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1.  Prominent Phenotypic Variability Associated with Mutations in Progranulin 
Neurobiology of aging  2007;30(5):739-751.
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.
doi:10.1016/j.neurobiolaging.2007.08.022
PMCID: PMC3164546  PMID: 17949857
Frontotemporal dementia; FTDP-17; Progranulin; PGRN; MRI
2.  Mild cognitive impairment associated with limbic and neocortical lewy body disease: a clinicopathological study 
Brain  2009;133(2):540-556.
There are little data on the relationship between Lewy body disease and mild cognitive impairment syndromes. The Mayo Clinic aging and dementia databases in Rochester, Minnesota, and Jacksonville, Florida were queried for cases who were diagnosed with mild cognitive impairment between 1 January 1996 and 30 April 2008, were prospectively followed and were subsequently found to have autopsy-proven Lewy body disease. The presence of rapid eye movement sleep behaviour disorder was specifically assessed. Mild cognitive impairment subtypes were determined by clinical impression and neuropsychological profiles, based on prospective operational criteria. The diagnosis of clinically probable dementia with Lewy bodies was based on the 2005 McKeith criteria. Hippocampal volumes, rate of hippocampal atrophy, and proton magnetic resonance spectroscopy were assessed on available magnetic resonance imaging and spectroscopy scans. Eight subjects were identified; six were male. Seven developed dementia with Lewy bodies prior to death; one died characterized as mild cognitive impairment. The number of cases and median age of onset (range) for specific features were: seven with rapid eye movement sleep behaviour disorder—60 years (27–91 years), eight with cognitive symptoms—69 years (62–89 years), eight with mild cognitive impairment—70.5 years (66–91 years), eight with parkinsonism symptoms—71 years (66–92 years), six with visual hallucinations—72 years (64–90 years), seven with dementia—75 years (67–92 years), six with fluctuations in cognition and/or arousal—76 years (68–92 years) and eight dead—76 years (71–94 years). Rapid eye movement sleep behaviour disorder preceded cognitive symptom onset in six cases by a median of 10 years (2–47 years) and mild cognitive impairment diagnosis by a median of 12 years (3–48 years). The mild cognitive impairment subtypes represented include: two with single domain non-amnestic mild cognitive impairment, three with multi-domain non-amnestic mild cognitive impairment, and three with multi-domain amnestic mild cognitive impairment. The cognitive domains most frequently affected were attention and executive functioning, and visuospatial functioning. Hippocampal volumes and the rate of hippocampal atrophy were, on average, within the normal range in the three cases who underwent magnetic resonance imaging, and the choline/creatine ratio was elevated in the two cases who underwent proton magnetic resonance spectroscopy when they were diagnosed as mild cognitive impairment. On autopsy, six had neocortical-predominant Lewy body disease and two had limbic-predominant Lewy body disease; only one had coexisting high-likelihood Alzheimer's disease. These findings indicate that among Lewy body disease cases that pass through a mild cognitive impairment stage, any cognitive pattern or mild cognitive subtype is possible, with the attention/executive and visuospatial domains most frequently impaired. Hippocampal volume and proton magnetic resonance spectroscopy data were consistent with recent data in dementia with Lewy bodies. All cases with rapid eye movement sleep behaviour disorder and mild cognitive impairment were eventually shown to have autopsy-proven Lewy body disease, indicating that rapid eye movement sleep behaviour disorder plus mild cognitive impairment probably reflects brainstem and cerebral Lewy body disease.
doi:10.1093/brain/awp280
PMCID: PMC2822633  PMID: 19889717
mild cognitive impairment; dementia; dementia with Lewy bodies; Lewy body disease; neuropathology
3.  Alzheimer's Disease-Like Phenotype Associated With the c.154delA Mutation in Progranulin 
Archives of neurology  2010;67(2):171-177.
Objective
To characterize a kindred with a familial neurodegenerative disorder associated with a mutation in progranulin (PGRN), emphasizing the unique clinical features in this kindred.
Design
Clinical, radiologic, pathologic, and genetic characterization of a kindred with a familial neurodegenerative disorder.
Setting
Multispecialty group academic medical center.
Patients
Affected members of a kindred with dementia +/- parkinsonism associated with a unique mutation in PGRN.
Main Outcome Measure
Genotype-phenotype correlation.
Results
Ten affected individuals were identified, among whom six presented with initial amnestic complaints resulting in initial diagnoses of AD or amnestic mild cognitive impairment (MCI). A minority of individuals presented with features characteristic of FTD. The ages of onset of generation II (mean 75.8 years, range 69-80 years) were far greater than those of generation III (mean 60.7 years, range 55-66 years). The pattern of cerebral atrophy varied widely among affected individuals. Neuropathology in six individuals showed frontotemporal lobar degeneration with ubiquitin positive neuronal cytoplasmic and intranuclear inclusions (FTLD-U + NII). PGRN analysis revealed a single base pair deletion in exon 2 (c.154delA), causing a frameshift (p.Thr52Hisfs×2) and therefore creation of a premature termination codon and likely null allele.
Conclusions
We describe a large kindred in which the majority of affected individuals had clinical presentations resembling AD or amnestic MCI in association with a mutation in PGRN and underlying FTLD-U + NII neuropathology. This is in distinct contrast to previously reported kindreds, where clinical presentations have typically been within the spectrum of FTLD. The basis for the large difference in age of onset between generations will require further study.
doi:10.1001/archneurol.2010.113
PMCID: PMC2902004  PMID: 20142525
MRI; progranulin; frontotemporal dementia; PGRN
4.  Comparison of 18F-FDG and PiB PET in Cognitive Impairment 
The purpose of this study was to compare the diagnostic accuracy of glucose metabolism and amyloid deposition as demonstrated by 18F-FDG and Pittsburg Compound B (PiB) PET to evaluate subjects with cognitive impairment.
Methods
Subjects were selected from existing participants in the Mayo Alzheimer’s Disease Research Center or Alzheimer’s Disease Patient Registry programs. A total of 20 healthy controls and 17 amnestic mild cognitive impairment (aMCI), 6 nonamnestic mild cognitive impairment (naMCI), and 13 Alzheimer disease (AD) subjects were imaged with both PiB and 18F-FDG PET between March 2006 and August 2007. Global measures for PiB and 18F-FDG PET uptake, normalized to cerebellum for PiB and pons for 18F-FDG, were compared. Partial-volume correction, standardized uptake value (SUV), and cortical ratio methods of image analysis were also evaluated in an attempt to optimize the analysis for each test.
Results
Significant discrimination (P < 0.05) between controls and AD, naMCI and aMCI, naMCI and AD, and aMCI and AD by PiB PET measurements was observed. The paired groupwise comparisons of the global measures demonstrated that PiB PET versus 18F-FDG PET showed similar significant group separation, with only PiB showing significant separation of naMCI and aMCI subjects.
Conclusion
PiB PET and 18F-FDG PET have similar diagnostic accuracy in early cognitive impairment. However, significantly better group discrimination in naMCI and aMCI subjects by PiB, compared with 18F-FDG, was seen and may suggest early amyloid deposition before cerebral metabolic disruption in this group.
doi:10.2967/jnumed.108.058529
PMCID: PMC2886669  PMID: 19443597
PET; dementia; 18F-FDG; PiB
5.  Longitudinal 1H MRS changes in mild cognitive impairment and Alzheimer’s disease 
Neurobiology of aging  2006;28(9):1330-1339.
Magnetic Resonance (MR)- based volume measurements of atrophy are potential markers of disease progression in patients with amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD). Longitudinal changes in 1H MR spectroscopy (1H MRS) metabolite markers have not been characterized in aMCI subjects. Our objective was to determine the longitudinal 1H MRS metabolite changes in patients with aMCI, and AD, and to compare 1H MRS metabolite ratios and ventricular volumes in tracking clinical disease progression in AD. The neuronal integrity marker N-acetylaspartate/Creatine ratio declined in aMCI and AD patients compared to cognitively normal elderly. The changein 1H MRS metabolite ratios correlated with clinical progression about as strongly as the rate of ventricular expansion, suggesting that 1H MRS metabolite ratios may be useful markers for the progression of AD. Choline/Creatine ratio declined in stable aMCI, compared to converter aMCI patients and cognitively normal elderly, which may be related to a compensatory mechanism in aMCI patients who did not to progress to AD.
doi:10.1016/j.neurobiolaging.2006.06.018
PMCID: PMC2766807  PMID: 16860440
1H MR spectroscopy; 1H MRS; imaging; Alzheimer’s disease; mild cognitive impairment; serial; longitudinal; N-acetylaspartate; choline

Results 1-5 (5)