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1.  Neuropsychiatric effects of neurodegeneration of the medial vs. lateral ventral prefrontal cortex in humans 
Animal evidence suggests that a brain network involving the medial and rostral ventral prefrontal cortex (PFC) is central for threat response and arousal and a network involving the lateral and caudal PFC plays an important role in reward learning and behavioral control. In this study, we contrasted the neuropsychiatric effects of degeneration of the medial versus lateral PFC in 43 patients with Frontotemporal dementia and 11 patients with Corticobasal Syndrome using MRI, the Neuropsychiatric Inventory (NPI), and the Sorting, Tower, Twenty Questions, and Fluency tests of the Delis-Kaplan Executive Function System (D-KEFS). Deviations in MRI grey matter volume from 86 age-matched healthy control subjects were determined for the patients using FreeSurfer. Multivariate regression was used to determine which brain areas were associated with specific neuropsychiatric and cognitive symptoms. Decreased grey matter volume of the right medial ventral PFC was associated with increased anxiety and apathy, decreased volume of the right lateral ventral PFC with apathy and inappropriate repetitive behaviors, and of the left lateral ventral PFC with poor performance on the sorting and Twenty Questions task in patients with FTD and CBS. Similar to in animal studies, damage to the medial OFC appears to be associated with a disruption of arousal, and damage to the lateral OFC appears to be associated with deficits in trial-and-error learning and behavioral dysregulation. Studies of brain dysfunction in humans are valuable to bridge animal and human neuropsychiatric research.
doi:10.1016/j.cortex.2015.08.002
PMCID: PMC4689656  PMID: 26343341
Neurodegeneration; Prefrontal cortex; Neuropsychiatry; Lesion studies
2.  Closing the tau loop: the missing tau mutation 
Brain  2015;138(10):3100-3109.
Twenty years ago McCarthy et al. described frontotemporal dementia parkinsonism linked to chromosome 17 (FTDP-17). They later identified a tau mutation (+14) in the exon/intron 10 splice site stem loop. Eleven of 12 predicted stem loop mutations were subsequently discovered. The authors now describe another Irish family with FTDP-17 due to missing stem loop mutation (+15).
Twenty years ago McCarthy et al. described frontotemporal dementia parkinsonism linked to chromosome 17 (FTDP-17). They later identified a tau mutation (+14) in the exon/intron 10 splice site stem loop. Eleven of 12 predicted stem loop mutations were subsequently discovered. The authors now describe another Irish family with FTDP-17 due to missing stem loop mutation (+15).
Frontotemporal lobar degeneration comprises a group of disorders characterized by behavioural, executive, language impairment and sometimes features of parkinsonism and motor neuron disease. In 1994 we described an Irish-American family with frontotemporal dementia linked to chromosome 17 associated with extensive tau pathology. We named this disinhibition-dementia-parkinsonism-amyotrophy complex. We subsequently identified mutations in the MAPT gene. Eleven MAPT gene splice site stem loop mutations were identified over time except for 5’ splice site of exon 10. We recently identified another Irish family with autosomal dominant early amnesia and behavioural change or parkinsonism associated with the ‘missing’ +15 mutation at the intronic boundary of exon 10. We performed a clinical, neuropsychological and neuroimaging study on the proband and four siblings, including two affected siblings. We sequenced MAPT and performed segregation analysis. We looked for a biological effect of the tau variant by performing real-time polymerase chain reaction analysis of RNA extracted from human embryonic kidney cells transfected with exon trapping constructs. We found a c.915+15A>C exon 10/intron 10 stem loop mutation in all affected subjects but not in the unaffected. The c.915+15A>C variant caused a shift in tau splicing pattern to a predominantly exon 10+ pattern presumably resulting in predominant 4 repeat tau and little 3 repeat tau. This strongly suggests that the c.915+15A>C variant is a mutation and that it causes frontotemporal dementia linked to chromosome 17 in this pedigree by shifting tau transcription and translation to +4 repeat tau. Tau (MAPT) screening should be considered in families where amnesia or atypical parkinsonism coexists with behavioural disturbance early in the disease process. We describe the final missing stem loop tau mutation predicted 15 years ago. Mutations have now been identified at all predicted sites within the ‘stem’ when the stem-loop model was first proposed and no mutations have been found within the ‘loop’ region as expected. Therefore we ‘close the tau loop’ having ‘opened the loop’ 21 years ago.
doi:10.1093/brain/awv234
PMCID: PMC5006396  PMID: 26297556
frontotemporal; dementia; MAPT; stem loop; FTDP-17
3.  The right insula contributes to memory awareness in cognitively diverse older adults 
Neuropsychologia  2015;75:163-169.
Unawareness of memory loss is a challenging characteristic of Alzheimer’s disease (AD) and other age-related neurodegenerative conditions at their earliest stages, adversely affecting important outcomes such as patient decision making and safety. The basis of this metacognitive disturbance has been elusive; however it is almost certainly determined in part by compromise to brain regions critical for self-assessment. The subjectivity of traditional measurements of self-awareness in dementia has likely limited the rigor with which its neuroanatomic correlates can be established. Here we objectively measure memory awareness (metamemory) using a Feeling of Knowing (FOK) task in a group of cognitively diverse older adults, including 14 with mild AD and 20 cognitively healthy older adults. Performance on the metamemory task was examined in relation to the structural integrity of 14 bilateral neuroanatomic regions hypothesized to support self-awareness. Less accurate metamemory was associated only with reduced right insular volume (r = .41, p = .019). Implications of the current findings for models of metacognitive aging are discussed, with attention to the role of the insula in the conscious detection of errors.
doi:10.1016/j.neuropsychologia.2015.05.032
PMCID: PMC4546518  PMID: 26049091
Awareness; Anosognosia; Metacognition; Alzheimer’s disease; Insula
4.  Depressive symptoms can amplify embarrassment in essential tremor 
Background
Embarrassment can be a considerable problem for patients with essential tremor (ET) and is a major motivator for treatment. Depression is also a common feature of ET; as many as 35 % of patients report moderate to severe depressive symptoms. Our goal was to assess the associations between these motor and psychosocial factors (tremor, depression, embarrassment) in ET, with a particular interest in more fully assessing the possible association between depression and embarrassment.
Methods
Ninety one ET cases (age 70.4 ± 12.8 years) enrolled in a prospective, clinical-epidemiological study. Depressive symptoms were assessed with the Center for Epidemiological Studies Depression Scale (CESD-10, 0–30 [maximum]), embarrassment, with the Essential Tremor Embarrassment Assessment (ETEA, 0–70 [maximum]), and action tremor, with a detailed in-person neurological examination.
Results
Higher CESD-10 score was significantly associated with higher ETEA score (p = 0.005), but not with increasing tremor severity (p = 0.94). In stratified analyses, cases with no or minimal depressive symptoms had the lowest ETEA scores, cases with moderate depressive symptoms had intermediate ETEA scores, and cases with severe depressive symptoms had the highest ETEA scores (p = 0.01). Furthermore, at each level of tremor severity, cases with more depressive symptoms had more embarrassment.
Conclusions
Depressive symptoms seem to be more than a secondary response to the tremor in ET; they seem to amplify the level of embarrassment and, in addition to their own importance, seem to be a driver of other important clinical outcomes. Earlier treatment of depressive symptoms in ET patients could lessen the burden of secondary embarrassment.
doi:10.1186/s40734-016-0039-6
PMCID: PMC4947359  PMID: 27429787
Essential tremor; Non-motor; Depression; Embarrassment; Clinical; Treatment
5.  A systematic review of neurotransmitter deficits and treatments in frontotemporal dementia 
Neurology  2006;66(1):17-22.
Objective
To evaluate neurotransmitter deficiencies and neurotransmitter-based treatments for frontotemporal dementia (FTD).
Methods
The authors conducted a systematic review of the literature on the mechanism and treatment of FTD and a meta-analysis of treatment studies of antidepressants for the behavioral symptoms of FTD.
Results
Patients with FTD show deficiencies in the serotonin and dopamine neurotransmitter systems, while the acetylcholine system appears relatively intact. Antidepressant treatment significantly improves behavioral symptoms in FTD, but most studies are small and uncontrolled. Serotonergic treatments appear to improve the behavioral but not cognitive symptoms of FTD.
Conclusions
Studies of neurotransmitter deficiencies in frontotemporal dementia (FTD) can be helpful in developing treatments. Treatment studies on FTD are scarce, given the prevalence and severity of this illness. Larger, well-controlled treatment studies are required to reach more definitive conclusions about treatment efficacy. Multicenter studies are likely the best way to complete treatment studies in a timely manner.
doi:10.1212/01.wnl.0000191304.55196.4d
PMCID: PMC4499854  PMID: 16401839
6.  Caregiver Burden in Frontotemporal Degeneration and Corticobasal Syndrome 
Background and Aims
Caregiver stress is often a serious problem when caring for a patient with frontal lobe dysfunction.
Methods
A total of 102 caregivers of both patients with frontotemporal degeneration and corticobasal syndrome completed the Frontal Systems Behavior Scale (FrSBe) and the Zarit Burden Interview (ZBI). To analyze the association between apathy or disinhibition (or both) and caregiver burden, the effects of the total FrSBe and the apathy and disinhibition subscales of the FrSBE on the total ZBI score were assessed with logistic regressions and t tests.
Results
Total FrSBE score and the apathy FrSBE subscore predicted caregiver burden. Apathy occurred without disinhibition, and the two occurred together, but disinhibition without apathy was very rare.
Conclusions
Disinhibition without apathy occurred very rarely. Apathy was more associated with caregiver burden than disinhibition.
doi:10.1159/000351670
PMCID: PMC4484601  PMID: 24022248
Caregiver burden; Frontotemporal degeneration; Corticobasal syndrome; Frontal Systems Behavior Scale; Zarit Burden Interview
7.  Impaired corticopontocerebellar tracts underlie pseudobulbar affect in motor neuron disorders 
Neurology  2014;83(7):620-627.
Objective:
The objectives of the study were (1) to determine the prevalence and characteristics of pseudobulbar affect (PBA) in patients with primary lateral sclerosis (PLS) and amyotrophic lateral sclerosis (ALS) in an outpatient clinic population, and (2) to test the hypothesis that damage of inputs to the cerebellum, leading to cerebellar dysmodulation, is associated with PBA.
Methods:
Chart review of all patients with PLS and ALS seen between 2000 and 2013. The examining neurologist documented the presence or absence of PBA in 87 patients. Forty-seven patients also had diffusion tensor imaging (DTI) studies. Tract-based spatial statistics were used to compare DTI of patients with and without PBA to identify altered white matter tracts associated with PBA.
Results:
Thirty-one of 50 patients with PLS and 12 of 37 patients with ALS had PBA. Psychiatric/emotional assessment found congruence between mood and affect during episodes, but excessive magnitude of the response. DTI studies of 25 PLS and 22 ALS patient brains showed reduced fractional anisotropy of the corticospinal and callosal white matter tracts in all patients. Patients with PBA additionally had increased mean diffusivity of white matter tracts underlying the frontotemporal cortex, the transverse pontine fibers, and the middle cerebellar peduncle.
Conclusions:
PBA is common in PLS. Imaging findings showing disruption of corticopontocerebellar pathways support the hypothesis that PBA can be viewed as a “dysmetria” of emotional expression resulting from cerebellar dysmodulation.
doi:10.1212/WNL.0000000000000693
PMCID: PMC4141995  PMID: 25008395
8.  A pilot study of the prevalence of psychiatric disorders in PLS and ALS 
The prevalence of psychiatric disorders in primary lateral sclerosis (PLS) is currently unknown. In the present study, we compared the prevalence of psychiatric illness in patients with PLS and amyotrophic lateral sclerosis (ALS). We hypothesized that if the psychosocial stress of motor neuron disease predisposes patients to depressive disorders, patients with ALS (with a poorer prognosis and more disability than patients with PLS) should have a higher prevalence of depressive disorders than patients with PLS. We administered the gold standard of psychiatric assessment, the SCID, to 19 PLS and 13 ALS patients. We found a prevalence of current depressive disorders in PLS patients that was, by a nonsignificant trend, lower than that of ALS patients. The prevalence of current depressive disorders in the ALS patients was higher than previously reported and similar to that observed in non-neurological medical disorders. Other psychiatric disorders were rare. In conclusion, depressive disorders were the most commonly observed psychiatric disorders in both PLS and ALS. By a non-significant trend, the PLS patients had a lower current prevalence of depressive disorders than the ALS patients. These data are consistent with the hypothesis that the psychosocial stress of MND is a risk factor for depression.
doi:10.3109/17482960903544576
PMCID: PMC4492446  PMID: 20132085
PLS; ALS; psychiatric disorder; depression; major depressive disorder
9.  Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy 
Nature Communications  2015;6:7247.
Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10−12), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10−8), and 2p22 at SOS1 (rs963731; P=1.76 × 10−7). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10−7) and MAPT H1c (17q21; rs242557; P=7.91 × 10−6). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein).
Corticobasal degeneration is a rare neurodegenerative disorder that can only be definitively diagnosed by autopsy. Here, Kouri et al. conduct a genome-wide-association study and identify two genetic susceptibility loci 17q21 (MAPT) and 3p12 (MOBP), and a novel susceptibility locus at 8p12.
doi:10.1038/ncomms8247
PMCID: PMC4469997  PMID: 26077951
11.  Factors associated with use of medications with potential to impair cognition or cholinesterase inhibitors among Alzheimer’s disease patients 
Background
The aim of this study was to use a signal detection method to examine the prevalence of, and patient characteristics associated with, medication with potential to impair cognition and cholinesterase inhibitor use in patients with Alzheimer’s disease.
Methods
A cross-sectional study was conducted of 1,954 patients with a diagnosis of probable or possible Alzheimer’s disease. Concurrent medications were measured, specifically: (1) a medication with potential to impair cognition or (2) a cholinesterase inhibitor. Predictor variables included age, gender, ethnic group, education, age of symptom onset, number of prescriptions, number of medical diagnoses, Mini-Mental State Examination (MMSE), Blessed-Roth Dementia Rating Scale (BRDRS), probable versus possible AD diagnosis.
Results
Fifteen percent of the Alzheimer’s disease patients were on a medication with potential to impair cognition, and 44% were on a cholinesterase inhibitor. Patient characteristics associated with the prescription of a medication with potential to impair cognition included total number of prescription medications, low education, low MMSE, older age, reported lack of vitamin use, and more medical diagnoses. Patient characteristics associated with the prescription of a cholinesterase inhibitor included reported use of vitamins, the total number of prescription medications, fewer medical diagnoses, lower age of symptom onset, and higher education.
Conclusions
Determining the patient characteristics associated with the prescription of a medication with potential to impair cognition can help clinicians identify patients who are at risk for drug-related morbidity. Patient characteristics unassociated with dementia appear to influence the prescription of cholinesterase inhibitors. Signal detection analysis is well suited to this type of research.
doi:10.1016/j.jalz.2006.08.003
PMCID: PMC4489699  PMID: 19595905
Alzheimer’s disease; inappropriate medications; cholinesterase inhibitors; Beers criteria; signal detection; receiver operating characteristic analysis
12.  FUS and TDP43 genetic variability in FTD and CBS 
Neurobiology of aging  2011;33(5):1016.e9-1016.17.
This study aimed to evaluate genetic variability in the FUS and TDP-43 genes, known to be mainly associated with amyotrophic lateral sclerosis (ALS), in patients with the diagnoses of frontotemporal lobar degeneration (FTLD) and corticobasal syndrome (CBS). We screened the DNA of 228 patients for all the exons and flanking introns of FUS and TDP-43 genes. We identified 2 novel heterozygous missense mutations in FUS: P106L (g.22508384>T) in a patient with behavioral variant frontotemporal dementia (bvFTD) and Q179H in several members of a family with behavioral variant FTD. We also identified the N267S mutation in TDP-43 in a CBS patient, previously only reported in 1 ALS family and 1 FTD patient. Additionally, we identified 2 previously reported heterozygous insertion and deletion mutations in Exon 5 of FUS; Gly174-Gly175 del GG (g. 4180–4185 delGAGGTG) in an FTD patient and Gly175-Gly176 ins GG (g. 4185–4186 insGAGGTG) in a patient with diagnosis of CBS. Not least, we have found a series of variants in FUS also in neurologically normal controls. In summary, we report that genetic variability in FUS and TDP-43 encompasses a wide range of phenotypes (including ALS, FTD, and CBS) and that there is substantial genetic variability in FUS gene in neurologically normal controls.
doi:10.1016/j.neurobiolaging.2011.08.004
PMCID: PMC4489700  PMID: 21943958
Frontotemporal dementia; Corticobasal syndrome; Genetics; FUS; TDP-43
13.  Frontotemporal dementia and its subtypes: a genome-wide association study 
Ferrari, Raffaele | Hernandez, Dena G | Nalls, Michael A | Rohrer, Jonathan D | Ramasamy, Adaikalavan | Kwok, John B J | Dobson-Stone, Carol | Brooks, William S | Schofield, Peter R | Halliday, Glenda M | Hodges, John R | Piguet, Olivier | Bartley, Lauren | Thompson, Elizabeth | Haan, Eric | Hernández, Isabel | Ruiz, Agustín | Boada, Mercè | Borroni, Barbara | Padovani, Alessandro | Cruchaga, Carlos | Cairns, Nigel J | Benussi, Luisa | Binetti, Giuliano | Ghidoni, Roberta | Forloni, Gianluigi | Galimberti, Daniela | Fenoglio, Chiara | Serpente, Maria | Scarpini, Elio | Clarimón, Jordi | Lleó, Alberto | Blesa, Rafael | Waldö, Maria Landqvist | Nilsson, Karin | Nilsson, Christer | Mackenzie, Ian R A | Hsiung, Ging-Yuek R | Mann, David M A | Grafman, Jordan | Morris, Christopher M | Attems, Johannes | Griffiths, Timothy D | McKeith, Ian G | Thomas, Alan J | Pietrini, P | Huey, Edward D | Wassermann, Eric M | Baborie, Atik | Jaros, Evelyn | Tierney, Michael C | Pastor, Pau | Razquin, Cristina | Ortega-Cubero, Sara | Alonso, Elena | Perneczky, Robert | Diehl-Schmid, Janine | Alexopoulos, Panagiotis | Kurz, Alexander | Rainero, Innocenzo | Rubino, Elisa | Pinessi, Lorenzo | Rogaeva, Ekaterina | George-Hyslop, Peter St | Rossi, Giacomina | Tagliavini, Fabrizio | Giaccone, Giorgio | Rowe, James B | Schlachetzki, J C M | Uphill, James | Collinge, John | Mead, S | Danek, Adrian | Van Deerlin, Vivianna M | Grossman, Murray | Trojanowsk, John Q | van der Zee, Julie | Deschamps, William | Van Langenhove, Tim | Cruts, Marc | Van Broeckhoven, Christine | Cappa, Stefano F | Le Ber, Isabelle | Hannequin, Didier | Golfier, Véronique | Vercelletto, Martine | Brice, Alexis | Nacmias, Benedetta | Sorbi, Sandro | Bagnoli, Silvia | Piaceri, Irene | Nielsen, Jørgen E | Hjermind, Lena E | Riemenschneider, Matthias | Mayhaus, Manuel | Ibach, Bernd | Gasparoni, Gilles | Pichler, Sabrina | Gu, Wei | Rossor, Martin N | Fox, Nick C | Warren, Jason D | Spillantini, Maria Grazia | Morris, Huw R | Rizzu, Patrizia | Heutink, Peter | Snowden, Julie S | Rollinson, Sara | Richardson, Anna | Gerhard, Alexander | Bruni, Amalia C | Maletta, Raffaele | Frangipane, Francesca | Cupidi, Chiara | Bernardi, Livia | Anfossi, Maria | Gallo, Maura | Conidi, Maria Elena | Smirne, Nicoletta | Rademakers, Rosa | Baker, Matt | Dickson, Dennis W | Graff-Radford, Neill R | Petersen, Ronald C | Knopman, David | Josephs, Keith A | Boeve, Bradley F | Parisi, Joseph E | Seeley, William W | Miller, Bruce L | Karydas, Anna M | Rosen, Howard | van Swieten, John C | Dopper, Elise G P | Seelaar, Harro | Pijnenburg, Yolande AL | Scheltens, Philip | Logroscino, Giancarlo | Capozzo, Rosa | Novelli, Valeria | Puca, Annibale A | Franceschi, M | Postiglione, Alfredo | Milan, Graziella | Sorrentino, Paolo | Kristiansen, Mark | Chiang, Huei-Hsin | Graff, Caroline | Pasquier, Florence | Rollin, Adeline | Deramecourt, Vincent | Lebert, Florence | Kapogiannis, Dimitrios | Ferrucci, Luigi | Pickering-Brown, Stuart | Singleton, Andrew B | Hardy, John | Momeni, Parastoo
Lancet neurology  2014;13(7):686-699.
Summary
Background
Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes—MAPT, GRN, and C9orf72—have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.
Methods
We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. All participants had European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10−8) and suggestive single-nucleotide polymorphisms.
Findings
We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10−8) that encompassed the HLA locus at 6p21.3 in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC, for the behavioural FTD subtype. Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation incis.
Interpretation
Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and possibly to shed light on the pathomechanisms contributing to FTD.
Funding
The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/ MRC Centre on Parkinson’s disease, Alzheimer’s Research UK, and Texas Tech University Health Sciences Center.
doi:10.1016/S1474-4422(14)70065-1
PMCID: PMC4112126  PMID: 24943344
15.  Childhood Learning Disabilities and Atypical Dementia: A Retrospective Chart Review 
PLoS ONE  2015;10(6):e0129919.
Objective
To further our understanding of the association between self-reported childhood learning disabilities (LDs) and atypical dementia phenotypes (Atypical Dementia), including logopenic primary progressive aphasia (L-PPA), Posterior Cortical Atrophy (PCA), and Dysexecutive-type Alzheimer’s Disease (AD).
Methods
This retrospective case series analysis of 678 comprehensive neuropsychological assessments compared rates of self-reported LD between dementia patients diagnosed with Typical AD and those diagnosed with Atypical Dementia. 105 cases with neuroimaging or CSF data available and at least one neurology follow-up were identified as having been diagnosed by the neuropsychologist with any form of neurodegenerative dementia. These cases were subject to a consensus diagnostic process among three dementia experts using validated clinical criteria for AD and PPA. LD was considered Probable if two or more statements consistent with prior LD were documented within the Social & Developmental History of the initial neuropsychological evaluation.
Results
85 subjects (Typical AD n=68, Atypical AD n=17) were included in the final analysis. In logistic regression models adjusted for age, gender, handedness, education and symptom duration, patients with Probable LD, compared to patients without Probable LD, were significantly more likely to be diagnosed with Atypical Dementia vs. Typical AD (OR 13.1, 95% CI 1.3-128.4). All three of the L-PPA cases reporting a childhood LD endorsed childhood difficulty with language. By contrast, both PCA cases reporting Probable childhood LD endorsed difficulty with attention and/or math.
Conclusions
In people who develop dementia, childhood LD may predispose to atypical phenotypes. Future studies are required to confirm whether atypical neurodevelopment predisposes to regional-specific neuropathology in AD and other dementias.
doi:10.1371/journal.pone.0129919
PMCID: PMC4481274  PMID: 26106899
16.  A Psychological and Neuroanatomical Model of Obsessive-Compulsive Disorder 
Imaging, surgical, and lesion studies suggest that the prefrontal cortex (orbitofrontal and anterior cingulate cortexes), basal ganglia, and thalamus are involved in the pathogenesis of obsessive-compulsive disorder (OCD). On the basis of these findings several models of OCD have been developed, but have had difficulty fully integrating the psychological and neuroanatomical findings of OCD. Recent research in the field of cognitive neuroscience on the normal function of these brain areas demonstrates the role of the orbitofrontal cortex in reward, the anterior cingulate cortex in error detection, the basal ganglia in affecting the threshold for activation of motor and behavioral programs, and the prefrontal cortex in storing memories of behavioral sequences (called “structured event complexes” or SECs). The authors propose that the initiation of these SECs can be accompanied by anxiety that is relieved with completion of the SEC, and that a deficit in this process could be responsible for many of the symptoms of OCD. Specifically, the anxiety can form the basis of an obsession, and a compulsion can be an attempt to receive relief from the anxiety by repeating parts of, or an entire, SEC. The authors discuss empiric support for, and specific experimental predictions of, this model. The authors believe that this model explains the specific symptoms, and integrates the psychology and neuroanatomy of OCD better than previous models.
doi:10.1176/appi.neuropsych.20.4.390
PMCID: PMC4476073  PMID: 19196924
17.  Management of Frontotemporal Dementia in Mental Health and Multidisciplinary Settings 
Diagnosis of frontotemporal dementia (FTD) in the mental health setting and issues pertaining to longitudinal care of this population in a specialty clinic are reviewed. FTD is often misdiagnosed as a psychiatric disorder, most commonly as a mood disorder. FTD has features that overlap with those of major depression, mania, obsessive-compulsive disorder and schizophrenia. We describe these features and how to differentiate FTD from these psychiatric disorders. This paper also describes practical issues in the management of FTD, specifically the issues that clinicians, patients and their families face in managing this disease. Areas of clinical care along the continuum are explored; FTD care involves collaborative management of symptoms and disability, and assisting patients and families in adapting to the disease.
doi:10.3109/09540261.2013.776949
PMCID: PMC3929950  PMID: 23611352
18.  Clinical–Pathological Agreement in Dementing Disorders: Embracing the Complexity 
In Response to:
Giorelli M, Losignore NA, Bagnoli J, et al. The progression of posterior cortical atrophy to corticobasal syndrome: Lumping or splitting neurodegenerative diseases? Tremor Other Hyperkinet Mov. 2014; 4. doi: 10.7916/D81G0JCQ
doi:10.7916/D84J0CDQ
PMCID: PMC4245484  PMID: 25469310
Dementia; clinico-pathologic agreement
19.  Course and etiology of dysexecutive MCI in a community sample 
Background
Amnestic MCI (aMCI) is associated with an elevated risk of progressing to Alzheimer’s disease. Much less is known about the course of dysexecutive MCI (dMCI). The goals of this study were to determine: How the profile of cognitive deficits differs over time between patients with dMCI, aMCI, and control subjects; if the type of dementia differs between dMCI and aMCI in patients who progress to dementia; and if dMCI is more associated with strokes and white matter hyperintensities on MRI than aMCI.
Methods
A prospective evaluation of an inception cohort of 1167 ethnically-diverse elders recruited from an urban community-based sample and followed with clinical and neuropsychological testing over an average of 4.5 years (SD=0.8). A subset of the subjects had MRI scans. We compared four groups of MCI patients: single domain amnestic and dysexecutive MCI and multiple domain MCI with and without executive dysfunction.
Results
Compared with aMCI, dMCI was less likely to involve other areas of cognition over time and progress to dementia. None of the 33 single domain dMCI patients progressed to dementia. The presence of executive dysfunction in multiple domain MCI did not increase risk of progression to dementia. Patients with multiple domain MCI with executive dysfunction who progressed to dementia were less likely to have an Alzheimer’s type dementia than MCI patients without executive dysfunction. Patients with dMCI were more likely to have strokes, but not white matter hyperintensities, detected on MRI than patients with aMCI.
Conclusions
DMCI appears to follow a different course, and be less associated with AD and more associated with stroke, than aMCI.
doi:10.1016/j.jalz.2012.10.014
PMCID: PMC3933297  PMID: 23452959
20.  Dysexecutive versus amnestic Alzheimer’s disease subgroups: Analysis of demographic, genetic, and vascular factors 
The objective of this study was to compare demographic and vascular characteristics and APOE genotypes of a dysexecutive subgroup of Alzheimer’s disease (AD) with an amnestic subgroup of AD early in the disease course. 2,224 participants from the National Alzheimer’s Coordinating Center (NACC) database who carried a diagnosis of MCI (n=1,188) or mild AD (clinical dementia rating ≤1) (n=1,036) were included in this study. A subset of the MCI (n=61) and mild AD (n=79) participants underwent autopsy. A dysexecutive subgroup (n=587) was defined as having executive performance >1 SD worse than memory performance and an amnestic subgroup (n=549) was defined conversely. Among the autopsy subset, the likelihood of an AD pathologic diagnosis was compared in the two subgroups. Demographics, APOEε4 status, and vascular risk factors were compared in the two subgroups. Among the autopsy subset, the likelihood of having an AD pathologic diagnosis did not differ between the dysexecutive and amnestic subgroups. Under an additive model, participants in the dysexecutive subgroup possessed the APOEε4 allele less frequently than those in the amnestic subgroup. The dysexecutive subgroup had a history of hypertension less frequently than the amnestic subgroup. These distinct characteristics add to accumulating evidence that a dysexecutive subgroup of AD may have a unique underlying pathophysiology.
doi:10.1097/WAD.0b013e31826a94bd
PMCID: PMC3748394  PMID: 23954887
21.  C9ORF72 repeat expansions in cases with previously identified pathogenic mutations 
Neurology  2013;81(15):1332-1341.
Objective:
To identify potential genetic modifiers contributing to the phenotypic variability that is detected in patients with repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), we investigated the frequency of these expansions in a cohort of 334 subjects previously found to carry mutations in genes known to be associated with a spectrum of neurodegenerative diseases.
Methods:
A 2-step protocol, with a fluorescent PCR and a repeat-primed PCR, was used to determine the presence of hexanucleotide expansions in C9ORF72. For one double mutant, we performed Southern blots to assess expansion sizes, and immunohistochemistry to characterize neuropathology.
Results:
We detected C9ORF72 repeat expansions in 4 of 334 subjects (1.2% [or 1.8% of 217 families]). All these subjects had behavioral phenotypes and also harbored well-known pathogenic mutations in either progranulin (GRN: p.C466LfsX46, p.R493X, p.C31LfsX35) or microtubule-associated protein tau (MAPT: p.P301L). Southern blotting of one double mutant with a p.C466LfsX46 GRN mutation demonstrated a long repeat expansion in brain (>3,000 repeats), and immunohistochemistry showed mixed neuropathology with characteristics of both C9ORF72 expansions and GRN mutations.
Conclusions:
Our findings indicate that co-occurrence of 2 evidently pathogenic mutations could contribute to the pleiotropy that is detected in patients with C9ORF72 repeat expansions. These findings suggest that patients with known mutations should not be excluded from further studies, and that genetic counselors should be aware of this phenomenon when advising patients and their family members.
doi:10.1212/WNL.0b013e3182a8250c
PMCID: PMC3806926  PMID: 24027057
22.  C9ORF72 repeat expansions not detected in a group of patients with schizophrenia 
Neurobiology of aging  2012;34(4):1309.e9-1309.10.
A hexanucleotide repeat expansion in C9ORF72 was recently found to cause some cases of FTLD, FTD-ALS, and ALS. FTLD patients with the C9ORF72 repeat expansion are more likely than those without to present with psychosis. In this study, we screened DNA samples from 192 unrelated subjects with schizophrenia for the C9ORF72 repeat expansion. None of the subjects with schizophrenia had the pathogenic expansion. C9ORF72 repeat expansions either do not cause schizophrenia, or do so rarely (less than 1% of cases).
doi:10.1016/j.neurobiolaging.2012.08.011
PMCID: PMC3584690  PMID: 23036583
FTLD; Schizophrenia; C9ORF72 repeat expansion; psychosis
23.  Different Demographic, Genetic, and Longitudinal Traits in Language versus Memory Alzheimer’s Subgroups 
Journal of Alzheimer's disease : JAD  2013;37(1):10.3233/JAD-130320.
The study’s objective was to compare demographics, APOE genotypes, and rate of rise over time in functional impairment in neuropsychologically defined language, typical, and memory subgroups of clinical Alzheimer’s disease (AD). 1,368 participants from the National Alzheimer’s Coordinating Center database with a diagnosis of probable AD (CDR 0.5–1.0) were included. A language subgroup (n = 229) was defined as having language performance >1 SD worse than memory performance. A memory subgroup (n = 213) was defined as having memory performance >1 SD worse than language performance. A typical subgroup (n = 926) was defined as having a difference in language and memory performance of <1 SD. Compared with the memory subgroup, the language subgroup was 3.7 years older and more frequently self-identified as African American (OR = 3.69). Under a dominant genetic model, the language subgroup had smaller odds of carrying at least one APOEε4 allele relative to the memory subgroup. While this difference was present for all ages, it was more striking at a younger age (OR = 0.19 for youngest tertile; OR = 0.52 for oldest tertile). Compared with the memory subgroup, the language subgroup rose 35% faster on the Functional Assessment Questionnaire and 44% faster on CDR sum of boxes over time. Among a subset of participants who underwent autopsy (n = 98), the language, memory, and typical subgroups were equally likely to have an AD pathologic diagnosis, suggesting that variation in non-AD pathologies across subtypes did not lead to the observed differences. The study demonstrates that a language subgroup of AD has different demographics, genetic profile, and disease course in addition to cognitive phenotype.
doi:10.3233/JAD-130320
PMCID: PMC3877683  PMID: 23788008
African Americans; age of onset; Alzheimer’s disease; aphasia; apolipoprotein E4; focal onset Alzheimer’s disease; demographic factors; language; longitudinal studies; memory
24.  FTD and ALS: a tale of two diseases 
Current Alzheimer research  2011;8(3):273-294.
The first reports of disorders that in terms of cognitive and behavioral symptoms resemble frontotemporal dementia (FTD) and in terms of motor symptoms resemble amyotrophic lateral sclerosis (ALS) bring us back to the second half of the 1800s. Over the last 150 years, and especially in the last two decades, there has been growing evidence that FTD signs can be seen in patients primarily diagnosed with ALS, implying clinical overlap among these two disorders. In the last decade pathological investigations and genetic screening have contributed tremendously in elucidating the pathology and genetic variability associated with FTD and ALS. To the most important recentdiscoveries belong TAR DNA binding protein [TARDBP or TDP-43] and the fused in sarcoma gene [FUS] and their implication in these disorders. FTD and ALS are the focus of this review which aims to 1. summarize clinical features by describing the diagnostic criteria and specific symptomatology, 2. describe the morphological aspects and related pathology, 3. describe the genetic factors associated with the diseases and 4. summarize the current status of clinical trials and treatment options.
A better understanding of the clinical, pathological and genetic features characterizing FTD and ALS will shed light into overlaps among these two disorders and the underpinning mechanisms that contribute to the onset and development. Nevertheless, advancements in the knowledge of the biology of these two disorders will help developing novel and, hopefully, more effective diagnostic and treatment options.
PMCID: PMC3801195  PMID: 21222600
ALS; FTD; FUS; motor disease; proteinopathies; TAU; TDP-43; ubiquitin inclusions
25.  Depressive Traits in Essential Tremor: Impact on Disability, Quality of Life and Medication Adherence 
Background
There is growing study of the psychiatric features of essential tremor. Depressive symptoms occur in a considerable number of patients. Yet their impact, as a primary factor, has received almost no attention. We assessed whether, independent of tremor severity, patients with more depressive symptoms have more perceived tremor-related disability, lower tremor-related quality of life, and poorer compliance with tremor medication.
Methods
Based on their Center for Epidemiological Studies Depression Scale score, we stratified 70 essential tremor patients into three groups: 41 with minimal depressive symptoms, 24 with moderate depressive symptoms, and 5 with severe depressive symptoms. Importantly, the three groups had similar tremor severity on neurological examination. We assessed: self-reported tremor-related disability, tremor-related quality of life (Quality of Life in Essential Tremor Questionnaire), and medication compliance.
Results
Cases with minimal depressive symptoms had the lowest quality of life scores, cases with moderate depressive symptoms had intermediate scores, and those with severe depressive symptoms had the highest scores (p<0.001). Depressive symptoms were a stronger predictor of tremor-related quality of life than was the main motor feature of ET itself (tremor). Self-reported medication compliance was lowest in cases with severe depressive symptoms and highest in cases with minimal depressive symptoms.
Conclusions
The physical disability caused by the tremor of ET has traditionally been regarded as the most important feature of the disease that causes distress, and it has received the most attention in the management of patients with this disease. Our data indicate that this may not be the case.
doi:10.1111/j.1468-1331.2012.03774.x
PMCID: PMC3434295  PMID: 22642492
essential tremor; psychiatric; depression; disability; quality of life; medication; treatment; clinical

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