We aimed to assess associations between clinical, imaging, pathological and genetic features and frontal lobe asymmetry in behavioral variant frontotemporal dementia (bvFTD). Volumes of the left and right dorsolateral, medial and orbital frontal lobes were measured in 80 bvFTD subjects and subjects were classified into three groups according to the degree of asymmetry (asymmetric left, asymmetric right, symmetric) using cluster analysis. The majority of subjects were symmetric (65%), with 20% asymmetric left and 15% asymmetric right. There were no clinical differences across groups, although there was a trend for greater behavioral dyscontrol in right asymmetric compared to left asymmetric subjects. More widespread atrophy involving the parietal lobe was observed in the symmetric group. Genetic features differed across groups with symmetric frontal lobes associated with C9ORF72 and tau mutations, while asymmetric frontal lobes were associated with progranulin mutations. These findings therefore suggest that neuroanatomical patterns of frontal lobe atrophy in bvFTD are influenced by specific gene mutations.
Frontotemporal dementia; frontal lobes; MRI; asymmetry; microtubule associated protein tau; progranulin; C9ORF72; pathology
Four subtypes of frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions have been described (types A–D). Of these four subtypes, motor neuron disease is more commonly associated with type B pathology, but has also been reported with type A pathology. We have noted, however, the unusual occurrence of cases of type C pathology having corticospinal tract degeneration. We aimed to assess the severity of corticospinal tract degeneration in a large cohort of cases with type C (n = 31). Pathological analysis included semi-quantitation of myelin loss of fibres of the corticospinal tract and associated macrophage burden, as well as axonal loss, at the level of the medullary pyramids. We also assessed for motor cortex degeneration and fibre loss of the medial lemniscus/olivocerebellar tract. All cases were subdivided into three groups based on the degree of corticospinal tract degeneration: (i) no corticospinal tract degeneration; (ii) equivocal corticospinal tract degeneration; and (iii) moderate to very severe corticospinal tract degeneration. Clinical, genetic, pathological and imaging comparisons were performed across groups. Eight cases had no corticospinal tract degeneration, and 14 cases had equivocal to mild corticospinal tract degeneration. Nine cases, however, had moderate to very severe corticospinal tract degeneration with myelin and axonal loss. In these nine cases, there was degeneration of the motor cortex without lower motor neuron degeneration or involvement of other brainstem tracts. These cases most commonly presented as semantic dementia, and they had longer disease duration (mean: 15.3 years) compared with the other two groups (10.8 and 9.9 years; P = 0.03). After adjusting for disease duration, severity of corticospinal tract degeneration remained significantly different across groups. Only one case, without corticospinal tract degeneration, was found to have a hexanucleotide repeat expansion in the C9ORF72 gene. All three groups were associated with anterior temporal lobe atrophy on MRI; however, the cases with moderate to severe corticospinal tract degeneration showed right-sided temporal lobe asymmetry and greater involvement of the right temporal lobe and superior motor cortices than the other groups. In contrast, the cases with no or equivocal corticospinal tract degeneration were more likely to show left-sided temporal lobe asymmetry. For comparison, the corticospinal tract was assessed in 86 type A and B cases, and only two cases showed evidence of corticospinal tract degeneration without lower motor neuron degeneration. These findings confirm that there exists a unique association between frontotemporal lobar degeneration with type C pathology and corticospinal tract degeneration, with this entity showing a predilection to involve the right temporal lobe.
TDP-43 type C; corticospinal tract; MRI; semantic dementia; right temporal lobe
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.
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).
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.
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.
Sleep disorders; REM sleep behavior disorder; dementia with Lewy bodies; synucleinopathy
White matter hyperintensities (WMHs) associate with both cognitive slowing and motor dysfunction in the neurologically normal elderly. A full understanding of the pathology underlying this clinicoradiologic finding is currently lacking in autopsy-confirmed normal brains. To determine the histopathologic basis of WMH seen on MRI, we studied the relationship between postmortem fluid-attenuated inversion recovery (FLAIR) intensity and neuropathologic markers of white matter lesions (WMLs) that correspond to WMH in cognitively normal aging brains. Samples of periventricular (n = 24), subcortical (n = 26), and normal-appearing white matter (NAWM, n = 31) from 4 clinically and pathologically-confirmed normal cases were examined. FLAIR intensity, vacuolation, and myelin basic protein (MBP) immunoreactivity loss were significantly higher in periventricular WML vs. subcortical WML; both were higher than in NAWM. The subcortical WML and NAWM had significantly less axonal loss, astrocytic burden, microglial density, and oligodendrocyte loss than the periventricular WML. Thus, vacuolation, myelin density and small vessel density contribute to the rarefaction of white matter whereas axonal density, oligodendrocyte density, astroglial burden and microglial density did not. These data suggest that the age-related loss of MBP and a decrease in small vessel density, may contribute to vacuolation of white matter. The vacuolation enables interstitial fluid to accumulate, which contributes to the prolonged T2 relaxation and elevated FLAIR intensity in the white matter.
Digital microscopy; Fluid attenuated inversion recovery; Normal aging; Oligodendrocytes; Postmortem magnetic resonance imaging; White matter
Atypical variants of Alzheimer’s disease (AD) have been pathologically defined based on the distribution of neurofibrillary tangles; hippocampal sparing (HpSp) AD shows minimal involvement of the hippocampus and limbic predominant (LP) AD shows neurofibrillary tangles restricted to the medial temporal lobe. We aimed to determine whether MRI patterns of atrophy differ across HpSp AD, LP AD and typical AD, and whether imaging could be a useful predictor of pathological subtype during life.
In this case-control study, we identified 177 patients who had been prospectively followed in the Mayo Clinic Alzheimer’s Disease Research Center, were demented during life, had AD pathology at autopsy (Braak stage ≥ IV, intermediate-high probability AD) and an antemortem MRI. Cases were assigned to one of three pathological subtypes (HpSp n=19, typical n=125, or LP AD n=33) based on neurofibrillary tangle counts and their ratio in association cortices to hippocampus, without reference to neuronal loss. Voxel-based morphometry and atlas-based parcellation were used to compare patterns of grey matter loss across groups, and to controls.
The severity of medial temporal and cortical grey matter atrophy differed across subtypes. The most severe medial temporal atrophy was observed in LP AD, followed by typical AD, and then HpSp AD. Conversely, the most severe cortical atrophy was observed in HpSp AD, followed by typical AD, and then LP AD. A ratio of hippocampal-to-cortical volume provided the best discrimination across all three AD subtypes. The majority of typical AD (98/125;78%) and LP AD (31/33;94%) subjects, but only 8/19 (42%) of the HpSp AD subjects, presented with a dominant amnestic syndrome.
Patterns of atrophy on MRI differ across the pathological subtypes of AD, suggesting that MR regional volumetrics reliably track the distribution of neurofibrillary tangle pathology and can predict pathological subtype during life.
US National Institutes of Health (National Institute on Aging)
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.
Dementia with Lewy bodies; MRI; PET; FDG; PiB; Alzheimer's disease
TAR DNA binding protein-43 (TDP-43) immunoreactive neuronal inclusions are detected in 20–30% of Alzheimer disease (AD) brains, but the distribution of this pathology has not been rigorously studied. In this report we describe region-specific distribution and density of TDP-43 positive neuronal cytoplasmic inclusions (NCIs) in clinically demented individuals with high probability AD pathology, all with Braak neurofibrillary tangle stages of V or VI. Sections of hippocampus, amygdala, as well as temporal, frontal and parietal neocortex were analyzed with TDP-43 immunohistochemistry, and the density of NCIs was assessed using a semiquantitative scoring method. Of the 29 cases, 6 had TDP-43 positive NCIs in the amygdala only, and 7 had TDP-43 inclusions restricted to amygdala and hippocampus. In 16 cases TDP-43 immunoreactivity was more widespread, affecting temporal, frontal or parietal neocortex. These findings indicate that medial temporal lobe limbic structures are vulnerable to TDP-43 pathology in advanced AD, and that the amygdala appears to be the most vulnerable region. The distribution of the lesions in this cross-sectional analysis may suggest a progression of TDP-43 pathology in AD, with limbic structures in the medial temporal lobe affected first followed by higher order association cortices.
Amygdala; FTLD-U; FTLD-MND; frontotemporal dementia; motor neuron disease
Central pontine myelinolysis (CPM) is a demyelinating disorder of the central basis pontis that is often associated with osmotic stress. The aquaporin water channels (AQPs) have been pathogenically implicated because serum osmolarity changes redistribute water and osmolytes among various central nervous system compartments.
We characterized the immunoreactivity of aquaporin-1 and aquaporin-4 (AQP1 and AQP4) and associated neuropathology in microscopic transverse sections from archival autopsied pontine tissue from 6 patients with pathologically confirmed CPM. Loss of both AQP1 and AQP4 was evident within demyelinating lesions in four of the six cases, despite the presence of glial fibrillary acidic protein (GFAP)-positive astrocytes. Lesional astrocytes were small, and exhibited fewer and shorter processes than perilesional astrocytes. In two of the six cases, astrocytes within demyelinating lesions exhibited increased AQP1 and AQP4 immunoreactivities, and gemistocytes and mitotic astrocytes were numerous. Blinded review of medical records revealed that all four cases lacking lesional AQP1 and AQP4 immunoreactivities were male, whereas the two cases with enhanced lesional AQP1 and AQP4 immunoreactivities were female.
This report is the first to establish astrocytic AQP loss in a subset of human CPM cases and suggests AQP1 and AQP4 may be involved in the pathogenesis of CPM. Further studies are required to determine whether the loss of AQP1 and AQP4 is restricted to male CPM patients, or rather may be a feature associated with specific underlying precipitants of CPM that may be more common among men. Non-rodent experimental models are needed to better clarify the complex and dynamic mechanisms involved in the regulation of AQPs in CPM, in order to determine whether it occurs secondary to the destructive disease process, or represents a compensatory mechanism protecting the astrocyte against apoptosis.
Osmotic demyelination syndrome; Astrocyte; Demyelination
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).
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.
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.
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.
α-synuclein; cholinergic; Lewy body; laterodorsal tegmentum; locus coeruleus; pedunculopontine nucleus; REM behaviour disorder; tau
Steroid-responsive encephalopathies can considered vasculitic or nonvasculitic. Clinicopathological studies of nonvasculitic steroid-responsive encephalopathy are unusual, but can explain the range of diagnoses consistent with a steroid responsive presentation in life.
To extend the range of clinical features and pathological findings consistent with steroid-responsive encephalopathy.
Design, Methods, and Patients
A clinicopathological case series of four patients (ages 54–71 years, 2 women) with steroid-responsive encephalopathy followed at this institution until the time of death.
Clinical features were suggestive of Creutzfeld-Jakob disease, dementia with Lewy Bodies, and parkinsonism, but pathological examination revealed only Alzheimer’s Disease-related findings without evidence of Lewy bodies or prion disease in all cases. All patients demonstrated marked, sustained improvement following steroid treatment, based on clinical, magnetic resonance imaging, and/or electroencephalogram studiesAlzheimer’s Disease was not diagnosed in life due to a lack of hippocampal atrophy on brain imaging and a dramatic symptomatic response to steroids.
Steroid-responsive encephalopathy is the clinical presentation of some patients with Alzheimer’s Disease related pathology at autopsy, and can be consistent with the clinical diagnoses of parkisonism, dementia with Lewy Bodies, or Creutzfeld-Jakob Disease in life.
Alzheimer’s Disease; corticosteroids; dementia; encephalopathy; Hashimoto’s encephalopathy; neuropathology
Patterns of atrophy in frontotemporal dementia (FTD) correlate with the clinical subtypes of behavioral variant FTD (bvFTD), semantic dementia, progressive non-fluent aphasia (PNFA) and FTD with motor neuron disease (FTD-MND). Right temporal variant FTD is associated with behavioral dyscontrol and semantic impairment, with tau abnormalities more common in right temporal bvFTD and TDP-43 accumulation in right temporal semantic dementia. However, no clinical and anatomical correlation has been described for patients with predominant right temporal atrophy and FTD-MND. Therefore, we performed a database screen for all patients diagnosed with FTD-MND at Mayo Clinic and reviewed their MRI scans to identify those with striking, dominant, right temporal lobe atrophy. For cases with volumetric MRI we performed voxel based morphometry and for those with brain tissue we performed pathological examination. Of three such patients identified, each patient had different presenting behavioral and/or aphasic characteristics. MRI, including DTI sequence in one patient, and FDG PET scan, revealed striking and dominant right temporal lobe atrophy, right corticospinal tract degeneration, and right temporal hypometabolism. Archived brain tissue was available in 2 patients; both demonstrating TDP-43 type 3 pathology (Mackenzie scheme) with predominant neuronal cytoplasmic inclusions. In one case, neurofibrillary tangles (Braak V) and neuritic plaques were also present in keeping with a diagnosis of Alzheimer's disease. There appears to be an association between FTD-MND and severe right temporal lobe atrophy. Until further characterization of such cases are determined, they may be best classified as right temporal variant FTD-MND.
Frontotemporal dementia; Motor neuron disease; TDP-43; Voxel based morphometry (VBM); positron emission tomography (PET
To determine whether dementia with Lewy bodies with or without probable rapid eye movement sleep behavior disorder differ clinically or pathologically.
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).
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.
Probable rapid eye movement sleep behavior disorder is associated with distinct clinical and pathologic characteristics of dementia with Lewy bodies.
Parkinson’s disease; REM sleep behavior disorder; Dementia with Lewy bodies; Lewy body disease; Alzheimer’s disease
To assess whether high school football played between 1946 and 1956, when headgear was less protective than today, was associated with development of neurodegenerative diseases later in life.
All male students who played football from 1946 to 1956 in the high schools of Rochester, Minnesota, plus a non–football-playing referent group of male students in the band, glee club, or choir were identified. Using the records-linkage system of the Rochester Epidemiology Project, we reviewed (from October 31, 2010, to March 30, 2011) all available medical records to assess later development of dementia, Parkinson disease (PD), or amyotrophic lateral sclerosis (ALS). We also compared the frequency of dementia, PD, or ALS with incidence data from the general population of Olmsted County, Minnesota.
We found no increased risk of dementia, PD, or ALS among the 438 football players compared with the 140 non–football-playing male classmates. Parkinson disease and ALS were slightly less frequent in the football group, whereas dementia was slightly more frequent, but not significantly so. When we compared these results with the expected incidence rates in the general population, only PD was significantly increased; however, this was true for both groups, with a larger risk ratio in the non–football group.
Our findings suggest that high school students who played American football from 1946 to 1956 did not have an increased risk of later developing dementia, PD, or ALS compared with non–football-playing high school males, despite poorer equipment and less regard for concussions compared with today and no rules prohibiting head-first tackling (spearing).
ALS, amyotrophic lateral sclerosis; CTE, chronic traumatic encephalopathy; PD, Parkinson disease; REP, Rochester Epidemiology Project
Multiple system atrophy (MSA) is a sporadic progressive neurodegenerative disorder characterised by autonomic failure, manifested as orthostatic hypotension or urogenital dysfunction, with combinations of parkinsonism that is poorly responsive to levodopa, cerebellar ataxia and corticospinal dysfunction. Published autopsy confirmed cases have provided reasonable neurological characterisation but have lacked adequate autonomic function testing.
To retrospectively evaluate if the autonomic characterisation of MSA is accurate in autopsy confirmed MSA and if consensus criteria are validated by autopsy confirmation.
29 autopsy confirmed cases of MSA evaluated at the Mayo Clinic who had undergone formalised autonomic testing, including adrenergic, sudomotor and cardiovagal functions and Thermoregulatory Sweat Test (TST), from which the Composite Autonomic Severity Score (CASS) was derived, were included in the study.
Patient characteristics: 17 men, 12 women; age of onset 57±8.1 years; disease duration to death 6.5±3.3 years; first symptom autonomic in 18, parkinsonism in seven and cerebellar in two. Clinical phenotype at first visit was MSA-P (predominant parkinsonism) in 18, MSA-C (predominant cerebellar involvement) in eight, pure autonomic failure in two and Parkinson’s disease in one. Clinical diagnosis at last visit was MSA for 28 cases. Autonomic failure was severe: CASS was 7.2±2.3 (maximum 10). TST% was 65.6±33.9% and exceeded 30% in 82% of patients. The most common pattern was global anhidrosis. Norepinephrine was normal supine (203.6±112.7) but orthostatic increment of 33.5±23.2% was reduced. Four clinical features (rapid progression, early postural instability, poor levodopa responsiveness and symmetric involvement) were common.
The pattern of severe and progressive generalised autonomic failure with severe adrenergic and sudomotor failure combined with the clinical phenotype is highly predictive of MSA.
Alzheimer's disease (AD) can present with non-amnestic clinical syndromes. We investigated whether there is an imaging signature of AD pathology in these atypical subjects. We identified 14 subjects that had pathological AD, a non-amnestic presentation (i.e. atypical AD), and MRI. These subjects were matched to 14 with clinical and pathological AD (i.e. typical AD), 14 with the same non-amnestic presentations with frontotemporal lobar degeneration (FTLD) pathology, and 20 controls. Voxel-based morphometry and region-of-interest (ROI) analysis were used to assess patterns of grey matter loss. Loss was observed in the temporoparietal cortex in both typical and atypical AD, and showed significantly greater loss than FTLD. However, the medial temporal lobes were more severely affected in typical AD and FTLD compared to atypical AD. A ratio of hippocampal and temporoparietal volumes provided excellent discrimination of atypical AD from FTLD subjects. Temporoparietal atrophy may therefore provide a useful marker of the presence of AD pathology even in subjects with atypical clinical presentations, especially in the context of relative sparing of the hippocampus.
Alzheimer's disease; pathology; voxel-based morphometry; atypical presentation; frontotemporal lobar degeneration; temporoparietal cortex; hippocampus
Pathology underlying behavioral variant frontotemporal dementia (bvFTD) is heterogeneous, with the most common pathologies being Pick’s disease (PiD), corticobasal degeneration (CBD), and FTLD-TDP type 1. Clinical features are unhelpful in differentiating these pathologies. We aimed to determine whether imaging atrophy patterns differ across these pathologies in bvFTD subjects. We identified 15 bvFTD subjects that had volumetric MRI during life and autopsy: five with PiD, five CBD and five FTLD-TDP type 1. Voxel-based morphometry was used to assess atrophy patterns in each bvFTD group compared to 20 age and gender-matched controls. All three pathological groups showed grey matter loss in frontal lobes, although specific patterns of atrophy differed across groups: PiD showed widespread loss in frontal lobes with additional involvement of anterior temporal lobes; CBD showed subtle patterns of loss involving posterior lateral and medial superior frontal lobe; FTLD-TDP type 1 showed widespread loss in frontal, temporal and parietal lobes. Greater parietal loss was observed in FTLD-TDP type 1 compared to both other groups, and greater anterior temporal and medial frontal loss was observed in PiD compared to CBD. Imaging patterns of atrophy in bvFTD vary according to pathological diagnosis and may therefore be helpful in predicting these pathologies in bvFTD.
Frontotemporal dementia; behavioral variant; Pick’s disease; corticobasal degeneration; TDP-43; atrophy; voxel-based morphometry; MRI
Cortical disease has emerged as a critical aspect of the pathogenesis of multiple sclerosis, being associated with disease progression and cognitive impairment. Most studies of cortical lesions have focused on autopsy findings in patients with long-standing, chronic, progressive multiple sclerosis, and the noninflammatory nature of these lesions has been emphasized. Magnetic resonance imaging studies indicate that cortical damage occurs early in the disease.
We evaluated the prevalence and character of demyelinating cortical lesions in patients with multiple sclerosis. Cortical tissues were obtained in passing during biopsy sampling of white-matter lesions. In most cases, biopsy was done with the use of stereotactic procedures to diagnose suspected tumors. Patients with sufficient cortex (138 of 563 patients screened) were evaluated for cortical demyelination. Using immunohistochemistry, we characterized cortical lesions with respect to demyelinating activity, inflammatory infiltrates, the presence of meningeal inflammation, and a topographic association between cortical demyelination and meningeal inflammation. Diagnoses were ascertained in a subgroup of 77 patients (56%) at the last follow-up visit (at a median of 3.5 years).
Cortical demyelination was present in 53 patients (38%) (104 lesions and 222 tissue blocks) and was absent in 85 patients (121 tissue blocks). Twenty-five patients with cortical demyelination had definite multiple sclerosis (81% of 31 patients who underwent long-term follow-up), as did 33 patients without cortical demyelination (72% of 46 patients who underwent long-term follow-up). In representative tissues, 58 of 71 lesions (82%) showed CD3+ T-cell infiltrates, and 32 of 78 lesions (41%) showed macrophage-associated demyelination. Meningeal inflammation was topographically associated with cortical demyelination in patients who had sufficient meningeal tissue for study.
In this cohort of patients with early-stage multiple sclerosis, cortical demyelinating lesions were frequent, inflammatory, and strongly associated with meningeal inflammation. (Funded by the National Multiple Sclerosis Society and the National Institutes of Health.)
Lewy pathology occurs in 8–17% of neurologically-normal people >age 60, termed incidental Lewy body disease, (iLBD). It is often assumed to represent preclinical Parkinson disease (PD). However, some iLBD cases have diffuse pathology inconsistent with preclinical PD. We analyzed iLBD cases (α-synuclein immunohistochemistry) using the Braak PD staging scheme and determined if some had a neuropathological pattern suggestive of preclinical Dementia with Lewy bodies (DLB). Of the 235 brains examined, 34 had iLBD (14.5%) and all but one could be assigned a Braak PD stage. The distribution of α-synuclein pathology in the 33 cases fell into three patterns: (1) Diffuse cortical and subcortical α-synuclein pathology; (2) No cortical a-synuclein pathology, but a caudal-to-rostral ascending pattern, primarily involving brainstem; (3) Intermediate between these two categories. Also, 6/33 cases failed to follow the pattern of contiguous spread proposed by Braak. These findings suggest dichotomy in the distribution of iLBD: some cases fit the Braak ascending scheme, conceptually consistent with preclinical PD, whereas others displayed prominent cortical involvement that might represent preclinical DLB.
incidental Lewy body disease; parkinson disease; dementia with Lewy bodies
To describe a case of childhood-onset progressive multiple sclerosis with dementia and brain biopsy evidence of extensive cortical demyelination.
A 26-year-old gentleman with a history of behavioral changes starting at the age of 13 years followed by progressive dementia.
Neurological examination, MRI, CSF studies, neuropsychological testing, and brain biopsy.
MRI showed numerous T2W hyperintensities throughout the central nervous system not associated with contrast enhancement. Brain biopsy showed cortical and subcortical demyelination. All three types of cortical demyelinating lesions were
leukococortical, intracortical, and subpial. Lesions were associated with profound microglial activation. The patient continued to progress despite attempts to treat with multiple sclerosis disease-modifying therapies.
Multiple sclerosis should be considered in the diagnosis of progressive dementia in children and young adults. Cortical demyelination may contribute to cognitive decline in patients with dementia due to multiple sclerosis.
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.
MRI; Alzheimer’s disease; Lewy body disease; Frontotemporal lobar degeneration
A major recent discovery was the identification of an expansion of a non-coding GGGGCC hexanucleotide repeat in the C9ORF72 gene in patients with frontotemporal dementia and amyotrophic lateral sclerosis. Mutations in two other genes are known to account for familial frontotemporal dementia: microtubule-associated protein tau and progranulin. Although imaging features have been previously reported in subjects with mutations in tau and progranulin, no imaging features have been published in C9ORF72. Furthermore, it remains unknown whether there are differences in atrophy patterns across these mutations, and whether regional differences could help differentiate C9ORF72 from the other two mutations at the single-subject level. We aimed to determine the regional pattern of brain atrophy associated with the C9ORF72 gene mutation, and to determine which regions best differentiate C9ORF72 from subjects with mutations in tau and progranulin, and from sporadic frontotemporal dementia. A total of 76 subjects, including 56 with a clinical diagnosis of behavioural variant frontotemporal dementia and a mutation in one of these genes (19 with C9ORF72 mutations, 25 with tau mutations and 12 with progranulin mutations) and 20 sporadic subjects with behavioural variant frontotemporal dementia (including 50% with amyotrophic lateral sclerosis), with magnetic resonance imaging were included in this study. Voxel-based morphometry was used to assess and compare patterns of grey matter atrophy. Atlas-based parcellation was performed utilizing the automated anatomical labelling atlas and Statistical Parametric Mapping software to compute volumes of 37 regions of interest. Hemispheric asymmetry was calculated. Penalized multinomial logistic regression was utilized to create a prediction model to discriminate among groups using regional volumes and asymmetry score. Principal component analysis assessed for variance within groups. C9ORF72 was associated with symmetric atrophy predominantly involving dorsolateral, medial and orbitofrontal lobes, with additional loss in anterior temporal lobes, parietal lobes, occipital lobes and cerebellum. In contrast, striking anteromedial temporal atrophy was associated with tau mutations and temporoparietal atrophy was associated with progranulin mutations. The sporadic group was associated with frontal and anterior temporal atrophy. A conservative penalized multinomial logistic regression model identified 14 variables that could accurately classify subjects, including frontal, temporal, parietal, occipital and cerebellum volume. The principal component analysis revealed similar degrees of heterogeneity within all disease groups. Patterns of atrophy therefore differed across subjects with C9ORF72, tau and progranulin mutations and sporadic frontotemporal dementia. Our analysis suggested that imaging has the potential to be useful to help differentiate C9ORF72 from these other groups at the single-subject level.
frontotemporal dementia; magnetic resonance imaging; C9ORF72; tau; progranulin
The periaqueductal gray (PAG) consists of distinct columns that participate in the integrated control of autonomic function. We sought to determine whether the PAG is affected in multiple system atrophy (MSA), a disorder characterized by prominent autonomic failure. Brains were obtained at autopsy from 13 MSA patients (10 M, 3 F, age 61 ± 3 years) and 13 controls (8 M, 5 F, age 67 ± 4 years). Transverse formalin-fixed 50 μm sections were obtained throughout the PAG and immunostained for the vesicular transporter 2 (VGLUT-2), nitric oxide synthase (NOS), or α-synuclein and co-stained with thionin. Some sections were processed for myelin or astrocyte staining. Stereological quantitation was performed separately in the ventrolateral, lateral, dorsolateral, and dorsomedial columns of the PAG. In MSA cases, there was a decrease in the total estimated number of VGLUT-2 immunoreactive neurons in the ventrolateral, lateral, and dorsomedial and to a lesser extent dorsolateral PAG compared to controls (ventrolateral PAG: 16,299 ± 1,612 vs. 27,906 ± 2,480 respectively, p<0.01; lateral PAG: 11,004 ± 1,401 vs. 16,078 ± 1,140 respectively, p< 0.05; and dorsomedial PAG: 8,847 ± 1,052 vs. 15,412 ± 1,097 respectively, p< 0.001). The number of NOS immunoreactive neurons in the dorsolateral PAG was similar to controls. In all columns, the number of non-immunolabelled Nissl-stained cells was similar between groups. There was accumulation of glial cytoplasmic inclusions in all PAG columns in MSA. Our findings indicate involvement of the PAG columns in MSA, which may contribute to autonomic disturbances in this disorder.
Central gray; VGLUT-2; nitric oxide synthase; glial cytoplasmic inclusions
We compare patterns of grey matter loss on MRI in subjects presenting as corticobasal syndrome (CBS) with Alzheimer disease pathology (CBS-AD) to those presenting as CBS with corticobasal degeneration pathology (CBS-CBD). Voxel-based morphometry was used to compare patterns of grey matter loss in pathologically confirmed CBS-AD subjects (n=5) and CBS-CBD subjects (n=6) to a group of normal controls (n=20), and to each other. Atlas based parcellation using the automated anatomic labeling atlas was also utilized in a region-of-interest analysis to account for laterality. The CBS-AD subjects were younger at the time of scan compared to CBS-CBD subjects (median: 60 years vs 69; P=0.04). After adjusting for age at time of MRI scan, the CBS-AD subjects showed loss in posterior frontal, temporal, and superior and inferior parietal lobes, while CBS-CBD showed more focal loss predominantly in the posterior frontal lobes, compared to controls. In both CBS-AD and CBS-CBD groups there was basal ganglia volume loss, yet relative sparing of hippocampi. On direct comparisons between the two subject groups, CBS-AD showed greater loss in both temporal and inferior parietal cortices than CBS-CBD. No regions showed greater loss in the CBS-CBD group compared to the CBS-AD group. These findings persisted when laterality was taken into account. In subjects presenting with CBS, prominent temporoparietal, especially posterior temporal and inferior parietal, atrophy may be a clue to the presence of underlying AD pathology.
Voxel based morphometry; Alzheimer’s disease; Corticobasal syndrome; Corticobasal degeneration; Region-of-Interest
Background and Purpose
Frontotemporal lobar degeneration (FTLD) can be subdivided into those in which the abnormal protein is tau (FTLD-TAU), the TAR DNA binding protein 43 (FTLD-TDP) and the fused in sarcoma protein (FTLD-FUS). We have observed severe caudate atrophy at autopsy in FTLD-FUS, and hence we aimed to determine whether caudate atrophy on MRI is a feature that can distinguish FTLD-FUS from FTLD-TDP and FTLD-TAU.
From a cohort of 207 cases of FTLD we identified all cases of FTLD-FUS that had a volumetric antemortem head MRI (n=3). Caudate and frontal lobe volumes were measured in all three cases using atlas based parcellation and SPM5, and were compared to 10 randomly selected cases of FTLD-TDP and 10 randomly selected cases of FTLD-TAU. Total grey matter volumes were also calculated for all cases.
The FTLD-FUS cases had significantly smaller caudate volumes (p=0.02) yet similar frontal lobe grey matter volumes (p=0.12) compared to FTLD-TDP and FTLD-TAU. Caudate volumes when corrected for total grey matter volume (p=0.01) or frontal lobe grey matter volume (p=0.01) were significantly smaller in FTLD-FUS than FTLD-TDP and FTLD-TAU, and showed no overlap with the other two groups.
Caudate atrophy on MRI appears to be significantly greater in FTLD-FUS compared with FTLD-TDP and FTLD-TAU suggesting that severe caudate atrophy may be a useful clinical feature to predict FTLD-FUS pathology.
TDP-43; FTLD-TAU; FTLD-FUS; atlas based parcellation; caudate atrophy