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1.  Nonamnestic mild cognitive impairment progresses to dementia with Lewy bodies 
Neurology  2013;81(23):2032-2038.
Objective:
To determine the rate of progression of mild cognitive impairment (MCI) to dementia with Lewy bodies (DLB).
Methods:
We followed 337 patients with MCI in the Mayo Alzheimer's Disease Research Center (range 2–12 years). Competing risks survival models were used to examine the rates of progression to clinically probable DLB and Alzheimer disease (AD). A subset of patients underwent neuropathologic examination.
Results:
In this clinical cohort, 116 remained as MCI, while 49 progressed to probable DLB, 162 progressed to clinically probable AD, and 10 progressed to other dementias. Among nonamnestic MCI, progression rate to probable DLB was 20 events per 100 person-years and to probable AD was 1.6 per 100 person-years. Among amnestic MCI, progression rate to probable AD was 17 events per 100 person-years, and to DLB was 1.5 events per 100 person-years. In 88% of those who developed probable DLB, the baseline MCI diagnosis included attention and/or visuospatial deficits. Those who developed probable DLB were more likely to have baseline daytime sleepiness and subtle parkinsonism. In 99% of the clinically probable AD group, the baseline MCI diagnosis included memory impairment. Neuropathologic confirmation was obtained in 24 of 30 of those with clinically probable AD, and in 14 of 18 of those with clinically probable DLB.
Conclusion:
In a clinical sample, patients with nonamnestic MCI were more likely to develop DLB, and those with amnestic MCI were more likely to develop probable AD.
doi:10.1212/01.wnl.0000436942.55281.47
PMCID: PMC3854825  PMID: 24212390
2.  MRI and pathology of REM sleep behavior disorder in dementia with Lewy bodies 
Neurology  2013;81(19):1681-1689.
Objective:
To determine structural MRI and digital microscopic characteristics of REM sleep behavior disorder in individuals with low-, intermediate-, and high-likelihood dementia with Lewy bodies (DLB) at autopsy.
Methods:
Patients with autopsy-confirmed low-, intermediate-, and high-likelihood DLB, according to the probability statement recommended by the third report of the DLB Consortium, and antemortem MRI, were identified (n = 75). The clinical history was assessed for presence (n = 35) and absence (n = 40) of probable REM sleep behavior disorder (pRBD), and patients' antemortem MRIs were compared using voxel-based morphometry. Pathologic burdens of phospho-tau, β-amyloid, and α-synuclein were measured in regions associated with early neuropathologic involvement, the hippocampus and amygdala.
Results:
pRBD was present in 21 patients (60%) with high-likelihood, 12 patients (34%) with intermediate-likelihood, and 2 patients (6%) with low-likelihood DLB. Patients with pRBD were younger, more likely to be male (p ≤ 0.001), and had a more frequent neuropathologic diagnosis of diffuse (neocortical) Lewy body disease. In the hippocampus and amygdala, phospho-tau and β-amyloid burden were lower in patients with pRBD compared with those without pRBD (p < 0.01). α-Synuclein burden did not differ in the hippocampus, but trended in the amygdala. Patients without pRBD had greater atrophy of temporoparietal cortices, hippocampus, and amygdala (p < 0.001) than those with pRBD; atrophy of the hippocampus (p = 0.005) and amygdala (p = 0.02) were associated with greater phospho-tau burdens in these regions.
Conclusion:
Presence of pRBD is associated with a higher likelihood of DLB and less severe Alzheimer-related pathology in the medial temporal lobes, whereas absence of pRBD is characterized by Alzheimer-like atrophy patterns on MRI and increased phospho-tau burden.
doi:10.1212/01.wnl.0000435299.57153.f0
PMCID: PMC3812105  PMID: 24107861
3.  Subtle gait changes in patients with REM Behavior Disorder 
Background
Many people with REM sleep behavior disorder have an underlying synucleinopathy, the most common of which is Lewy body disease. Identifying additional abnormal clinical features may help in identifying those at greater risk of evolving to a more severe syndrome. As gait disorders are common in the synucleinopathies, early abnormalities in gait in those with REM sleep behavior disorder could help in identifying those at increased risk of developing overt parkinsonism and/or cognitive impairment.
Methods
We identified 42 probable REM sleep behavior disorder subjects and 492 controls using the Mayo Sleep Questionnaire and assessed gait velocity, cadence and stride dynamics with an automated gait analysis system.
Results
Cases and controls were similar in age (79.9 ± 4.7 & 80.1 ± 4.7, p= 0.74), UPDRS score (3.3 ± 5.5 & 1.9 ± 4.1, p=0.21) and Mini-Mental State Examination scores (27.2 ± 1.9 & 27.7 ± 1.6, p=0.10). A diagnosis of probable REM sleep behavior disorder was associated with decreased velocity (−7.9 cm/sec, 95%CI −13.8 to −2.0, p<0.01), cadence (−4.4 steps/min, 95%CI −7.6 to −1.3, p<0.01), and significantly increased double limb support variability (30%, 95%CI 6 – 60, p=0.01), greater stride time variability (29%, 95%CI 2 – 63, p=0.03) and swing time variability (46%, 95%CI 15 – 84, p<0.01).
Conclusions
Probable REM sleep behavior disorder is associated with subtle gait changes prior to overt clinical parkinsonism. Diagnosis of probable REM sleep behavior disorder supplemented by gait analysis may help as a screening tool for disorders of α-synuclein.
doi:10.1002/mds.25653
PMCID: PMC3952497  PMID: 24130124
REM Sleep Behavior Disorder; gait; gait variability
4.  Risk factors for dementia with Lewy bodies 
Neurology  2013;81(9):833-840.
Objective:
To determine the risk factors associated with dementia with Lewy bodies (DLB).
Methods:
We identified 147 subjects with DLB and sampled 2 sex- and age-matched cognitively normal control subjects for each case. We also identified an unmatched comparison group of 236 subjects with Alzheimer disease (AD). We evaluated 19 candidate risk factors in the study cohort.
Results:
Compared with controls, subjects with DLB were more likely to have a history of anxiety (odds ratio; 95% confidence interval) (7.4; 3.5–16; p < 0.0001), depression (6.0; 3.7–9.5; p < 0.0001), stroke (2.8; 1.3–6.3; p = 0.01), a family history of Parkinson disease (PD) (4.6; 2.5–8.6; p < 0.0001), and carry APOE ε4 alleles (2.2; 1.5–3.3; p < 0.0001), but less likely to have had cancer (0.44; 0.27–0.70; p = 0.0006) or use caffeine (0.29; 0.14–0.57; p < 0.0001) with a similar trend for alcohol (0.65; 0.42–1.0; p = 0.0501). Compared with subjects with AD, subjects with DLB were younger (72.5 vs 74.9 years, p = 0.021) and more likely to be male (odds ratio; 95% confidence interval) (5.3; 3.3–8.5; p < 0.0001), have a history of depression (4.3; 2.4–7.5; p < 0.0001), be more educated (2.5; 1.1–5.6; p = 0.031), have a positive family history of PD (5.0; 2.4–10; p < 0.0001), have no APOE ε4 alleles (0.61; 0.40–0.93; p = 0.02), and to have had an oophorectomy before age 45 years (7.6; 1.5–39; p = 0.015).
Conclusion:
DLB risk factors are an amalgam of those for AD and PD. Smoking and education, which have opposing risk effects on AD and PD, are not risk factors for DLB; however, depression and low caffeine intake, both risk factors for AD and PD, increase risk of DLB more strongly than in either.
doi:10.1212/WNL.0b013e3182a2cbd1
PMCID: PMC3908463  PMID: 23892702
5.  Polysomnographic Findings in Dementia With Lewy Bodies 
The neurologist  2013;19(1):1-6.
Introduction
The clinical features of dementia with Lewy bodies (DLB) during wakefulness are well known. Other than REM sleep behavior disorder (RBD), only limited data exists on other sleep disturbances and disorders in DLB. We sought to characterize the polysomnographic (PSG) findings in a series of DLB patients with sleep-related complaints.
Methods
Retrospective study of patients with DLB who underwent clinical PSG at Mayo Clinic Rochester or Mayo Clinic Jacksonville over an almost 11 year span for evaluation of dream enactment behavior, excessive nocturnal movements, sleep apnea, hypersomnolence, or insomnia. The following variables were analyzed: respiratory disturbance index (RDI) in disordered breathing events/hour, periodic limb movement arousal index (PLMAI), arousals for no apparent reason (AFNAR), total arousal index (TAI), presence of REM sleep without atonia (RSWA), and percent sleep efficiency (SE).
Results
Data on 78 patients (71M, 7F) were analyzed. The mean age was 71 ± 8 years. Seventy-five (96%) patients had histories of recurrent dream enactment during sleep with 83% showing confirmation of RSWA +/- dream enactment during PSG. Mean RDI = 11.9 ± 5.8, PLMAI = 5.9 ± 8.5, AFNARI = 10.7 ± 12.0, and TAI = 26.6 ± 17.4. SE was <80% in 72% of the sample, <70% in 49%, and <60% in 24%. In patients who did not show evidence of significant disordered breathing (23 with RDI<5), 62% of arousals were AFNARs. In those patients who had significant disordered breathing (55 with RDI ≥ 5), 36% of arousals were AFNARs. Six patients underwent evaluations with PSG plus MSLT. Two patients had mean initial sleep latencies less than five minutes, and both had RDI<5. No patient had any sleep onset rapid eye movement periods. Nineteen patients have undergone neuropathologic examination, and 18 have had limbic- or neocortical-predominant Lewy body pathology. One had progressive supranuclear palsy, but no REM sleep was recorded in prior PSG.
Conclusions
In patients with DLB and sleep-related complaints, several sleep disturbances in addition to RBD are frequently present. In this sample, about three quarters had a significant number of arousals not accounted for by a movement or breathing disturbance, and the primary sleep disorders do not appear to entirely account for the poor sleep efficiency in DLB, especially in those without a significant breathing disorder. Further studies are warranted to better understand the relationship between disturbed sleep, arousal and DLB; such characterization may provide insights into potential avenues of treatment of symptoms which could impact quality of life.
doi:10.1097/NRL.0b013e31827c6bdd
PMCID: PMC3587292  PMID: 23269098
Sleep disorders; REM sleep behavior disorder; dementia with Lewy bodies; synucleinopathy
6.  Multimodality Imaging Characteristics of Dementia with Lewy Bodies 
Neurobiology of Aging  2011;33(9):2091-2105.
Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia after Alzheimer's disease (AD). Our objective was to determine whether the 11C–Pittsburgh Compound-B (PiB) retention and regional hypometabolism on PET and regional cortical atrophy on MRI are complementary in characterizing patients with DLB and differentiating them from AD. We studied age, gender and education matched patients with a clinical diagnosis of DLB (n=21), AD (n=21), and cognitively normal subjects (n=42). Hippocampal atrophy, global cortical PiB retention and occipital lobe metabolism in combination distinguished DLB from AD better than any of the measurements alone (area under the receiver operating characteristic=0.98).Five of the DLB and AD patients who underwent autopsy were distinguished through multimodality imaging. These data demonstrate that MRI and PiB PET contribute to characterizing the distinct pathological mechanisms in patients with AD compared to DLB. Occipital and posterior parietotemporal lobe hypometabolism is a distinguishing feature of DLB and this regional hypometabolic pattern is independent of the amyloid pathology.
doi:10.1016/j.neurobiolaging.2011.09.024
PMCID: PMC3288845  PMID: 22018896
Dementia with Lewy bodies; MRI; PET; FDG; PiB; Alzheimer's disease
7.  Focal atrophy on MRI and neuropathologic classification of dementia with Lewy bodies 
Neurology  2012;79(6):553-560.
Objective:
To determine the association between the focal atrophy measures on antemortem MRI and postmortem neuropathologic classification of dementia with Lewy bodies (DLB) using the Third Report of the DLB Consortium criteria.
Methods:
We retrospectively identified 56 subjects who underwent antemortem MRI and had Lewy body (LB) pathology at autopsy. Subjects were pathologically classified as high (n = 25), intermediate (n = 22), and low likelihood DLB (n = 9) according to the Third Report of the DLB Consortium criteria. We included 2 additional pathologic comparison groups without LBs: one with low likelihood Alzheimer disease (AD) (control; n = 27) and one with high likelihood AD (n = 33). The associations between MRI-based volumetric measurements and the pathologic classification of DLB were tested with analysis of covariance by adjusting for age, sex, and MRI-to-death interval.
Results:
Antemortem hippocampal and amygdalar volumes increased from low to intermediate to high likelihood DLB (p < 0.001, trend test). Smaller hippocampal and amygdalar volumes were associated with higher Braak neurofibrillary tangle stage (p < 0.001). Antemortem dorsal mesopontine gray matter (GM) atrophy was found in those with high likelihood DLB compared with normal control subjects (p = 0.004) and those with AD (p = 0.01). Dorsal mesopontine GM volume decreased from low to intermediate to high likelihood DLB (p = 0.01, trend test).
Conclusion:
Antemortem hippocampal and amygdalar volumes increase and dorsal mesopontine GM volumes decrease in patients with low to high likelihood DLB according to the Third Report of the DLB Consortium criteria. Patients with high likelihood DLB typically have normal hippocampal volumes but have atrophy in the dorsal mesopontine GM nuclei.
doi:10.1212/WNL.0b013e31826357a5
PMCID: PMC3413765  PMID: 22843258
8.  Imaging and acetylcholinesterase inhibitor response in dementia with Lewy bodies 
Brain  2012;135(8):2470-2477.
Acetylcholinesterase inhibitors are commonly used to treat patients with dementia with Lewy bodies. Hippocampal atrophy on magnetic resonance imaging and amyloid-β load on positron emission tomography are associated with the Alzheimer’s disease-related pathology in patients with dementia with Lewy bodies. To date, few studies have investigated imaging markers that predict treatment response in patients with dementia with Lewy bodies. Our objective was to determine whether imaging markers of Alzheimer’s disease-related pathology such as hippocampal volume, brain amyloid-β load on 11C Pittsburgh compound B positron emission tomography predict treatment response to acetylcholinesterase inhibitors in patients with dementia with Lewy bodies. We performed a retrospective analysis on consecutive treatment-naive patients with dementia with Lewy bodies (n = 54) from the Mayo Clinic Alzheimer’s Disease Research Centre who subsequently received acetylcholinesterase inhibitors and underwent magnetic resonance imaging with hippocampal volumetry. Baseline and follow-up assessments were obtained with the Mattis Dementia Rating Scale. Subjects were divided into three groups (reliable improvement, stable or reliable decline) using Dementia Rating Scale reliable change indices determined previously. Associations between hippocampal volumes and treatment response were tested with analysis of covariance adjusting for baseline Dementia Rating Scale, age, gender, magnetic resonance field strength and Dementia Rating Scale interval. Seven subjects underwent 11C Pittsburgh compound B imaging within 12 weeks of magnetic resonance imaging. Global cortical 11C Pittsburgh compound B retention (scaled to cerebellar retention) was calculated in these patients. Using a conservative psychometric method of assessing treatment response, there were 12 patients with reliable decline, 29 stable cases and 13 patients with reliable improvement. The improvers had significantly larger hippocampi than those that declined (P = 0.02) and the stable (P = 0.04) group. An exploratory analysis demonstrated larger grey matter volumes in the temporal and parietal lobes in improvers compared with those who declined (P < 0.05). The two patients who had a positive 11C Pittsburgh compound B positron emission tomography scan declined and those who had a negative 11C Pittsburgh compound B positron emission tomography scan improved or were stable after treatment. Patients with dementia with Lewy bodies who do not have the imaging features of coexistent Alzheimer’s disease-related pathology are more likely to cognitively improve with acetylcholinesterase inhibitor treatment.
doi:10.1093/brain/aws173
PMCID: PMC3407425  PMID: 22810436
dementia with Lewy bodies; acetylcholinesterase inhibitors; MRI; PiB; PET; amyloid
9.  Neuropathological analysis of brainstem cholinergic and catecholaminergic nuclei in relation to REM sleep behaviour disorder 
Aims
Rapid eye movement (REM) sleep behaviour disorder (RBD) is characterized by loss of muscle atonia during REM sleep and is associated with dream enactment behaviour. RBD is often associated with α-synuclein pathology, and we examined if there is a relationship of RBD with cholinergic neuronal loss in the pedunculopontine/laterodorsal tegmental nucleus (PPN/LDT), compared to catecholaminergic neurons in a neighbouring nucleus, the locus coeruleus (LC).
Methods
This retrospective study, utilized human brain banked tissues of 11 Lewy body disease (LBD) cases with RBD, 10 LBD without RBD, 19 AD and 10 neurologically normal controls. Tissues were stained with choline acetyl transferase immunohistochemistry to label neurons of PPN/LDT and tyrosine hydroxylase for the LC. The burden of tau and α-synuclein pathology was measured in the same regions with immunohistochemistry.
Results
Both the LC and PPN/LDT were vulnerable to α-synuclein pathology in LBD and tau pathology in AD, but significant neuronal loss was only detected in these nuclei in LBD. Greater cholinergic depletion was found in both LBD groups, regardless of RBD status, when compared with normals and AD. There were no differences in either degree of neuronal loss or burden of α-synuclein pathology in LBD with and without RBD.
Conclusions
Whether decreases in brainstem cholinergic neurons in LBD contribute to RBD is uncertain, but our findings indicate these neurons are highly vulnerable to α-synuclein pathology in LBD and tau pathology in AD. The mechanism of selective α-synuclein-mediated neuronal loss in these nuclei remains to be determined.
doi:10.1111/j.1365-2990.2011.01203.x
PMCID: PMC3218297  PMID: 21696423
α-synuclein; cholinergic; Lewy body; laterodorsal tegmentum; locus coeruleus; pedunculopontine nucleus; REM behaviour disorder; tau
10.  Probable REM Sleep Behavior Disorder Increases Risk for Mild Cognitive Impairment and Parkinson’s Disease: A Population-Based Study 
Annals of Neurology  2012;71(1):49-56.
Objective
REM sleep behavior disorder (RBD) is associated with neurodegenerative disease and particularly with the synucleinopathies. Convenience samples involving subjects with idiopathic RBD have suggested an increased risk of incident mild cognitive impairment (MCI), dementia (usually dementia with Lewy bodies) or Parkinson’s disease (PD). There is no data on such risk in a population-based sample.
Methods
Cognitively normal subjects aged 70–89 in a population-based study of aging who screened positive for probable RBD using the Mayo Sleep Questionnaire were followed at 15 month intervals. In a Cox Proportional Hazards Model, we measured the risk of developing MCI, dementia, PD among the exposed (pRBD+) and unexposed (pRBD−) cohorts.
Results
Forty-four subjects with pRBD+ at enrollment (median duration of pRBD features was 7.5 years), and 607 pRBD− subjects, were followed prospectively for a median of 3.8 years. Fourteen of the pRBD+ subjects developed MCI and one developed PD (15/44=34% developed MCI / PD); none developed dementia. After adjustment for age, sex, education, and medical comorbidity, pRBD+ subjects were at increased risk of MCI / PD [Hazard Ratio (HR) 2.2, 95% Confidence Interval (95%CI) 1.3 – 3.9; p=0.005]. Inclusion of subjects who withdrew from the study produced similar results, as did exclusion of subjects with medication-associated RBD. Duration of pRBD symptoms did not predict the development of MCI / PD (HR 1.05 per 10 years, 95%CI 0.84 – 1.3; p=0.68).
Interpretation
In this population-based cohort study, we observed that pRBD confers a 2.2-fold increased risk of developing MCI / PD over four years.
doi:10.1002/ana.22655
PMCID: PMC3270692  PMID: 22275251
sleep disorders; parasomnias; dementia; Alzheimer’s disease; dementia with Lewy bodies; parkinsonism; synuclein
11.  Rapid eye movement sleep behavior disorder and subtypes in autopsy-confirmed dementia with Lewy bodies 
OBJECTIVE
To determine whether dementia with Lewy bodies with or without probable rapid eye movement sleep behavior disorder differ clinically or pathologically.
METHODS
Patients with dementia with Lewy bodies who have probable rapid eye movement sleep behavior sleep disorder (n=71) were compared to those without it (n=19) on demographics, clinical variables (core features of dementia with Lewy bodies, dementia duration, rate of cognitive/motor changes) and pathologic indices (Lewy body distribution, neuritic plaque score, Braak neurofibrillary tangle stage).
RESULTS
Individuals with probable rapid eye movement sleep behavior disorder were predominantly male (82% versus 47%), and had a shorter duration of dementia (mean 8 years versus 10 years), earlier onset of parkinsonism (mean 2 years versus 5 years), and earlier onset of visual hallucinations (mean 3 years versus 6 years). These patients also had a lower Braak neurofibrillary tangle stage (Stage IV versus Stage VI) and lower neuritic plaque scores (18% frequent versus 85% frequent), but no difference in Lewy body distribution. When probable rapid eye movement sleep behavior disorder developed early (at or before dementia onset), the onset of parkinsonism and hallucinations was earlier and Braak neurofibrillary tangle stage was lower compared to those who developed the sleep disorder after dementia onset. Women with autopsy-confirmed DLB without a history of dream enactment behavior during sleep had a later onset of hallucinations and parkinsonism and a higher Braak NFT stage.
CONCLUSIONS
Probable rapid eye movement sleep behavior disorder is associated with distinct clinical and pathologic characteristics of dementia with Lewy bodies.
doi:10.1002/mds.24003
PMCID: PMC3513369  PMID: 22038951
Parkinson’s disease; REM sleep behavior disorder; Dementia with Lewy bodies; Lewy body disease; Alzheimer’s disease
12.  Validation of the Mayo Sleep Questionnaire to Screen for REM Sleep Behavior Disorder in an Aging and Dementia Cohort 
Sleep medicine  2011;12(5):445-453.
Objective
To validate a questionnaire focused on REM sleep behavior disorder (RBD) among participants in an aging and dementia cohort.
Background
RBD is a parasomnia that can develop in otherwise neurologically-normal adults as well as in those with a neurodegenerative disease. Confirmation of RBD requires polysomnography (PSG). A simple screening measure for RBD would be desirable for clinical and research purposes.
Methods
We had previously developed the Mayo Sleep Questionnaire (MSQ), a 16 item measure, to screen for the presence of RBD and other sleep disorders. We assessed the validity of the MSQ by comparing the responses of patients’ bed partners with the findings on PSG. All subjects recruited in the Mayo Alzheimer’s Disease Research Center at Mayo Clinic Rochester and Mayo Clinic Jacksonville from 1/00 to 7/08 who had also undergone a PSG were the focus of this analysis.
Results
The study sample was comprised of 176 subjects [150 male; median age 71 years (range 39–90)], with the following clinical diagnoses: normal (n=8), mild cognitive impairment (n=44), Alzheimer’s disease (n=23), dementia with Lewy bodies (n=74), as well as other dementia and/or parkinsonian syndromes (n=27). The core question on recurrent dream enactment behavior yielded a sensitivity (SN) of 98% and specificity (SP) of 74% for the diagnosis of RBD. The profile of responses on four additional subquestions on RBD and one on obstructive sleep apnea improved specificity.
Conclusions
These data suggest that among aged subjects with cognitive impairment and/or parkinsonism, the MSQ has adequate SN and SP for the diagnosis of RBD. The utility of this scale in other patient populations will require further study.
doi:10.1016/j.sleep.2010.12.009
PMCID: PMC3083495  PMID: 21349763
sleep disorders; parasomnias; dementia; Alzheimer’s disease; dementia with Lewy bodies; parkinsonism
13.  Antemortem Differential Diagnosis of Dementia Pathology using Structural MRI: Differential-STAND 
NeuroImage  2010;55(2):522-531.
The common neurodegenerative pathologies underlying dementia are Alzheimer’s disease (AD), Lewy body disease (LBD) and Frontotemporal lobar degeneration (FTLD). Our aim was to identify patterns of atrophy unique to each of these diseases using antemortem structural-MRI scans of pathologically-confirmed dementia cases and build an MRI-based differential diagnosis system. Our approach of creating atrophy maps using structural-MRI and applying them for classification of new incoming patients is labeled Differential-STAND (Differential-diagnosis based on STructural Abnormality in NeuroDegeneration). Pathologically-confirmed subjects with a single dementing pathologic diagnosis who had an MRI at the time of clinical diagnosis of dementia were identified: 48 AD, 20 LBD, 47 FTLD-TDP (pathology-confirmed FTLD with TDP-43). Gray matter density in 91 regions-of-interest was measured in each subject and adjusted for head-size and age using a database of 120 cognitively normal elderly. The atrophy patterns in each dementia type when compared to pathologically-confirmed controls mirrored known disease-specific anatomic patterns: AD-temporoparietal association cortices and medial temporal lobe; FTLD-TDP-frontal and temporal lobes and LBD-bilateral amygdalae, dorsal midbrain and inferior temporal lobes. Differential-STAND based classification of each case was done based on a mixture model generated using bisecting k-means clustering of the information from the MRI scans. Leave-one-out classification showed reasonable performance compared to the autopsy gold-standard and clinical diagnosis: AD (sensitivity:90.7%; specificity:84 %), LBD (sensitivity:78.6%; specificity:98.8%) and FTLD-TDP (sensitivity:84.4%; specificity:93.8%). The proposed approach establishes a direct a priori relationship between specific topographic patterns on MRI and “gold standard” of pathology which can then be used to predict underlying dementia pathology in new incoming patients.
doi:10.1016/j.neuroimage.2010.12.073
PMCID: PMC3039279  PMID: 21195775
MRI; Alzheimer’s disease; Lewy body disease; Frontotemporal lobar degeneration
14.  Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72 
Brain  2012;135(3):765-783.
Numerous kindreds with familial frontotemporal dementia and/or amyotrophic lateral sclerosis have been linked to chromosome 9, and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 has recently been identified as the pathogenic mechanism. We describe the key characteristics in the probands and their affected relatives who have been evaluated at Mayo Clinic Rochester or Mayo Clinic Florida in whom the hexanucleotide repeat expansion were found. Forty-three probands and 10 of their affected relatives with DNA available (total 53 subjects) were shown to carry the hexanucleotide repeat expansion. Thirty-six (84%) of the 43 probands had a familial disorder, whereas seven (16%) appeared to be sporadic. Among examined subjects from the 43 families (n = 63), the age of onset ranged from 33 to 72 years (median 52 years) and survival ranged from 1 to 17 years, with the age of onset <40 years in six (10%) and >60 in 19 (30%). Clinical diagnoses among examined subjects included behavioural variant frontotemporal dementia with or without parkinsonism (n = 30), amyotrophic lateral sclerosis (n = 18), frontotemporal dementia/amyotrophic lateral sclerosis with or without parkinsonism (n = 12), and other various syndromes (n = 3). Parkinsonism was present in 35% of examined subjects, all of whom had behavioural variant frontotemporal dementia or frontotemporal dementia/amyotrophic lateral sclerosis as the dominant clinical phenotype. No subject with a diagnosis of primary progressive aphasia was identified with this mutation. Incomplete penetrance was suggested in two kindreds, and the youngest generation had significantly earlier age of onset (>10 years) compared with the next oldest generation in 11 kindreds. Neuropsychological testing showed a profile of slowed processing speed, complex attention/executive dysfunction, and impairment in rapid word retrieval. Neuroimaging studies showed bilateral frontal abnormalities most consistently, with more variable degrees of parietal with or without temporal changes; no case had strikingly focal or asymmetric findings. Neuropathological examination of 14 patients revealed a range of transactive response DNA binding protein molecular weight 43 pathology (10 type A and four type B), as well as ubiquitin-positive cerebellar granular neuron inclusions in all but one case. Motor neuron degeneration was detected in nine patients, including five patients without ante-mortem signs of motor neuron disease. While variability exists, most cases with this mutation have a characteristic spectrum of demographic, clinical, neuropsychological, neuroimaging and especially neuropathological findings.
doi:10.1093/brain/aws004
PMCID: PMC3286335  PMID: 22366793
frontotemporal dementia; amyotrophic lateral sclerosis; motor neuron disease; TDP-43; neurogenetics; chromosome 9
15.  Dementia with Lewy bodies 
Neurologic clinics  2007;25(3):741-vii.
Synopsis
The advent of new immunostains have improved our ability to detect limbic and cortical Lewy bodies, and it is now evident that Dementa with Lewy bodies (DLB) is the second most common neurodegenerative dementia, after Alzheimer’s disease (AD). Distinguishing DLB from AD has important implications for treatment, in terms of substances that may worsen symptoms (i.e., anticholinergic and certain neuroleptic medications) and those that may improve them (i.e., cholinesterase inhibitors, carbidopa-levodopa). Neurocognitive patterns, psychiatric features, extrapyramidal signs and sleep disturbance are helpful in differentiating DLB from AD early in the disease course. Differences in the severity of cholinergic depletion as well as type and distribution of neuropathology contribute to these clinical differences, though DLB patients with a high density of co-occuring AD pathology are less clinical distinguishable from AD.
doi:10.1016/j.ncl.2007.03.001
PMCID: PMC3181471  PMID: 17659188
Lewy bodies; dementia; parkinsonism; hallucinations; fluctuations
16.  1H MR SPECTROSCOPY IN COMMON DEMENTIAS 
Neurology  2004;63(8):1393-1398.
Objective
To determine the 1H MR spectroscopic (MRS) findings and inter-group differences among common dementias: Alzheimer's disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration (FTLD).
Methods
We consecutively recruited 206 normal elderly, 121 patients with AD, 41 with FTLD, 20 with DLB, and 8 with VaD. We evaluated the 1H MRS metabolite ratio changes in common dementias with respect to normal, and also differences among the common dementias.
Results
N-acetylaspartate/Creatine (NAA/Cr) was lower than normal in patients with AD, FTLD, and VaD. Myo-inositol (mI)/Cr was higher than normal in patients with AD and FTLD. Choline (Cho)/Cr was higher than normal in patients with, AD, FTLD, and DLB. There were no metabolite differences between patients with AD and FTLD, nor between patients with DLB and VaD. NAA /Cr was lower in patients with AD and FTLD than DLB. MI /Cr was higher in patients with AD and FTLD than VaD. MI /Cr was also higher in patients with FTLD than DLB.
Conclusions
NAA/Cr levels are decreased in dementias that are characterized by neuron loss such as AD, FTLD, and VaD. MI/Cr levels are elevated in dementias that are pathologically characterized by gliosis such as AD and FTLD. Cho/Cr levels are elevated in dementias that are characterized by a profound cholinergic deficit such as AD and DLB.
PMCID: PMC2766798  PMID: 15505154
17.  Rates of cerebral atrophy differ in different degenerative pathologies 
Brain : a journal of neurology  2007;130(Pt 4):1148-1158.
SUMMARY
Neurodegenerative disorders are pathologically characterized by the deposition of abnormal proteins in the brain. It is likely that future treatment trials will target the underlying protein biochemistry and it is therefore increasingly important to be able to distinguish between different pathologies during life. The aim of this study was to determine whether rates of brain atrophy differ in neurodegenerative dementias that vary by pathological diagnoses and characteristic protein biochemistry. Fifty-six autopsied subjects were identified with a clinical diagnosis of dementia and two serial head MRI. Subjects were subdivided based on pathological diagnoses into Alzheimer's disease (AD), dementia with Lewy bodies (DLB), mixed AD/DLB, frontotemporal lobar degeneration with ubiquitin-only-immunoreactive changes (FTLD-U), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). Twenty-five controls were matched by age, gender, and scan interval, to the study cohort. The boundary-shift integral was used to calculate change over time in whole brain (BBSI) and ventricular volume (VBSI). All BSI results were annualized by adjusting for scan interval. The rates of whole brain atrophy and ventricular expansion were significantly increased compared to controls in the AD, mixed AD/DLB, FTLD-U, CBD and PSP groups. However, atrophy rates in the DLB group were not significantly different from control rates of atrophy. The largest rates of atrophy were observed in the CBD group which had a BBSI of 2.3% and VBSI of 16.2%. The CBD group had significantly greater rates of BBSI and VBSI than the DLB, mixed AD/DLB, AD and PSP groups, with a similar trend observed when compared to the FTLD-U group. The FTLD-U group showed the next largest rates with a BBSI of 1.7% and VBSI of 9.6% which were both significantly greater than the DLB group. There was no significant difference in the rates of atrophy between the AD, mixed AD/DLB and PSP groups, which all showed similar rates of atrophy; BBSI of 1.1, 1.3 and 1.0% and VBSI of 8.3, 7.2 and 10.9% respectively. Rates of atrophy therefore differ according to the pathological diagnoses and underlying protein biochemistry. While rates are unlikely to be useful in differentiating AD from cases with mixed AD/DLB pathology, they demonstrate important pathophysiological differences between DLB and those with mixed AD/DLB and AD pathology, and between those with CBD and PSP pathology.
doi:10.1093/brain/awm021
PMCID: PMC2752409  PMID: 17347250
magnetic resonance imaging; Alzheimer's disease; dementia with Lewy bodies; frontotemporal lobar degeneration; progressive supranuclear palsy
18.  Validation of the Neuropathologic Criteria of the Third Consortium for Dementia with Lewy Bodies for Prospectively Diagnosed Cases 
There is limited information on the validity of the pathological criteria of the Third Consortium on Dementia with Lewy bodies (CDLB) and none based upon prospectively diagnosed cases. In this study the core clinical features of dementia with Lewy bodies (DLB) and the suggestive clinical feature of rapid eye movement sleep behavior disorder were assessed using a battery of standardized clinical instruments in 76 patients with the clinical diagnosis of either DLB or Alzheimer disease. At autopsy, 29 patients had high-likelihood, 17 had intermediate-likelihood and 6 had low-likelihood DLB pathology. The frequency of core clinical features and the accuracy of the clinical diagnosis of probable DLB were significantly greater in high-likelihood than in low-likelihood cases. This is consistent with the concept that the DLB clinical syndrome is directly related to Lewy body pathology and inversely related to Alzheimer pathology. Thus, the Third CDLB neuropathological criteria scheme performed reasonably well and is useful for estimating the likelihood of the premortem DLB syndrome based upon postmortem findings. In view of differences in the frequency of clinically probable DLB in cases with Braak NFT stages V (90%) and VI (20%) and diffuse cortical Lewy bodies, a possible modification of the scheme considering cases with NFT stage VI to be low-likelihood DLB is suggested.
doi:10.1097/NEN.0b013e31817d7a1d
PMCID: PMC2745052  PMID: 18596548
Alzheimer disease; α-synuclein; Clinicopathologic correlation; Diagnostic criteria; Dementia with Lewy bodies; Prospective study; REM behavior disorder

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