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1.  Changes to Saccade Behaviors in Parkinson’s Disease Following Dancing and Observation of Dancing 
Background: The traditional view of Parkinson’s disease (PD) as a motor disorder only treated by dopaminergic medications is now shifting to include non-pharmacologic interventions. We have noticed that patients with PD obtain an immediate, short-lasting benefit to mobility by the end of a dance class, suggesting some mechanism by which dancing reduces bradykinetic symptoms. We have also found that patients with PD are unimpaired at initiating highly automatic eye movements to visual stimuli (pro-saccades) but are impaired at generating willful eye movements away from visual stimuli (anti-saccades). We hypothesized that the mechanisms by which a dance class improves movement initiation may generalize to the brain networks impacted in PD (frontal lobe and basal ganglia, BG), and thus could be assessed objectively by measuring eye movements, which rely on the same neural circuitry.
Methods: Participants with PD performed pro- and anti-saccades before, and after, a dance class. “Before” and “after” saccade performance measurements were compared. These measurements were then contrasted with a control condition (observing a dance class in a video), and with older and younger adult populations, who rested for an hour between measurements.
Results: We found an improvement in anti-saccade performance following the observation of dance (but not following dancing), but we found a detriment in pro-saccade performance following dancing.
Conclusion: We suggest that observation of dance induced plasticity changes in frontal-BG networks that are important for executive control. Dancing, in contrast, increased voluntary movement signals that benefited mobility, but interfered with the automaticity of efficient pro-saccade execution.
doi:10.3389/fneur.2013.00022
PMCID: PMC3593609  PMID: 23483834
action observation; anti-saccade; basal ganglia; dance; Parkinson’s disease; pro-saccade
2.  Trajectories of Behavioral Disturbance in Dementia 
Predicting the progression of dementia is a challenge for clinicians yet this information is highly valued by patients’ families. An informally observed 4-stage model of dementia can be helpful in educating caregivers and preparing them for what lies ahead. In the behavioral variant of frontotemporal dementia (bvFTD), this model describes the evolution of behavioral disturbances and is characterized by an inflection point between stage 2 (progressively severe behavioral aberration) and stage 3 (increasing apathy and remission of behavior problems). In this study we sought evidence for this model using a database of serial Neuropsychiatric Inventory (NPI) scores for 45 patients with FTD and 47 patients with Alzheimer’s disease (AD). We transformed the NPI scores into a single variable for each participant that represented the rate of change in NPI score over time (NPI slope) and used this as the dependent variable in a multivariate linear regression. Age at onset of dementia, NPI score at initial visit, and duration of illness at first NPI all contributed significantly to the regression model for NPI slope in the bvFTD group. Participants with an initial NPI acquired before 6 years of disease duration tended to have a more positive NPI slope (representing worsening behavioral disturbances) than those with an initial NPI performed after 6 years. None of the aforementioned variables were significantly associated with NPI slope in the AD group. These results support a crescendo-decrescendo trajectory of behavioral symptoms in bvFTD but do not suggest that there is a similar pattern in AD, and further longitudinal data collection is necessary.
doi:10.3233/JAD-2012-111916
PMCID: PMC4309273  PMID: 22531424
Alzheimer’s disease; agitation; apathy; behavioral symptoms; disease progression; frontotemporal dementia; longitudinal study; neurobehavioral manifestations
3.  FDG-PET in Semantic Dementia after 6 Months of Memantine: an Open-Label Pilot Study 
Objectives
To follow up on the increases we reported in normalized metabolic activity in salience network hubs from a 2-month open label study of memantine in frontotemporal dementia (FTD).
Methods
We repeated fluoro-deoxyglucose positron emission tomography (PET) after 6 months of drug use and subjected the data to an SPM analysis to reveal clusters of significant change from baseline. We also sought correlations between changes in behavioral disturbances on the Frontal Behavioral Inventory (FBI).
Results
Recruitment of one progressive nonfluent aphasia and one behavioral variant FTD precluded statistical analysis for any FTD subtype other than semantic dementia. The baseline-to-6-month interval showed increased normalized metabolic activity in the left orbitofrontal cortex (p<0.002) for 5 participants with semantic dementia. The 2–6 month interval revealed a late increase in normalized metabolic activity in the left insula (p<0.013), right insula (p<0.009), and left anterior cingulate (p<0.005). The right anterior cingulate showed both an initial increase and a delayed, further increase (2–6 month, p<0.016). FBI scores worsened by 43.3%. One participant with semantic dementia opted not to continue memantine beyond 2 months yet showed similar FDG-PET increases.
Conclusions
Increases in normalized cortical metabolic activity in salience network hubs were sustained in SD over a 6-month period. Since one participant without medication also showed these changes, further investigation is recommended through a double-blind, placebo-controlled study with FDG-PET as an outcome measure.
doi:10.1002/gps.3832
PMCID: PMC3467357  PMID: 22674572
frontotemporal dementia; metabolism; PET scan; semantic dementia
4.  Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia 
Brain  2011;134(9):2456-2477.
Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, ‘possible’ behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). ‘Probable’ behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia ‘with definite frontotemporal lobar degeneration’ requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer’s disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met ‘possible’ criteria, and 104 (76%) met criteria for ‘probable’ behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P < 0.001 for comparison with ‘possible’ and ‘probable’ criteria). Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration. Greater sensitivity of the proposed criteria may reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations. Future studies will be needed to establish the reliability and specificity of these revised diagnostic guidelines.
doi:10.1093/brain/awr179
PMCID: PMC3170532  PMID: 21810890
behavioural variant frontotemporal dementia; diagnostic criteria; frontotemporal lobar degeneration; FTD; pathology
5.  Occupation attributes relate to location of atrophy in frontotemporal lobar degeneration 
Neuropsychologia  2010;48(12):3634-3641.
Frontotemporal lobar degeneration (FTLD) often presents with asymmetric atrophy. We assessed whether premorbid occupations in FTLD patients were associated with these hemispheric asymmetries. In a multi-center chart review of 588 patients, occupation information was related to location of tissue loss or dysfunction. Patients with atrophy lateralized to the right had professions more dependent on verbal abilities than patients with left-lateralized or symmetrical atrophy. In a subgroup of 96 well-characterized patients with quantified neuroimaging data, the lateralization effect was localized to the temporal lobes and included verbal and mathematical ability. Patients whose professions placed high demands on language and mathematics had relatively preserved left temporal relative to right temporal volumes. Thus, occupation selection occurring in early adulthood is related to lateralized brain asymmetry in patients who develop FTLD decades later in the relatively deficient hemisphere. The finding suggests that verbal and mathematical occupations may have been pursued due to developmental right-lateralized functional impairment that precedes the neurodegenerative process. Alternatively, long-term engagement of activities associated with these occupations contributed to left-lateralized reserve, right-lateralized dysfunction, or both.
doi:10.1016/j.neuropsychologia.2010.08.020
PMCID: PMC2957479  PMID: 20800604
Frontotemporal dementia; laterality; reserve
6.  Open-label study of the short-term effects of memantine on FDG-PET in frontotemporal dementia 
Background
Memantine has shown effects on cortical metabolism in Alzheimer’s disease (AD), and the mechanism of action may not be specific to AD alone. We hypothesized that participants with frontotemporal dementia taking memantine would show an increased cortical metabolic activity in frontal regions, temporal regions, or in salience network hubs.
Methods
Sixteen participants with behavioral or language variant frontotemporal dementia syndromes (FTD) were recruited from tertiary FTD clinics and treated with memantine hydrochloride 10 mg twice daily in this fixed-dose, open-label pilot study. The primary endpoint was enhancement of cortical metabolic activity after 7–8 weeks of treatment. Secondary endpoints were measures of mood and behavior disturbance, frontal executive function, and motor disturbance.
Results
Voxel-wise parametric image analysis of positron emission tomography (PET) data from seven behavioral variant FTD patients, eight semantic dementia patients, and one progressive nonfluent aphasia patient, of mean age 64.3 years, mean duration of illness 4.25 years, and baseline mean sum of boxes Clinical Dementia Rating score 6.59, revealed an increase in [18F]-fluorodeoxyglucose (FDG) normalized metabolic activity in bilateral insulae and the left orbitofrontal cortex (P < 0.01). The increase on FDG-PET did not correlate with changes on behavioral inventories. Post hoc analysis indicated that semantic dementia participants drove this finding.
Conclusion
This open-label clinical PET study suggests that memantine induces an increase in metabolism in the salience network in FTD. A placebo-controlled follow-up study is warranted.
doi:10.2147/NDT.S22635
PMCID: PMC3140294  PMID: 21792308
Alzheimer’s disease; frontotemporal dementia; metabolism; PET scan; semantic dementia
7.  Apathy is not Associated with Basal Ganglia Atrophy in Frontotemporal Dementia 
Objective
To determine whether basal ganglia atrophy known to be associated with apathy in non-dementia populations was associated with presence of apathy in patients with frontotemporal dementia (FTD).
Methods
A cross-sectional case study was conducted at two tertiary dementia care clinics in Toronto, Ontario. Striatal and thalamic grey matter volumes and apathy measures were collected from 21 subects with FTD; 6 of whom did not show apathy on the Neuropsychatric Inventory (NPI).
Results
No significant differences in grey matter volumes were found between apathetic and non-apathetic groups for the striatum or for the thalamus.
Conclusions
Our findings imply that the etiology of apathy seen in FTD patients differs from that of patients with apathy after acquired injuries to the basal ganglia. Further study is needed to determine whether posterior thalamic atrophy correlates with apathy in FTD, or functional imaging techniques might successfully find a relationship between basal ganglia dysfunction and apathy.
doi:10.1097/JGP.0b013e3181b047ff
PMCID: PMC2747035  PMID: 19700954
frontotemporal dementia; basal ganglia; apathy; atrophy
8.  Apathy Symptom Profile and Behavioral Associations in Frontotemporal Dementia vs. Alzheimer's Disease 
Archives of neurology  2009;66(7):888-893.
Objective:
Apathy is a very common and significant problem in patients with dementia, regardless of etiology. Observations on frontosubcortical circuit (FSC) syndromes indicate that apathy may have affective, behavioral or cognitive manifestations. We explored whether the apathy manifested in frontotemporal dementia (FTD) with its predominantly anterior brain neuropathology differs from the apathy in Alzheimer's disease (DAT) with its predominantly hippocampal and temporoparietal-based neuropathology. We also sought to determine whether other behavioral disturbances reported in FSC syndromes correlate with apathy.
Design:
Survey. Analyses included individual items within Neuropsychiatric Inventory (NPI) subscale items. Items of the Apathy/Indifference subscale were designated by consensus as: A) affective = lacking in emotions, B) behavioral = inactive, chores abandoned or C) cognitive = no interest in others' activities. Proportions of correlated non-apathy NPI items were calculated and displayed using Chernoff faces to facilitate comparison of apathy domains and dementia diagnoses.
Setting and Patients:
Several neurology specialty clinics contributed to our dataset of 92 participants with FTD and 457 with DAT.
Results:
Apathy was more prevalent in FTD than DAT, but when present, the specific apathy symptoms in both dementias were rarely restricted to one of the three domains of apathy. Dysphoria concurrent with apathy was unique to the DAT group and negatively correlated in FTD. Participants with affective apathy more frequently co-presented with an orbitofrontosubcortical syndrome in FTD (impulsivity and compulsions). Affective apathy also co-presented with uncooperative agitation, anger, and physical agitation in both dementias.
Conclusions:
Apathy is common in FTD and in DAT, although it is more common in FTD. When present, it usually involves changes in affect, behavior, and cognition. It is associated with behaviors that have previously been shown to impact on patient safety, independence and quality of life.
doi:10.1001/archneurol.2009.92
PMCID: PMC2875777  PMID: 19597092
Alzheimer's Disease; Apathy; Frontotemporal Dementia; Frontotemporal Degeneration
9.  Test-retest variability of high resolution positron emission tomography (PET) imaging of cortical serotonin (5HT2A) receptors in older, healthy adults 
BMC Medical Imaging  2009;9:12.
Background
Position emission tomography (PET) imaging using [18F]-setoperone to quantify cortical 5-HT2A receptors has the potential to inform pharmacological treatments for geriatric depression and dementia. Prior reports indicate a significant normal aging effect on serotonin 5HT2A receptor (5HT2AR) binding potential. The purpose of this study was to assess the test-retest variability of [18F]-setoperone PET with a high resolution scanner (HRRT) for measuring 5HT2AR availability in subjects greater than 60 years old. Methods: Six healthy subjects (age range = 65–78 years) completed two [18F]-setoperone PET scans on two separate occasions 5–16 weeks apart.
Results
The average difference in the binding potential (BPND) as measured on the two occasions in the frontal and temporal cortical regions ranged between 2 and 12%, with the lowest intraclass correlation coefficient in anterior cingulate regions.
Conclusion
We conclude that the test-retest variability of [18F]-setoperone PET in elderly subjects is comparable to that of [18F]-setoperone and other 5HT2AR radiotracers in younger subject samples.
doi:10.1186/1471-2342-9-12
PMCID: PMC2722606  PMID: 19580676
10.  Potential cognitive enhancing and disease modification effects of SSRIs for Alzheimer’s disease 
Objective
Selective serotonin reuptake inhibitors (SSRIs) have increased cognitive performance in some clinical studies of Alzheimer’s disease (AD), but it is has been difficult to dissociate whether this is due to direct effects on cognition (neurochemical or disease-modifying) or a secondary effect of mood stabilization. We performed a systematic review for preclinical and human clinical trial evidence to support the use of SSRIs specifically for the management of cognitive decline in AD.
Data sources
(1) PUBMED without language restrictions from 1950s until 2004 and updated August 2006, terms: “serotonin uptake inhibitors”[MeSH] AND (“Alzheimer disease”[MeSH] OR “Cognition Disorders”[MeSH]) NOT “Parkinson disease”[MeSH] AND (Clinical Trial[ptyp] OR Letter[ptyp] OR Meta-Analysis[ptyp] OR Randomized Controlled Trial[ptyp]) AND “alzheimer disease” [MESH] OR “Alzheimer*” combined with AND to “ssri*” OR “serotonin reuptake inhibitors” [MESH] NOT Review[ptyp]. (2) Cochrane Database of Systematic Reviews, keywords “SSRI” and “Alzheimer’s”.
Study selection
The PubMed search yielded 57 hits. Of these, 23 were included in this review for their specificity to SSRI use in AD or indications on efficacy beyond depressive symptoms. The other 34 citations were excluded because: (1) depression or other mood or behavioral disturbance severity was the reported outcome measure, (2) effects of SSRIs on cognition were confounded by concomitant use of other drugs, (3) subjects described were young adults, and/or (4) subjects had traumatic brain injury. The Cochrane Database of Systematic Reviews, 3rd Quarter 2006, yielded six citations related to SSRIs.
Data extraction
Data extracted from clinical trials included name of SSRI tested, cognitive outcome measures, and adverse events reported, which could include cognitive worsening.
Data synthesis
Preclinical evidence for use of SSRIs to enhance cognition in AD includes an effect at the hippocampus through carbonic anhydrase activation or stimulation of hippocampal neurogenesis. The chemical structure of paroxetine, and not intrinsic SSRI activity, may also affect APP ectodomain expression to reduce amyloid plaque formation. Clinical trials in AD generally have not assessed cognitive outcomes independently from mood or behavior stabilization. Currently, clinical studies in AD only indirectly support the use of SSRIs for disease modification by confirming a serotonergic deficit during the course of illness.
Conclusions
Lack of supportive evidence for SSRIs as cognition enhancers or disease modifiers in AD is the result of omissions in clinical trial design, as opposed to reporting of negative outcomes. The preclinical evidence warrants the study of SSRIs in AD using mood, behavior, cognition, neurochemistry, and possibly neuroimaging as outcome variables.
PMCID: PMC2656299  PMID: 19300592
Alzheimer’s disease; Amyloid precursor protein; APP ectodomain; carbonic anhydrase; selective serotonergic reuptake inhibitor
11.  MMSE Scores Decline at a Greater Rate in Frontotemporal Degeneration Than in AD 
The clinical diagnostic criteria for frontotemporal degeneration (FTD) include relative preservation of memory and visuospatial function, in contradistinction to characteristics of Alzheimer’s disease (AD). The Mini-Mental State Examination (MMSE) contains items to assess these areas of cognition. In a retrospective case-control study of participants at two institutionally-based AD centers, we determined whether total MMSE and MMSE subscores would reflect the disease progression projected by the clinical criteria of FTD vs. AD. Participants were 44 subjects with FTD (7 pathologically confirmed) and 45 with pathologically confirmed AD. Each subject had at least two MMSEs with minimum inter-test intervals of 9 months. We compared annualized rates of change for total MMSE scores and cognitive domain subscores over time and between groups by two independent samples t-tests and proportion tests. The total MMSE score (p = 0.03) and language subscore (p = 0.02) showed a greater rate of decline for the FTD group than the AD group, although the constructional praxis item declined less rapidly in the FTD group (p = 0.018). Changes in MMSE subscores paralleled the clinical diagnostic criteria for FTD. The more rapid progression on the language subscore was observed in both language and behavioral variants of FTD.
doi:10.1159/000094870
PMCID: PMC1592245  PMID: 16899996
Alzheimer’sdisease; Frontotemporal dementia; Frontotemporal degeneration; Mini-Mental State Examination
12.  Referral Patterns for Syndromes Associated With Frontotemporal Lobar Degeneration 
We compared demographics of subjects diagnosed with frontotemporal degeneration (FTD) at a group of 5 clinics specializing in this non-Alzheimer dementia against those subjects diagnosed at standard Alzheimer disease centers, to determine any differences in referral patterns between such clinics.
Of the two major phenotypes of FTD, behavior and language, the latter more frequently presented to the specialty clinics (46% of FTD diagnoses versus 19%, P < 0.001). Mean age at onset for the behavioral presentation phenotype was one year younger at the specialty clinics (P < 0.01). Mean age at onset for the language phenotype was 3 years older (P < 0.001) than for the behavioral phenotype at standard centers but did not differ between the two evaluating groups.
Cases with FTD referred to all of the dementia evaluation sites in this study did not differ significantly from those previously reported in the literature. Clinics specializing in FTD recruit more language presentation cases. There were statistical but not clinically significant differences in ages at onset.
PMCID: PMC1578638  PMID: 15764866
frontotemporal degeneration; gender; referral onset age
13.  Novel Tau Polymorphisms, Tau Haplotypes, and Splicing in Familial and Sporadic Frontotemporal Dementia 
Archives of neurology  2003;60(5):698-702.
Background
A subset of familial cases (FTDP-17) of frontotemporal dementia (FTD) are caused by mutations in the tau gene. The role of tau gene mutations and haplotypes in sporadic FTD and the functional consequences of tau polymorphisms are unknown.
Objectives
To investigate (1) the frequency of known FTDP-17 mutations in familial and sporadic FTD and compare these results with previous studies; (2) whether the tau H1 haplotype is associated with FTD; and (3) the functional effect of intronic tau sequence variations.
Patients and Methods
Patients with familial and sporadic FTD were screened for mutations in the microtubule-binding region of tau. The frequencies of tau haplotypes and genotypes were compared between patients with FTD and control subjects. We analyzed the splicing effect of novel intronic polymorphisms associated with FTD.
Results
The P301L mutation was detected in 11% of familial FTD cases. The H1 haplotype was not overrepresented in patients with FTD, but the P301L mutation appeared on the background of the H2 tau haplotype. We identified 4 novel single nucleotide polymorphisms in intron 9 and a 9–base pair deletion in intron 4A. A C-to-T transition 177 base pairs upstream from exon 10 was significantly increased in patients with FTD compared with controls. Direct analysis of brain tissue from a patient with this variant showed an increase in exon 10–containing tau transcripts.
Conclusions
Sequence variations in intronic or regulatory regions of tau may have previously unrecognized consequences leading to tau dysfunction and neurodegeneration.
doi:10.1001/archneur.60.5.698
PMCID: PMC2072863  PMID: 12756133
14.  Comparison of manual and semi-automated delineation of regions of interest for radioligand PET imaging analysis 
Background
As imaging centers produce higher resolution research scans, the number of man-hours required to process regional data has become a major concern. Comparison of automated vs. manual methodology has not been reported for functional imaging. We explored validation of using automation to delineate regions of interest on positron emission tomography (PET) scans. The purpose of this study was to ascertain improvements in image processing time and reproducibility of a semi-automated brain region extraction (SABRE) method over manual delineation of regions of interest (ROIs).
Methods
We compared 2 sets of partial volume corrected serotonin 1a receptor binding potentials (BPs) resulting from manual vs. semi-automated methods. BPs were obtained from subjects meeting consensus criteria for frontotemporal degeneration and from age- and gender-matched healthy controls. Two trained raters provided each set of data to conduct comparisons of inter-rater mean image processing time, rank order of BPs for 9 PET scans, intra- and inter-rater intraclass correlation coefficients (ICC), repeatability coefficients (RC), percentages of the average parameter value (RM%), and effect sizes of either method.
Results
SABRE saved approximately 3 hours of processing time per PET subject over manual delineation (p < .001). Quality of the SABRE BP results was preserved relative to the rank order of subjects by manual methods. Intra- and inter-rater ICC were high (>0.8) for both methods. RC and RM% were lower for the manual method across all ROIs, indicating less intra-rater variance across PET subjects' BPs.
Conclusion
SABRE demonstrated significant time savings and no significant difference in reproducibility over manual methods, justifying the use of SABRE in serotonin 1a receptor radioligand PET imaging analysis. This implies that semi-automated ROI delineation is a valid methodology for future PET imaging analysis.
doi:10.1186/1471-2385-7-2
PMCID: PMC1802071  PMID: 17261193

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