Defining imaging biomarker cut points for brain aging and Alzheimer's disease

Introduction

Our goal was to develop cut points for amyloid positron emission tomography (PET), tau PET, flouro-deoxyglucose (FDG) PET, and MRI cortical thickness.

NEUROPSYCHOLOGICAL MEASURES AND SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY IN THE DIFFERENTIATION AND CLASSIFICATION OF CEREBRAL PERFUSION DEFICITS IN ALZHEIMER'S DEMENTIA

The accurate diagnosis of Dementia of the Alzheimer's Type (DAT) continues to be an area of difficulty for the fields of neuropsychology and neurology. The introduction of new medications that appear to mediate the insidious progression of the disorder increases the need for timely differentiation of DAT from other dementia-related disorders. The present study examined the relationship between hemispheric differences in regional cerebral blood flow with corresponding lateral neuropsychological processing deficits in patients with DAT. Eighty patients with a diagnosis of DAT were administered Single Photon Emission Computerized Tomography (SPECT) scans and a battery of left and right hemisphere neuropsychological-based tasks. The results of ANOVA indicated that patients with DAT who were not suffering from perfusion deficits exhibited significantly fewer neuropsychological deficits than did patients with DAT who had perfusion deficits. The neuropsychological tests that measured verbal ability, logical memory, word-pair learning, reading, arithmetic, and visual-perceptual organization were all significantly lower in the group with perfusion deficits. Further analysis indicated that patients with left hemisphere perfusion deficits tended to have poorer neuropsychological skills than did individuals with right hemisphere perfusion deficits, diffuse perfusion deficits, and no perfusion deficits. A Stepwise Discriminant Analysis was unable to use the neuropsychological variables to classify patients accurately into perfusion deficit groups.     

Anti‐cyclic citrullinated peptide antibody (anti‐CCP antibody) is present in the sera of patients with dementia of Alzheimer’s type in Asian

Satoh K, Kawakami A, Shirabe S, Tamai M, Sato A, Tsujihata M, Nagasato K, Eguchi K. Anti‐cyclic citrullinated peptide antibody (anti‐CCP antibody) is present in the sera of patients with dementia of Alzheimer’s type in Asian.
Acta Neurol Scand. 2010: 121: 338–341.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Background – In the hippocampi of Alzheimer’s disease (AD) patients, aberrant expression of citrullinated proteins and peptidylarginase 2 (PADI2) has been identified. We explored the functional roles of these proteins by means of detection of serum anti‐cyclic citrullinated peptide antibody (anti‐CCP antibody) in patients with dementia of Alzheimer’s type (DAT). Methods – Sera were obtained from 42 patients with DAT, 30 patients with other neurological disorders and 42 healthy controls. Gender ratio and age were comparable among the three groups. The level of anti‐CCP antibody in sera was examined by ELISA. Findings – Anti‐CCP antibody was not found in the 30 patients with other neurological disorders, and only one of the 42 healthy controls (2.4%) was positive. However, surprisingly, anti‐CCP antibody was clearly detected in eight of the 42 DAT patients. Interpretation – Anti‐CCP antibody appears to be a simple and early serologic biomarker for DAT among dementia patients. Additionally, our data imply that citrullinated proteins accumulated in the astrocytes of AD patients acquire neo‐antigenicity, inducing anti‐CCP antibody production.     

Behavioural disturbances in psychiatric inpatients with dementia of the Alzheimer's type in Taiwan

This report studied behavioural disturbances in psychiatric inpatients with dementia of the Alzheimer's type (DAT) in Taiwan. The sample consisted of 75 inpatients with DAT who were consecutively admitted to the geropsychiatric ward. Their behavioural disturbances were obtained from semistructured interviews with families and ward observation. There were eight main behavioural disturbances: getting lost, repetitive phenomena, sleep disturbance, aggression, wandering, hyperphagia, hoarding behaviour, and inappropriate sexual behaviour. Number of behavioural disturbances, wandering, hyperphagia and sleep disturbance were significantly associated with the severity of cognitive impairment. © 1997 John Wiley & Sons, Ltd.     

CAN FRONTOTEMPORAL DEMENTIA AND ALZHEIMER'S DISEASE BE DIFFERENTIATED USING A BRIEF BATTERY OF TESTS?

Objective. To compare the performance of patients with frontotemporal dementia (FTD) and Alzheimer's disease (AD) on a range of simple neuropsychological tests. Design. A battery of neuropsychological tests easily applied at the bedside, consisting of traditional tests of memory, attention and executive function, were given together with tests of motor sequencing and examination of frontal release signs. In addition, we devised a theoretically motivated test of dual attention—a story with distraction which also contained a ‘social dilemma’. Setting. Specialist memory and cognitive disorders clinic. Patients. 12 patients with FTD and 12 patients with AD, matched for overall level of dementia on the Mini-Mental State Examination, were selected. Results. In general, the difference in results between FTD and AD patients was small. However, a composite score derived from the presence of a grasp and pout reflex, the number of perseverations during category fluency for animals and response to the social dilemma within the two stories produced a sensitivity of 83.3% and specificity of 91.6%. There was also a highly significant difference between patients with FTD and AD in scores achieved on the Clinical Dementia Rating Scale reflecting the marked change in behaviour that patients with FTD suffer, even at a stage when memory functions are well preserved. Conclusion. Traditional neuropsychological tests were poor at differentiating cases of FTD and AD; however, a composite (SIFTD) score appears potentially useful but requires prospective validation. Better methods of assessing the changes in comportment that characterize the early stages of FTD are required. © 1997 by John Wiley & Sons, Ltd.     

Dopamine-β-hydroxylase activities in serum and cerebrospinal fluid of aged and demented patients

Age-related changes in dopamine-β-hydroxylase (DBH) activities in serum and cerebrospinal fluid (CSF) were determined. In normal subjects, serum DBH activity increased gradually from the 3rd to the 8th decade, but decreased prominently in the 9th decade. DBH activity in CSF did not differ between younger and older subjects.Serum DBH activity decreased significantly in senile dementia of Alzheimer's type (SDAT, $\text{12.2 ± 8.8}\text{nmoles/min/ml}$, $\text{P < 0.05}$), but not in multi-infarct dementia (MID, $\text{13.9 ± 9.1}\text{nmoles/min/ml}$) compared to control subjects ($\text{17.1 ± 9.5}\text{nmoles/min/ml}$). The decrease of serum DBH in SDAT was more prominent in patients with severe dementia and/or severe brain atrophy. DBH activity in CSF was much lower than that in serum and did not correlate with each other. DBH activity in CSF obained from SDAT patients ($\text{1.60 ± 0.94}\text{nmoles/h/ml}$) and from MID patients ($\text{2.01 ± 0.99}\text{nmoles/h/ml}$) were both lower than that from other neurological diseases without dementia ($\text{4.04 ± 3.81}\text{nmoles/h/ml}$). DBH in CSF from SDAT patients was significantly lower ($\text{P < 0.05}$) than that from controls, but that from MID did not differ from controls.Noradrenergic nervous dysfunction is partly associated with pathophysiology and life expectancy of senile dementia of Alzheimer's type (SDAT).     

A white-matter disease in dementia of Alzheimer's type – clinical and neuropathological correlates

A correlative neuropathological-clinical study was undertaken in order to analyse the possible clinical effects of the selective incomplete white-matter infarctions (SIWI) frequently found in dementia of Alzheimer's type (DAT). The cases studied represent DAT with and without concomitant SIWI, non-Alzheimer dementia with SIWI and cerebrovascular dementia, including multi-infarct dementia and Binswanger's disease. The structural grey and white matter changes were examined and the clinical symptoms and signs were analysed. The occurrence of cardiovascular disease and abnormal blood pressure was studied as well. The results show that cardiovascular disease and systemic hypotension occur frequently in cases with SIWI and they are considered of pathogenetic importance for SIWI. Symptoms and signs of a non-focal cerebrovascular/ischaemic type, mainly vertigo, fainting and a fluctuating course, are associated with SIWI. In DAT and SIWI, the clinical picture of DAT is altered accordingly, compared to DAT with normal white matter.     

β‐amyloid in lewy body disease is related to Alzheimer's disease‐like atrophy

The aim of this study was to investigate whether amyloid deposition is associated with Alzheimer's disease (AD)‐like cortical atrophy in Lewy body (LB) disease (LBD). Participants included 15 LBD with dementia patients (8 with dementia with Lewy bodies [DLB] and 7 with Parkinson's disease [PD] with dementia [PDD]), 13 AD patients, and 17 healthy controls. Age, gender, and Mini–Mental State Examination scores were matched between patient groups. All subjects underwent PET scans with [¹¹C]Pittsburgh Compound B to measure brain amyloid deposition as well as three‐dimensional T1‐weighted MRI. Gray‐matter volumes (GMVs) were estimated by voxel‐based morphometry. Volumes‐of‐interest analyses were also performed. Forty percent of the 15 DLB/PDD patients were amyloid positive, whereas all AD patients and none of the healthy controls were amyloid positive. Amyloid‐positive DLB/PDD and AD patients showed very similar patterns of cortical atrophy in the parahippocampal area and lateral temporal and parietal cortices, with 95.2% of cortical atrophy distribution being overlapped. In contrast, amyloid‐negative DLB/PDD patients had no significant cortical atrophy. Compared to healthy controls, parahippocampal GMVs were reduced by 26% in both the amyloid‐positive DLB/PDD and AD groups and by 10% in the amyloid‐negative DLB/PDD group. The results suggest that amyloid deposition is associated with AD‐like atrophy in DLB/PDD patients. Early intervention against amyloid may prevent or delay AD‐like atrophy in DLB/PDD patients with amyloid deposition. © 2012 Movement Disorder Society     

Three presenile patients in which neuropsychological and neuroimaging examinations suggest possible progression to dementia with Lewy bodies

We report three presenile patients who were initially suspected of having Alzheimer's disease (AD) or being in the prodromal stage of AD, regardless of visuoperceptual dysfunctions in daily living, because they lacked the core features and prodromal non‐motor symptoms of dementia with Lewy bodies. Subsequently, progression to dementia with Lewy bodies was suspected based on neuropsychological and neuroimaging findings; additionally, one of the three patients suffered from visual hallucinations. Neuropsychological examinations such as subjective contours, cube copying and block design in the Wechsler Adult Intelligence Scale‐III revealed visuoperceptual dysfunction in all three patients even when other cognitive functions were rather preserved. Brain magnetic resonance imaging revealed no significant brain atrophy, including in the parieto‐occipital area and the hippocampus, while brain ¹⁸F‐fluorodeoxyglucose positron emission tomography demonstrated right dominant metabolic reductions in the occipital lobe, including the primary visual cortex, in all three patients. We suggest the possibility of progression to dementia with Lewy bodies, but not AD or posterior cortical atrophy. Regardless of the presence of core features and prodromal non‐motor symptoms, this progression is suggested when there are difficulties only in higher‐level visual processing such as subjective contours and block design in the Wechsler Adult Intelligence Scale‐III, no significant atrophy of the parieto‐occipital area and hippocampus on brain magnetic resonance imaging, and hypometabolism in the occipital lobe including the primary visual cortex on brain ¹⁸F‐fluorodeoxyglucose positron emission tomography.     

Longitudinal uncoupling of cerebral perfusion,glucose metabolism,and tau deposition in Alzheimer's disease

Introduction

Cross-sectional findings using the tau tracer [¹⁸F]THK5317 (THK5317) have shown that [¹⁸F]fluorodeoxyglucose (FDG) positron emission tomography (PET) data can be approximated using perfusion measures (early-frame standardized uptake value ratio; ratio of tracer delivery in target to reference regions). In this way, a single PET study can provide both functional and molecular information.

Abnormal information processing in dementia of Alzheimer type. A study using the event-related potential's field

Electrical field changes of event-related potentials (ERPs) were investigated in 26 patients with dementia of Alzheimer's type (DAT) and 12 age-matched normal subjects. The patients were assessed with the Clinical Dementia Rating and Mini-Mental State. Each patient selected had only mild to moderate mental disability. Auditory oddball stimulation was presented at 1.5 s intervals and 1000 Hz for the nontarget and 2000 Hz for the target tones, both at 85 dB. The target tones were 20% of all the tones. The reference-independent data (latency, global field power: GFP, dissimilarity index: DISS and location of centroids) were obtained and analyzed for each ERP component. The momentary electric strength or ‘hilliness’ of the ERPs landscape was indicated by GFP. The patients showed prolonged latencies and decreased P300 GFP amplitudes and of N100 GFP. These findings suggest that the abnormal electrical field of ERP may reflect abnormal information processing following the attentional process for target stimuli in DAT patients. Received: 2 July 1999 / Accepted: 27 January 2000     

TYPES AND PHENOMENOLOGIC SUBTYPES OF DEMENTIA IN TAIWAN: A PSYCHIATRIC INPATIENT STUDY

An investigation of 91 consecutive psychiatric inpatients with suspected dementia was designed to evaluate the relative frequency of different types and phenomenologic subtypes of dementia in Taiwan. The type of dementia was reviewed to determine different aetiologies. Phenomenologic subtypes of dementia were investigated according to the classifications of theDiagnostic and Statistical Manual of Mental Disorders. In contrast to previous studies in Taiwan, dementia of the Alzheimer's type (59.3%) was more frequent than vascular dementia (26.4%). The relative frequencies of phenomenologic subtypes were as follows; uncomplicated, 43%; with delusion, 38%; with delirium, 14%; with depression, 5%. This is the first report regarding the clinical subtypes of psychiatric demented inpatients in Taiwan. In spite of correct aetiological diagnosis of dementia, this report highlights the non-cognitive problems of dementia.