caspase-1 and pro-IL-1b were analysed by immunoblottings. Secretion of IL-1b was measured by ELISA. The frontal cortex of human brains from AD and no clinical evidence of dementia were used for immunohistochemical analyses.

Gene expression profiling of choroid plexus in Alzheimer's disease reveals important implications of CSF dynamics

(entorhinal and temporal cortices, and hippocampus) assembled in tissuemicroarray (TMA), immunohistochemistry was performed to examine the expression patterns of Rb in the following groups: 1) asymptomatic AD elderly individuals with AD-related pathology, but no clinical evidence of dementia (Braak IV-VI, CERAD B or C, CDR 0); 2) symptomatic AD elderly individuals with AD-related pathology and dementia (Braak IV-VI, CERAD B or C, CDR 1⁄4 2); and 3) healthy normal individuals (controls) (Braak I-III, CERAD 0 or A, CDR 0). Results: The nuclear staining was low in all groups, although in the group of normal individuals the number of positive nucleus was higher than in the Alzheimer’s groups. However, there also was cytoplasmatic staining with a stronger immunoreactivity in the normal group and a progressive decrease of reactivity in the asymptomatic and symptomatic AD groups, respectively. Conclusions: Our results show a progressive lost of Rb expression in AD patient’s brain, mainly in the cytoplasm. This shift at the subcellular localization of several makers implicated with cell cycle has been shown in AD, but the real biological significance of this change is still unclear. Considering that Rb function as a cell cycle suppressor, this expression lost could facilitate the cell cycle re-entry and neuronal death. In asymptomatic AD individuals, the Rb expression level higher than in symptomatic AD subjects could be helping, together with other mechanisms, the keeping of their normal cognitive function.

Myeloid Sarcoma in the Nasal Cavities that Developed during the Course of Acute Myelomonocytic Leukemia

In December 2006, a 95-year-old Japanese woman was transferred to our hospital for the evaluation of her leukocytosis. In September 2006, the patient was medicated for hypertension by her family physician and she was found to have leukocytopenia (2,500/mL) without abnormal cells in the peripheral blood (PB). During the middle of November, the patient’s white blood cell (WBC) count was found to be elevated. Upon admission to our hospital, the patient had no complaints and presented no remarkable findings on physical examination. She had no clinical evidence of dementia. A complete blood count showed WBC count of 58,300/mL (myeloblasts 7%, neutrophils 27%, metamyelocytes 1%, monocytes 58%, and lymphocytes 7%), hemoglobin of 9.1 g/dL, and platelet count of 149,000/mL. Most of the monocytes were immature and positive for CD11b, CD13, CD14, CD15, CD33, and CD64. Hypersegmented neutrophils and giant neutrophils were seen. Since the patient and her family refused bone marrow aspiration (BMA), we considered from the above PB profile and the progressive clinical features that the patient likely had acute myelomonocytic leukemia (AMMoL). Following chemotherapy with low-dose cytarabine (Ara-C) (20 mg/day subcutaneously, on days 1-25), her WBC count gradually decreased, and myeloblasts and abnormal monocytes disappeared. Her general condition was seen to be stable. At the end of March 2007, her WBC count again elevated with myeloblasts and abnormal monocytes (15% and 8%, respectively) being around 10,000/mL. BMA could be carried out at that time, and it showed elevation of myeloblast and monoblast percentages (19.3% and 22.5%, respectively) (Fig. 1). Blasts were positive for myeloperoxidase (MPO) and monoblasts were positive for non-specific esterase, CD11b, and CD64. Since dysplasia in the myeloid series, characterized by hypersegmented neutrophils, giant neutrophils and Pelger-Huet nuclear anomaly, was detected, a diagnosis of AMMoL, which had been most likely progressed from myelodysplastic syndrome (MDS), was further confirmed. The possibility that the present case was chronic myelomonocytic leukemia could be excluded because of the presence of excessive myeloblasts. Chromosomal analysis of BM revealed no abnormalities. At that time, the patient also presented bilateral nasal obstruction with swelling. A computed tomography (CT) scan revealed a soft tissue mass occupying both of the nasal cavities by involving the nasal septum (Fig. 2a, b). No destruction of the bone was evident. Biopsy of the tumor showed diffuse proliferation of large mononuclear cells which was covered by focally erosive mucosal tissue with the infiltration of mature neutrophils and plasma cells. The large mononuclear cells had immature-appearing nuclei with mitotic features and weakly eosinophilic cytoplasm. (Fig. 3a, b). Immunohistochemically, the cells were positive for MPO, a1antitrypsin (AAT), lysozyme, CD4, CD15, CD68, and CD163, and were negative for CD3e, CD20, CD34, CD56, and CD123 (Fig. 4). Among the proliferating cells, MPO, AAT, lysozyme, and CD68 were positive in the vast majority of cells, while the positive rates of CD15, CD4, and CD163 were estimated to be 80%, 60%, and 40%, respectively. Although these findings are not precise, the proliferating cells appeared to be composed of granulocytic, monocytic, and granulomonocytic (a cell having both granulocyte-related and monocyte-related molecules) lineages. Based on these findings, the lesion was diagnosed as one of myeloid sarcoma (MS), and could be classified as myelomonocytic sarcoma. Chemotherapy consisting of low-dose Ara-C (20 mg/day subcutaneously, on days 1-14) and aclarubicin (10 mg/day intravenously, on days 1-4) resulted in a decrease of WBC count

Attentional deficits in Alzheimer's, Parkinson's, and Huntington's diseases.

Attentional deficits have been shown in Alzheimer's disease but it is unknown whether this reflects disease specific impairment or is present in other neurodegenerative disorders. We administered a verbal dichotic listening task (free recall and selective allocation to the left or right ear) to 17 patients with Alzheimer's disease, 19 patients with Huntington's disease, 10 patients with idiopathic Parkinson's disease with clinical evidence of dementia (DemPD), 22 non-demented patients with Parkinson's disease (PD), and 22 healthy controls. Patients with dementia were matched for dementia severity and performance in the 3 recall conditions was used as a measure of attentional capacity. Patients with dementia (Alzheimer and Huntington patients, DemPD) were less accurate than those without dementia (PD and normal subjects). Demented subjects performed at comparable levels regardless of specific diagnosis; likewise those without dementia also achieved similar levels. All groups had a right ear preference under the free recall condition. Alzheimer and Huntington patients showed consistent right ear preference under all recall conditions, while PD patients, like controls, could selectively allocate attention to the left under left ear recall, regardless of the presence of dementia. The findings suggest a double dissociation. Non-selective attentional processing is affected by dementia presence versus absence but not by specific disease, while selective attentional processing shows disease specific impairments, regardless of the presence of dementia.

Fluoro-2-Deoxy-D-Glucose (FDG)-PET in APOEε4 Carriers in the Australian Population

Apolipoprotein E-epsilon4 (APOEepsilon4) has been associated with increased risk of developing Alzheimer's disease (AD) and regional cerebral glucose hypometabolism, as measured by fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET). We report here preliminary data from studies that aim to determine whether cerebral glucose hypometabolism is observed in APOEepsilon4 positive, cognitively intact individuals between the ages of 50 and 80, and whether there is an additional impact of subjective memory complainer (SMC) status on glucose metabolism determined by NeuroStat analysis. FDG-PET was conducted in 30 community dwelling, APOE-epsilon4 carriers without clinical evidence of dementia and objective cognitive impairment as assessed using a neuropsychological battery. Neurological soft-signs (NSS) were also assessed. Glucose hypometabolism was demonstrated in the anterior and posterior cingulate cortex and in the temporal association cortices in APOEepsilon4 carriers compared to the normative NeuroStat database. This pattern was particularly evident in APOEepsilon4 heterozygous individuals. SMC showed hypometabolism in the aforementioned brain regions, whereas non-SMC showed no significant pattern of glucose hypometabolism. FDG-PET with NeuroStat analysis showed that APOEepsilon4 carriers have mild glucose hypometabolism in areas associated with AD. SMC may be associated with AD-related differences in regional cerebral glucose metabolism. These findings are currently being investigated in a larger group of APOEepsilon4 carriers.

Fifteen‐year follow‐up of 92 hospitalized adults with Down’s syndrome: incidence of cognitive decline, its relationship to age and neuropathology

The clinical and neuropathological features associated with dementia in Down's syndrome (DS) are not well established. Aims To examine clinico-pathological correlations and the incidence of cognitive decline in a cohort of adults with DS. A total of 92 hospitalized persons with DS were followed up from 1985 to December 2000. At outset, 87 participants were dementia-free, with a median age of 38 years. Assessments included the Prudhoe Cognitive Function Test (PCFT) and the Adaptive Behavior Scale (ABS), to measure cognitive and behavioural deterioration. Dementia was diagnosed from case records and caregivers' reports. Eighteen (21%) patients developed dementia during follow-up, with a median age of onset 55.5 years (range 45-74). The PCFT demonstrated cognitive decline among those with a less severe intellectual disability (mild and moderate) but not among the profoundly disabled people (severe and profound). Clinical dementia was associated with neuropathological features of Alzheimer's disease, and correlated with neocortical neurofibrillary tangle densities. At the age of 60 years and above, a little more than 50% of patients still alive had clinical evidence of dementia. Clinical dementia associated with measurable cognitive and functional decline is frequent in people with DS after middle age, and can be readily diagnosed among less severely intellectually disabled persons using measures of cognitive function such as the PCFT and behavioural scales such as the ABS. In the more profoundly disabled people, the diagnosis of dementia is facilitated by the use of behavioural and neurological criteria. In this study, the largest prospective DS series including neuropathology on deceased patients, the density of neurofibrillary tangles related more closely to the dementia of DS than senile plaques. In people with DS surviving to middle and old age, the development of dementia of Alzheimer type is frequent but not inevitable, and some people with DS reach old age without clinical features of dementia.

Neuropathology of Down syndrome and Alzheimer disease

Patients with Down syndrome (DS) over 40 years of age, prematurely and consistently develop neurofibrillary tangles (NFT), intracytoplasmic inclusions of highly insoluble straight or paired helical 12-16 nm filaments, and senile plaques (SP) composed of abnormal neurites surrounding a core of beta amyloid. These two lesions occur in distributions similar to those seen in Alzheimer disease (AD). SP and NFT are detected also in some younger individuals with DS (10-30+ years) when immunocytochemical and/or silver staining techniques are used. Retrospective and prospective attempts to relate neuropathological lesions and clinical dementia in DS have produced conflicting results. Clinical evidence of dementia and large numbers of SP and NFT were not always concordant. The predictable and consistent appearance of the AD-like neuropathologic changes in DS provides an unusual opportunity to examine the sequential development of SP and NFT. By combining morphological, immunocytochemical, and morphometric techniques with molecular biological approaches, the evolution of the structural and chemical changes in DS and AD can be examined and their relationship to clinical deficits can be evaluated.

Gender differences in upper extremity motor performance of older persons.

Motor performance declines with age. Although gender differences in motor strength and speed have been widely reported, the extent to which these differences are maintained in old age has not been well established. Upper extremity motor performance was assessed in 234 men and 530 women Catholic clergy members aged 65 years or older with no clinical evidence of dementia who were participants in the Religious Orders Study. As part of a uniform clinical evaluation, upper extremity motor performance including strength (grip and pinch dynamometry), movement speed including finger tapping and Purdue pegboard and muscle bulk of the arm were collected. Men were stronger than women at all ages but this difference became less prominent at older ages. Women scored higher on the Purdue Pegboard than men whereas men had faster maximal finger tapping rates than women. Gender differences in speed were not modified by age. Men had greater muscle bulk than women at all ages and these differences were not modified by age. These relationships were not modified by participants with a clinical diagnosis of Parkinson's disease or stroke or by hormone replacement therapy in women. Gender differences in upper extremity speed and muscle bulk appear to be relatively stable with increasing age, whereas gender differences in strength were reduced in the oldest old. Longitudinal studies are needed to determine if men and women differ in the rate of decline of strength in old age.

Co-occurrence of essential tremor and Parkinson's disease: clinical study of a large kindred with autopsy findings

A multigenerational family complex with an admixture of essential tremor (ET) and PD is presented. Medical information obtained either by historic documentation and/or examination was available for five generations and included 36 members. Of these, 11 family members had tremor of the limbs and/or head. In all these instances ET made its first appearance at an early age, usually prior to the second decade of life. In one case focal dystonia of the hand, a possible prelude to PD occurred, while in three brothers of the third generation, two of them identical twins, classical Parkinson's disease (PD) developed. They had ET develop at an early age, which persisted and in their 50s began showing evidence of PD. Two decades later the twin brothers succumbed to cancer of the colon and at autopsy typical findings of PD with cell loss in the substantia nigra and Lewy-body formation positive for α-synuclein by immunohistochemistry was found. Additionally, more than the usual number of senile plaques and neurofibrillatory tangles were present without clinical evidence of dementia or significant decline in cognitive function. This unusual set of clinical and pathological circumstances can hardly be attributed to chance occurrence and raise the question of a specific genetic mutation and/or clustering, which may link ET with PD.

Mild cognitive impairment in older people

As public awareness of Alzheimer's disease increases, more people are asking for help and advice about memory problems. Memory complaints may be secondary to psychiatric, psychological, and physical conditions and is an almost universal early symptom of dementia. The concept of amnestic mild cognitive impairment attempts to describe those people in whom memory loss is not of such severity to merit a diagnosis of dementia. The importance of this group of people is not just the need to develop interventions which ameliorate individual suffering but that they represent a population at high risk of developing dementia, especially Alzheimer's disease, and are an appropriate target for dementia prevention strategies. K Kantarci and colleagues (Dement Geriatr Cogn Disord 2002; 14: 198-207) looked at the diagnostic accuracy of magnetic-resonance hippocampal volumetry and spectroscopy in patients with mild cognitive impairment, in normal older people, and in patients with Alzheimer's disease. Hippocampal volumes and N-acetyl aspartate/creatine spectroscopy were the most sensitive assessments discriminating people with mild cognitive impairment from Alzheimer's disease. Combination assessments were better at discriminating these two groups from normal controls. The histological underpinning of cognitive symptoms in older people has been demonstrated by the Cognitive Function and Ageing study (Lancet 2001; 357: 169-75), which showed that a third of people with no clinical evidence of dementia had histopathological hallmarks of Alzheimer's disease. WHERE NEXT? 25 million people across the world have dementia. Mild cognitive impairment, if a validated concept, represents an opportunity for preventing dementia. As more information becomes available about the cause of Alzheimer's disease and prospects emerge for prevention, identification of predementia states offers considerable scope to reduce the individual and societal cost of the illness. Continued validation of the criteria for mild cognitive impairment and studies of intervention should be a priority. As more evidence becomes available highlighting the relatively arbitrary nature of dementia diagnosis (based largely on interference with activities) and interventions become available for the prevention of dementia, mild cognitive impairment and related conditions will become more important.

The apolipoprotein E epsilon 4 allele and decline in different cognitive systems during a 6-year period.

Impairment of episodic memory is an early and defining feature of Alzheimer disease (AD). The apolipoprotein E (APOE) epsilon 4 allele is known to influence risk of AD but it has been difficult to establish whether it affects episodic memory differently from other cognitive functions. To examine the association of epsilon 4 with decline in different cognitive systems. Longitudinal cohort study. More than 40 groups of Catholic clergy from across the United States. Older Catholic clergy members without clinical evidence of dementia at baseline underwent annual clinical evaluations for up to 6 years. Of 624 persons eligible for follow-up, 611 (98%) participated, of whom 161 (26%) had at least 1 epsilon 4 allele. They completed an average of 5.5 evaluations (range, 2-7). Incident AD and annual rates of change in episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability. The presence of epsilon 4 was associated with risk of developing AD on follow-up (relative risk, 1.92; 95% confidence interval, 1.27-2.89). In a series of random effects models, epsilon 4 was associated with impaired baseline function in episodic memory and visuospatial ability and with more rapid decline in all domains. The effect of epsilon 4 on annual decline in episodic memory (>3-fold increase) was significantly stronger than its effect on decline in other cognitive systems (P<.01), and at baseline, its effect on episodic memory was marginally stronger than its effect on other cognitive domains (P =.06). The results suggest that the APOE epsilon 4 allele influences risk of AD by a relatively selective effect on episodic memory.

Cognitive impairment in motor neuron disease with bulbar onset

Twenty-three patients with bulbar onset motor neuron disease/amyotrophic lateral sclerosis (MND/ALS) were clinically assessed. They subsequently underwent serial neuropsychological testing, event-related potentials (ERP) and SPECT studies. Cognitive impairment was defined by clinical evidence of dementia (DSM-IV and frontal evaluation) or by significant alteration indicated by neuropsychological testing (excluding patients with depression and major anxiety), or both. Eleven patients (48%) were found to be cognitively impaired. Abnormalities indicated fronto-temporal involvement, with memory impairment, alteration of judgement and reasoning, reduced speech, behavioural dyscontrol and alteration of daily living activities. This impairment correlated well with event-related potentials and SPECT studies. Event-related potentials were the most sensitive test as 100% of the impaired patients had abnormal ERP (p = 0.04). The cognitively impaired group differed from the other group mainly by gender ratio (male/female) with an important male predominance: 1.75 vs. 0.33. MND/ALS was also more severe when cognitive decline was present. This study adds further arguments for a cognitive impairment in MND/ALS. This also reinforces the hypothesis that there is continuum between MND/ALS and fronto-temporal lobe dementia.

Self-reported walking ability predicts functional mobility performance in frail older adults.

To determine how self-reported physical function relates to performance in each of three mobility domains: walking, stance maintenance, and rising from chairs. Cross-sectional analysis of older adults. University-based laboratory and community-based congregate housing facilities. Two hundred twenty-one older adults (mean age, 79.9 years; range, 60-102 years) without clinical evidence of dementia (mean Folstein Mini-Mental State score, 28; range, 24-30). We compared the responses of these older adults on a questionnaire battery used by the Established Populations for the Epidemiologic Study of the Elderly (EPESE) project, to performance on mobility tasks of graded difficulty. Responses to the EPESE battery included: (1) whether assistance was required to perform seven Katz activities of daily living (ADL) items, specifically with walking and transferring; (2) three Rosow-Breslau items, including the ability to walk up stairs and walk a half mile; and (3) five Nagi items, including difficulty stooping, reaching, and lifting objects. The performance measures included the ability to perform, and time taken to perform, tasks in three summary score domains: (1) walking ("Walking," seven tasks, including walking with an assistive device, turning, stair climbing, tandem walking); (2) stance maintenance ("Stance," six tasks, including unipedal, bipedal, tandem, and maximum lean); and (3) chair rise ("Chair Rise," six tasks, including rising from a variety of seat heights with and without the use of hands for assistance). A total score combines scores in each Walking, Stance, and Chair Rise domain. We also analyzed how cognitive/ behavioral factors such as depression and self-efficacy related to the residuals from the self-report and performance-based ANOVA models. Rosow-Breslau items have the strongest relationship with the three performance domains, Walking, Stance, and Chair Rise (eta-squared ranging from 0.21 to 0.44). These three performance domains are as strongly related to one Katz ADL item, walking (eta-squared ranging from 0.15 to 0.33) as all of the Katz ADL items combined (eta-squared ranging from 0.21 to 0.35). Tests of problem solving and psychomotor speed, the Trails A and Trails B tests, are significantly correlated with the residuals from the self-report and performance-based ANOVA models. Compared with the rest of the EPESE self-report items, self-report items related to walking (such as Katz walking and Rosow-Breslau items) are better predictors of functional mobility performance on tasks involving walking, stance maintenance, and rising from chairs. Compared with other self-report items, self-reported walking ability may be the best predictor of overall functional mobility.

Verbal memory in non-demented patients withidiopathic Parkinsons disease

This study assessed the verbal memory functions of 20 patients with idiopathicParkinsons Disease (PD) without any clinical evidence of dementia and 20 Medical Control(MC) patients with similar levels of physical disability. Performance was compared on tests ofimmediate recall, word list learning in intentional and incidental contexts, word completionpriming, remote memory, metamemory and awareness of mnestic abilities. Significantdifferences were found in new learning of verbal material under incidental but not intentionallearning conditions. Group differences were also observed on measures of remote memory andmetamemory. The groups did not differ in word completion priming performance or recognitionmemory. These findings are consistent with other evidence suggesting that PD patients withoutdementia may have subtle cognitive deficits that affect memory performance. These may beattributable to impairments of attention allocation, formulation of retrieval strategies, andeffortful learning associated with frontal lobe dysfunction. The group differences could not beattributed to impairments of intellectual functions, verbal fluency, level of physical disability, ormood disturbance.

Circular forms of unintegrated human immunodeficiency virus type 1 DNA and high levels of viral protein expression: association with dementia and multinucleated giant cells in the brains of patients with AIDS.

Thirty-one histologically abnormal brains from patients with AIDS were studied in order to establish the relationship between multinucleated giant cells, viral protein expression, the various forms of human immunodeficiency virus type 1 (HIV-1) DNA, and clinical evidence of dementia. Unintegrated HIV-1 DNA of 2 to 8 kb was found in 22 of the 31 brains. Multinucleated giant cells without any other pathology were found in 14 cases; unintegrated 1-long terminal repeat (1-LTR) circular forms of HIV-1 DNA and strongly positive immunohistochemistry for gp41 and p24 were found in most of these brains. Most of these patients had a clinical diagnosis of HIV-1-associated dementia and cerebral atrophy. In all the other brains studied, 1-LTR circles were absent and immunohistochemistry for gp41 and p24 was usually negative. Very few of these patients had a clinical diagnosis of dementia. Sequence comparison of the LTR region from integrated HIV-1 DNA with that from unintegrated 1-LTR circular forms of HIV-1 DNA in 12 cases showed no significant differences. A further comparison of these brain-derived LTR sequences with LTR sequences derived directly from lymphoid tissue also showed strong sequence conservation. The V3 loop of the virus from the brain was sequenced in 6 cases and had a non-syncytium inducing-macrophage-tropic genotype. Our results show that (i) although unintegrated HIV-1 DNA was present in most brains from patients with AIDS, molecular evidence of high levels of viral replication was associated with the presence of multinucleated giant cells and dementia, and that (ii) the HIV-1 LTR is not a determinant of neurotropism. These observations suggest that replication of HIV-1 and not just the presence of HIV-1 DNA within giant cells makes the important contribution to central nervous system damage.

Effect of apolipoprotein E genotype on Alzheimer's disease neuropathology in a cohort of elderly Norwegians

A cohort of elderly Norwegians dying in nursing homes in the Oslo region have been genotyped for the Apolipoprotein E (ApoE) gene. Alzheimer's disease (AD) cortical neuropathology and clinical evidence of dementia were used to assign cases without evidence of other confounding neuropathology. Senile plaque (SP) and neurofibrillary tangle (NFT) densities in frontal, temporal and parietal cortex were then correlated with ApoE genotype to determine any relationship between ApoE genotype and AD pathology. Comparisons with ApoE ε3, ε4 and ε2 allele dosage failed to show any significant effect on cortical SP densities in any cortical area. NFT densities were increased by ε4 allele dosage in the frontal cortex but not in other cortical regions. A reduction was seen in cortical NFT densities with ε2 allele, though again this was not consistently significant in any of the groups. The ε3 allele failed to show any consistent effect on cortical NFT densities. Assessment by individual genotypes showed ε2 3 < ε2 4 < ε3 3 < ε3 4 < ε4 4 which had highest cortical NFT densities in all areas. By genotype, SP densities were generally of the order ε2 4 < ε2 3 < ε3 3 < ε4 4 < ε3 4 though in none of the groups was this significant. Duration of disease showed no consistent effect on neuropathological burden. ApoE genotype may have an effect on determining whether individuals suffer from AD and the age at onset of disease but may only have a minimal effect on pathology burden.