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1.  Association of hypometabolism and amyloid levels in aging, normal subjects 
Neurology  2014;82(22):1959-1967.
We evaluated the relationship of amyloid, seen on Pittsburgh compound B (PiB)-PET, and metabolism, seen on [18F]-fluorodeoxyglucose (FDG)-PET, in normal subjects to better understand pathogenesis and biomarker selection in presymptomatic subjects.
Normal participants (aged 70–95 years; 600 with PiB-PET, FDG-PET, and MRI) were included. We performed a cross-sectional evaluation and subcategorized participants into amyloid-negative (<1.4), high-normal (1.4–1.5), positive (1.5–2.0), and markedly positive (>2.0) PiB standardized uptake value ratio groups representing different levels of amyloid brain load. Associations with metabolism were assessed in each group. Relationships with APOE ε4 carriage were evaluated.
Hypometabolism in “Alzheimer disease (AD)-signature” regions was strongly associated with PiB load. Hypometabolism was greater with more positive PiB levels. Additional, more-diffuse cortical hypometabolism was also found to be associated with PiB, although less so. No hypermetabolism was seen in any subset. No significant incremental hypometabolism was seen in APOE-positive vs -negative subjects.
Hypometabolism in PiB-positive, cognitively normal subjects in a population-based cohort occurs in AD-signature cortical regions and to a lesser extent in other cortical regions. It is more pronounced with higher amyloid load and supports a dose-dependent association. The effect of APOE ε4 carriage in this group of subjects does not appear to modify their hypometabolic “AD-like” neurodegeneration. Consideration of hypometabolism associated with amyloid load may aid trials of AD drug therapy.
PMCID: PMC4105262  PMID: 24793183
2.  Profilin-1 mutations are rare in patients with amyotrophic lateral sclerosis and frontotemporal dementia 
Mutations in profilin-1 (PFN1) have recently been identified in patients with amyotrophic lateral sclerosis (ALS). Because of the considerable overlap between ALS and the common subtype of frontotemporal dementia, which is characterized by transactive response DNA-binding protein 43 pathology (FTLD-TDP), we tested cohorts of ALS and FTLD-TDP patients for PFN1 mutations.
DNA was obtained from 342 ALS patients and 141 FTLD-TDP patients at our outpatient clinic and brain bank for neurodegenerative diseases at the Mayo Clinic Florida, Jacksonville, USA. We screened these patients for mutations in coding regions of PFN1 by Sanger sequencing. Subsequently, we used TaqMan genotyping assays to investigate the identified variant in 1167 control subjects.
One variant, p.E117G, was detected in 1 ALS patient, 1 FTLD-TDP patient, and 2 control subjects. The mutation frequency of patients versus control subjects was not significantly different (p-value = 0.36). Moreover, PFN1 and TDP-43 staining of autopsy material did not differ between patients with or without this variant.
The p.E117G variant appears to represent a benign polymorphism. PFN1 mutations, in general, are rare in ALS and FTLD-TDP patients.
PMCID: PMC3923463  PMID: 23634771
Amyotrophic lateral sclerosis; frontotemporal dementia; profilin-1; TDP-43; genetics
3.  Probable RBD is Increased in Parkinson’s Disease But Not in Essential Tremor or Restless Legs Syndrome 
Parkinsonism & related disorders  2011;17(6):456-458.
Compare the frequency of REM sleep behavior disorder (RBD) and excessive daytime sleepiness (EDS) in Parkinson’s disease (PD), restless legs syndrome (RLS), essential tremor (ET), and control subjects.
Subjects enrolled in a longitudinal clinicopathologic study, and when available an informant, completed the Mayo Sleep Questionnaire, which asks “Have you ever been told that you act out your dreams?”, and the Epworth Sleepiness Scale (ESS).
Probable RBD (based on informant response to the questionnaire) was much more frequent in PD (34/49, 69%, p<0.001) than in RLS (6/30, 20%), ET (7/53, 13%), or control subjects (23/175, 13%), with an odds ratio of 11 for PD compared to controls. The mean ESS and the number of subjects with an ESS ≥ 10 was higher in PD (29/60, 48%, p<0.001) and RLS (12/39, 31%, p<0.001) compared with ET (12/93, 13%) and Controls (34/296, 11%).
Probable RBD is much more frequent in PD with no evidence to suggest an increase in either RLS or ET. Given the evidence that RBD is a synucleinopathy, the lack of an increased frequency of RBD in subjects with ET or RLS suggests the majority of ET and RLS subjects are unlikely to be at increased risk for developing PD.
PMCID: PMC3119772  PMID: 21482171
Parkinson’s disease; REM sleep behavior disorder; essential tremor; restless legs syndrome; excessive daytime sleepiness
4.  A computerized technique to assess language use patterns in patients with frontotemporal dementia 
Journal of neurolinguistics  2010;23(2):127-144.
Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder that affects language. We applied a computerized information-theoretic technique to assess the type and severity of language-related FTLD symptoms. Audio-recorded samples of 48 FTLD patients from three participating medical centers were elicited using the Cookie Theft picture stimulus. The audio was transcribed and analyzed by calculating two measures: a perplexity index and an out-of-vocabulary (OOV) rate. The perplexity index represents the degree of deviation in word patterns used by FTLD patients compared to patterns of healthy adults. The OOV rate represents the proportion of words used by FTLD patients that were not used by the healthy speakers to describe the stimulus. In this clinically well-characterized cohort, the perplexity index and the OOV rate were sensitive to spontaneous language manifestations of semantic dementia and the distinction between semantic dementia and progressive logopenic aphasia variants of FTLD. Our study not only supports a novel technique for the characterization of language-related symptoms of FTLD in clinical trial settings, it also validates the basis for the clinical diagnosis of semantic dementia as a distinct syndrome.
PMCID: PMC3043371  PMID: 21359164
frontotemporal lobar degeneration; semantic dementia; perplexity; entropy; statistical language modeling
5.  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.
PMCID: PMC2822633  PMID: 19889717
mild cognitive impairment; dementia; dementia with Lewy bodies; Lewy body disease; neuropathology
6.  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.
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.
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.
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.
PMCID: PMC2886669  PMID: 19443597
PET; dementia; 18F-FDG; PiB
7.  Off-Label Medication Use in Frontotemporal Dementia 
There are no Food and Drug Administration (FDA)-approved medications indicated for the treatment of frontotemporal dementia (FTD). We sought to determine the most commonly used drugs used to treat behavioral variant FTD (bvFTD) in specialized dementia clinics.
Medication and demographic data from the Alzheimer’s Disease Research Centers of California (ARCC) and a multicenter FTD natural history study (NHS) data set were compared in bvFTD and Alzheimer’s disease (AD), and effects of demographic variables were assessed using logistic regression.
Overall, the percentage of patients taking one or more FDA-approved AD or psychiatric medications was similar in bvFTD and AD; however, after controlling for demographic variables, acetylcholinesterase inhibitor (AChI) use was less common in bvFTD, whereas memantine use remained similar in the 2 groups.
Despite lack of evidence for efficacy, the use of AChIs and memantine is common in bvFTD. Clinical trials should be pursued to determine the optimal therapeutic interventions for bvFTD.
PMCID: PMC2862544  PMID: 20124256
frontotemporal dementia; Alzheimer’s disease; treatment; donepezil; memantine; galantamine; antipsychotic agents
8.  Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members 
Brain  2009;132(3):583-591.
Mutations in the progranulin gene (GRN) are an important cause of frontotemporal lobar degeneration (FTLD) with ubiquitin and TAR DNA-binding protein 43 (TDP43)-positive pathology. The clinical presentation associated with GRN mutations is heterogeneous and may include clinical probable Alzheimer's disease. All GRN mutations identified thus far cause disease through a uniform disease mechanism, i.e. the loss of functional GRN or haploinsufficiency. To determine if expression of GRN in plasma could predict GRN mutation status and could be used as a biological marker, we optimized a GRN ELISA and studied plasma samples of a consecutive clinical FTLD series of 219 patients, 70 control individuals, 72 early-onset probable Alzheimer's disease patients and nine symptomatic and 18 asymptomatic relatives of GRN mutation families. All FTLD patients with GRN loss-of-function mutations showed significantly reduced levels of GRN in plasma to about one third of the levels observed in non-GRN carriers and control individuals (P < 0.001). No overlap in distributions of GRN levels was observed between the eight GRN loss-of-function mutation carriers (range: 53–94 ng/ml) and 191 non-GRN mutation carriers (range: 115–386 ng/ml). Similar low levels of GRN were identified in asymptomatic GRN mutation carriers. Importantly, ELISA analyses also identified one probable Alzheimer's disease patient (1.4%) carrying a loss-of-function mutation in GRN. Biochemical analyses further showed that the GRN ELISA only detects full-length GRN, no intermediate granulin fragments. This study demonstrates that using a GRN ELISA in plasma, pathogenic GRN mutations can be accurately detected in symptomatic and asymptomatic carriers. The ∼75% reduction in full-length GRN, suggests an unbalanced GRN metabolism in loss-of-function mutation carriers whereby more GRN is processed into granulins. We propose that plasma GRN levels could be used as a reliable and inexpensive tool to identify all GRN mutation carriers in early-onset dementia populations and asymptomatic at-risk individuals.
PMCID: PMC2664450  PMID: 19158106
Progranulin; ELISA; frontotemporal lobar degeneration; Alzheimer's disease
9.  Novel Mutations in TARDBP (TDP-43) in Patients with Familial Amyotrophic Lateral Sclerosis 
PLoS Genetics  2008;4(9):e1000193.
The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43–positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the ∼25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis.
Author Summary
The abnormal accumulation of disease proteins in neuronal cells of the brain is a characteristic feature of many neurodegenerative diseases. Rare mutations in the genes that encode the accumulating proteins have been identified in these disorders and are crucial for the development of cell and animal models used to study neurodegeneration. Recently, the TAR DNA-binding protein 43 (TDP-43) was identified as the disease accumulating protein in patients with frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U) and in amyotrophic lateral sclerosis (ALS). TDP-43 was also found in the brains of 20–30% of patients with Alzheimer's disease (AD). Here, we evaluated whether mutations in TDP-43 cause disease in a cohort of 296 patients presenting with FTLD, ALS or AD. We identified three missense mutations in three out of 92 familial ALS patients (3.3%), and no mutations in AD or FTLD patients. All the identified mutations clustered in exon 6, which codes for a highly conserved region in the C-terminal part of the TDP-43 protein, which is known to be involved in the interaction of TDP-43 with other proteins. We conclude that mutations in TDP-43 are a rare cause of familial ALS, but so far are not found in other neurodegenerative diseases.
PMCID: PMC2527686  PMID: 18802454

Results 1-9 (9)