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)
To describe the brain MRI characteristics of hereditary diffuse leukoencephalopathy with spheroids (HDLS) with known mutations in the colony-stimulating factor 1 receptor gene (CSF1R) on chromosome 5.
We reviewed 20 brain MRI scans of 15 patients with autopsy- or biopsy-verified HDLS and CSF1R mutations. We assessed sagittal T1-, axial T1-, T2-, proton density-weighted and axial fluid-attenuated inversion recovery images for distribution of white matter lesions (WMLs), gray matter involvement, and atrophy. We calculated a severity score based on a point system (0−57) for each MRI scan.
Of the patients, 93% (14 of 15) demonstrated localized WMLs with deep and subcortical involvement, whereas one patient revealed generalized WMLs. All WMLs were bilateral but asymmetric and predominantly frontal. Fourteen patients had a rapidly progressive clinical course with an initial MRI mean total severity score of 16.7 points (range 10−33.5). Gray matter pathology and brainstem atrophy were absent, and the corticospinal tracts were involved late in the disease course. There was no enhancement, and there was minimal cerebellar pathology.
Recognition of the typical MRI patterns of HDLS and the use of an MRI severity score might help during the diagnostic evaluation to characterize the natural history and to monitor potential future treatments. Indicators of rapid disease progression were symptomatic disease onset before 45 years, female sex, WMLs extending beyond the frontal regions, a MRI severity score greater than 15 points, and mutation type of deletion.
Few studies have assessed parkinsonian motor features features across variants of primary progressive aphasia (PPA). Our objective was to compare degree of parkinsonian motor features features between two PPA variants.
Parkinsonian motor features were assessed with the Unified Parkinson’s Disease Rating scale in prospectively recruited PPA subjects, classified based on recently published criteria. Comparisons across groups were performed with Fisher’s exact test for binary data and Mann-Whitney U test for continuous data.
Twenty-three PPA subjects were diagnosed with logopenic (n=11) or nonfluent/agrammatic (n=12) aphasia. There were no significant differences in illness duration (agrammatic=3.4 years; logopenic=3.3 years) or age at onset (nonfluent/agrammatic =67.3; logopenic=62.0), but those with logopenic aphasia were more impaired on Mini-Mental State Examination (21.7/30 points vs. 26.1/30; p=0.04). In contrast, those with logopenic aphasia had fewer parkinsonian motor features than those with agrammatic aphasia (5.7/132 vs. 16.8/132; p=0.003) which was driven by bradykinesia (p=0.02) and speech facial/expression (p=0.04); less so rigidity (p=0.06). Dysarthria was more frequent in the nonfluent/agrammatic subgroup.
Nonfluent/agrammatic subjects have more parkinsonian motor features than logopenic subjects, likely reflecting underlying tau pathology in the agrammatic variant.
Parkinsonism; primary progressive aphasia; logopenic aphasia; agrammatic aphasia; extrapyramidal
A rare variant in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene has been reported to be a genetic risk factor for Alzheimer’s disease by two independent groups (Odds ratio between 2.9-4.5). Given the key role of TREM2 in the effective phagocytosis of apoptotic neuronal cells by microglia, we hypothesized that dysfunction of TREM2 may play a more generalized role in neurodegeneration. With this in mind we set out to assess the genetic association of the Alzheimer’s disease-related risk variant in TREM2 (rs75932628, p.R47H) with other related neurodegenerative disorders.
The study included 609 patients with frontotemporal dementia, 765 with amyotrophic lateral sclerosis, 1493 with Parkinson’s disease, 772 with progressive supranuclear palsy, 448 with ischemic stroke and 1957 controls subjects free of neurodegenerative disease. A significant association was observed for the TREM2 p.R47H substitution in susceptibility to frontotemporal dementia (OR = 5.06; p-value = 0.001) and Parkinson’s disease (OR = 2.67; p-value = 0.026), while no evidence of association with risk of amyotrophic lateral sclerosis, progressive supranuclear palsy or ischemic stroke was observed.
Our results suggest that the TREM2 p.R47H substitution is a risk factor for frontotemporal dementia and Parkinson’s disease in addition to Alzheimer’s disease. These findings suggest a more general role for TREM2 dysfunction in neurodegeneration, which could be related to its role in the immune response.
TREM2; Frontotemporal dementia; Parkinson disease; Genetic association
Obsessions and compulsive (OC) behaviors are a frequent feature of behavioral variant frontotemporal dementia (bvFTD), but their structural correlates have not been definitively established.
Patients with bvFTD presenting to the Mayo Clinic Alzheimer’s Disease Research Center were recruited. Each patient’s caregiver was given the Yale-Brown Obsessive-Compulsive scale (YBOCS) to document the type and presence of OC behaviors and to rate their severity. All subjects underwent a standardized MRI which was evaluated using VBM. 17 patients with bvFTD were recruited and 11 were included in the study and compared to 11 age and gender matched controls. Six were excluded for lack of MRI at time of survey or a pre-existing neurodegenerative condition.
Nine of the 11 reported OC behaviors, with the most frequent compulsions being checking, hoarding, ordering/arranging, repeating rituals, and cleaning. In the VBM analysis, total YBOCS score correlated with grey matter loss in the bilateral globus pallidus, left putamen, and in the lateral temporal lobe, particularly the left middle and inferior temporal gyri (p<0.001 uncorrected for multiple comparisons).
Obsessive-compulsive behaviors were frequent among these patients. The correlation with basal ganglia atrophy may point to involvement of frontal subcortical neuronal networks. Left lateral temporal lobe volume loss likely reflects the number of MAPT mutation patients included but also provides additional data implicating temporal lobe involvement in OC behaviors.
Frontotemporal dementia; magnetic resonance imaging; obsessive behavior; compulsive behavior
Evaluating the integrity of white matter tracts with diffusion tensor imaging may differentiate primary lateral sclerosis from progressive supranuclear palsy.
Thirty-three prospectively recruited subjects had standardized evaluations and diffusion tensor imaging: 3 with primary lateral sclerosis who presented with features suggestive of progressive supranuclear palsy, 10 with probable or definite progressive supranuclear palsy, and 20 matched controls. We compared fractional anisotropy of the corticospinal tract, superior cerebellar peduncle and body of the corpus callosum between groups.
Both the primary lateral sclerosis and progressive supranuclear palsy subjects showed reduced fractional anisotropy in superior cerebellar peduncles and body of the corpus callosum compared to controls, but only primary lateral sclerosis subjects showed reductions in the corticospinal tracts. A ratio of corticospinal tract/superior cerebellar peduncle best distinguished the disorders (p<0.02).
The corticospinal tract/superior cerebellar peduncle ratio is a marker to differentiate primary lateral sclerosis from progressive supranuclear palsy.
Progressive supranuclear palsy; primary lateral sclerosis; motor neuron disease; diffusion tensor imaging
The logopenic variant of primary progressive aphasia is an atypical clinical variant of Alzheimer’s disease which is typically characterized by left temporoparietal atrophy on magnetic resonance imaging and hypometabolism on F-18 fluorodeoxyglucose positron emission tomography. We aimed to characterize and compare patterns of atrophy and hypometabolism in logopenic primary progressive aphasia, and determine which brain regions and imaging modality best differentiates logopenic primary progressive aphasia from typical dementia of the Alzheimer’s type.
A total of 27 logopenic primary progressive aphasia subjects underwent fluorodeoxyglucose positron emission tomography and volumetric magnetic resonance imaging. These subjects were matched to 27 controls and 27 subjects with dementia of the Alzheimer’s type. Patterns of atrophy and hypometabolism were assessed at the voxel and region-level using Statistical Parametric Mapping. Penalized logistic regression analysis was used to determine what combinations of regions best discriminate between groups.
Atrophy and hypometabolism was observed in lateral temporoparietal and medial parietal lobes, left greater than right, and left frontal lobe in the logopenic group. The logopenic group showed greater left inferior, middle and superior lateral temporal atrophy (inferior p = 0.02; middle p = 0.007, superior p = 0.002) and hypometabolism (inferior p = 0.006, middle p = 0.002, superior p = 0.001), and less right medial temporal atrophy (p = 0.02) and hypometabolism (p<0.001), and right posterior cingulate hypometabolism (p<0.001) than dementia of the Alzheimer’s type. An age-adjusted penalized logistic model incorporating atrophy and hypometabolism achieved excellent discrimination (area under the receiver operator characteristic curve = 0.89) between logopenic and dementia of the Alzheimer’s type subjects, with optimal discrimination achieved using right medial temporal and posterior cingulate hypometabolism, left inferior, middle and superior temporal hypometabolism, and left superior temporal volume.
Patterns of atrophy and hypometabolism both differ between logopenic primary progressive aphasia and dementia of the Alzheimer’s type and both modalities provide excellent discrimination between groups.
Adult-onset primary lower limb dystonia (AOPLLD) has been reported as an early sign of Parkinson’s disease (PD) or Parkinson-plus syndrome in case series. No prior systematic analysis has assessed clinical clues predicting later development of PD or Parkinson-plus syndrome.
We identified patients with AOPLLD from medical records. We excluded patients who had not been diagnosed by a neurologist, and who had a pre-existing diagnosis of PD, psychogenic, or secondary dystonia. Records were subdivided into those who later developed PD or Parkinson-plus disorders and those who did not. The following clinical characteristics were compared between the two groups: dystonia onset age, type of dystonia, levodopa response, anticholinergic response, and family history of Parkinsonism or tremor.
Twenty-two AOPLLD patients were identified: 77% female; the median dystonia onset age was 53 years. Eight (37%) developed Parkinson’s disease; 2 (9%) developed corticobasal syndrome. Twelve patients (54%) did not develop Parkinsonism after a median follow-up period of 1.5 years. There was a significant difference in leg dystonia levodopa response between the two groups (p = 0.02).
In patients with AOPLLD, leg dystonia with levodopa response is associated with the future development of PD.
Dystonia; Parkinson’s disease; leg dystonia; levodopa
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
Our objective was to document the clinical and imaging features of Othello's syndrome (delusional jealousy).
The study design was a retrospective case series of 105 patients with Othello's syndrome that were identified by using the Electronic Medical Record system of Mayo Clinic.
The average age at onset of Othello's syndrome was 68 (25–94) years with 61.9% of patients being male. Othello's syndrome was most commonly associated with a neurological disorder (73/105) compared with psychiatric disorders (32/105). Of the patients with a neurological disorder, 76.7% had a neurodegenerative disorder. Seven of eight patients with a structural lesion associated with Othello's syndrome had right frontal lobe pathology. Voxel-based morphometry showed greater grey matter loss predominantly in the dorsolateral frontal lobes in the neurodegenerative patients with Othello's compared to matched patients with neurodegenerative disorders without Othello's syndrome. Treatment success was notable for patients with dopamine agonist induced Othello's syndrome in which all six patients had improvement in symptoms following decrease in medication.
This study demonstrates that Othello's syndrome occurs most frequently with neurological disorders. This delusion appears to be associated with dysfunction of the frontal lobes, especially right frontal lobe.
Othello's Syndrome; Right frontal lobe; Delusions; Dementia
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
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are part of a disease spectrum associated with TDP-43 pathology. Strong evidence supporting this is the existence of kindreds with family members affected by FTD, ALS or mixed features of FTD and ALS, referred to as FTD-MND. Some of these families have linkage to chromosome 9, with hexanucleotide expansion mutation in a noncoding region of C9ORF72. Discovery of the mutation defines c9FTD/ALS. Prior to discovery of mutations in C9ORF72, it was assumed that TDP-43 pathology in c9FTD/ALS was uniform. In this study, we examined the neuropathology and clinical features of 20 cases of c9FTD/ALS from a brain bank for neurodegenerative disorders. Included are six patients clinically diagnosed with ALS, eight FTD, one FTD-MND and four Alzheimer type dementia. Clinical information was unavailable for one patient. Pathologically, the cases all had TDP-43 pathology, but there were three major pathologic groups: ALS, FTLD-MND and FTLD-TDP. The ALS cases were morphologically similar to typical sporadic ALS with almost no extramotor TDP-43 pathology; all had oligodendroglial cytoplasmic inclusions. The FTLD-MND showed predominantly Mackenzie Type 3 TDP-43 pathology, and all had ALS-like pathology in motor neurons, but more extensive extramotor pathology, with oligodendroglial cytoplasmic inclusions and infrequent hippocampal sclerosis. The FTLD-TDP cases had several features similar to FTLD-TDP due to mutations in the gene for progranulin, including Mackenzie Type 1 TDP-43 pathology with neuronal intranuclear inclusions and hippocampal sclerosis. FTLD-TDP patients were older and some were thought to have Alzheimer type dementia. In addition to the FTD and ALS clinical presentations, the present study shows that c9FTD/ALS can have other presentations, possibly related to age of onset and presence of hippocampal sclerosis. Moreover, there is pathologic heterogeneity not only between ALS and FTLD, but within the FTLD group. Further studies are needed to address the molecular mechanism of clinical and pathological heterogeneity of c9FTD/ALS due to mutations in C9ORF72.
A clinically and pathologically heterogeneous type of frontotemporal lobar degeneration has abnormal tau pathology in neurons and glia (FTLD-tau). Familial FTLD-tau is usually due to mutations in the tau gene (MAPT). Even FTLD-tau determined by MAPT mutations ha s clinical and pathologic heterogeneity. Tauopathies are subclassified according to the predominant species of tau that accumulates, with respect to alternative splicing of MAPT, with tau proteins containing 3 (3R) or 4 repeats (4R) of ~ 32 amino acids in the microtubule binding domain. In Pick's disease (PiD), 3R tau predominates, whereas 4R tau is characteristic of corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). Depending upon the specific mutation in MAPT, familial FTLD-tau can have 3R, 4R or a combination of 3R and 4R tau. PiD is the least common FTLD-tau characterized by neuronal Pick bodies in a stereotypic neuroanatomical distribution. PSP and CBD are more common than PiD and have extensive clinical and pathologic overlap, with no distinctive clinical syndrome or biomarker that permits their differentiation. Diagnosis rests upon postmortem examination of the brain and demonstration of globose tangles, oligodendroglial coiled bodies and tufted astrocytes in PSP or threads, pretangles and astrocytic plaques in CBD. The anatomical distribution of tau pathology determines the clinical presentation of PSP and CBD, as well as PiD. The basis for this selective cortical vulnerability in FTLD-tau is unknown.
corticobasal degeneration; corticobasal syndrome; frontotemporal lobar degeneration – tau; Pick’s disease; progressive supranuclear palsy; Richardson syndrome
Patients with corticobasal degeneration can present with several different clinical syndromes, making ante-mortem diagnosis a challenge. Corticobasal syndrome is the clinical phenotype originally described for corticobasal degeneration, characterized by asymmetric rigidity and apraxia, cortical sensory deficits, dystonia and myoclonus. Some patients do not develop these features, but instead have clinical features consistent with the Richardson syndrome presentation of progressive supranuclear palsy, characterized by postural instability, early unexplained falls, vertical supranuclear gaze palsy, symmetric motor disability and dysphagia. The aim of this study was to identify differences in corticobasal degeneration presenting with corticobasal syndrome (n = 11) or Richardson syndrome (n = 15) with respect to demographic, clinical and neuropathological features. Corticobasal degeneration cases were also compared with patients with pathologically proven progressive supranuclear palsy with Richardson syndrome (n = 15). Cases with corticobasal degeneration, regardless of presentation, shared histopathological and tau biochemical characteristics, but they had differing densities of tau pathology in neuroanatomical regions that correlated with their clinical presentation. In particular, those with corticobasal syndrome had greater tau pathology in the primary motor and somatosensory cortices and putamen, while those with Richardson syndrome had greater tau pathology in limbic and hindbrain structures. Compared with progressive supranuclear palsy, patients with corticobasal degeneration and Richardson syndrome had less neuronal loss in the subthalamic nucleus, but more severe neuronal loss in the medial substantia nigra and greater atrophy of the anterior corpus callosum. Clinically, they had more cognitive impairment and frontal behavioural dysfunction. The results suggest that Richardson syndrome can be a clinicopathological presentation of corticobasal degeneration. Atrophy of anterior corpus callosum may be a potential neuroimaging marker to differentiate corticobasal degeneration from progressive supranuclear palsy in patients with Richardson syndrome.
pathology; immunocytochemistry; progressive supranuclear palsy; tau protein; corticobasal degeneration
Several families have been reported with autosomal dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), genetically linked to chromosome 9p21. Here we report an expansion of a non-coding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with disease in a large FTD/ALS kindred, previously reported to be conclusively linked to chromosome 9p. This same repeat expansion was identified in the majority of our families with a combined FTD/ALS phenotype and TDP-43 based pathology. Analysis of extended clinical series found the C9ORF72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (22.5%). The repeat expansion leads to the loss of one alternatively spliced C9ORF72 transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms. Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS.
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
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
Progressive supranuclear palsy (PSP) is associated with pathological changes along the dentatorubrothalamic tract and in premotor cortex. We aimed to assess whether functional neural connectivity is disrupted along this pathway in PSP, and to determine how functional changes relate to changes in structure and diffusion. Eighteen probable PSP subjects and 18 controls had resting-state (task-free) fMRI, diffusion tensor imaging and structural MRI. Functional connectivity was assessed between thalamus and the rest of the brain, and within the basal ganglia, salience and default mode networks (DMN). Patterns of atrophy were assessed using voxel-based morphometry, and patterns of white matter tract degeneration were assessed using tract-based spatial statistics. Reduced in-phase functional connectivity was observed between the thalamus and premotor cortex including supplemental motor area (SMA), striatum, thalamus and cerebellum in PSP. Reduced connectivity in premotor cortex, striatum and thalamus were observed in the basal ganglia network and DMN, with subcortical salience network reductions. Tract degeneration was observed between cerebellum and thalamus and in superior longitudinal fasciculus, with grey matter loss in frontal lobe, premotor cortex, SMA and caudate. SMA functional connectivity correlated with SMA volume and measures of cognitive and motor dysfunction, while thalamic connectivity correlated with degeneration of superior cerebellar peduncles. PSP is therefore associated with disrupted thalamocortical connectivity that is associated with degeneration of the dentatorubrothalamic tract and the presence of cortical atrophy.
Resting state fMRI; functional connectivity; white matter tracts; atrophy; dentatorubrothalamic tract
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.
behavioural variant frontotemporal dementia; diagnostic criteria; frontotemporal lobar degeneration; FTD; pathology
Corticobasal syndrome (CBS), once thought to be pathognomonic for corticobasal degeneration pathology, is increasingly reported with various underlying pathologies. Alzheimer’s disease is one such pathology, also once believed to be unique for its clinical syndrome of dementia of the Alzheimer’s type. CBS is believed to result from topography of asymmetric parietofrontal cortical lesion involvement, rather than lesion subtype. However, this topographical pattern is strikingly different to that typically associated with AD for unclear reasons. This article will focus on CBS with underlying AD pathology (CBS-AD), and will review associated clinical, imaging and demographic factors. Predicting AD pathology is of marked interest as disease-modifying therapies loom on the horizon, with biomarkers and imaging research underway. By reviewing the literature for CBS-AD case reports and series and contrasting them with CBS with underlying corticobasal degeneration pathology cases, the article aims to examine factors that may predict AD pathology. How AD pathology may produce this clinical phenotype, rather than the prototype dementia of the Alzheimer’s type, will also be reviewed.
alien limb; Alzheimer’s disease; apraxia; corticobasal degeneration; corticobasal syndrome; dementia; myoclonus; rigidity; tau; voxel-based morphometry
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
Progressive supranuclear palsy (PSP) is associated with degeneration of white matter tracts that can be detected using diffusion tensor imaging (DTI). However, little is known about whether tract degeneration is associated with the clinical symptoms of PSP. The aim of this study was to use DTI to assess white matter tract degeneration in PSP and to investigate correlates, between tract integrity and clinical measures.
Tertiary care medical centre
Twenty subjects with probable PSP and 20 age and gender-matched healthy controls. All PSP subjects underwent standardized clinical testing, including the Frontal Behavioral Inventory and Frontal Assessment Battery to assess behavioral change; the PSP Rating Scale to measure disease severity, the Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (parts I, II and III) to measure motor function, and the PSP Saccadic Impairment Scale to measure eye movement abnormalities.
Main outcome measures
Fractional anisotropy and mean diffusivity measured using both region-of-interest analysis and Track Based Spatial Statistics.
Abnormal diffusivity was observed predominantly in superior cerebellar peduncles, body of the corpus callosum, inferior longitudinal fasciculus and superior longitudinal fasciculus in PSP compared to controls. Fractional anisotropy values in the superior cerebellar peduncles correlated with disease severity; inferior longitudinal fasciculus correlated with motor function, and superior longitudinal fasciculus correlated with severity of saccadic impairments.
These results demonstrate that PSP is associated with degeneration of brainstem, association and commissural fibers and that this degeneration likely plays an important role in clinical dysfunction.
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