The role of routine laboratory studies and neuroimaging in the diagnosis of dementia: a clinicopathological study

OBJECTIVE: To determine the neuropathological diagnoses of longitudinally followed patients with potentially reversible causes of dementia and to examine the results of the "dementia work-up," especially neuroimaging, by comparison with the pathological diagnosis. DESIGN: A neuropathologic series of 61 consecutive patients, with review of clinical, laboratory, neuroimaging, and pathological results. RESULTS: Of the 61 patients, forty-eight (79%) had a clinical diagnosis of probable or possible Alzheimer's disease (AD). Compared with the pathological diagnosis, the sensitivity and specificity of the clinical diagnosis of AD were 96% and 79%, respectively. Of the 61 patients, 9 had abnormal laboratory tests, the correction of which did not improve the subsequent course. These patients were found to have AD8 and frontotemporal dementia on pathology. In two patients, neuroimaging was helpful in the clinical diagnoses of frontotemporal dementia and progressive supranuclear palsy (PSP). Neuroimaging revealed cerebrovascular disease in 18 patients, only two of whom were suspected clinically. Pathology confirmed AD in 17 and PSP in 1 of these patients. Sensitivity and specificity for the clinical diagnosis of cerebrovascular disease in comparison with pathology were 6% and 98%, respectively. With the added information from neuroimaging, that sensitivity increased to 59% and specificity decreased to 81%. CONCLUSIONS: All cases with abnormal laboratory or neuroimaging results had AD or some other neurodegenerative disease on pathology. The "dementia work-up" did not reveal any reversible causes for dementia in this group of patients. Neuroimaging may have a role, especially in the diagnosis of possible AD with concomitant cerebrovascular disease.     

CSF biomarkers for mild cognitive impairment

A correct clinical diagnosis of Alzheimer's disease (AD) early in the course of the disease is of importance to initiate symptomatic treatment with acetylcholine esterase inhibitors, and will be even more important when disease-arresting drugs, such as beta-sheet breakers or gamma-secretase inhibitors, will reach the clinic. However, there is no clinical method to determine if a patient with mild cognitive impairment (MCI) has incipient AD, i.e. will progress to AD with dementia, or have a benign form of MCI without progression. Thus, there is a great clinical need for diagnostic biomarkers to identify incipient AD in MCI cases. Three cerebrospinal fluid (CSF) biomarkers; total-tau (T-tau), phospho-tau (P-tau) and the 42 amino acid form of beta-amyloid (Abeta42) have been evaluated in numerous scientific papers. These CSF markers have high sensitivity to differentiate early and incipient AD from normal ageing, depression, alcohol dementia and Parkinson's disease, but lower specificity against other dementias, such as frontotemporal and Lewy body dementia. However, if the CSF biomarkers are used in the right clinical context, i.e. together with the cumulative information from the clinical examination, standard laboratory tests and brain-imaging techniques [single photon emission tomography (SPECT) and magnetic resonance tomography (MRT) scans], they may have a role in the clinical evaluation of MCI cases.     

Non-invasive assessment of liver fibrosis in patients with alcoholic liver disease

Alcoholic liver disease(ALD) consists of a broad spectrum of disorders, ranging from simple steatosisto alcoholic steatohepatitis and cirrhosis. Fatty liver develops in more than 90% of heavy drinkers, however only 30%-35% of them develop more advanced forms of ALD. Therefore, even if the current "gold standard" for the assessment of the stage of alcohol-related liver injury is histology, liver biopsy is not reasonable in all patients who present with ALD. Currently, although several non-invasive fibrosis markers have been suggested as alternatives to liver biopsy in patients with ALD, none has been sufficiently validated. As described in other liver disease, the diagnostic accuracy of such tests in ALD is acceptable for the diagnosis of significant fibrosis or cirrhosis but not for lesser fibrosis stages. Existing data suggest that the use of noninvasive tests could be tailored to first tier screening of patients at risk, in order to diagnose early patients with progressive liver disease and offer targeted interventions for the prevention of decompensation. We review these tests and critically appraise the existing evidence.     

Italian Project on Epidemiology of Alzheimer's disease (I.PR.E.A.): study design and methodology of cross-sectional survey

BACKGROUND AND AIMS: The purpose of this paper is to describe the design and diagnostic procedures of the multicenter community-based prospective Italian Project on the Epidemiology of Alzheimer's disease (I.PR.E.A.). The study is aimed at estimating the prevalence and incidence of Alzheimer's disease (AD) in the preclinical phase, examining the natural history of cognitive decline without dementia (mainly AD) in the Italian population, and identifying risk factors or health determinants related or associated with various health outcomes. METHODS: Both cross-sectional and longitudinal phases will be performed in 4800 elderly subjects aged 65-84 years. The sample will be selected from the registries of 12 Italian rural and urban municipalities, with an interval of one year between examinations. The study population will undergo several screening examinations, including personal and informant interviews by means of a structured ad hoc questionnaire, physical and neurological examination, laboratory tests, genetic markers and a neuropsychological battery. Neuroimaging screening will also be carried out in a subgroup of subjects positive for cognitive impairment without dementia. The longitudinal phase will include all subjects who, during the cross-sectional survey, are identified as affected by cognitive impairment without dementia, and will aim at assessing the incidence and natural history of cognitive impairment without dementia and the degree of disease progression from the earliest stage. This is the first systematic prospective study on the preclinical phase of AD in Italy.     

Alzheimer's disease. Sleep and sleep/wake patterns

Significant changes in sleep/wake patterns, particularly loss of SWS and increased amount and frequency of nighttime wakefulness, apparently occur even at an early stage of the AD process. These disruptions of nighttime sleep increase in magnitude with increasing severity of dementia. While the REM sleep of early stage AD patients is relatively unaffected by the disease process, later stages of AD are marked by significant losses of REM sleep and perhaps more importantly the breakdown of the sleep/wake circadian rhythm with significant amounts of sleep occurring during the day. This daytime sleep is of poor quality however, consisting almost exclusively of stages 1 and 2 sleep and does not compensate for the nighttime losses of SWS and REM sleep experienced by AD patients. These findings clearly support the clinical observations and anecdotal reports of sleep disturbance in AD patients. It is of interest to note that sleep is disrupted quite early in the disease process. In our study of early stage AD patients all were community dwelling and had relatively mild cognitive impairment (average MMS scores of 22.7). Despite this, significant increases in frequency and duration of awakening from sleep and reductions of SWS were observed in these patients. These findings indicate that when a patient is suspected of having AD it may be worthwhile as part of the evaluative and diagnostic process to caution both the patient and the patient's family that they might expect to see significant changes in sleep/wake patterns even though the patient's level of day-to-day functioning may still be high. It is also important to consider warning AD patients' families that as the disease progresses they should expect to see not only a worsening of nocturnal sleep quality but a breakdown of the circadian sleep/wake rhythm and an increase in daytime napping behavior by the patient. Families need to be encouraged to try and minimize the napping behavior of the patient in an effort to consolidate sleep into the night. This may have the effect of somewhat attenuating the amount of nocturnal disruption of sleep that accompanies progression of the disease.     

The world of dementia beyond 2020

Counterpoised against dire projections of the tripling of the prevalence of dementia over the next 40 years are major developments in diagnostic biomarkers, neuroimaging, the molecular biology of Alzheimer's disease (AD), epidemiology of risk and protective factors, and drug treatments-mainly targeting the amyloid pathway, tau protein, and immunotherapy-that may have the potential to modify the progression of AD. Drug combinations and presymptomatic treatments are also being investigated. Previous trials of dementia-modifying drugs have not shown benefit, and even if current Phase III trials prove successful, these drugs will not eradicate other dementias, could (if not curative) increase dementia duration and prevalence, and are unlikely to come onto the market before 2020. In the meantime, delaying the onset of dementia by even 2 years would have significant economic and societal effects. This article provides an overview of current achievements and potentials of basic and clinical research that might affect the development of dementia prevalence and care within the near future.     

Diagnostic tests in the evaluation of dementia. A prospective study of 200 elderly outpatients

We studied the components of the diagnostic evaluation in 200 patients older than 60 years of age with suspected dementia who received standardized diagnostic evaluation and follow-up. The most common dementia diagnoses were Alzheimer's-type dementia (74.5%) and dementia due to toxic effects of drugs (9.5%). Eleven patients with hypothyroidism, metabolic encephalopathies due to hyponatremia, hyperparathyroidism, and hypoglycemia required laboratory tests for diagnosis, whereas the other dementia diagnoses were made primarily on the basis of data available on the history and physical and neurologic examinations. The complete blood cell count, blood chemistry battery (especially sodium, calcium, and glucose concentrations), and thyroid function tests were of definite value for the diagnosis of unsuspected disease and were useful as routine tests in evaluating patients for dementia. A careful history and physical examination accompanied by complete blood cell count, chemistry battery, and a thyroid function test would have been effective in diagnosing treatable illnesses causing cognitive impairment. Other diagnostic tests could have been used selectively based on results of the examination and screening tests. Estimated diagnostic charges from a selective approach would be 25% to 34% of those for the "routine" evaluation.     

Korean Addenbrooke's Cognitive Examination Revised (K‐ACER) for differential diagnosis of Alzheimer's disease and subcortical ischemic vascular dementia

Aim: Sensitive, specific neuropsychological screening tests, such as the Addenbrooke's Cognitive Examination Revised (ACE‐R), are essential for dementia diagnosis. We aimed to validate the use of the Korean version of ACE‐R (K‐ACER) to differentiate Alzheimer's disease (AD) from subcortical ischemic vascular dementia (SIVD). Methods: Standard tests for dementia screening were applied to 156 subjects (84 controls, 30 AD, 42 SIVD), and total and sub‐domain scores on the K‐ACER, as well as the sub‐domain ratio (VLOM), were compared. Results: The reliability of the K‐ACER was very good (α‐coefficient 0.84), and cut‐off score for dementia was determined (cut‐off value 78, sensitivity 0.93, specificity 0.95). The likelihood ratio for dementia was calculated as between 78 and 82. At a cut‐off of 78, the likelihood of dementia was 18.6:1. Although a comparison of K‐ACER scores between AD and SIVD patients revealed significant differences in verbal fluency, language domain and VLOM ratio, sensitivity and specificity for differential diagnosis between AD and SVID proved less accurate. Conclusion: The K‐ACER is a rapid, sensitive and specific dementia screening test. Though sub‐domains of items may be useful for differentiating between AD and SIVD, sensitivity and specificity is less accurate than dementia screening itself. Geriatr Gerontol Int 2010; 10: 295–301.     

Monitoring progression in Alzheimer's disease.

OBJECTIVE: To compare several clinical methods of following change in Alzheimer's disease (AD) over time. DATA SOURCES: MEDLINE search (restricted to English language); bibliographies of pertinent articles or books. STUDY SELECTION: Studies included only if aim was to follow a cohort of AD patients; diagnosis of AD used DSM-III-R or NINCDS-ADRDA guidelines; techniques or scales used for serial assessment were well-established in terms of validity and reliability. DATA EXTRACTION: All 3 authors reviewed all studies cited and reached consensus about interpretation. RESULTS: Global instruments detect long term deterioration in AD and describe distinct through possibly artificial stages. Cognitive screening tests decline at a consistent rate for groups of AD patients but show considerable variability. Scales measuring activities of daily living (ADLs) need further study to determine annual rate of change. Instrumental ADLs decline early in AD and reach a floor before cognitive screening tests. Electrophysiologic or radiographic techniques do not necessarily change over time and are not superior to clinical methods for following AD. Variability in rate of cognitive change and prognosis in AD has not been adequately explained. CONCLUSIONS: Cognitive screening tests provide useful measures of rate of change in AD for clinical and therapeutic studies. Further studies should take advantage of longer follow-up and more sophisticated statistical techniques to optimize use of these measures.     

Value of screening instruments in the diagnosis of post-stroke dementia.

Brief dementia screening instruments, or mental status tests are frequently used to screen for cognitive impairment. We discuss the strengths and weaknesses of existing mental status tests in dementia screening in general. Most screening instruments that are used in clinical practice are developed to detect dementia compatible with Alzheimer's disease, and their value in detecting dementia after stroke is less well known. A stroke may cause both cortical and subcortical deficits, and the clinical expression of post-stroke dementia is different from that of Alzheimer's disease. Existing brief mental status tests have limited value in this patient group because they tend to ignore specific problems which may occur in stroke patients. Some expanded screening instruments, like the CAMCOG, are more useful and have additional diagnostic value. With the growing interest in research for vascular factors in dementia over the past years, however, a specific screening instrument for post-stroke dementia would be a valuable contribution.     

Clinico-neuropathological correlation of Alzheimer's disease in a community-based case series.

OBJECTIVES: Most clinico-neuropathological correlative studies of Alzheimer's Disease (AD) are based on research cohorts that are not necessarily generalizable to patients seen in the general medical community. In this study, we examine the accuracy of the criteria used in diagnosing AD in a community-based case series of patients with memory complaints. DESIGN AND PARTICIPANTS: Clinical and neuropathological diagnoses were obtained from 134 patients evaluated for dementia who subsequently underwent autopsy. SETTING: Subjects who exhibited new symptoms of dementia and were enrolled in the University of Washington/Group Health Cooperative Alzheimer's Disease Patient Registry were eligible for this study. MEASUREMENTS: Clinico-pathological correlation was performed using NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association) and CERAD (Consortium to Establish a Registry for Alzheimer's Disease) criteria. RESULTS: Ninety-five of the 134 cases studied met CERAD neuropathological criteria for AD. The sensitivity of NINCDS-ADRDA "probable AD" was 83% (diagnosing AD correctly) and overall clinical diagnostic accuracy was 75%. However, there was a high rate of additional neuropathological findings. Only 34 of the 94 cases had pure AD on neuropathology, whereas the remainder frequently had coexisting vascular or Parkinson's disease lesions. CONCLUSIONS: This study of a large series of community-based incident dementia cases provides a way of judging the adequacy of currently available clinical diagnostic criteria. It also shows that co-existing neuropathological findings are common in community-based AD.     

Auswirkungen der erweiterten klinischen Diagnostik auf das Diagnosespektrum einer Gedächtnisambulanz

OBJECTIVES: In an outpatient memory clinic, the methods of extended clinical diagnostics pertaining to imaging and neuropsychology were changed but the modus of assignment to the clinic remained unchanged at different times. Expected changes in the diagnostic spectrum can be attributed to the changed diagnostics. Consistent with reports from the literature regarding the consequences of such changes, the associated costs have to be taken into consideration as well. METHODS: The clinical final diagnoses of 174 patients referred in 2000/2001 for the diagnostics and differential diagnostics of dementia ("current population") were compared with those of 169 patients who visited the same outpatient clinic in 1998/1999 ("former population"). The diagnostic spectra of the two populations were compared. The diagnoses were differentiated in "no dementia" (XD), "neurodegenerative dementia" (ND), "vascular dementia" (VD), and "dementia of the mixed type" (MIXD). For all patients, the same clinical diagnostic criteria (ICD-10) and laboratory tests were implemented. Only the neuroradiological and neuropsychological methods changed from 1998/1999 to 2000/2001: The current population was examined with MRI instead of CT and underwent an expanded neuropsychological test battery with additional power and speed tests. RESULTS: The diagnoses of the two populations differed significantly in their frequency distribution. A dementia was excluded in 51.1% of the "current" patients vs 19.5% of the "former" patients. The frequencies of the dementia diagnoses were significantly different for the diagnoses ND (29.9 vs 47.9%) and MIXD (1.1 vs 7.7%), but not for VD (13.2 vs 12.4%). Beside other independent modalities, the improvement of imaging with MRI is discussed as recording atrophy size and vascular lesions better than CT. The improvement of the neuropsychological test battery containing additional speed tests is discussed as being able to differentiate even minimal cognitive disturbances. CONCLUSION: Using optimized imaging and neuropsychological methods, the diagnostic spectrum of an outpatient memory clinic changed. The clinical diagnosis was improved by the more sensitive, extended clinical diagnostics. Through optimized differential diagnostic allocation and the exclusion of dementia, expenses can be reduced by early and indication-related medication and by the resulting delay of institutionalized care.     

Health economic evaluation of treatments for Alzheimer′s disease: impact of new diagnostic criteria

The socio‐economic impact of Alzheimer′s disease (AD) and other dementias is enormous, and the potential economic challenges ahead are clear given the projected future numbers of individuals with these conditions. Because of the high prevalence and cost of dementia, it is very important to assess any intervention from a cost‐effectiveness viewpoint. The diagnostic criteria for preclinical AD suggested by the National Institute on Aging and Alzheimer's Association workgroups in combination with the goal of effective disease‐modifying treatment (DMT) are, however, a challenge for clinical practice and for the design of clinical trials. Key issues for future cost‐effectiveness studies include the following: (i) the consequences for patients if diagnosis is shifted from AD‐dementia to predementia states, (ii) bridging the gap between clinical trial populations and patients treated in clinical practice, (iii) translation of clinical trial end‐points into measures that are meaningful to patients and policymakers/payers and (iv) how to measure long‐term effects. To improve cost‐effectiveness studies, long‐term population‐based data on disease progression, costs and outcomes in clinical practice are needed not only in dementia but also in predementia states. Reliable surrogate end‐points in clinical trials that are sensitive to detect effects even in predementia states are also essential as well as robust and validated modelling methods from predementia states that also take into account comorbidities and age. Finally, the ethical consequences of early diagnosis should be considered.     

Palliative care in dementia

ObjectivesTo analyze the current literature on the various aspects of palliative care in advanced dementia (AD).Material and methodsA narrative review focused on the literature available regarding the final stages of dementia: prognosis, decision-making, assessment of patient needs, support/alleviation of symptoms and the integration of palliative care into the comprehensive care of AD.ResultsAD is a terminal disease associated with extensive suffering and having to make difficult decisions in its most severe stages. Estimating prognosis is difficult, which may explain why most patients are not included in palliative care programs. The decision-making process is characterized by uncertainty due to the lack of scientific evidence backing the efficacy of treatments and the need to reconcile conflictive points of view, as well as due to the difficulty of understanding patient wishes. Caring for these patients is difficult; for them, non-verbal communication is essential and careful attention to the presence of symptoms is required. It is also necessary to take into consideration the suffering of caregivers. The few studies that have developed specific tools for guiding the final phase of life in AD and the specific measurements of outcomes have demonstrated what can be achieved and the significant work ahead.ConclusionsFurther research on end-of-life care for persons with dementia is needed in order to develop interventions that address the particular challenges of dying with this disease and to be able to improve the end-of-life care provided to these patients in the environments where the majority of them live and die.     

Is dementia a disease?

BACKGROUND: It is customary for many neurologists to think that dementia is a disease. This view is based on the following reasons: (1) a brain disease is the cause of cognitive impairment; (2) therefore, such cognitive impairment is substituted for the disease, becoming dementia, which is then also regarded as a mental disease. OBJECTIVE: In this brief article, I take exception to such a view, contrary to the common belief in the medical field, on the ground that senile plaques and/or neurofibrillary tangles or any other factors cause neuronal apoptosis but they do not cause dementia directly. METHODS: Literature on dementia and aphasia are critically and briefly reviewed to get the historical perspective that it is the progressive neuronal losses, losing brain functions as a result, that cause dementia; that is, brain diseases cause neuronal losses which then result in the decrease of brain functions, thereby leading to dementia. RESULTS: There is no direct cause-effect relationship between brain disease, be it caused by vascular factors or not, and dementia which is the consequence or sequela of neuronal losses. CONCLUSIONS: It is concluded that dementia is not a disease and yet it occurs not only in Parkinson's disease, Alzheimer's disease (AD), Huntington's disease and Pick's disease, but also in any other neurodegenerative disease, e.g., spinocerebellar ataxia, or vascular disease, e.g., Binswanger's disease, as part of the process of aging; in fact, AD is now regarded by some as a vascular disorder with neurodegenerative consequence, rather than a neurodegenerative disorder with vascular consequence. But vascular disorder is misleading if AD includes both neurofibrillary tangles and senile plaques; on the other hand, AD cannot be a vascular disorder if it includes only neurofibrillary tangles, as it should. Dementia, in this context, is re-defined as the differential manifestation of deteriorating brain functions over time as a part of aging due to cell deaths in the brain caused by any neurodegenerative disease. Its prominent symptoms are language disorders which must be distinguished from aphasias. It is also suggested that in fairness to Fischer, senile plaques be designated as Fischer's disease separate from neurofibrillary tangles for which AD was originally named as an eponym.     

Dementia and Alzheimer's disease incidence in relationship to cardiovascular disease in the Cardiovascular Health Study cohort

OBJECTIVES: To determine whether coronary artery disease, peripheral arterial disease (PAD), or noninvasive markers of cardiovascular disease (CVD) predict the onset of dementia and Alzheimer's disease (AD). DESIGN: Longitudinal cohort study. SETTING: Four U.S. communities. PARTICIPANTS: Men and women (N=3,602) with a brain magnetic resonance imaging (MRI) scan but no dementia were followed for 5.4 years. Participants with stroke were excluded. MEASUREMENTS: Neurologists and psychiatrists classified incident cases of dementia and subtype using neuropsychological tests, examination, medical records and informant interviews. CVD was defined at the time of the MRI scan. Noninvasive tests of CVD were assessed within 1 year of the MRI. Apolipoprotein E allele status, age, race, sex, education, Mini-Mental State Examination score, and income were assessed as potential confounders. RESULTS: The incidence of dementia was higher in those with prevalent CVD, particularly in the subgroup with PAD. The rate of AD was 34.4 per 1,000 person-years for those with a history of CVD, versus 22.2 per 1,000 person-years without a history of CVD (adjusted hazard ratio (HR)=1.3, 95% confidence interval (CI)=1.0-1.7). Rates of AD were highest in those with PAD (57.4 vs 23.7 per 100 person-years, adjusted HR=2.4, 95% CI=1.4-4.2). Results were similar with further exclusion of those with vascular dementia from the AD group. A gradient of increasing risk was noted with the extent of vascular disease. CONCLUSION: Older adults with CVD other than stroke had a higher risk of dementia and AD than did those without CVD. The risk was highest in people with PAD, suggesting that extensive peripheral atherosclerosis is a risk factor for AD.     

Sensitivity of SPECT for the Diagnosis of Alzheimer's Disease

Abstract

The objective of this study was to define the technical and clinical variables which affect the sensitivity of single photon emission computed tomography (SPECT) for the diagnosis of Alzheimer's disease (AD). This was a retrospective analysis of 250 consecutive SPECT studies performed for the diagnostic evaluation of degenerative dementia or memory disorder. The sensitivity of bilateral temporoparie-tal perfusion defects for probable AD cases was not affected by age, education, or technical factors such as the interpreting radiologist, type of radionuclide, and use of a ring detector system. Sensitivity increased with severity of dementia and duration of disease. Sensitivity also increased with male gender due to a higher prevalence of unilateral defects in women with probable AD. This gender effect was absent if unilateral temporoparietal defects were considered diagnostic of AD. Due to the high prevalence of AD, the most common outcome of SPECT in this series was to confirm the clinical diagnosis of AD; however, SPECT may be of greatest value for ruling in a diagnosis of AD in questionable or early dementia cases. For this purpose, the maximum yield of positive diagnosis came from examination of those who had dementia symptoms greater than one year and those who were male.