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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.  Childhood Onset Multiple Sclerosis with Progressive Dementia and Pathological Cortical Demyelination 
Archives of neurology  2011;68(4):525-528.
Objective
To describe a case of childhood-onset progressive multiple sclerosis with dementia and brain biopsy evidence of extensive cortical demyelination.
Design
Case report
Patient
A 26-year-old gentleman with a history of behavioral changes starting at the age of 13 years followed by progressive dementia.
Interventions
Neurological examination, MRI, CSF studies, neuropsychological testing, and brain biopsy.
Results
MRI showed numerous T2W hyperintensities throughout the central nervous system not associated with contrast enhancement. Brain biopsy showed cortical and subcortical demyelination. All three types of cortical demyelinating lesions were
observed
leukococortical, intracortical, and subpial. Lesions were associated with profound microglial activation. The patient continued to progress despite attempts to treat with multiple sclerosis disease-modifying therapies.
Conclusions
Multiple sclerosis should be considered in the diagnosis of progressive dementia in children and young adults. Cortical demyelination may contribute to cognitive decline in patients with dementia due to multiple sclerosis.
doi:10.1001/archneurol.2011.50
PMCID: PMC3077570  PMID: 21482934
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.  Survival Profiles of Patients With Frontotemporal Dementia and Motor Neuron Disease 
Archives of neurology  2009;66(11):1359-1364.
Background
Frontotemporal dementia and amyotrophic lateral sclerosis are neurodegenerative diseases associated with TAR DNA-binding protein 43– and ubiquitin-immunoreactive pathologic lesions.
Objective
To determine whether survival is influenced by symptom of onset in patients with frontotemporal dementia and amyotrophic lateral sclerosis.
Design, Setting, and Patients
Retrospective review of patients with both cognitive impairment and motor neuron disease consecutively evaluated at 4 academic medical centers in 2 countries.
Main Outcome Measures
Clinical phenotypes and survival patterns of patients.
Results
A total of 87 patients were identified, including 60 who developed cognitive symptoms first, 19 who developed motor symptoms first, and 8 who had simultaneous onset of cognitive and motor symptoms. Among the 59 deceased patients, we identified 2 distinct subgroups of patients according to survival. Long-term survivors had cognitive onset and delayed emergence of motor symptoms after a long monosymptomatic phase and had significantly longer survival than the typical survivors (mean, 67.5 months vs 28.2 months, respectively; P<.001). Typical survivors can have simultaneous or discrete onset of cognitive and motor symptoms, and the simultaneous-onset patients had shorter survival (mean, 19.2 months) than those with distinct cognitive or motor onset (mean, 28.6 months) (P=.005).
Conclusions
Distinct patterns of survival profiles exist in patients with frontotemporal dementia and motor neuron disease, and overall survival may depend on the relative timing of the emergence of secondary symptoms.
doi:10.1001/archneurol.2009.253
PMCID: PMC2881327  PMID: 19901167
5.  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
6.  Rapidly Progressive Neurodegenerative Dementias 
Archives of neurology  2009;66(2):201-207.
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.
Setting
Tertiary Care Medical Center.
Design/Methods
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 1/1/00−9/30/07 with brain autopsy (N=96). Of these 96, we included only those with disease duration of <4 years to death and with histological diagnosis of a neurodegenerative disease.
Results
We identified 22 cases (10 males). Although 36% were Creutzfeldt-Jakob disease (CJD), the rest included frontotemporal lobar degenerative with motor neuron degeneration (FTLD-MND; 23%); a tauopathy (progressive supranuclear palsy or corticobasal degeneration; 18%); diffuse Lewy body disease (DLBD; 14%) or Alzheimer's disease 9%. All CJD cases died ≤12 months after onset while the others had illness duration of >12 months. Notably, all three DLBD patients, but no others, initially experienced a transient postoperative- or illness-associated encephalopathy, then relative normality for two years, before a rapidly progressive dementia and decline to death in 4−12 months.
Conclusions
Based on this cohort, although CJD is the most likely cause of a rapidly progressive neurodegenerative dementia, FTLD-MND, DLBD, tauopathies and Alzheimer's disease can also cause a rapidly progressive dementia. If illness duration is beyond 12-months, a non-CJD neurodegenerative disease may be more likely the diagnosis, than CJD.
doi:10.1001/archneurol.2008.534
PMCID: PMC2764283  PMID: 19204156

Results 1-6 (6)