Alzheimer Disease: Josephs KA

Ridha B, Josephs KA. · Dementia Research Center, Institute of Neurology and Neurosurgery, Queen Square, London, UK. · Neurologist. · Pubmed #16547442 No free full text.

Abstract: BACKGROUND: Young-onset dementia is best defined as dementia presenting at age less than 65 years. And, while cognitive impairment in the elderly is dominated by dementia of the Alzheimer type, young-onset dementia has a vast differential diagnosis. REVIEW SUMMARY: This article reviews an extensive differential diagnosis for young-onset dementia by utilizing different clues in the historical records and laboratory findings to aid with diagnosis. Laboratory testing should be completed in at least 2 stages. In the first stage, referred to as the first "wave," we suggest more routine testing, particularly for treatable causes of dementia. The second "wave," which we also outline, emphasizes more esoteric testing that may require referral to a tertiary care medical facility. The manuscript is divided into 2 parts, with part 1 focusing on clues from the historical data, while part 2 focuses on laboratory abnormalities. CONCLUSION: Unlike dementia presenting in the elderly, the differential diagnosis in young-onset dementia is vast. A thorough historical review of the symptoms, with special emphasis on the pattern of cognitive impairment, temporal profile of the disease, detailed family history, and extensive but coordinated laboratory and ancillary testing, may yield subtle clues to the diagnosis.

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.

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).

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.

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.

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.

Josephs KA. · Divisions of Behavioral Neurology and Movement Disorders, Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA. · Arch Neurol. · Pubmed #18071040 links to  free full text

Abstract: BACKGROUND: Capgras syndrome is characterized by a delusional belief that a person has been replaced by an imposter. It has been described in psychiatric and neurological (neurodegenerative and nonneurodegenerative) diseases. OBJECTIVES: To determine whether the clinical and demographic features of subjects with Capgras syndrome differ when the syndrome is associated with neurodegenerative compared with nonneurodegenerative diseases, and whether features differ across different neurodegenerative diseases. DESIGN: Retrospective study. SETTING: Tertiary care medical center. Patients Forty-seven subjects with Capgras syndrome. RESULTS: Thirty-eight of the subjects with Capgras syndrome (81%) had a neurodegenerative disease, most commonly Lewy body disease. Capgras syndrome occurred at a younger age of onset in those with a nonneurodegenerative disease (51 vs 72 years) (P < .001) co-occurring with paranoid schizophrenia, schizoaffective disorder, and methamphetamine abuse and immediately after cerebrovascular events. Of those with Capgras syndrome and Lewy body disease, 100% had visual hallucinations compared with only one of those with Alzheimer disease (14%). CONCLUSIONS: Capgras syndrome is more commonly associated with neurodegenerative diseases, especially Lewy body disease, where visual hallucinations always coexist. In the absence of a neurodegenerative disease, the onset of Capgras syndrome occurs at a significantly younger age and can be associated with psychiatric disease, cerebrovascular events, and illicit drug use.

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.

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, Jack CR, Parisi JE, Knopman DS, Boeve BF, Petersen RC, Ferman TJ, Dickson DW, Josephs KA. · Department of Radiology, Mayo Clinic Rochester, Rochester, MN 55905, USA. · Brain. · Pubmed #17347250 links to  free full text

Abstract: Neurodegenerative disorders are pathologically characterized by the deposition of abnormal proteins in the brain. It is likely that future treatment trials will target the underlying protein biochemistry and it is therefore increasingly important to be able to distinguish between different pathologies during life. The aim of this study was to determine whether rates of brain atrophy differ in neurodegenerative dementias that vary by pathological diagnoses and characteristic protein biochemistry. Fifty-six autopsied subjects were identified with a clinical diagnosis of dementia and two serial head MRI. Subjects were subdivided based on pathological diagnoses into Alzheimer's disease, dementia with Lewy bodies (DLB), mixed Alzheimer's disease/DLB, frontotemporal lobar degeneration with ubiquitin-only-immunoreactive changes (FTLD-U), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). Twenty-five controls were matched by age, gender and scan interval, to the study cohort. The boundary-shift integral was used to calculate change over time in whole brain (BBSI) and ventricular volume (VBSI). All BSI results were annualized by adjusting for scan interval. The rates of whole brain atrophy and ventricular expansion were significantly increased compared to controls in the Alzheimer's disease, mixed Alzheimer's disease/DLB, FTLD-U, CBD and PSP groups. However, atrophy rates in the DLB group were not significantly different from control rates of atrophy. The largest rates of atrophy were observed in the CBD group which had a BBSI of 2.3% and VBSI of 16.2%. The CBD group had significantly greater rates of BBSI and VBSI than the DLB, mixed Alzheimer's disease/DLB, Alzheimer's disease and PSP groups, with a similar trend observed when compared to the FTLD-U group. The FTLD-U group showed the next largest rates with a BBSI of 1.7% and VBSI of 9.6% which were both significantly greater than the DLB group. There was no significant difference in the rates of atrophy between the Alzheimer's disease, mixed Alzheimer's disease/DLB and PSP groups, which all showed similar rates of atrophy; BBSI of 1.1, 1.3 and 1.0% and VBSI of 8.3, 7.2 and 10.9%, respectively. Rates of atrophy therefore differ according to the pathological diagnoses and underlying protein biochemistry. While rates are unlikely to be useful in differentiating Alzheimer's disease from cases with mixed Alzheimer's disease/DLB pathology, they demonstrate important pathophysiological differences between DLB and those with mixed Alzheimer's disease/DLB and Alzheimer's disease pathology, and between those with CBD and PSP pathology.

Whitwell JL, Weigand SD, Shiung MM, Boeve BF, Ferman TJ, Smith GE, Knopman DS, Petersen RC, Benarroch EE, Josephs KA, Jack CR. · Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA. · Brain. · Pubmed #17267521 links to  free full text

Abstract: Dementia with Lewy bodies (DLB) is the second most common cause of degenerative dementia after Alzheimer's disease. However, unlike the latter, the patterns of cerebral atrophy associated with DLB have not been well established. The aim of this study was to identify a signature pattern of cerebral atrophy in DLB and to compare it with the pattern found in Alzheimer's disease. Seventy-two patients that fulfilled clinical criteria for probable DLB were age- and gender-matched to 72 patients with probable Alzheimer's disease and 72 controls. Voxel-based morphometry (VBM) was used to assess patterns of grey matter (GM) atrophy in the two patient groups, relative to controls, after correction for multiple comparisons (P < 0.05). Study-specific templates and prior probability maps were used to avoid normalization and segmentation bias. Region-of-interest (ROI) analyses were also performed comparing loss of the midbrain, substantia innominata (SI), temporoparietal cortex and hippocampus between the groups. The DLB group showed very little cortical involvement on VBM with regional GM loss observed primarily in the dorsal midbrain, SI and hypothalamus. In comparison, the Alzheimer's disease group showed a widespread pattern of GM loss involving the temporoparietal association cortices and the medial temporal lobes. The SI and dorsal midbrain were involved in Alzheimer's disease; however, they were not identified as a cluster of loss discrete from uninvolved surrounding areas, as observed in the DLB group. On direct comparison between the two groups, the Alzheimer's disease group showed greater loss in the medial temporal lobe and inferior temporal regions than the DLB group. The ROI analysis showed reduced SI and midbrain GM in both patient groups, with a trend for more reduction of SI GM in Alzheimer's disease than DLB, and more reduction of midbrain in DLB than Alzheimer's disease. Significantly greater loss in the hippocampus and temporo-parietal cortex was observed in the Alzheimer's disease patients when the two patient groups were compared. A pattern of relatively focused atrophy of the midbrain, hypothalamus and SI, with a relative sparing of the hippocampus and temporoparietal cortex is, therefore, suggestive of DLB and this may aid in the differentiation of DLB from Alzheimer's disease. These findings support recent pathological studies showing an ascending pattern of Lewy body progression from brainstem to basal areas of the brain. Damage to this network of structures in DLB may affect a number of different neurotransmitter systems which in turn may contribute to a number of the core clinical features of DLB.

Klos KJ, Ahlskog JE, Kumar N, Cambern S, Butz J, Burritt M, Fealey RD, Cowl CT, Parisi JE, Josephs KA. · Department of Neurology, Mayo Clinic, Rochester, MN, USA. · Neurology. · Pubmed #17159105 No free full text.

Abstract: BACKGROUND: Chronic liver failure may be associated with pallidal MRI T1 hyperintensity and heterogeneous neurologic syndromes, including parkinsonism, cognitive impairment, and others. Manganese accumulation may be responsible for the imaging and clinical findings. OBJECTIVE: To measure manganese plus other metal concentrations in pallidum and additional brain regions and to examine the corresponding neuropathology in cases of chronic liver failure. METHODS: Regional brain metal concentrations were measured in seven chronic liver failure cases, four with pallidal T1 hyperintensity and three with normal MRI, plus five controls. Neuropathologic examination employed alpha-synuclein and tau immunohistochemistry. RESULTS: In patients with pallidal T1 hyperintensity, pallidal manganese concentrations were increased sevenfold over controls and over fourfold vs liver patients with normal MRI; manganese concentrations were also significantly elevated in all other brain regions. Copper was additionally increased in all brain regions, whereas other metal concentrations were similar to control values. Neuropathology revealed mild to moderate Alzheimer type II gliosis in the liver failure groups and negative alpha-synuclein and tau immunostaining except for one case (intermediate Alzheimer disease pathology). CONCLUSION: In chronic liver failure, manganese accumulation is responsible for the pallidal MRI T1 hyperintensity. Pallidal copper was also elevated in affected cases, but copper does not have the paramagnetic properties to generate isolated T1 hyperintensity. Basal ganglia manganese or copper accumulation may be responsible for the parkinsonism sometimes seen in chronic liver failure. Pallidal MRI T1 hyperintensity is a biomarker of manganese overload.

Josephs KA, Whitwell JL, Jack CR, Parisi JE, Dickson DW. · Department of Neurology, Division of Behavioral Neurology and Movement Disorders, Mayo Clinic, Rochester, MN 55905, USA. · Arch Neurol. · Pubmed #17101834 links to  free full text

Abstract: BACKGROUND: Frontotemporal lobar degeneration with ubiquitin-only-immunoreactive neuronal inclusions (FTLD-U) is the most common form of frontotemporal dementia. Neuronal loss and gliosis in cornu ammonis 1 and the subiculum of the hippocampus are features of hippocampal sclerosis (HpScl), which occurs in many cases of FTLD-U. OBJECTIVE: To determine if there were any clinical or magnetic resonance imaging correlates of HpScl in FTLD-U. DESIGN: We reviewed demographics and clinical features of 24 cases of FTLD-U and subjectively assessed the severity of neuronal loss and frequency of ubiquitin-positive neuronal lesions in the frontal and temporal cortices and the dentate gyrus of the hippocampus. SETTING: Mayo Clinic, Rochester, Minn. Patients Twenty-six cases were identified from the medical records linkage system query that met clinical criteria and had autopsy material available for additional studies. Two cases were excluded from further analysis after pathologic studies revealed coexisting Alzheimer disease, leaving 24 cases included in the study. Cases were subdivided based on the presence or absence of HpScl. MAIN OUTCOME MEASURES: Patterns of gray matter atrophy were assessed in cases of FTLD-U with and without HpScl using voxel-based morphometry. RESULTS: Six of the 24 cases of FTLD-U did not have HpScl. No differences were found in demographic or clinical features, including disease duration, between cases with and without HpScl; however, voxel-based morphometry analysis revealed minimal cortical atrophy in cases without HpScl, which was significantly different from the pattern of moderate to severe frontal and temporal lobe atrophy in FTLD-U with HpScl. This finding was in keeping with histopathologic observations. CONCLUSIONS: Despite similar clinical features, cases of FTLD-U with HpScl differ from those without HpScl with respect to pathologic findings and structural imaging. Specifically, FTLD-U without HpScl showed on average minimal or no cortical atrophy, even at end-stage disease. Consequently, FTLD-U without HpScl does not conform to the proposed FTLD staging scheme, is underrecognized, and may have different genetic and environmental underpinnings.

Barnes J, Whitwell JL, Frost C, Josephs KA, Rossor M, Fox NC. · Dementia Research Centre, University College London, Institute of Neurology, London, England. · Arch Neurol. · Pubmed #17030660 links to  free full text

Abstract: BACKGROUND: Differentiating between Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD) can be difficult, particularly in the earliest stages of the diseases. Patterns of atrophy on magnetic resonance imaging may help distinguish these diseases and aid diagnosis. OBJECTIVE: To assess the diagnostic utility of magnetic resonance imaging-derived amygdala and hippocampal volumes from patients with pathologically proved AD and FTLD. DESIGN: Cross-sectional volumetric magnetic resonance imaging study of the hippocampus and amygdala. SETTING: Specialist cognitive disorders clinic.Subjects Thirty-seven subjects, including 10 patients with pathologically proved AD, 17 patients with pathologically proved FTLD, and 10 age-matched control subjects. MAIN OUTCOME MEASURES: Hippocampal and amygdala volumes. RESULTS: Geometric mean amygdala and hippocampal volumes were, respectively, 15.0% (95% confidence interval [CI], 4.2%-24.5%) and 16.4% (95% CI, 5.9%-25.6%) lower in the AD than in the control group. In FTLD, the equivalent differences were 43.1% (95% CI, 31.9%-52.6%) in the amygdala and 36.1% (95% CI, 27.5%-43.7%) in the hippocampus. Volumes were significantly lower in the FTLD than in the AD group (P<.01 in both regions). Within the FTLD clinical subgroups, there was evidence of a difference in pattern of atrophy with greater asymmetry (left smaller than right) in semantic dementia compared with frontal variant FTLD (P<.001). On average, the left hippocampus was 14% smaller in semantic dementia than in frontal variant FTLD, whereas the right hippocampus was 37% larger. On average, the left amygdala was 39% smaller in semantic dementia than in frontal variant FTLD, whereas the right amygdala was only 1% smaller. CONCLUSIONS: Hippocampal atrophy is not specific to AD or FTLD. However, severe or asymmetrical amygdala atrophy should suggest FTLD. Atrophy patterns follow clinical syndromes rather than pathology.

Whitwell JL, Jack CR, Kantarci K, Weigand SD, Boeve BF, Knopman DS, Drubach DA, Tang-Wai DF, Petersen RC, Josephs KA. · Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA. · Neurobiol Aging. · Pubmed #16797786 No free full text.

Abstract: The aim of this study was to compare patterns of cerebral atrophy on MRI, and neurochemistry on magnetic resonance spectroscopy (MRS), in patients with posterior cortical atrophy (PCA) and typical Alzheimer's disease (AD). Voxel-based morphometry was used to assess grey matter atrophy in 38 patients with PCA, 38 patients with typical AD, and 38 controls. Clinical data was assessed in all PCA patients. Single voxel (1)H MRS located in the posterior cingulate was analyzed in a subset of patients with PCA, typical AD, and control subjects. PCA showed a pattern of atrophy affecting occipital, parietal and posterior temporal lobes, compared to controls. The pattern was bilateral, but more severe on the right. Patients with PCA showed greater atrophy in the right visual association cortex than patients with typical AD, whereas those with AD showed greater atrophy in the left hippocampus than those with PCA. (1)H MRS suggested loss of neuronal integrity and glial activation in subjects with PCA and typical AD. The differing patterns of atrophy on MRI suggest that PCA should be considered a distinct entity from typical AD.

Godbolt AK, Josephs KA, Revesz T, Warrington EK, Lantos P, King A, Fox NC, Al Sarraj S, Holton J, Cipolotti L, Khan MN, Rossor MN. · Dementia Research Centre, Institute of Neurology, University College London, England. · Arch Neurol. · Pubmed #16009765 links to  free full text

Abstract: BACKGROUND: Frontotemporal lobar degeneration comprises a group of diseases with clinical presentations and underlying histopathologies that overlap. Familial disease occurs in up to 50% of frontotemporal lobar degeneration cases. One of several underlying histopathological abnormalities is of ubiquitin-positive tau-negative inclusions, similar to those in motor neuron disease. OBJECTIVE: To compare clinical features of familial and sporadic cases in this pathological subgroup. DESIGN AND PATIENTS: Case note review of dementia patients with ubiquitin-positive tau-negative inclusion pathological abnormalities proven by autopsy. SETTING: United Kingdom tertiary referral center. MAIN OUTCOME MEASURES: Analysis of clinical features. RESULTS: Eleven familial cases (autosomal dominant) and 18 sporadic cases were identified. Most familial case patients presented with behavioral disturbances similar to those seen in sporadic behavioral cases. Semantic dementia was only seen in sporadic cases. Atypical features occurred in a minority. Sporadic and familial behavioral cases showed no differences in age at onset or disease duration. Neuropsychological test results revealed frontal or temporal deficits in most, but unexpected early parietal deficits in 1. CONCLUSIONS: Behavioral features in familial and sporadic cases were similar, but semantic dementia only occurred in sporadic cases. Diagnostic confusion with Alzheimer disease and corticobasal degeneration occurred in some cases.

Rippon GA, Boeve BF, Parisi JE, Dickson DW, Ivnik RI, Jack CR, Hutton M, Baker M, Josephs KA, Knopman DS, Petersen RC. · Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905, USA. · Neurocase. · Pubmed #16006341 No free full text.

Abstract: Progressive supranuclear palsy (PSP) is typically manifested by vertical supranuclear gaze palsy, frequent falls early in the disease course, axial rigidity and poor response to levodopa. Prominent anterograde memory dysfunction with subsequent impairment in other cognitive domains is characteristic of Alzheimer's disease (AD). No clear clinical syndrome has been identified in argyrophilic grain disease (AGD). Frontotemporal dementia (FTD) is characterized by apathy, emotional blunting, disinhibition, and impairment in executive functioning despite relatively preserved memory and visuospatial abilities. Cognitive deficits are known to occur in PSP; however, overt clinical FTD without parkinsonism or supranuclear gaze palsy associated with PSP pathology has rarely been documented. We report an elderly patient with the typical clinical, neuropsychometric, and neuroimaging features of FTD who had autopsy findings most consistent with PSP plus AGD and AD in limbic structures. We suggest that PSP with or without coexisting AD and AGD be included in the differential diagnosis of patients presenting with FTD.

Knopman DS, Boeve BF, Parisi JE, Dickson DW, Smith GE, Ivnik RJ, Josephs KA, Petersen RC. · Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, USA. · Ann Neurol. · Pubmed #15786453 No free full text.

Abstract: The objective of this article is to study the accuracy of antemortem clinical diagnoses of frontotemporal lobar degenerations (FTLDs). From brain autopsies performed on subjects enrolled in the Mayo Alzheimer Center between 1991 and 2003, cases with neuropathological diagnoses of FTLD were identified. Neuropathological diagnoses of FTLDs were based on consensus criteria for FTLD. The initial clinical histories, neuropsychological test results, brain imaging studies, and initial clinical diagnoses were reviewed. There were 34 pathological FTLD cases among 433 subjects who underwent autopsy; 29 of these 34 cases were diagnosed as FTLD antemortem based on the sum of clinical, neuropsychological, and imaging features (sensitivity, 85%). The specificity was 99%. Among the 34 cases with pathological FTLD, 27 (79%) had clinical histories diagnostic of an FTLD syndrome, 20 (62%) had neuropsychological profiles consistent with FTLD, 17 (50%) had magnetic resonance scans consistent with FTLD, and 7 of 8 who had functional imaging studies had ones consistent with FTLD. In those with incorrect antemortem diagnoses, three were thought to have Alzheimer's disease, one was considered hard to classify, and one was diagnosed with vascular dementia. The antemortem consensus diagnosis of FTLD was moderately sensitive and very specific. With experienced clinicians and awareness of the unique manifestations of FTLD, accurate antemortem diagnosis was feasible.

Josephs KA, Tsuboi Y, Cookson N, Watt H, Dickson DW. · Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA. · Arch Neurol. · Pubmed #15477512 links to  free full text

Abstract: OBJECTIVES: To determine if apolipoprotein E epsilon 4 influences the frequency of Alzheimer-type pathologic features in tauopathies, synucleinopathies, and frontotemporal degeneration and to determine if the frequency of Alzheimer-type pathologic features in synucleinopathies is similar to the frequency of such features in tauopathies and frontotemporal degeneration. METHODS: A total of 285 patients with pathologically proven neurodegenerative disorders, including diffuse and transitional Lewy body disease, frontotemporal degeneration, progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy, with a mean age of 75.1 +/- 9.3 years, were suitable for genetic and pathological analysis. Disorders were grouped as tauopathies (progressive supranuclear palsy and corticobasal degeneration), synucleinopathies (Lewy body disease and multiple system atrophy), and frontotemporal degeneration. Braak neurofibrillary tangle staging and quantitative scores of senile plaques were used to determine the degree of concomitant Alzheimer-type pathologic features in each case, and apolipoprotein E genotype was determined from DNA isolated from frozen brain tissue. The relationship of apolipoprotein E epsilon 4 to Alzheimer-type pathologic features was determined. RESULTS: Across all neurodegenerative disorders, apolipoprotein E epsilon 4 and older age independently predicted the co-occurrence of Alzheimer-type pathologic features (P<.001), whereas female sex had a lesser effect (P = .03). When divided into the 3 subgroups (tauopathies, synucleinopathies, and frontotemporal degeneration), apolipoprotein E epsilon 4 had a similar effect, whereas older age and female sex were less predictive. There was a significant difference between the frequency of Alzheimer-type pathologic features in synucleinopathies and the frequency of such features in tauopathies and frontotemporal degeneration (P<.001 for both). The frequency of apolipoprotein E epsilon 4 allele was not significantly different among the 3 groups. CONCLUSIONS: Apolipoprotein E epsilon 4, independent of older age and sex, contributes to the co-occurrence of Alzheimer-type pathologic features in tauopathies, synucleinopathies, and frontotemporal degeneration, but this does not explain why Alzheimer-type pathologic features are significantly more likely to coexist with synucleinopathies than with either tauopathies or frontotemporal degeneration.

Tsuboi Y, Josephs KA, Cookson N, Dickson DW. · Department of Neurology, Mayo Clinic, Jacksonville, FL, USA. · Neurology. · Pubmed #12552038 No free full text.

Abstract: OBJECTIVE: To assess demographic and genetic determinants of Alzheimer type pathology in progressive supranuclear palsy (PSP).METHODS: From a total of 173 pathologically proven cases of PSP in the Society for PSP Brain Bank, 143 patients (mean age = 74.4 years, ranging from 42 to 98 years) were suitable for genetic and pathologic study. Senile plaques (SPs) and neurofibrillary tangles (NFTs) were counted in five cortical areas, Braak stage was given, and APOE genotype was determined from DNA isolated from frozen brain tissue. The APOE allele frequency in PSP with varying degrees of concomitant Alzheimer type pathology was compared with pure PSP and autopsy controls. The relationship of APOE epsilon4 to quantitative pathologic measures was also assessed. RESULTS: Most patients with PSP (103 cases) had either minimal or no Alzheimer type pathology (Braak stage III or less), but 14 patients had many SPs (>20 per low power field) and a Braak stage of IV or higher consistent with pathologic criteria for AD, and 26 patients had many diffuse plaques with minimal neurofibrillary degeneration (Braak stage III or less) consistent with pathologic aging. Alzheimer type pathology was more frequent in women and older individuals with PSP, and 19 of the 40 patients with PSP with Alzheimer type pathology carried at least one APOE epsilon4 allele. The epsilon4 allele frequency was significantly higher in PSP with AD or pathologic aging than in pure PSP, and APOE epsilon4 correlated with the average maximal density of both neocortical SPs and NFTs. CONCLUSION: APOE epsilon4 is a risk factor for Alzheimer type pathology in PSP. Alzheimer type pathology is an independent process unrelated to PSP in cases with both types of pathologies.

Josephs KA, Wai DF, Parisi JE. · No affiliation provided · Eur J Neurol. · Pubmed #12752417 No free full text.

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