Alzheimer Disease: Del Ser T

McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M, Anonymous00346. · Institute for Ageing and Health, University of Newcastle upon Tyne, UK. · Neurology. · Pubmed #16237129 No free full text.

Abstract: The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Robles A, Del Ser T, Alom J, Peña-Casanova J, Anonymous00167. · Servicio de Neurología. Hospital Clínico Universitario. Santiago de Compostela. La Coruña. Spain. · Neurologia. · Pubmed #11834194 links to  free full text

Abstract: The most widely accepted criteria for Alzheimer's disease (AD) diagnosis (NINCDS-ADRDA and DSM-IV) do not allow to differentiate accurately between AD and other degenerative dementias which have recently formulated criteria for its clinical diagnosis. Therefore, it is necessary to bring AD diagnostic criteria up to date in order to optimise their specificity, by assessing its most specific clinical manifestations, its most representative markers and those features typical of other diseases which are usually taken into account for a differential diagnosis.According to the latest reports on the subject, the disturbances suffered by memory, behaviour and the rest of cognitive and executive functions must be equally considered when establishing the syndromic diagnosis of dementia; this will always require the coexistence of an evident functional impairment. Due to this, the concepts of "dementia" and "mild cognitive impairment" should be clearly distinguished. For the time being, AD can only be diagnosed when dementia has been proved and this shows a series of cognitive, behavioural and neurological features which are representative of it. Nevertheless, some diagnostic markers appear to be precocious and specific enough to try to identify those patients who suffer from mild cognitive impairment due to an incipient stage of AD. We are suggesting some criteria for the clinical diagnosis of dementia, mild cognitive impairment and AD that seem to be more detail

Gómez-Isla T, Blesa R, Boada M, Clarimón J, Del Ser T, Domenech G, Ferro JM, Gómez-Ansón B, Manubens JM, Martínez-Lage JM, Muñoz D, Peña-Casanova J, Torres F, Anonymous00218. · Neurology Department, Hospital Santa Cruz y San Pablo and Centro de Investigación Biomédica en Red (CIBERNED), Lisboa, Spain. · Alzheimer Dis Assoc Disord. · Pubmed #18317243 No free full text.

Abstract: BACKGROUND: Amnestic mild cognitive impairment represents, in many cases, the earliest clinical phases of Alzheimer disease. Anti-inflammatory agents have epidemiologic support as drugs potentially beneficial in Alzheimer disease. In vivo studies have shown that Triflusal and its active metabolite 2-hydroxy-4-trifluoromethyl-benzoic acid have potent anti-inflammatory actions in the central nervous system. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of Triflusal in patients with amnestic mild cognitive impairment. Subjects were randomly assigned to receive 900 mg of Triflusal or placebo for 18 months. The primary outcome was a change in Cognitive subscale of the Alzheimer Disease Assessment Scale; conversion to dementia was a secondary outcome. RESULTS: A slow rate of recruitment forced a premature cessation of the study. Two hundred and fifty-seven subjects were enrolled and followed-up for an average of 13 months. The significance level was not reached for the primary outcome even though a trend in favor of Triflusal was observed. However, there was a significant difference in the probability of progression to dementia of Alzheimer's type with a lower risk in the Triflusal compared with the placebo group (hazard ratio, 2.10; 95% confidence interval, 1.10-4.01; P=0.024). CONCLUSIONS: In this study, Triflusal therapy was associated with a significant lower rate of conversion to dementia that is likely to be clinically relevant. Because the trial was prematurely halted, these results should be interpreted with caution and require further confirmation.

Holmes C, Ballard C, Lehmann D, David Smith A, Beaumont H, Day IN, Nadeem Khan M, Lovestone S, McCulley M, Morris CM, Munoz DG, O'Brien K, Russ C, Del Ser T, Warden D. · University of Southampton, Clinical Neurosciences Research Division, Memory Assessment and Research Centre, Moorgreen Hospital, Botley Road, Southampton, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #15834019 links to  free full text

Abstract: OBJECTIVE: To determine whether individuals with Alzheimer's disease (AD) and the K variant allele of butyrylcholinesterase have a slower rate of cognitive decline than those without the K variant allele of butyrylcholinesterase. METHOD: The cognitive status of 339 community based subjects with AD was assessed with the Mini Mental State Examination at baseline and yearly over a three year follow up period. The rates of cognitive decline of subjects with and without the K variant allele were compared. RESULT: Presence of the K allele was associated with a slower average rate of cognitive decline in subjects with severe AD. CONCLUSIONS: This finding is consistent with the suggestion that the K variant of butyrylcholinesterase has an important role in disease progression in AD, and this may have implications for treatment.

Del Ser T, Hachinski V, Merskey H, Munoz DG. · Sección de Neurología, Hospital Severo Ochoa, Avda. Orellana s/n, Leganés, 28911 Madrid, Spain. · J Neurol Sci. · Pubmed #15792814 No free full text.

Abstract: OBJECTIVE: To compare the clinical and pathological features of Alzheimer's disease (AD) patients with and without associated cerebral infarcts (CI). METHODS: The consecutive records of 57 prospectively studied demented patients fulfilling the CERAD criteria for the pathological diagnosis of AD were reviewed. Cases with cortical Lewy bodies were excluded. CI were found in 22 cases (39%) (AD+CI group): large infarcts (5), lacunes (13) and/or hippocampal sclerosis (4), and were absent in 35 cases (AD group). Microscopic infarcts, cribiform change, amyloid angiopathy, and white matter rarefaction were not considered in this classification, but were quantified. Cortical atrophy, neurofibrillary tangle and senile plaque (diffuse and neuritic) load were also measured. Pathological evaluation was independent of clinical information. Clinical and pathological data were compared between both groups. RESULTS: AD+CI cases were significantly older, more commonly female, less educated, and more often had blue collar occupations, sleep disturbances, frontal release signs, and EEG spikes than AD cases. Other differences found (acute/subacute onset, behavioral disturbances, and leukoaraiosis on CT scan) disappeared after controlling for age. The frequency of known vascular risk factors and focal motor and sensory signs did not differ between the groups, which showed remarkable clinical similarity overall. The only significant differences on pathological exam were hippocampal microinfarcts and white matter lesions, although there was a trend for lower neurodegenerative lesion load in the AD+CI group. The ischemic lesions were located in temporal lobe in 50% of AD+CI patients; these cases had a significantly lower neocortical neurodegenerative lesion load than those with CI in other sites. CONCLUSIONS: The presence of CI in AD increases significantly with age, but has scarce influence on the clinical features, and cannot be predicted from common vascular risk factors. In spite of a trend, there are no major differences in neurodegenerative lesion load between AD and AD+CI groups, except when CI are located in the temporal lobe (including hippocampus), suggesting that this location may be important in the physiopathology of mixed vascular and AD dementia.

Ballard CG, Jacoby R, Del Ser T, Khan MN, Munoz DG, Holmes C, Nagy Z, Perry EK, Joachim C, Jaros E, O'Brien JT, Perry RH, McKeith IG. · Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK. · Am J Psychiatry. · Pubmed #15121649 links to  free full text

Abstract: OBJECTIVE: This investigation was undertaken to clarify the neuropathological substrates of key psychiatric symptoms in dementia with Lewy bodies. METHOD: The authors studied 112 autopsy-confirmed cases of dementia with Lewy bodies in patients who had had annual standardized clinical evaluations until their death. The relationships of persistent psychiatric symptoms (visual hallucinations, delusions, depression) to plaques (Consortium to Establish a Registry for Alzheimer's Disease protocol), tangles (Braak staging), and Lewy bodies (consensus Lewy body staging) were evaluated. In addition, symptom frequency and persistent symptoms were compared in the patients with Lewy body dementia and 90 patients with autopsy-confirmed Alzheimer's disease studied prospectively during life. RESULTS: The main neuropathological correlate of persistent visual hallucinations was the presence of less severe tangle pathology, but there was no significant association between tangle pathology and persistent delusions. Lewy body staging was associated with the presence of persistent visual hallucinations and persistent delusions. All baseline psychiatric features were significantly more frequent in dementia with Lewy bodies than in Alzheimer's disease, as were persistent visual hallucinations, but patients who had dementia with Lewy bodies and severe tangle pathology had a clinical symptom profile more similar to that of Alzheimer's disease patients and were less likely to have neocortical Lewy bodies. CONCLUSIONS: The modest proportion of patients with Lewy body dementia and more severe tangle pathology resembled Alzheimer's disease patients clinically. Unlike Alzheimer's disease, dementia with Lewy bodies showed a significant inverse association between tangle burden and psychosis.

Del Ser T, Hachinski V, Merskey H, Munoz DG. · Sección de Neurología, Hospital Severo Ochoa, Leganés, Madrid, Spain. · Alzheimer Dis Assoc Disord. · Pubmed #11236823 No free full text.

Abstract: The objectives of this study were to examine the clinical and pathologic features of two subgroups of patients with dementia with Lewy bodies (DLB) differing in Alzheimer disease (AD)-type pathology load and to identify clinical variables useful in the differential diagnosis from AD. The records of 64 consecutive demented patients were reviewed. Pathologic diagnoses were independently established [35 AD cases, 11 cases of pure dementia with Lewy bodies (pDLB), and 18 cases of combined AD plus Lewy bodies (AD+LB)], and several neurodegenerative lesions were quantified. Clinical and pathologic data were compared between groups with univariate and multivariate analyses. Compared with the other groups, pDLB cases had more frequent acute-subacute onset of dementia [45% vs. AD (3%) and AD+LB (16%)], early parkinsonism [45% vs. AD (0%) and AD+LB (0%)], early [27% vs. AD (0%) and AD+LB (0%)] and late [73% vs. AD (11%) and AD+LB (16%)] hallucinations, fluctuating course [46% vs. AD (9%) and AD+LB (22%)], delusions [45% vs. AD (11%) and AD+LB (6%)], spontaneous parkinsonism [63% vs. AD (8%) and AD+LB (16%)], less frequent ideomotor apraxia and loss of insight, earlier urinary incontinence [3.2 +/- 1.4 years after onset vs. AD (6.3 years) and AD+LB (5.8 years)], shorter duration of dementia [7.7 +/- 2.4 years vs. AD (9.6 years) and AD+LB (11 years)], milder atrophy in computed tomography scans, greater brain weight, more transcortical spongiosis, wider cortex and subcortex, and less amyloid angiopathy. All pDLB cases but no AD cases had abnormal CA2 neurites. The clinical features of AD+LB patients were similar to those of AD patients other than more frequent acute-subacute onset and fluctuating evolution. Discriminant analyses selected four clinical variables differentiating pDLB from the other two groups as a whole: acute-subacute onset, early parkinsonism, early hallucinations, and early onset of urinary incontinence. Two or more of these features identified pDLB with a sensitivity of 81.8% and a specificity of 95.9%. Differentiation between the three groups (pDLB, AD+LB, and AD) or between both groups with LB (DLB) from AD could be only attained in 70% of cases. We conclude that early symptomatology is the main clue for the diagnosis of pDLB. We identified by discriminant analysis a set of clinical diagnostic criteria similar to those proposed by the Consortium on Dementia With Lewy Bodies. Accuracy was excellent for the diagnosis of pDLB but only mediocre for separating AD+LB as well as the entire DLB group from AD.

Zunzunegui MV, Gutiérrez Cuadra P, Béland F, Del Ser T, Wolfson C. · Escuela Andaluza de Salud Pública, Campus Universitario Cartuja, Granada, Spain. · Int J Geriatr Psychiatry. · Pubmed #10679845 No free full text.

Abstract: OBJECTIVE: To develop and assess the consistency and validity of simple cognitive function measures for an elderly population with low levels of formal education for use in a longitudinal study of dementia. METHODS: Data were from the population longitudinal study 'Growing old in Leganés' (Spain). In 1993, a random sample of 1540 people over 65 was drawn from the City Roll of Leganés from which 1284 (83%) were successfully interviewed. Measures of memory and orientation were based on the SPMSQ (Short Portable Mental Status Questionnaire), the Barcelona test and the short story from EPESE (Established Populations Epidemiologic Studies of the Elderly). Non-response to a test item was coded as an error. Internal consistency was assessed by factor analysis and Cronbach's alpha. Construct validity was examined with multiple linear regressions of the proposed measurements on variables chosen from the existing literature on cognitive function. RESULTS: Two factors, memory and orientation, emerged from the factor analysis. Internal consistency of the proposed indexes for memory and orientation was acceptable. Memory and orientation scores were summed into one summary index of cognition. Associations between covariates and both cognitive indexes were in the expected direction. Among those highly functional, orientation was influenced by illiteracy due to higher error rates in the time orientation items based on dates; however, memory and summary scores were not significantly different by literacy status. A large proportion of the variance in IADL was explained by the memory and orientation measures. CONCLUSION: The memory and orientation indexes are valid and reliable measurements of cognitive function for use in a population of community dwelling elderly with low levels of formal education and high rates of illiteracy.

Del Ser T, Hachinski V, Merskey H, Munoz DG. · Sección de Neurología, Hospital Severo Ochoa, Leganés, Madrid, Spain. · Brain. · Pubmed #10581224 links to  free full text

Abstract: A longitudinal study of the relationship between education and age of onset, rate of progression and cerebral lesion burden in a series of autopsy-confirmed demented patients with clinical and 6-monthly psychometric follow-up and autopsy was carried out. The study was conducted at the London Health Sciences Centre University Campus of the University of Western Ontario on 87 patients with pathologically confirmed Alzheimer's disease (60), dementia with Lewy bodies (11) or dementia with Lewy bodies plus Alzheimer's disease (16). Their educational attainment was classified as below high school, high school or above high school, and was similar to that of the age-adjusted general Ontario population. The age of onset of dementia, age at death, progression of cognitive decline, amount of neurodegenerative changes (senile plaques, neurofibrillary tangles and Lewy bodies) and cerebrovascular lesions (infarcts, lacunar state and white matter rarefaction) were assessed. Less educated patients became demented later and died later, but cognitive function declined at the same rate in all educational groups and there was no difference in the burden of neurodegenerative lesions between them. However, the less educated patients had more cerebrovascular lesions. It can be concluded that higher education does not modify the course of Alzheimer's disease, but lower education relates to the occurrence of cerebral infarcts. Our results suggest that a 'brain battering' model related to the higher prevalence of small vascular lesions in less educated individuals may explain their increased risk of dementia described by epidemiological studies better than the prevalent 'brain reserve' hypothesis.