General introduction

Transcription

1 1 General introduction

2 10 Chapter 1

3 General Introduction Dementia Dementia is defined as an acquired impairment of cognitive function in at least two domains, including memory, which interferes with normal social or occupational performance and is not attributable to delirium or psychiatric disorders. The most commonly used criteria for the diagnosis of dementia are those defined in the DSM-IV. 1 Epidemiology Dementia is a chronic disorder that is particularly common in the elderly. Worldwide, 24.3 million people have dementia, with 4.6 million new cases of dementia every year. 2 In Europe, the prevalence of dementia in subjects aged over 65 years has been estimated to be 6.4% of the population in a meta-analysis pooling data of 11 European population-based studies. 3 Age is a major risk factor for dementia, with the prevalence nearly doubling every five years of age-increase between ages 60 and It is estimated that within the next 50 years the number of patients with dementia in Europe will rise to over 16 million, due to the increasing life-expectancy in Western society. 4 Besides the physical, social and psychological burden on carers of patients with dementia, the financial burden on society will grow exponentially too. 4 Types of dementia Dementia can be caused by various underlying diseases. The most common type of dementia is Alzheimer s disease (AD), which accounts for about 70% of cases in the elderly. The second most common cause of dementia is vascular dementia (VaD). Other, less common, causes include dementia with Lewy bodies (DLB) and frontotemporal lobar degeneration (FTLD). Below the age of 65 years dementia is far less common, and the distribution of underlying causes differs from that observed in the elderly; thus in this age-category, whilst AD remains the most common cause, the prevalence of AD is reduced to one third of patients, with VaD accounting for approximately 18%. Other types of dementia, such as FTLD are relatively more prevalent, accounting for 12% of dementia cases in these younger patients. 5 Due to overlap in clinical presentation, differentiating between the various types of dementia can be difficult in clinical practice. Alzheimer s disease Clinical features AD is characterized by an insidious onset of cognitive decline, typically starting with deficits in episodic memory. Patients and their family complain for example of forget 11

4 Chapter 1 Table 1 NINCDS-ADRDA criteria for the diagnosis of probable Alzheimer s disease 7 1. Dementia established by clinical examination and confirmed by neuropsychological tests 2. Deficits in two or more areas of cognition, including memory impairment 3. Progressive worsening of memory and other cognitive functions 4. No disturbances of consciousness 5. Onset between ages 40 and Absence of systemic disorders or other brain disease that in and of themselves could account for the progressive deficits in memory and cognition ting recent personal and family events, losing items around the house, and repetitive questioning. As the disease progresses, deficits in other cognitive domains, such as aphasia, apraxia, agnosia, visuo-spatial difficulties and executive dysfunction, arise gradually. Psychological and behavioral problems such as mood disorders, psychosis, agitation and sleep disorders, occur more frequently as the disease becomes more severe. The patient becomes increasingly dependent on others and often has to be cared for in a nursing home. The average survival in AD is typically about 6 years from the onset of symptoms to death, depending on age at onset, ranging from about 8 years in those with an onset before the age of 75 to 4 years in those with an onset after the age of 85 years. 6 Diagnosis and neuropathology In everyday practice the diagnosis of AD is made using clinical criteria, the most frequently used of which are those proposed by the National Institute of Neurological and Communicating Disorders and Stroke and the Alzheimer s Disease and Related Disorders Association (NINCDS-ADRDA) Work Group (table 1). 7 A definitive diagnosis of AD can only be made by pathological examination of the brain at autopsy or after brain biopsy. Alzheimer-type pathology is characterized by extracellular neuritic plaques, consisting of beta amyloid, and intracellular neurofibrillary tangles consisting of hyperphosphorylated tau-protein. This pathology, which in AD starts to accumulate years before the first cognitive symptoms arise, 8 is present, to a much lesser extent, in normal aging too. The staging system developed 12

5 General Introduction Table 2 Criteria for amnestic Mild Cognitive Impairment by Petersen et al Memory complaint, preferably corroborated by an informant 2. Objective memory impairment for age and education, at neuropsychological testing 3. Normal general cognition 4. Preserved activities of daily living 5. No dementia by Braak and Braak describes the extent, location and sequence of accumulating neurofibrillary tangle pathology, which in AD progresses in a typical fashion, starting in the transentorhinal and entorhinal areas, before spreading to the hippocampus, the association cortices, and the rest of the cortex. 9 The accumulation of beta amyloid and tau is associated with neuronal cell death, the result of which can be appreciated at a macroscopic level as atrophy, with widening of sulci and the ventricular system and thinning of the cortex. The focality of atrophy in AD reflects the typical pattern of progression of neuropathology. Medial temporal lobe structures, such as the hippocampus, are prominently affected in early stages of the disease. There is evidence that, besides Alzheimer-type pathology, cerebrovascular pathology plays a role in AD. The majority of subjects with late-onset AD show co-existing vascular pathology at post-mortem, 10 and previous studies have suggested that the two pathologies interact. 11,12 Mild cognitive impairment As the transition from normal aging to dementia occurs gradually, a stage exists in which subjects who are developing dementia experience cognitive decline not yet severe enough to fulfill diagnostic criteria for dementia. Several clinical definitions for this intermediate phase exist, of which the criteria for amnestic mild cognitive impairment (MCI) developed by Petersen et al. 13,14 are most frequently used (table 2). Subjects who fulfill criteria for amnestic MCI are at an increased risk of developing clinical AD at a rate of about 12% per year, as compared to 1-2% per year in the age-matched general population. 13 However, it is increasingly recognized that the application of current MCI criteria results in a heterogeneous group of subjects. Not all subjects with MCI will develop AD: some will develop other types of dementia, 13

6 Chapter 1 whereas others will remain stable or even improve. 15,16 The neuropathologic outcome of patients dying with dementia, who had a prior diagnosis of amnestic MCI, has been shown to be heterogeneous, often consisting of two or more distinct pathologic entities. 17 On the other hand, criteria for amnestic MCI exclude subjects who present with first cognitive symptoms in a non-memory domain. Recently, clinical subtypes of MCI have been proposed, based on the presence or absence of memory impairment (amnestic versus non-amnestic), and on the number of cognitive domains affected (single versus multiple domains). 18 It is presumed that subjects with single-domain amnestic MCI will mainly progress to clinical AD, but the outcome of the other subtypes remains unknown. Pathological studies have shown that subjects with amnestic MCI have increased numbers of neurofibrillary tangles in medial temporal lobe structures compared to cognitively normal controls. 19 However, many concomitant pathologic abnormalities such as argyrophilic grain disease, hippocampal sclerosis and vascular lesions were also observed. 19,20 A better understanding of the pathological processes that play a role in MCI, may lead to clues for a more accurate identification of subjects with neurodegenerative diseases in the early stages. This in turn may permit accurate and early implementation of preventive and therapeutic strategies. Magnetic resonance imaging (MRI), which allows for a non-invasive, repeatable, in vivo, assessment of brain structure, is increasingly used as a diagnostic tool in these patients. Hippocampal atrophy on MRI Additional markers adding support to clinical diagnoses of AD are sought. A wellknown diagnostic marker for AD is hippocampal atrophy on MRI. Anatomy and function of the hippocampus The hippocampus is a small, arched structure in the medial temporal lobe, bulging in the temporal horn of the lateral ventricle (figure 1). Three segments can be distinguished, a head, body and tail. Anteriorly, the hippocampal head is bordered by the amygdala, and posteriorly, the hippocampal tail disappears under the splenium of the corpus callosum. Medially, the hippocampus is bordered by the entorhinal cortex, to which it is connected via the subiculum. The hippocampus is a bilaminar structure, consisting of the cornu Ammonis (hippocampus proper) and the gyrus dentatus, with one lamina rolled up inside the other. 21 The role of the hippocampus and adjacent structures in memory function has been firmly established since the effects of bilateral medial temporal lobe resection were 14

7 General Introduction Figure 1 Anatomy of the hippocampal region 21 Coronal section through hippocampal head 1: Hippocampal head 1 : internal digitations 2: temporal horn of lateral ventricle 3: amygdala 4: uncal sulcus 5: parahippocampal gyrus 6: collateral sulcus 7: fusiform gyrus 8: inferior temporal gyrus 9: middle temporal gyrus 10: superior temporal sulcus Coronal section through hippocampal body 1: Hippocampal body, cornu Ammonis 2:hippocampal body, dentate gyrus 2 : fimbria 3:subiculum 4: parahippocampal gyrus 5: temporal horn of lateral ventricle 6: collateral sulcus 7: fusiform gyrus 8: inferior temporal gyrus 9: middle temporal gyrus 10: superior temporal sulcus Coronal section through hippocampal tail 1: Hippocampal tail, cornu Ammonis 2:hippocampal tail, dentate gyrus 3: crus of fornix 4: lateral ventricle 5: isthmus 6: anterior calcarine sulcus 7: parahippocampal gyrus 8: collateral suclus 9: collateral trigone 10: fusiforme gyrus 11: inferior temporal gyrus 12: middle temporal gyrus 13 superior temporal sulcus described in patient H.M. in the 1950 s. 23 This patient had a severe amnesia after a bilateral medial temporal lobe resection because of epilepsy. Since then animal and human studies have shown that the hippocampus is involved in all modalities of declarative memory: episodic, semantic and spatial memory. 21,24 Furthermore, the hippocampus is involved in emotional behavior, motor control and regulation of hypothalamic function. 21 Hippocampal atrophy on MRI in AD Focal atrophy in the hippocampal region on MRI has been the focus of extensive study as a marker for AD, as it reflects the typical pattern of progression of Alzheimer-type neuropathology (figure 2). Neuropathological studies have shown that hippocampal volumes, as measured using MRI, correlate well with the neuropathological burden at post-mortem. 25,26 Furthermore, hippocampal atrophy has been shown to be associated with cognitive performance and especially memory function in healthy controls and patients with AD. 27,28 Many studies initially using CT and later MRI, 15

8 Chapter 1 Figure 2 Hippocampal atrophy Coronal T1-weighted MRI scans of control subject (left) and patient with mild AD (right). Note the relatively focal hippocampal atrophy in the patient with AD in comparison with the control subject. have assessed the diagnostic value of hippocampal atrophy for AD, using various visual, linear and volumetric measurements (for overview see: 29,30 ). In a meta-analysis of studies using visual and linear measurements of medial temporal lobe atrophy (MTA) on MRI, the overall sensitivity and specificity for detection of AD compared with controls was estimated to be 85% and 88% respectively. 30 It has been suggested that the medial temporal lobe structures may be less involved in AD with a presenile onset (<65 years); 31 on the other hand, it has been speculated that hippocampal atrophy might loose its sensitivity as a marker for AD in the oldest old, 32 as hippocampal atrophy occurs, to a lesser extent, in normal aging as well. 33 Besides Alzheimer-type pathology, other types of pathology, such as vascular pathology, mesiotemporal sclerosis, argyrophyllic grain disease and other neurodegenerative diseases can affect the hippocampus too. 17,34,35 Hippocampal atrophy on MRI has also been described in subjects with non-alzheimer types of dementia This may potentially limit the diagnostic value of hippocampal atrophy as a marker for AD in the differential diagnosis with other types of dementia. Studies in MCI have shown that hippocampal atrophy is detectable before subjects are clinically demented, in parallel with the accumulation of Alzheimer-type pathology which may start decades before cognitive deficits become apparent. 8 Hippocampal volumes in MCI have been shown to be intermediate between those in normal aging and AD, and the presence of hippocampal atrophy in subjects with amnestic MCI is associated with a diagnosis of dementia at follow-up

9 General Introduction Figure 3 Small vessel disease From left to right: Normal, Confluent white matter hyperintensities, and Lacunar infarct on axial Fluid Attenuated Inversion Recovery MRI scans Longitudinal studies of hippocampal atrophy Cross-sectional studies using hippocampal volumes to differentiate between diagnostic groups have limited value, due to large inter-individual variability in brain volumes. Analysis of hippocampal volume change using serial MRI reduces this problem, as each subject is used as its own control. Rates of hippocampal atrophy in controls increase with age, and are estimated to be about 1-2% above age ,48 However, longitudinal studies have shown that in AD hippocampal atrophy rates are markedly increased to about 4-8%/year In MCI, rates of hippocampal atrophy are intermediate to those observed in controls and patients with AD, with accelerated rates in amnestic MCI predicting progression to AD. 50,51 Rate of hippocampal atrophy could be a useful tool to identify subjects at risk of developing AD. Furthermore, rates of hippocampal atrophy are promising markers of disease progression, as they have been shown to correlate with change in cognitive measures, such as the Mini-Mental State Examination (MMSE) and memory tests. 51,52 However, apart from AD itself, risk factors associated with accelerated rates of hippocampal atrophy are not yet clear. Small vessel disease White matter hyperintensities (WMH) and lacunar infarcts (lacunes) are generally viewed as evidence of microvascular pathology. Both are commonly observed on MRI throughout the cognitive spectrum (figure 3). 53,54 The clinical significance of WMH remains unclear. In both AD and normal aging, WMH have been associated with subtle cognitive deficits, especially in executive function and psychomotor speed. In MCI with concomitant WMH, an increased risk of dementia has been reported. 55 The neuropsychological correlates of lacunes remain unclear as well. 17

10 Chapter 1 Table 3 Medial temporal lobe atrophy visual rating scale by Scheltens et al. 32 Score Width of choroid fissure Width of temporal horn Height of the hippocampus 0 Normal Normal Normal 1 # Normal Normal 2 ## # $ 3 ### ## $$ 4 ### ### $$$ A score of 0 to 4 is given separately for the left and right side. (#) = increase; ($) = decrease. MRI methodology Previous studies have assessed atrophy of the hippocampal region using a variety of different methods, ranging from relatively simple visual rating scales and linear measurements using either CT or MRI to more complicated volumetric and semiautomated measurements using MRI. The methods used in this thesis are reviewed below in more detail. Medial temporal lobe atrophy scale The MTA-scale developed by Scheltens et al., 32 provides a measure for global atrophy of the medial temporal lobe, and is based on visually scoring the height of the hippocampus and the width of the surrounding CSF. The severity of MTA is scored from 0 (no atrophy) to 4 (most severe atrophy), on each side of the brain on a coronal T1-weighted MRI sequence (table 3 and figure 4). This simple scale is easy to learn and has been proven to have fair to good interrater reliability and good intra-rater reliability, and has a reasonably good correlation with hippocampal volumes measurements. 57,58 Clinical studies have shown that this measure can differentiate between AD and controls, 32 and is predictive of dementia in subjects with MCI. 42 Hippocampal volumetry Compared to visual rating scales, volumetric analysis is a more detailed method to assess accurately regional volumes of a number of brain structures, including the hippocampus. This method involves manual delineation of a region of interest on 18

11 General Introduction Figure 4 Medial temporal lobe atrophy visual rating scale Examples of medial temporal lobe atrophy (MTA) score (right hemisphere), on coronal T1-weighted MRI scans. sequential slices of a volumetrically acquired scan (figure 5). Different anatomical protocols can be used to outline the hippocampus, one of which is that designed by Jack et al. 59 The dentate gyrus, subiculum, fimbria and alveus are measured, and referred to as hippocampus. Hippocampal volume can then be computed by summing the delineated area of the region of interest on each slice, and multiplying by the slice thickness. Measuring hippocampal volumes from serially acquired scans from the same individual, provided the scans are accurately spatially matched (registered), provides a measure of change over time. This hippocampal volume loss can then be divided by the inter-scan interval to provide the rate of hippocampal atrophy, usually described as a percentage per year. Various new techniques are being developed to allow automated rather than manual assessment of hippocampal atrophy rates, 44,47,60 with the aim of reducing operator 19

12 Chapter 1 Figure 5 Hippocampal volumetry Example of manually delineated hippocampal regions of interest on coronal T1-weighted MRI scan. time and variability. However, most of these techniques still require some manual intervention and have not been tested in a clinical setting to date. Thus, manual segmentation is currently considered the gold standard for hippocampal volume analysis. Unfortunately, this is a time-consuming method that requires well-trained operators and is subject to human errors in delineation. Especially, in longitudinal analysis of volume change, uncorrelated errors on serial scans may decrease reli ability of measurements. More time-efficient and reliable techniques to measure hip pocampal volume change on MRI are needed. 20 proefschrift.indd :57:23

13 General Introduction References 1. (APA). APA. Diagnostic and statistical manual of mental disorders (DSM IV).IV ed.:apa, Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a Delphi consensus study. Lancet 2005;366: Lobo A, Launer LJ, Fratiglioni L, et al. Prevalence of dementia and major subtypes in Europe: A collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology 2000;54:S Wancata J, Musalek M, Alexandrowicz R, Krautgartner M. Number of dementia sufferers in Europe between the years 2000 and Eur Psychiatry 2003;18: Harvey RJ, Skelton-Robinson M, Rossor MN. The prevalence and causes of dementia in people under the age of 65 years. J Neurol Neurosurg Psychiatry 2003;74: Ganguli M, Dodge HH, Shen C, Pandav RS, DeKosky ST. Alzheimer disease and mortality: a 15-year epidemiological study. Arch Neurol 2005;62: McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer s Disease. Neurology 1984;34: Price JL, Morris JC. Tangles and plaques in nondemented aging and preclinical Alzheimer s disease. Ann Neurol 1999;45: Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol (Berl) 1991;82: Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). Lancet 2001;357: Nagy Z, Esiri MM, Jobst KA, et al. The effects of additional pathology on the cognitive deficit in Alzheimer disease. J Neuropathol Exp Neurol 1997;56: Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. Jama 1997;277: Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999;56: Petersen RC, Doody R, Kurz A, et al. Current concepts in mild cognitive impairment. Arch Neurol 2001;58: Bennett DA, Wilson RS, Schneider JA, et al. Natural history of mild cognitive impairment in older persons. Neurology 2002;59: Visser PJ, Kester A, Jolles J, Verhey F. Ten-year risk of dementia in subjects with mild cognitive impairment. Neurology 2006;67: Jicha GA, Parisi JE, Dickson DW, et al. Neuropathologic outcome of mild cognitive impairment following progression to clinical dementia. Arch Neurol 2006;63: Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med 2004;256: Petersen RC, Parisi JE, Dickson DW, et al. Neuropathologic features of amnestic mild cognitive impairment. Arch Neurol 2006;63: Markesbery WR, Schmitt FA, Kryscio RJ, Davis DG, Smith CD, Wekstein DR. Neuropathologic substrate of mild cognitive impairment. Arch Neurol 2006;63: Duvernoy HM. The human hippocampus. Springer-Verlag. Berlin Heidelberg Milner B. Disorders of learning and memory after temporal lobe lesions in man. Clin Neurosurg 1972;19: Scoville WB, Milner B. Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry 1957;20: Squire LR, Stark CE, Clark RE. The medial temporal lobe. Annu Rev Neurosci 2004;27: Gosche KM, Mortimer JA, Smith CD, Markesbery WR, Snowdon DA. Hippocampal volume as an index of Alzheimer neuropathology: findings from the Nun Study. Neurology 2002;58: Jack CR, Jr., Dickson DW, Parisi JE, et al. Antemortem MRI findings correlate with hippocampal neuropathology in typical aging and dementia. Neurology 2002;58: Laakso MP, Soininen H, Partanen K, et al. Volumes of hippocampus, amygdala and frontal lobes in the MRI-based diagnosis of early Alzheimer s disease: correlation with memory functions. J Neural Transm Park Dis Dement Sect 1995;9: Petersen RC, Jack CR, Jr., Xu YC, et al. Memory and MRI-based hippocampal volumes in aging and AD. Neurology 2000;54: Bosscher L, Scheltens P. MRI of the temporal lobe. In: Qizilbash N SL, Chui H,, editors. Evidence based dementia. Oxford: Blackwell Publishing Scheltens P, Fox N, Barkhof F, De Carli C. Structural magnetic resonance imaging in the practical assessment of dementia: beyond exclusion. Lancet Neurol 2002;1: Frisoni GB, Testa C, Sabattoli F, Beltramello A, Soininen H, Laakso MP. Structural correlates of early and late onset Alzheimer s disease: voxel based morphometric study. J Neurol Neurosurg Psychiatry 2005;76: Scheltens P, Leys D, Barkhof F, et al. Atrophy of medial temporal lobes on MRI in «probable» Alzheimer s disease and normal ageing: diagnostic value and neuropsychological correlates. J Neurol Neurosurg Psychiatry 1992;55:

14 Chapter Jernigan TL, Archibald SL, Fennema-Notestine C, et al. Effects of age on tissues and regions of the cerebrum and cerebellum. Neurobiol Aging 2001;22: Cervos-Navarro J, Diemer NH. Selective vulnerability in brain hypoxia. Crit Rev Neurobiol 1991;6: Togo T, Cookson N, Dickson DW. Argyrophilic grain disease: neuropathology, frequency in a dementia brain bank and lack of relationship with apolipoprotein E. Brain Pathol 2002;12: Chan D, Fox NC, Scahill RI, et al. Patterns of temporal lobe atrophy in semantic dementia and Alzheimer s disease. Ann Neurol 2001;49: Frisoni GB, Laakso MP, Beltramello A, et al. Hippocampal and entorhinal cortex atrophy in frontotemporal dementia and Alzheimer s disease. Neurology 1999;52: Kril JJ, Patel S, Harding AJ, Halliday GM. Patients with vascular dementia due to microvascular pathology have significant hippocampal neuronal loss. J Neurol Neurosurg Psychiatry 2002;72: Laakso MP, Partanen K, Riekkinen P, et al. Hippocampal volumes in Alzheimer s disease, Parkinson s disease with and without dementia, and in vascular dementia: An MRI study. Neurology 1996;46: Barber R, Gholkar A, Scheltens P, Ballard C, McKeith IG, O Brien JT. Medial temporal lobe atrophy on MRI in dementia with Lewy bodies. Neurology 1999;52: Jack CR, Jr., Petersen RC, Xu YC, et al. Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment. Neurology 1999;52: Korf ES, Wahlund LO, Visser PJ, Scheltens P. Medial temporal lobe atrophy on MRI predicts dementia in patients with mild cognitive impairment. Neurology 2004;63: Visser PJ, Verhey FR, Hofman PA, Scheltens P, Jolles J. Medial temporal lobe atrophy predicts Alzheimer s disease in patients with minor cognitive impairment. J Neurol Neurosurg Psychiatry 2002;72: Barnes J, Scahill RI, Schott JM, Frost C, Rossor MN, Fox NC. Does Alzheimer s disease affect hippocampal asymmetry? Evidence from a crosssectional and longitudinal volumetric MRI study. Dement Geriatr Cogn Disord 2005;19: Du AT, Schuff N, Kramer JH, et al. Higher atrophy rate of entorhinal cortex than hippocampus in AD. Neurology 2004;62: Jack CR, Jr., Petersen RC, Xu Y, et al. Rate of medial temporal lobe atrophy in typical aging and Alzheimer s disease. Neurology 1998;51: Thompson PM, Hayashi KM, De Zubicaray GI, et al. Mapping hippocampal and ventricular change in Alzheimer disease. Neuroimage 2004;22: Scahill RI, Frost C, Jenkins R, Whitwell JL, Rossor MN, Fox NC. A longitudinal study of brain volume changes in normal aging using serial registered magnetic resonance imaging. Arch Neurol 2003;60: Jack CR, Jr., Petersen RC, Xu Y, et al. Rates of hippocampal atrophy correlate with change in clinical status in aging and AD. Neurology 2000;55: Jack CR, Jr., Shiung MM, Gunter JL, et al. Comparison of different MRI brain atrophy rate measures with clinical disease progression in AD. Neurology 2004;62: Hampel H, Burger K, Pruessner JC, et al. Correlation of cerebrospinal fluid levels of tau protein phosphorylated at threonine 231 with rates of hippocampal atrophy in Alzheimer disease. Arch Neurol 2005;62: Mungas D, Harvey D, Reed BR, et al. Longitudinal volumetric MRI change and rate of cognitive decline. Neurology 2005;65: Burns JM, Church JA, Johnson DK, et al. White matter lesions are prevalent but differentially related with cognition in aging and early Alzheimer disease. Arch Neurol 2005;62: de Leeuw FE, de Groot JC, Achten E, et al. Prevalence of cerebral white matter lesions in elderly people: a population based magnetic resonance imaging study. The Rotterdam Scan Study. J Neurol Neurosurg Psychiatry 2001;70: Wolf H, Ecke GM, Bettin S, Dietrich J, Gertz HJ. Do white matter changes contribute to the subsequent development of dementia in patients with mild cognitive impairment? A longitudinal study. Int J Geriatr Psychiatry 2000;15: Scheltens P, Launer L, Barkhof F, Weinstein HC, van Gool WA. Visual assesment of medial temporal lobe atrophy on magnetic resonance imaging: interobserver reliability. J Neurol 1995;242: Wahlund LO, Julin P, Johansson SE, Scheltens P. Visual rating and volumetry of the medial temporal lobe on magnetic resonance imaging in dementia: a comparative study. J Neurol Neurosurg Neuropsychiatry 2000:69: Rossi R, Testa C, Geroldi C, Galluzzi S, Laakso MP, Beltramello A, Soininen H, Frisoni GB. Visual assessment of medial temporal atrophy on MR films in Alzheimer s disease: comparison with volumetry. Aging Clin Exp Res. 2005;17(1): Jack CR, Jr. MRI-based hippocampal volume measurements in epilepsy. Epilepsia 1994;35 Suppl 6: S Csernansky JG, Joshi S, Wang L, et al. Hippocampal morphometry in schizophrenia by high dimensional brain mapping. Proc Natl Acad Sci U S A 1998;95: