Alzheimer Disease: Boeve BF

Knopman DS, Boeve BF, Petersen RC. · Department of Neurology and Alzheimer's Disease Research Center, Mayo Clinic, Rochester Minn 55905, USA. · Mayo Clin Proc. · Pubmed #14531488 links to  free full text

Abstract: Loss of cognitive function in the elderly population is a common condition encountered in general medical practice. Diagnostic criteria and approaches have become more refined and explicit in the past several years. Precise diagnosis is feasible clinically. In this article, the precursor state and major subtypes of dementia are considered. Mild cognitive impairment is the term given to patients with cognitive impairment that is detectable by clinical criteria but does not produce impairment in daily functioning. When daily functioning is impaired as a result of cognitive decline, dementia is the appropriate syndromic label. Specific causes of dementia tend to have distinctive clinical presentations: the anterograde amnesic syndrome of Alzheimer disease; the syndrome of dementia with cerebrovascular disease; the syndrome of Lewy body dementia with its distinctive constellation of extrapyramidal features, disordered arousal, and dementia; the behavioral-cognitive syndrome of frontotemporal dementia; the primary progressive aphasias; and the rapidly progressive dementias. Because dementia syndromes have distinctive natural histories, precise diagnosis leads to a better understanding of prognosis. As new treatments become available for Alzheimer disease, the most common of the dementias, accurate diagnosis allows the appropriate patients to receive treatment.

Jack CR, Petersen RC, Xu Y, O'Brien PC, Smith GE, Ivnik RJ, Boeve BF, Tangalos EG, Kokmen E. · Department of Diagnostic Radiology, Mayo Clinic and Foundation, Rochester, MN 55905, USA. · Neurology. · Pubmed #10953178 No free full text.

Abstract: BACKGROUND: The cognitive continuum in the elderly population can be conceptually divided into those who are functioning normally (control subjects), those with a mild cognitive impairment (MCI), and those with probable AD. OBJECTIVES: To test the hypothesis that the annualized rates of hippocampal atrophy differ as a function of both baseline and change in clinical group membership (control, MCI, or AD). METHODS: The authors identified 129 subjects from the Mayo Clinic AD Research Center/AD Patient Registry who met established criteria for normal control subjects, MCI, or probable AD, both at entry and at the time of a subsequent clinical follow-up evaluation 3 +/- 1 years later. Each subject underwent an MRI examination of the head at the time of the initial assessment and at follow-up clinical assessment; the annualized percentage change in hippocampal volume was computed. Subjects who were classified as controls or patients with MCI at baseline could either remain cognitively stable or could decline to a lower functioning group over the period of observation. RESULTS: The annualized rates of hippocampal volume loss for each of the three initial clinical groups decreased progressively in the following order: AD > MC > control. Within the control and MCI groups, those who declined had a significantly greater rate of volume loss than those who remained clinically stable. The mean annualized rates of hippocampal atrophy by follow-up clinical group were: control-stable 1.73%, control-decliner 2.81%, MCI-stable 2.55%, MCI-decliner 3.69%, AD 3. 5%. CONCLUSION: Rates of hippocampal atrophy match both baseline cognitive status and the change in cognitive status over time in elderly persons who lie along the cognitive continuum from normal to MCI to AD.

Jack CR, Lowe VJ, Weigand SD, Wiste HJ, Senjem ML, Knopman DS, Shiung MM, Gunter JL, Boeve BF, Kemp BJ, Weiner M, Petersen RC, Anonymous00039. · Clifford R. Jack, Mayo Clinic, Diagnostic Radiology, 200 First Street SW, Rochester, MN 55905, USA. · Brain. · Pubmed #19339253 links to  free full text

Abstract: The purpose of this study was to use serial imaging to gain insight into the sequence of pathologic events in Alzheimer's disease, and the clinical features associated with this sequence. We measured change in amyloid deposition over time using serial (11)C Pittsburgh compound B (PIB) positron emission tomography and progression of neurodegeneration using serial structural magnetic resonance imaging. We studied 21 healthy cognitively normal subjects, 32 with amnestic mild cognitive impairment and 8 with Alzheimer's disease. Subjects were drawn from two sources--ongoing longitudinal registries at Mayo Clinic, and the Alzheimer's disease Neuroimaging Initiative (ADNI). All subjects underwent clinical assessments, MRI and PIB studies at two time points, approximately one year apart. PIB retention was quantified in global cortical to cerebellar ratio units and brain atrophy in units of cm(3) by measuring ventricular expansion. The annual change in global PIB retention did not differ by clinical group (P = 0.90), and although small (median 0.042 ratio units/year overall) was greater than zero among all subjects (P < 0.001). Ventricular expansion rates differed by clinical group (P < 0.001) and increased in the following order: cognitively normal (1.3 cm(3)/year) < amnestic mild cognitive impairment (2.5 cm(3)/year) < Alzheimer's disease (7.7 cm(3)/year). Among all subjects there was no correlation between PIB change and concurrent change on CDR-SB (r = -0.01, P = 0.97) but some evidence of a weak correlation with MMSE (r =-0.22, P = 0.09). In contrast, greater rates of ventricular expansion were clearly correlated with worsening concurrent change on CDR-SB (r = 0.42, P < 0.01) and MMSE (r =-0.52, P < 0.01). Our data are consistent with a model of typical late onset Alzheimer's disease that has two main features: (i) dissociation between the rate of amyloid deposition and the rate of neurodegeneration late in life, with amyloid deposition proceeding at a constant slow rate while neurodegeneration accelerates and (ii) clinical symptoms are coupled to neurodegeneration not amyloid deposition. Significant plaque deposition occurs prior to clinical decline. The presence of brain amyloidosis alone is not sufficient to produce cognitive decline, rather, the neurodegenerative component of Alzheimer's disease pathology is the direct substrate of cognitive impairment and the rate of cognitive decline is driven by the rate of neurodegeneration. Neurodegeneration (atrophy on MRI) both precedes and parallels cognitive decline. This model implies a complimentary role for MRI and PIB imaging in Alzheimer's disease, with each reflecting one of the major pathologies, amyloid dysmetabolism and neurodegeneration.

Josephs KA, Ahlskog JE, Parisi JE, Boeve BF, Crum BA, Giannini C, Petersen RC. · Department of Neurology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. · Arch Neurol. · Pubmed #19204156 No free full text.

Abstract: BACKGROUND: Neurodegenerative dementias are typically characterized by an insidious onset and a relatively slowly progressive course. Less common are patients with a rapidly progressive course to death. OBJECTIVE: To characterize patients with a neurodegenerative disease and a rapidly progressive course to death. DESIGN, SETTING, AND PATIENTS: Using a text word search for "rapid" and "dementia" in the same sentence, the Mayo Clinic Medical Records Linkage system was used to identify all patients evaluated between January 1, 2000, and September 30, 2007, with brain autopsy (N = 96) at a tertiary care medical center. Of these 96 patients, we included only those with disease duration of less than 4 years to death and with histological diagnosis of a neurodegenerative disease. MAIN OUTCOME MEASURES: Rapidly progressive dementia with death sooner than 4 years after onset and pathological diagnosis at our institution of a neurodegenerative disease. RESULTS: We included 22 patients (10 men). Although 8 cases (36%) had Creutzfeldt-Jakob disease (CJD), the rest had frontotemporal lobar degeneration with motor neuron degeneration (5 cases [23%]), a tauopathy (progressive supranuclear palsy or corticobasal degeneration) (4 cases [18%]), diffuse Lewy body disease (3 cases [14%]), or Alzheimer disease (2 cases [9%]). All of the patients with CJD died 12 months or sooner after onset, whereas the others had an illness duration longer than 12 months. Notably, all of the 3 patients with diffuse Lewy body disease but no others initially experienced a transient postoperative or illness-associated encephalopathy, then relative normality for 2 years, and finally a rapidly progressive dementia and decline to death in 4 to 12 months. CONCLUSIONS: Based on this cohort, although CJD is the most likely cause of a rapidly progressive neurodegenerative dementia, frontotemporal lobar degeneration with motor neuron degeneration, diffuse Lewy body disease, tauopathies, and Alzheimer disease can also cause a rapidly progressive dementia. If illness duration is beyond 12 months, a non-CJD neurodegenerative disease may be more likely than CJD to be the diagnosis.

Kantarci K, Petersen RC, Przybelski SA, Weigand SD, Shiung MM, Whitwell JL, Negash S, Ivnik RJ, Boeve BF, Knopman DS, Smith GE, Jack CR. · Department of Diagnostic Radiology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. · Arch Neurol. · Pubmed #19064749 No free full text.

Abstract: BACKGROUND: Although a majority of patients with amnestic mild cognitive impairment (aMCI) progress to Alzheimer disease, the natural history of nonamnestic MCI (naMCI) is less clear. Noninvasive imaging surrogates for underlying pathological findings in MCI would be clinically useful for identifying patients who may benefit from disease-specific treatments at the prodromal stage of dementia. OBJECTIVE: To determine the characteristic magnetic resonance imaging (MRI) and proton MR spectroscopy (1H MRS) profiles of MCI subtypes. DESIGN: Case-control study. SETTING: Community-based sample at a tertiary referral center. PATIENTS: Ninety-one patients with single-domain aMCI, 32 patients with multiple-domain aMCI, 20 patients with single- or multiple-domain naMCI, and 100 cognitively normal elderly subjects frequency-matched by age and sex. MAIN OUTCOME MEASURES: Posterior cingulate gyrus 1H MRS metabolite ratios, hippocampal volumes, and cerebrovascular disease on MRI. RESULTS: Patients with single-domain aMCI were characterized by small hippocampal volumes and elevated ratios of myo-inositol to creatine levels. Patients with naMCI on average had normal hippocampal volumes and 1H MRS metabolite ratios, but a greater proportion (3 of 20 patients [15%]) had cortical infarctions compared with patients with single-domain aMCI (6 of 91 [7%]). For characterization of MCI subtypes, 1H MRS and structural MRI findings were complementary. CONCLUSIONS: The MRI and 1H MRS findings in single-domain aMCI are consistent with a pattern similar to that of Alzheimer disease. Absence of this pattern on average in patients with naMCI suggests that cerebrovascular disease and other neurodegenerative diseases may be contributing to the cognitive impairment in many individuals with naMCI.

Kelley BJ, Boeve BF, Josephs KA. · Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA. · Arch Neurol. · Pubmed #19001170 No free full text.

Abstract: BACKGROUND: Onset of dementia before age 45 years presents a difficult clinical circumstance, having a broad differential diagnosis and numerous psychosocial implications for the patient and their family. Few data exist regarding the demographics characterizing this population or the etiologic diagnoses among those affected. OBJECTIVES: To characterize the demographic characteristics and the etiologic causes of dementia with age at onset younger than 45 years. DESIGN: Observational, retrospective, single-cohort study. SETTING: Multispecialty group academic medical center. PATIENTS: We searched the Mayo Clinic Rochester electronic Medical Record Linkage System to identify individuals who were seen for evaluation of progressive cognitive decline between the ages of 17 and 45 years from January 1996 through December 2006. This search identified 235 individuals who met the established inclusion and exclusion criteria. MAIN OUTCOME MEASURES: All available clinical, laboratory, magnetic resonance imaging, and pathological data were reviewed. RESULTS: Causes varied, with neurodegenerative etiologies accounting for 31.1% of the cohort; Alzheimer disease was uncommon. Autoimmune or inflammatory causes accounted for 21.3%. At last follow-up, 44 patients (18.7%) had an unknown etiology, despite exhaustive evaluation. Cause varied with age, with inborn errors of metabolism being more common before age 30 years and with neurodegenerative etiologies being more common after age 35 years. CONCLUSIONS: Young-onset dementia (age at onset, <45 years) includes a broad variety of etiologies, with few patients having a potentially treatable disorder. The etiologic spectrum and the relative percentages of patients within etiologic groups differed in important ways from existing reports of early-onset dementia (ie, age at onset, <65 years).

Geda YE, Roberts RO, Knopman DS, Petersen RC, Christianson TJ, Pankratz VS, Smith GE, Boeve BF, Ivnik RJ, Tangalos EG, Rocca WA. · Department of Psychiatry and Psychology, College of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. · Arch Gen Psychiatry. · Pubmed #18838636 No free full text.

Abstract: CONTEXT: Little is known about the population-based prevalence of neuropsychiatric symptoms in mild cognitive impairment (MCI). OBJECTIVE: To estimate the prevalence of neuropsychiatric symptoms in MCI and normal cognitive aging in a defined population. DESIGN: Cross-sectional study derived from an ongoing population-based prospective cohort study. SETTING: The Mayo Clinic Study of Aging. PARTICIPANTS: We studied a random sample of 1969 individuals without dementia from the target population of 9965 elderly persons residing in Olmsted County (Minnesota) on the prevalence date (October 1, 2004). Neuropsychiatric data were available for 319 of 329 subjects with MCI (97.0%) and 1590 of 1640 subjects with normal cognition (97.0%). Neurologic, cognitive, and neuropsychiatric data were obtained from the study participants. A classification of MCI, dementia, and normal cognitive aging was adjudicated by an expert consensus panel. Accordingly, 329 subjects were classified as having MCI and the remaining 1640 subjects were classified as having normal cognition. MAIN OUTCOME MEASURE: Neuropsychiatric Inventory Questionnaire score. RESULTS: Multivariate logistic regression analyses were conducted after adjusting for age, sex, and educational status. By considering both the odds ratio (OR) and the frequency of a symptom, the most distinguishing features between the 2 groups were apathy (OR, 4.53; 95% confidence interval [CI], 3.11-6.60; P < .001), agitation (3.60; 2.18-5.92; P < .001), anxiety (3.00; 2.01-4.48; P < .001), irritability 2.99; 2.11-4.22; P < .001), and depression (2.78; 2.06-3.76; P < .001). The OR was highest for delusion (8.12; 95% CI, 2.92-22.60; P < .001); however, it was rare in both subjects with MCI (11 of 319 [3.4%]) and those with normal cognition (6 of 1590 [0.4%]). Thus, the population attributable risk for delusion was only 2.62% compared with 14.60% for apathy. CONCLUSIONS: Nonpsychotic symptoms affected approximately 50% of subjects with MCI and 25% of subjects with normal cognition. In contrast, psychotic symptoms were rare.

Whitwell JL, Josephs KA, Murray ME, Kantarci K, Przybelski SA, Weigand SD, Vemuri P, Senjem ML, Parisi JE, Knopman DS, Boeve BF, Petersen RC, Dickson DW, Jack CR. · Department of Radiology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA. · Neurology. · Pubmed #18765650 No free full text.

Abstract: BACKGROUND: Neurofibrillary tangles (NFTs), composed of hyperphosphorylated tau proteins, are one of the pathologic hallmarks of Alzheimer disease (AD). We aimed to determine whether patterns of gray matter atrophy from antemortem MRI correlate with Braak staging of NFT pathology. METHODS: Eighty-three subjects with Braak stage III through VI, a pathologic diagnosis of low- to high-probability AD, and MRI within 4 years of death were identified. Voxel-based morphometry assessed gray matter atrophy in each Braak stage compared with 20 pathologic control subjects (Braak stages 0 through II). RESULTS: In pairwise comparisons with Braak stages 0 through II, a graded response was observed across Braak stages V and VI, with more severe and widespread loss identified at Braak stage VI. No regions of loss were identified in Braak stage III or IV compared with Braak stages 0 through II. The lack of findings in Braak stages III and IV could be because Braak stage is based on the presence of any NFT pathology regardless of severity. Actual NFT burden may vary by Braak stage. Therefore, tau burden was assessed in subjects with Braak stages 0 through IV. Those with high tau burden showed greater gray matter loss in medial and lateral temporal lobes than those with low tau burden. CONCLUSIONS: Patterns of gray matter loss are associated with neurofibrillary tangle (NFT) pathology, specifically with NFT burden at Braak stages III and IV and with Braak stage itself at higher stages. This validates three-dimensional patterns of atrophy on MRI as an approximate in vivo surrogate indicator of the full brain topographic representation of the neurodegenerative aspect of Alzheimer disease pathology.

Jicha GA, Parisi JE, Dickson DW, Cha RH, Johnson KA, Smith GE, Boeve BF, Petersen RC, Knopman DS. · Department of Neurology, Mayo Clinic, Rochester, MN, Jacksonville, FL, United States. · J Neurol Sci. · Pubmed #18653200 No free full text.

Abstract: The risk for Alzheimer's disease (AD) is influenced by both age and ApoE status. The present study addresses the associations of age and ApoE status on complex pathologic features in AD (n=81) including coexistent cerebrovascular disease (CVD), argyrophilic grain disease (AGD), and Lewy body disease (LBD). The frequency of coexistent cerebrovascular disease increased with increasing age. Age and ApoE status were differentially associated with atherosclerosis, lacunar infarctions, and microvascular pathology. Coexistent Lewy body pathology was negatively associated with age, dropping off abruptly after age 90. The presence of an ApoE epsilon4 allele was associated with an increased frequency of coexistent LBD. Logistic regression analyses demonstrated both dependent and independent effects of age and ApoE status on the presence of coexistent Lewy body pathology in AD. While the decreasing frequency of LBD in AD after age 90 could be partly accounted for by a lower probability of an ApoE epsilon4 allele, the independent association with age suggests either 1) a survival effect, 2) decreased incidence with advancing age, or 3) both.

Fujishiro H, Ferman TJ, Boeve BF, Smith GE, Graff-Radford NR, Uitti RJ, Wszolek ZK, Knopman DS, Petersen RC, Parisi JE, Dickson DW. · Department of Pathology and Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. · J Neuropathol Exp Neurol. · Pubmed #18596548 No free full text.

Abstract: There is limited information on the validity of the pathologic criteria of the Third Consortium on Dementia with Lewy bodies (CDLB), and none are based on prospectively diagnosed cases. In this study, the core clinical features of dementia with Lewy bodies (DLB) and the suggestive clinical feature of rapid eye movement sleep behavior disorder were assessed using a battery of standardized clinical instruments in 76 patients with the clinical diagnosis of either DLB or Alzheimer disease. At autopsy, 29 patients had high-likelihood, 17 had intermediate-likelihood, and 6 had low-likelihood DLB pathology. The frequency of core clinical features and the accuracy of the clinical diagnosis of probable DLB were significantly greater in high-likelihood than in low-likelihood cases. This is consistent with the concept that the DLB clinical syndrome is directly related to Lewy body pathology and inversely related to Alzheimer pathology. Thus, the Third Consortium on DLB neuropathologic criteria scheme performed reasonably well and are useful for estimating the likelihood of the premortem DLB syndrome based on postmortem findings. In view of differences in the frequency of clinically probable DLB in cases with Braak neurofibrillary tangle stages V (90%) and VI (20%) and diffuse cortical Lewy bodies, a possible modification of the scheme is to consider cases with neurofibrillary tangle stage VI to be low-likelihood DLB.

Hu WT, Josephs KA, Knopman DS, Boeve BF, Dickson DW, Petersen RC, Parisi JE. · Department of Neurology, Mayo Clinic, Rochester, MN, USA. · Acta Neuropathol. · Pubmed #18592255 No free full text.

Abstract: TAR DNA binding protein-43 (TDP-43) immunoreactive neuronal inclusions are detected in 20-30% of Alzheimer disease (AD) brains, but the distribution of this pathology has not been rigorously studied. In this report, we describe region-specific distribution and density of TDP-43 positive neuronal cytoplasmic inclusions (NCIs) in clinically demented individuals with high probability AD pathology, all with Braak neurofibrillary tangle stages of V or VI. Sections of hippocampus, amygdala, as well as temporal, frontal, and parietal neocortex, were analyzed with TDP-43 immunohistochemistry, and the density of NCIs was assessed using a semiquantitative scoring method. Of the 29 cases, six had TDP-43 positive NCIs in the amygdala only and seven had TDP-43 inclusions restricted to amygdala and hippocampus. In 16 cases, TDP-43 immunoreactivity was more widespread, affecting temporal, frontal or parietal neocortex. These findings indicate that medial temporal lobe limbic structures are vulnerable to TDP-43 pathology in advanced AD, and that the amygdala appears to be the most susceptible region. The distribution of the lesions in this cross-sectional analysis may suggest a progression of TDP-43 pathology in AD, with limbic structures in the medial temporal lobe affected first, followed by higher order association cortices.

Vemuri P, Whitwell JL, Kantarci K, Josephs KA, Parisi JE, Shiung MS, Knopman DS, Boeve BF, Petersen RC, Dickson DW, Jack CR. · Department of Radiology, Mayo Clinic Rochester, Rochester, MN 55905, USA. · Neuroimage. · Pubmed #18572417 No free full text.

Abstract: The clinical diagnosis of Alzheimer's disease (AD) does not exactly match the pathological findings at autopsy in every subject. Therefore, in-vivo imaging measures, such as Magnetic Resonance Imaging (MRI) that reflect underlying pathology, would be clinically useful independent supplementary measures of disease stage. We have developed an algorithm that extracts atrophy information from individual patient's 3D MRI scans and assigns a STructural Abnormality iNDex (STAND)-score to the scan based on the degree of atrophy in comparison to patterns extracted from a large library of clinically well characterized AD and CN (cognitively normal) subject's MRI scans. STAND-scores can be adjusted for demographics to give adjusted-STAND (aSTAND)-scores which are >0 for subjects with brains identified as abnormal by the algorithm. Since histopathological findings are considered to represent the "ground truth", our objective was to assess the sensitivity of aSTAND-scores to pathological AD staging. This was done by comparing antemortem MRI based aSTAND-scores with postmortem grading of disease severity in 101 subjects who had both antemortem MRI and postmortem Braak neurofibrillary tangle (NFT) staging. We found a rank correlation of 0.62 (p<0.0001) between Braak NFT stage and aSTAND-scores. The results show that optimally extracted information from MRI scans such as STAND-scores accurately capture the severity of neuronal pathology and can be used as an independent approximate surrogate marker for in-vivo pathological staging as well as for early identification of AD in individual subjects.

Kantarci K, Knopman DS, Dickson DW, Parisi JE, Whitwell JL, Weigand SD, Josephs KA, Boeve BF, Petersen RC, Jack CR. · Departments of Radiology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. · Radiology. · Pubmed #18566174 links to  free full text

Abstract: PURPOSE: To determine the neuropathologic correlates of antemortem hydrogen 1 ((1)H) magnetic resonance (MR) spectroscopy metabolite measurements in subjects with Alzheimer disease (AD)-type pathology. MATERIALS AND METHODS: This study was approved by the institutional review board and was compliant with HIPAA regulations. Informed consent was obtained from each subject. The authors identified 54 subjects who underwent antemortem (1)H MR spectroscopy and were clinically healthy or had AD-type pathology with low to high likelihood of AD according to National Institute on Aging-Reagan neuropathologic criteria at autopsy. They investigated the associations between (1)H MR spectroscopy metabolite measurements and Braak neurofibrillary tangle stage (Braak stage), neuritic plaque score, and AD likelihood, with adjustments for subject age, subject sex, and time between (1)H MR spectroscopy and death. RESULTS: Decreases in N-acetylaspartate-to-creatine ratio, an index of neuronal integrity, and increases in myo-inositol-to-creatine ratio were associated with higher Braak stage, higher neuritic plaque score, and greater likelihood of AD. The N-acetylaspartate-to-myo-inositol ratio proved to be the strongest predictor of the pathologic likelihood of AD. The strongest association observed was that between N-acetylaspartate-to-myo-inositol ratio and Braak stage (R(N)(2) = 0.47, P < .001). CONCLUSION: Antemortem (1)H MR spectroscopy metabolite changes correlated with AD-type pathology seen at autopsy. The study findings validated (1)H MR spectroscopy metabolite measurements against the neuropathologic criteria for AD, and when combined with prior longitudinal (1)H MR spectroscopy findings, indicate that these measurements could be used as biomarkers for disease progression in clinical trials.

Josephs KA, Whitwell JL, Knopman DS, Hu WT, Stroh DA, Baker M, Rademakers R, Boeve BF, Parisi JE, Smith GE, Ivnik RJ, Petersen RC, Jack CR, Dickson DW. · Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA. · Neurology. · Pubmed #18401022 No free full text.

Abstract: BACKGROUND: TAR DNA-binding protein 43 (TDP-43) is one of the major disease proteins in frontotemporal lobar degeneration with ubiquitin immunoreactivity. Approximately one-fourth of subjects with pathologically confirmed Alzheimer disease (AD) have abnormal TDP-43 (abTDP-43) immunoreactivity. The aim of this study was to determine whether subjects with pathologically confirmed AD and abTDP-43 immunoreactivity have distinct clinical, neuropsychological, imaging, or pathologic features compared with subjects with AD without abTDP-43 immunoreactivity. METHODS: Eighty-four subjects were identified who had a pathologic diagnosis of AD, neuropsychometric testing, and volumetric MRI. Immunohistochemistry for TDP-43 was performed on sections of hippocampus and medial temporal lobe, and positive cases were classified into one of three types. Neuropsychometric data were collated and compared in subjects with and without abTDP-43 immunoreactivity. Voxel-based morphometry was used to assess patterns of gray matter atrophy in subjects with and without abTDP-43 immunoreactivity compared with age- and sex-matched controls. RESULTS: Twenty-nine (34%) of the 84 AD subjects had abTDP-43 immunoreactivity. Those with abTDP-43 immunoreactivity were older at onset and death and performed worse on the Clinical Dementia Rating scale, Mini-Mental State Examination, and Boston Naming Test than subjects without abTDP-43 immunoreactivity. Subjects with and without abTDP-43 immunoreactivity had medial temporal and temporoparietal gray matter loss compared with controls; however, those with abTDP-43 immunoreactivity showed greater hippocampal atrophy. Multivariate logistic regression adjusting for age at death demonstrated that hippocampal sclerosis was the only pathologic predictor of abTDP-43 immunoreactivity. CONCLUSIONS: The presence of abnormal TDP-43 immunoreactivity is associated with a modified Alzheimer disease clinicopathologic and radiologic phenotype.

Jack CR, Lowe VJ, Senjem ML, Weigand SD, Kemp BJ, Shiung MM, Knopman DS, Boeve BF, Klunk WE, Mathis CA, Petersen RC. · Department of Diagnostic Radiology, Mayo Clinic and Foundation, Rochester, MN 55905, USA. · Brain. · Pubmed #18263627 links to  free full text

Abstract: To date, most diagnostic imaging comparisons between amyloid labelling ligands and other imaging modalities have been between the use of amyloid labelling ligand (11)C Pittsburgh Compound B (PiB) and FDG-PET. Our objectives were to compare cognitive performance and diagnostic group-wise discrimination between cognitively normal, amnestic mild cognitive impairment (MCI) and Alzheimer's disease subjects with MRI-based measures of hippocampal volume and PiB retention, and secondly to evaluate the topographic distribution of PiB retention and grey matter loss using 3D voxel-wise methods. Twenty cognitively normal, 17 amnestic MCI and 8 probable Alzheimer's disease subjects were imaged with both MRI and PiB. PiB retention was quantified as the ratio of uptake in cortical to cerebellar regions of interest (ROIs) 40-60 min post-injection. A global cortical PiB retention summary measure was derived from six cortical ROIs. Statistical parametric mapping (SPM) and voxel-based morphometry (VBM) were used to evaluate PiB retention and grey matter loss on a 3D voxel-wise basis. Alzheimer's disease subjects had high global cortical PiB retention and low hippocampal volume; most cognitively normal subjects had low PiB retention and high hippocampal volume; and on average amnestic MCI subjects were intermediate on both PiB and hippocampal volume. A target-to-cerebellar ratio of 1.5 was used to designate subjects with high or low PiB cortical retention. All Alzheimer's disease subjects fell above this ratio, as did 6 out of 20 cognitively normal subjects and 9 out of 17 MCI subjects, indicating bi-modal PiB retention in the latter two groups. Interestingly, we found no consistent differences in learning and memory performance between high versus low PiB cognitively normal or amnestic MCI subjects. The SPM/VBM voxel-wise comparisons of Alzheimer's disease versus cognitively normal subjects provided complementary information in that clear and meaningful similarities and differences in topographical distribution of amyloid deposition and grey matter loss were shown. The frontal lobes had high PiB retention with little grey matter loss, anteromedial temporal areas had low PiB retention with significant grey matter loss, whereas lateral temporoparietal association cortex displayed both significant PiB retention and grey matter loss. A voxel-wise SPM conjunction analysis revealed that subjects with high PiB retention shared a common PiB retention topographical pattern regardless of clinical category, and this matched that of amyloid plaque distribution from autopsy studies of Alzheimer's disease. Both global cortical PiB retention and hippocampal volumes demonstrated significant correlation in the expected direction with cognitive testing performance; however, correlations were stronger with MRI than PiB. Pair-wise inter-group diagnostic separation was significant for all group-wise pairs for both PiB and hippocampal volume with the exception of the comparison of cognitively normal versus amnestic MCI, which was not significant for PiB. PiB and MRI provided complementary information such that clinical diagnostic classification using both methods was superior to using either in isolation.

Josephs KA, Whitwell JL, Duffy JR, Vanvoorst WA, Strand EA, Hu WT, Boeve BF, Graff-Radford NR, Parisi JE, Knopman DS, Dickson DW, Jack CR, Petersen RC. · Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA. · Neurology. · Pubmed #18166704 No free full text.

Abstract: BACKGROUND: The pathology causing progressive aphasia is typically a variant of frontotemporal lobar degeneration, especially with ubiquitin-positive inclusions (FTLD-U). Less commonly the underlying pathology is Alzheimer disease (AD). OBJECTIVE: To compare clinicopathologic and MRI features of subjects with progressive aphasia and AD pathology to subjects with aphasia and FTLD-U pathology and subjects with typical AD. METHODS: We identified 5 subjects with aphasia and AD pathology and 5 with aphasia and FTLD-U pathology with an MRI from a total of 216 aphasia subjects. Ten subjects with typical AD clinical features and AD pathology were also identified. All subjects with AD pathology underwent pathologic reanalysis with TDP-43 immunohistochemistry. Voxel-based morphometry (VBM) was used to assess patterns of gray matter atrophy in the aphasia cases with AD pathology, aphasia cases with FTLD-U, and typical AD cases with AD pathology, compared with a normal control group. RESULTS: All aphasic subjects had fluent speech output. However, those with AD pathology had better processing speed than those with FTLD-U pathology. Immunohistochemistry with TDP-43 antibodies was negative. VBM revealed gray matter atrophy predominantly in the temporoparietal cortices, with notable sparing of the hippocampus in the aphasia with AD subjects. In comparison, the aphasic subjects with FTLD-U showed sparing of the parietal lobe. Typical AD subjects showed temporoparietal and hippocampal atrophy. CONCLUSIONS: A temporoparietal pattern of atrophy on MRI in patients with progressive fluent aphasia and relatively preserved processing speed is suggestive of underlying Alzheimer disease pathology rather than frontotemporal lobar degeneration with ubiquitin-only immunoreactive changes.

Vemuri P, Gunter JL, Senjem ML, Whitwell JL, Kantarci K, Knopman DS, Boeve BF, Petersen RC, Jack CR. · Department of Radiology, Mayo Clinic 200 1st St SW, Rochester, MN 55905, USA. · Neuroimage. · Pubmed #18054253 links to  free full text

Abstract: OBJECTIVE: To develop and validate a tool for Alzheimer's disease (AD) diagnosis in individual subjects using support vector machine (SVM)-based classification of structural MR (sMR) images. BACKGROUND: Libraries of sMR scans of clinically well characterized subjects can be harnessed for the purpose of diagnosing new incoming subjects. METHODS: One hundred ninety patients with probable AD were age- and gender-matched with 190 cognitively normal (CN) subjects. Three different classification models were implemented: Model I uses tissue densities obtained from sMR scans to give STructural Abnormality iNDex (STAND)-score; and Models II and III use tissue densities as well as covariates (demographics and Apolipoprotein E genotype) to give adjusted-STAND (aSTAND)-score. Data from 140 AD and 140 CN were used for training. The SVM parameter optimization and training were done by four-fold cross validation (CV). The remaining independent sample of 50 AD and 50 CN was used to obtain a minimally biased estimate of the generalization error of the algorithm. RESULTS: The CV accuracy of Model II and Model III aSTAND-scores was 88.5% and 89.3%, respectively, and the developed models generalized well on the independent test data sets. Anatomic patterns best differentiating the groups were consistent with the known distribution of neurofibrillary AD pathology. CONCLUSIONS: This paper presents preliminary evidence that application of SVM-based classification of an individual sMR scan relative to a library of scans can provide useful information in individual subjects for diagnosis of AD. Including demographic and genetic information in the classification algorithm slightly improves diagnostic accuracy.

Jack CR, Weigand SD, Shiung MM, Przybelski SA, O'Brien PC, Gunter JL, Knopman DS, Boeve BF, Smith GE, Petersen RC. · Department of Radiology, Mayo Clinic and Foundation, Rochester, MN 55905, USA. · Neurology. · Pubmed #18032747 No free full text.

Abstract: BACKGROUND: We tested if rates of brain atrophy accelerate in individuals with amnestic mild cognitive impairment (aMCI) as they progress to typical late onset Alzheimer disease (AD). We included comparisons to subjects with aMCI who did not progress (labeled aMCI-S) and also to cognitively normal elderly subjects (CN). METHODS: We studied 46 subjects with aMCI who progressed to AD (labeled aMCI-P), 46 CN, and 23 aMCI-S. All subjects must have had three or more serial MRI scans. Rates of brain shrinkage and ventricular expansion were measured across all available serial MRI scans in each subject. Change in volumes relative to the point at which subjects progressed to a clinical diagnosis of AD (the index date) was modeled in aMCI-P. Change in volumes relative to age was modeled in all three clinical groups. RESULTS: In aMCI-P the change in pre to post index rate (i.e., acceleration) of ventricular expansion was 1.7 cm(3)/year, and acceleration in brain shrinkage was 5.3 cm(3)/year. Brain volume declined and ventricular volume increased in all three groups with age. Volume changes decelerated with increasing age in aMCI-P, and to a lesser extent in aMCI-S, but were linear in the matched CN. Among all subjects with aMCI, rates of atrophy were greater in apolipoprotein E epsilon 4 carriers than noncarriers. CONCLUSIONS: Rates of atrophy accelerate as individuals progress from amnestic mild cognitive impairment (aMCI) to typical late onset Alzheimer disease (AD). Rates of atrophy are greater in younger than older subjects with aMCI who progressed to AD and subjects with aMCI who did not progress. We did not find that atrophy rates varied with age in 70- to 90-year-old cognitively normal subjects.

Whitwell JL, Jack CR, Pankratz VS, Parisi JE, Knopman DS, Boeve BF, Petersen RC, Dickson DW, Josephs KA. · Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA. · Neuroimage. · Pubmed #17988893 links to  free full text

Abstract: Rates of brain loss have been shown to accelerate over time in early Alzheimer disease (AD); however the trajectory of change in frontotemporal lobar degeneration with ubiquitin immunoreactive-changes (FTLD-U) is unknown. This study compared the progression of atrophy over multiple MRI in subjects with autopsy-confirmed AD and FTLD-U. Nine subjects with autopsy-confirmed FTLD-U and nine with autopsy-confirmed AD were identified that had three or more serial MRI. The boundary-shift integral was used to calculate change over time in whole-brain and ventricular volume. A hierarchical regression model was used to estimate the slope of volume change in AD and FTLD-U over time and to estimate differences in the slopes across the subject groups. Whole-brain volume loss did not deviate from a linear rate over time in both AD and FTLD-U subjects, although this may be due to limited sample size. The FTLD-U subjects had a faster rate (23 ml/year) than the AD subjects (10 ml/year). The rate of ventricular expansion accelerated over time. At the point when each subject had a Clinical Dementia Rating Sum-of-Boxes score of 6, the annual rate was 7 ml/year in FTLD-U and 5 ml/year in AD. These rates of change increased by an estimated 1.66 ml/year in FTLD-U and 0.44 ml/year in AD, although these estimates were not significantly different between the two groups. The trajectories of brain and ventricular changes were similar in AD and FTLD-U suggesting that it is independent of pathology, although subjects with FTLD-U show a more rapidly progressive decline.

Kelley BJ, Haidar W, Boeve BF, Baker M, Graff-Radford NR, Krefft T, Frank AR, Jack CR, Shiung M, Knopman DS, Josephs KA, Parashos SA, Rademakers R, Hutton M, Pickering-Brown S, Adamson J, Kuntz KM, Dickson DW, Parisi JE, Smith GE, Ivnik RJ, Petersen RC. · Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA. · Neurobiol Aging. · Pubmed #17949857 No free full text.

Abstract: Mutations in progranulin (PGRN) are associated with frontotemporal dementia with or without parkinsonism. We describe the prominent phenotypic variability within and among eight kindreds evaluated at Mayo Clinic Rochester and/or Mayo Clinic Jacksonville in whom mutations in PGRN were found. All available clinical, genetic, neuroimaging and neuropathologic data was reviewed. Age of onset ranged from 49 to 88 years and disease duration ranged from 1 to 14 years. Clinical diagnoses included frontotemporal dementia (FTD), primary progressive aphasia, FTD with parkinsonism, parkinsonism, corticobasal syndrome, Alzheimer's disease, amnestic mild cognitive impairment, and others. One kindred exhibited maximal right cerebral hemispheric atrophy in all four affected individuals, while another had maximal left hemisphere involvement in all three of the affected. Neuropathologic examination of 13 subjects revealed frontotemporal lobar degeneration with ubiquitin-positive inclusions plus neuronal intranuclear inclusions in all cases. Age of onset, clinical phenotypes and MRI findings associated with most PGRN mutations varied significantly both within and among kindreds. Some kindreds with PGRN mutations exhibited lateralized topography of degeneration across all affected individuals.

Whitwell JL, Shiung MM, Przybelski SA, Weigand SD, Knopman DS, Boeve BF, Petersen RC, Jack CR. · Department of Radiology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA. · Neurology. · Pubmed #17898323 No free full text.

Abstract: OBJECTIVE: To compare the patterns of gray matter loss in subjects with amnestic mild cognitive impairment (aMCI) who progress to Alzheimer disease (AD) within a fixed clinical follow-up time vs those who remain stable. METHODS: Twenty-one subjects with aMCI were identified from the Mayo Clinic Alzheimer's research program who remained clinically stable for their entire observed clinical course (aMCI-S), where the minimum required follow-up time from MRI to last follow-up assessment was 3 years. These subjects were age- and gender-matched to 42 aMCI subjects who progressed to AD within 18 months of the MRI (aMCI-P). Each subject was then age- and gender-matched to a control subject. Voxel-based morphometry (VBM) was used to assess patterns of gray matter atrophy in the aMCI-P and aMCI-S groups compared to the control group, and compared to each other. RESULTS: The aMCI-P group showed bilateral loss affecting the medial and inferior temporal lobe, temporoparietal association neocortex, and frontal lobes, compared to controls. The aMCI-S group showed no regions of gray matter loss when compared to controls. When the aMCI-P and aMCI-S groups were compared directly, the aMCI-P group showed greater loss in the medial and inferior temporal lobes, the temporoparietal neocortex, posterior cingulate, precuneus, anterior cingulate, and frontal lobes than the aMCI-S group. CONCLUSIONS: The regions of loss observed in subjects with amnestic mild cognitive impairment (aMCI) who progressed to Alzheimer disease (AD) within 18 months of the MRI are typical of subjects with AD. The lack of gray matter loss in subjects with aMCI who remained clinically stable for their entire observed clinical course is consistent with the notion that patterns of atrophy on MRI at baseline map well onto the subsequent clinical course.

Josephs KA, Whitwell JL, Ahmed Z, Shiung MM, Weigand SD, Knopman DS, Boeve BF, Parisi JE, Petersen RC, Dickson DW, Jack CR. · Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA. · Ann Neurol. · Pubmed #17894374 No free full text.

Abstract: OBJECTIVE: To test the hypothesis that beta-amyloid (Abeta) burden is associated with rates of brain atrophy. METHODS: Forty-five subjects who had been prospectively studied, died, and had an autopsy diagnosis of low, intermediate, or high probability of Alzheimer's disease who had two volumetric head magnetic resonance imaging scans were identified. Compact and total (compact + diffuse) Abeta burden was measured using a computerized image analyzer with software program to detect the proportion of gray matter occupied by Abeta. Visual ratings of Abeta burden were also performed. The boundary shift integral was used to calculate change over time in whole-brain and ventricular volume. All boundary shift integral results were annualized by adjusting for scan interval. Demographics, cognitive measures, clinical diagnoses, apolipoprotein E genotype, neurofibrillary tangle (NFT) pathology, and vascular lesion burden were determined. RESULTS: There was no correlation between compact or total Abeta burden, or visual Abeta ratings, and rates of brain loss or ventricular expansion in all subjects. However, significant correlations were observed between rates of brain loss and age, Braak NFT stage, and change over time in cognitive measures. These features also correlated with rates of ventricular expansion. The rates of brain loss and ventricular expansion were greater in demented compared with nondemented subjects. INTERPRETATION: These findings suggest that rate of brain volume loss is not determined by the amount of insoluble Abeta in the gray matter.

Whitwell JL, Petersen RC, Negash S, Weigand SD, Kantarci K, Ivnik RJ, Knopman DS, Boeve BF, Smith GE, Jack CR. · Department of Radiology, Mayo Clinic, Rochester, Minnesota 55905, USA. · Arch Neurol. · Pubmed #17698703 links to  free full text

Abstract: BACKGROUND: In most patients, mild cognitive impairment (MCI) represents the clinically evident prodromal phase of dementia. This is most well established in amnestic MCI, which is most commonly a precursor to Alzheimer disease (AD). It follows, however, that subjects with MCI who have impairment in nonmemory domains may progress to non-AD degenerative dementias. OBJECTIVE: To investigate patterns of cerebral atrophy associated with specific subtypes of MCI. DESIGN: Case-control study. SETTING: Community-based sample at a tertiary referral center. PATIENTS: One hundred forty-five subjects with MCI and 145 age- and sex-matched cognitively normal control subjects. Mild cognitive impairment was classified as amnestic, single cognitive domain; amnestic, multiple domain; nonamnestic, single domain; and nonamnestic, multiple domain. Subjects with nonamnestic single-domain MCI were classified into language, attention/executive, and visuospatial subgroups on the basis of specific cognitive impairment. MAIN OUTCOME MEASURE: Patterns of gray matter loss in the MCI groups compared with control subjects, assessed using voxel-based morphometry. RESULTS: Subjects in the amnestic single- and multiple-domain groups showed loss in the medial and inferior temporal lobes compared with control subjects, and those in the multiple-domain group also had involvement of the posterior temporal lobe, parietal association cortex, and posterior cingulate. Subjects in the nonamnestic single-domain group with language impairment showed loss in the left anterior inferior temporal lobe. The group with attention/executive deficits showed loss in the basal forebrain and hypothalamus. No coherent patterns of loss were observed in the other subgroups. CONCLUSIONS: The pattern of atrophy in the amnestic MCI groups is consistent with the concept that MCI in most of these subjects represents prodromal AD. However, the varying patterns in the language and attention/executive subgroups suggest that these subjects may have a different underlying disorder.

Smith GE, Pankratz VS, Negash S, Machulda MM, Petersen RC, Boeve BF, Knopman DS, Lucas JA, Ferman TJ, Graff-Radford N, Ivnik RJ. · Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN 55905, USA. · Neurology. · Pubmed #17620545 No free full text.

Abstract: OBJECTIVE: To compare logistic and bilogistic models to describe the pattern of cognitive decline in the preclinical phase of Alzheimer disease (AD). METHODS: We conducted mixed effects modeling of Mayo Cognitive Factors Scores to determine the longitudinal pattern of cognitive decline in the period 10 years prior to and 5 years following a clinical diagnosis of AD. Our analysis included 199 people that eventually received a diagnosis of clinically probable AD. Participants had at least two neuropsychological evaluations including one before the evaluation at which they received the AD diagnosis. RESULTS: A bilogistic model, including terms for a plateau in the course of cognitive decline, better fit longitudinal memory scores than a simple logistic model. On average the plateau began about 4 years prior to the clinical diagnosis of AD and ended with a decline that probably contributed to the clinical diagnosis of AD. A similar plateau was not evident in four other cognitive domains. CONCLUSIONS: The current findings may support proposed compensatory hypotheses involving redundant memory systems, up-regulation of neurotransmitters, or recruitment of other neural networks.

Whitwell JL, Przybelski SA, Weigand SD, Knopman DS, Boeve BF, Petersen RC, Jack CR. · Department of Radiology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA. · Brain. · Pubmed #17533169 links to  free full text

Abstract: Mild cognitive impairment (MCI), particularly the amnestic subtype (aMCI), is considered as a transitional stage between normal aging and a diagnosis of clinically probable Alzheimer's disease (AD). The aMCI construct is particularly useful as it provides an opportunity to assess a clinical stage which in most subjects represents prodromal AD. The aim of this study was to assess the progression of cerebral atrophy over multiple serial MRI during the period from aMCI to progression to AD. Thirty-three subjects were selected that fulfilled clinical criteria for aMCI and had three serial MRI scans: the first scan approximately 3 years before the diagnosis of AD, the second scan approximately 1 year before, and the third scan at the time of the diagnosis of AD. A group of 33 healthy controls were age and gender-matched to the study cohort. Voxel-based morphometry (VBM) was used to assess patterns of grey matter atrophy in the aMCI subjects at each time-point compared to the control group. Customized templates and prior probability maps were used to avoid normalization and segmentation bias. The pattern of grey matter loss in the aMCI subject scans that were 3 years before the diagnosis of AD was focused primarily on the medial temporal lobes, including the amygdala, anterior hippocampus and entorhinal cortex, with some additional involvement of the fusiform gyrus, compared to controls. The extent and magnitude of the cerebral atrophy further progressed by the time the subjects were 1 year before the diagnosis of AD. At this point atrophy in the temporal lobes spread to include the middle temporal gyrus, and extended into more posterior regions of the temporal lobe to include the entire extent of the hippocampus. The parietal lobe also started to become involved. By the time the subjects had progressed to a clinical diagnosis of AD the pattern of grey matter atrophy had become still more widespread with more severe involvement of the medial temporal lobes and the temporoparietal association cortices and, for the first time, substantial involvement of the frontal lobes. This pattern of progression fits well with the Braak and Braak neurofibrillary pathological staging scheme in AD. It suggests that the earliest changes occur in the anterior medial temporal lobe and fusiform gyrus, and that these changes occur at least 3 years before progression to the diagnosis of AD. These results also suggest that 3D patterns of grey matter atrophy may help to predict the time to the first diagnosis of AD in subjects with aMCI.