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issn:0003-99.2
1.  Clinical Characterization of a Kindred with a Novel Twelve Octapeptide Repeat Insertion in the Prion Protein Gene 
Archives of Neurology  2011;68(9):1165-1170.
Objective
To report the clinical, electroencephalographic, and neuroradiologic findings in a kindred with a novel insertion in the prion protein gene (PRNP).
Design
Clinical description of a kindred.
Setting
Mayo Clinic Alzheimer’s Disease Research Center (Rochester).
Subjects
Two pathologically-confirmed cases and their relatives.
Main outcome measures
Clinical features, electroencephalographic patterns, magnetic resonance imaging abnormalities, genetic analyses and neuropathological features.
Results
The proband presented with clinical and neuroimaging features of atypical frontotemporal dementia (FTD) and ataxia. Generalized tonic-clonic seizures developed later in her course, and electroencephalography revealed spike and wave discharges but no periodic sharp wave complexes. Her affected sister and father also exhibited FTD-like features, and both experienced generalized tonic-clonic seizures and gait ataxia late in their course. Genetic analyses in the proband identified a novel defect in PRNP with one mutated allele carrying a 288 base pair insertion (BPI) consisting of 12 octapeptide repeats. Neuropathologic examination of the sister and proband revealed PrP-positive plaques and widespread tau-positive tangles.
Conclusion
This kindred has a unique combination of clinical and neuropathologic features associated with the largest BPI identified to date in PRNP, and underscores the need to consider familial prion disease in the differential diagnosis of a familial FTD-like syndrome.
doi:10.1001/archneurol.2011.187
PMCID: PMC3326586  PMID: 21911696
frontotemporal dementia; FTD; nonfluent aphasia; Gerstmann–Straüssler–Scheinker syndrome (GSS); Creutzfeldt-Jakob disease (CJD); prion; PRNP
2.  Genetic and Clinical Features of Progranulin-Associated Frontotemporal Lobar Degeneration 
Archives of neurology  2011;68(4):488-497.
Objective
To assess the relative frequency of unique mutations and their associated characteristics in 97 individuals with mutations in progranulin (GRN), an important cause of frontotemporal lobar degeneration (FTLD).
Participants and Design
A 46-site International Frontotemporal Lobar Degeneration Collaboration was formed to collect cases of FTLD with TAR DNA-binding protein of 43-kDa (TDP-43)–positive inclusions (FTLD-TDP). We identified 97 individuals with FTLD-TDP with pathogenic GRN mutations (GRN+ FTLD-TDP), assessed their genetic and clinical characteristics, and compared them with 453 patients with FTLD-TDP in which GRN mutations were excluded (GRN− FTLD-TDP). No patients were known to be related. Neuropathologic characteristics were confirmed as FTLD-TDP in 79 of the 97 GRN+ FTLDTDP cases and all of the GRN− FTLD-TDP cases.
Results
Age at onset of FTLD was younger in patients with GRN+ FTLD-TDP vs GRN− FTLD-TDP (median, 58.0 vs 61.0 years; P<.001), as was age at death (median, 65.5 vs 69.0 years; P<.001). Concomitant motor neuron disease was much less common in GRN+ FTLDTDP vs GRN− FTLD-TDP (5.4% vs 26.3%; P<.001). Fifty different GRN mutations were observed, including 2 novel mutations: c.139delG (p.D47TfsX7) and c.378C>A (p.C126X). The 2 most common GRN mutations were c.1477C>T (p.R493X, found in 18 patients, representing 18.6% of GRN cases) and c.26C>A (p.A9D, found in 6 patients, representing 6.2% of cases). Patients with the c.1477C>T mutation shared a haplotype on chromosome 17; clinically, they resembled patients with other GRN mutations. Patients with the c.26C>A mutation appeared to have a younger age at onset of FTLD and at death and more parkinsonian features than those with other GRN mutations.
Conclusion
GRN+ FTLD-TDP differs in key features from GRN− FTLD-TDP.
doi:10.1001/archneurol.2011.53
PMCID: PMC3160280  PMID: 21482928
3.  Replication of CLU, CR1 and PICALM associations with Alzheimer’s disease 
Archives of neurology  2010;67(8):961-964.
Background
Harold et al. and Lambert et al. recently published two large genome-wide association studies of late onset Alzheimer’s disease (LOAD) in which CLU, CR1, and PICALM were identified as novel LOAD genes.
Objective
To test for replication of the association between variants in the CLU, CR1 and PICALM genes with Alzheimer’s disease.
Design
Case-control association study
Setting
Community-based ascertainment of patients seen at the Mayo Clinic Jacksonville, FL and Rochester, MN, and autopsy-confirmed cases and controls whose pathology was evaluated at the Mayo Clinic Jacksonville. Additional samples were obtained from the National Cell Repository for Alzheimer’s Disease (NCRAD).
Participants
LOAD case-control series of European descent consisting of 1,829 LOAD cases and 2,576 controls
Main Outcome Measure
Clinical or pathology-confirmed diagnosis of LOAD
Results
In our follow-up study of 1,829 LOAD cases and 2,576 controls, the most significant SNPs in CLU (rs11136000), CR1 (rs3818361), and PICALM (rs3851179) were tested for allelic association and gave ORs of 0.82, 1.15, and 0.80 respectively that were comparable in direction and magnitude to those originally reported with p values of 8.6×10−5, 0.014, and 1.3×10−5 that were significant even after Bonferroni correction for 3 SNPs tested.
Conclusion
These results showing near perfect replication provide the first additional evidence that CLU, CR1, and PICALM are LOAD genes.
doi:10.1001/archneurol.2010.147
PMCID: PMC2919638  PMID: 20554627
4.  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
5.  Functional Impact of White Matter Hyperintensities in Cognitively Normal Elderly 
Archives of neurology  2010;67(11):1379-1385.
Objective
To investigate the impact white matter hyperintensities (WMH) detected on MRI have on motor dysfunction and cognitive impairment in non-demented elderly subjects.
Design
Cross-sectional study.
Setting
Population-based study on the incidence and prevalence of cognitive impairment in Olmsted County, MN.
Participants
A total of 148 non-demented elderly (65 males) ranging in age from 73 to 91 years.
Main Outcome Measures
We measured the percentage of the total white matter volume classified as WMH (WMHp) in a priori defined brain regions (i.e. frontal, temporal, parietal, occipital, periventricular or subcortical). Motor impairment was evaluated qualitatively using the Unified Parkinson’s Disease Rating Scale (UPDRS) summary measures of motor skills and quantitatively using a digitized portable walkway system. Four cognitive domains were evaluated using z-scores of memory, language, executive function, and visuospatial reasoning.
Results
A higher WMHp in all regions except occipital was associated with lower executive function z-score (p-value<0.01). A higher WMHp in all regions, but most strongly for parietal lobe, correlated with higher gait/postural-stability/posture UPDRS sum (p-value<0.01). A higher WMHp whether periventricular, subcortical or lobar correlated with reduced velocity (p-value<0.001).
Conclusions
We conclude that executive function is the primary cognitive domain affected by WMH burden. The data suggests that WMH in the parietal lobe are chiefly responsible for reduced balance and postural support compared to the other three lobes and may alter integration of sensory information via parietal lobe dysfunction in the aging brain. It is of interest that parietal WM changes were not the predominant correlate with motor speed, lending evidence to a global involvement of neural networks in gait velocity.
doi:10.1001/archneurol.2010.280
PMCID: PMC3025610  PMID: 21060015
6.  Is Incidental Lewy Body Disease Related to Parkinson Disease? Comparison of Risk Factor Profiles 
Archives of neurology  2009;66(9):1114.
Objective
To explore whether associations of potential risk factors for incidental Lewy Body Disease (iLBD) may be similar to Parkinson Disease (PD).
Design, Setting, and Patients
We identified brain-autopsied residents of Olmsted County, MN and immediate vicinity(1988–2004), age>60, without evidence of neurodegenerative disease or tremor, and evaluated by at least one physician within one year of death. Analysis for “incidental” Lewy pathology was done blinded to clinical abstraction.
Main Outcome Measures
Whether risk factors previously associated with PD in Olmsted County, MN are also associated with iLBD.
Results
Of 235 subjects, 34 had iLBD(14.5%). The overall risk factor profiles for iLBD and PD were fairly similar between the two sets of OR estimates, with 11/16 ORs in the same direction. Prior Olmsted County studies documented 7 risk factors with statistically significant associations with PD; for two of these, the ORs for iLBD were in the same direction and statistically significant (physician, caffeine), whereas for three, they were in the same direction but not significant (education, head injury, number-of-children); they were in the opposite direction but not statistically significant for 2 (depression, anxiety). ILBD was not associated with various end-of-life conditions or causes-of-death, although they were slightly older and more likely cachectic.
Conclusions
Based on this exploratory study, iLBD and PD appear to have similar risk factor profiles. Thus, at least some cases of ILBD might represent preclinical PD, arrested PD or a partial syndrome due to a lesser burden of causative factors. ILBD is not explained by non-specific end-of-life brain insults.
doi:10.1001/archneurol.2009.170
PMCID: PMC2813519  PMID: 19752300
7.  Voxel-based morphometry in frontotemporal lobar degeneration with ubiquitin-positive inclusions with and without progranulin mutations 
Archives of neurology  2007;64(3):371-376.
Background
Mutations in the progranulin gene (PGRN) have recently been identified as a cause of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) in some families.
Objective
To determine whether there is a difference in the patterns of atrophy in cases with FTLD-U with and without a mutation in PGRN.
Design
Case control study
Setting
Brain bank of a tertiary care medical center
Patients
All subjects that had screened positive for mutations in PGRN and had a volumetric MRI were identified (n=8, PGRN (+)). Subjects were then matched by clinical diagnosis to a group of eight subjects with a pathological diagnosis of FTLD-U that had screened negative for mutations in PGRN (PGRN (−)). All subjects were then age and gender-matched to a control subject.
Main outcome Measures
Voxel-based morphometry was used to assess the patterns of grey matter atrophy in the PGRN (+) and (−) groups compared to controls, and compared to each other.
Results
The PGRN (+) group showed a widespread and severe pattern of grey matter loss predominantly affecting the frontal, temporal and parietal lobes. In comparison, the PGRN (−) group showed a less severe pattern of loss restricted mainly to the temporal and frontal lobes. On direct comparison the PGRN (+) group showed greater loss in the frontal and parietal lobes compared to the PGRN (−) group.
Conclusions
This study suggests that PGRN mutations may be associated with a specific and severe pattern of cerebral atrophy in subjects with FTLD-U.
doi:10.1001/archneur.64.3.371
PMCID: PMC2752412  PMID: 17353379
Frontotemporal dementia; Voxel-based morphometry; Ubiquitin; Dentate; Progranulin

Results 1-7 (7)