Publications by authors named "Julie S Snowden"

90 Publications

Distinct performance profiles on the Brixton test in frontotemporal dementia.

J Neuropsychol 2021 Jun 15;15(2):162-185. Epub 2020 Oct 15.

Cerebral Function Unit, Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, UK.

The Brixton Spatial Anticipation Test is a well-established test of executive function that evaluates the capacity to abstract, follow, and switch rules. There has been remarkably little systematic analysis of Brixton test performance in the prototypical neurodegenerative disorder of the frontal lobes: behavioural variant frontotemporal dementia (bvFTD) or evaluation of the test's ability to distinguish frontal from temporal lobe degenerative disease. We carried out a quantitative and qualitative analysis of Brixton performance in 76 patients with bvFTD and 34 with semantic dementia (SD) associated with temporal lobe degeneration. The groups were matched for demographic variables and illness duration. The bvFTD group performed significantly more poorly (U = 348, p < .0001, r = .58), 53% of patients scoring in the poor-impaired range compared with 6% of SD patients. Whereas bvFTD patients showed problems in rule acquisition and switching, SD patients did not, despite their impaired conceptual knowledge. Error analysis revealed more frequent perseverative errors in bvFTD, particularly responses unconnected to the stimulus, as well as random responses. Stimulus-bound errors were rare. Within the bvFTD group, there was variation in performance profile, which could not be explained by demographic, neurological, or genetic factors. The findings demonstrate sensitivity and specificity of the Brixton test in identifying frontal lobe degenerative disease and highlight the clinical value of qualitative analysis of test performance. From a theoretical perspective, the findings provide evidence that semantic knowledge and the capacity to acquire rules are dissociable. Moreover, they exemplify the separable functional contributions to executive performance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jnp.12228DOI Listing
June 2021

Cognition and behaviour in frontotemporal dementia with and without amyotrophic lateral sclerosis.

J Neurol Neurosurg Psychiatry 2020 12 14;91(12):1304-1311. Epub 2020 Oct 14.

Cerebral Function Unit, Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, Salford, UK

Objective: The precise relationship between frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is incompletely understood. The association has been described as a continuum, yet data suggest that this may be an oversimplification. Direct comparisons between patients who have behavioural variant FTD (bvFTD) with and without ALS are rare. This prospective comparative study aimed to determine whether there are phenotypic differences in cognition and behaviour between patients with FTD-ALS and bvFTD alone.

Methods: Patients with bvFTD or FTD-ALS and healthy controls underwent neuropsychological testing, focusing on language, executive functions and social cognition. Behavioural change was measured through caregiver interview. Blood samples were screened for known FTD genes.

Results: 23 bvFTD, 20 FTD-ALS and 30 controls participated. On cognitive tests, highly significant differences were elicited between patients and controls, confirming the tests' sensitivities to FTD. bvFTD and FTD-ALS groups performed similarly, although with slightly greater difficulty in patients with ALS-FTD on category fluency and a sentence-ordering task that assesses grammar production. Patients with bvFTD demonstrated more widespread behavioural change, with more frequent disinhibition, impulsivity, loss of empathy and repetitive behaviours. Behaviour in FTD-ALS was dominated by apathy. The repeat expansion was associated with poorer performance on language-related tasks.

Conclusions: Differences were elicited in cognition and behaviour between bvFTD and FTD-ALS, and patients carrying the repeat expansion. The findings, which raise the possibility of phenotypic variation between bvFTD and FTD-ALS, have clinical implications for early detection of FTD-ALS and theoretical implications for the nature of the relationship between FTD and ALS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jnnp-2020-323969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677467PMC
December 2020

The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) in frontotemporal dementia.

Amyotroph Lateral Scler Frontotemporal Degener 2020 11 19;21(7-8):606-613. Epub 2020 Aug 19.

Cerebral Function Unit, Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, Salford, UK.

Objectives: To examine the usefulness of the Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis (ALS) Screen (ECAS) as a cognitive screening tool for the detection of behavioral variant frontotemporal dementia (bvFTD). A secondary aim was to determine whether people with FTD combined with ALS (ALS-FTD) exhibit a similar ECAS profile to that of people with bvFTD alone. Patients with ALS-FTD and bvFTD and healthy controls were recruited. Participants were administered the ECAS, which comprises tests of language, verbal fluency, executive functions, memory, and visual-spatial functions. They also carried out analogous, full-length cognitive tests that examine naming, spelling, sentence completion, and social cognition skills. The study cohort comprised 20 ALS-FTD patients, 23 with bvFTD, and 30 controls. Highly significant group differences were elicited for all cognitive domains, reflecting poorer performance in patients compared to controls. No significant differences in overall test scores were found between ALS-FTD and bvFTD patients, although ALS-FTD patients showed a higher frequency of impairment on verbal fluency. Correlative analyses revealed inter-relationships in patients (but not controls) between scores in different domains, most marked in bvFTD. There were strong correlations between performance on ECAS subtests and analogous cognitive tasks. The ECAS is a sensitive and valuable tool for the assessment of FTD. Executive, language and behavioral breakdown may, however, compromise performance in other cognitive domains, reducing the specificity of the 'frontotemporal' cognitive profile. Subtle differences observed between ALS-FTD and bvFTD raise questions regarding the precise relationship between bvFTD with and without ALS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21678421.2020.1797090DOI Listing
November 2020

Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study.

Lancet Neurol 2020 02 3;19(2):145-156. Epub 2019 Dec 3.

Institut du Cerveau et de la Moelle épinière & Centre de Référence des Démences Rares ou précoces, Institut de la Mémoire et de la Maladie d'Alzheimer, Assistance Publique-Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, Paris, France.

Background: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72.

Methods: In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried.

Findings: Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49·5 years (SD 10·0; onset) and 58·5 years (11·3; death) in the MAPT group, 58·2 years (9·8; onset) and 65·3 years (10·9; death) in the C9orf72 group, and 61·3 years (8·8; onset) and 68·8 years (9·7; death) in the GRN group. Mean disease duration was 6·4 years (SD 4·9) in the C9orf72 group, 7·1 years (3·9) in the GRN group, and 9·3 years (6·4) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0·45 between individual and parental age at onset, r=0·63 between individual and mean family age at onset, r=0·58 between individual and parental age at death, and r=0·69 between individual and mean family age at death) than in either the C9orf72 group (r=0·32 individual and parental age at onset, r=0·36 individual and mean family age at onset, r=0·38 individual and parental age at death, and r=0·40 individual and mean family age at death) or the GRN group (r=0·22 individual and parental age at onset, r=0·18 individual and mean family age at onset, r=0·22 individual and parental age at death, and r=0·32 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35-62, for age at onset; 61%, 47-73, for age at death), and even more by family membership (66%, 56-75, for age at onset; 74%, 65-82, for age at death). In the GRN group, only 2% (0-10) of the variability of age at onset and 9% (3-21) of that of age of death was explained by the specific mutation, whereas 14% (9-22) of the variability of age at onset and 20% (12-30) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11-26) of the variability of age at onset and 19% (12-29) of that of age at death.

Interpretation: Our study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates.

Funding: UK Medical Research Council, National Institute for Health Research, and Alzheimer's Society.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1474-4422(19)30394-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007771PMC
February 2020

Reading, semantic loss and neural networks in Japanese ALS patients.

Authors:
Julie S Snowden

EBioMedicine 2019 09 4;47:10-11. Epub 2019 Sep 4.

Cerebral Function Unit, Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, Salford and Division of Neuroscience and Experimental Psychology, School of Biological Sciences, University of Manchester, UK. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2019.08.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796589PMC
September 2019

Naming and conceptual understanding in frontotemporal dementia.

Cortex 2019 11 28;120:22-35. Epub 2019 May 28.

Cerebral Function Unit, Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, Salford, UK; Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

Behavioural variant frontotemporal dementia (bvFTD) is characterised by behaviour change and impaired executive skills. There is growing evidence that naming difficulties may also be present but the basis for these is unclear. A primary semantic deficit has been proposed, although executive contributions to naming breakdown are also possible. The study aimed to improve understanding of the naming disorder in bvFTD through direct comparison with semantic dementia (SD), and examination of neural correlates. It aimed also to address current controversies about the role of the anterior temporal lobes in semantic memory. We studied 71 bvFTD and 32 SD patients. Naming data were elicited by two picture naming tests (one challenging and one less demanding) and word comprehension by word-picture matching. Structural magnetic resonance images were rated blind using a standardised visual rating scale. Around half of bvFTD patients showed impaired naming and 17% impaired word-picture matching. Deficits in bvFTD were less severe than in SD, but showed a similar pattern. There were strong inverse correlations between naming scores and atrophy in temporal structures, particularly temporal pole and fusiform gyrus. Word comprehension scores correlated more strongly with posterior than anterior temporal lobe atrophy in SD. Error analysis highlighted a significant relationship in both groups between associative-type responses and temporal pole atrophy. By contrast, 'don't know' responses, suggesting a loss of conceptual knowledge, correlated with more posterior temporal regions. There was some correlation in bvFTD between naming and executive test performance but not with frontal lobe atrophy. The findings support the view that naming problems can arise in bvFTD independently of patients' 'frontal' executive impairment and highlight clinical overlap between bvFTD and SD. We discuss the findings in relation to the hub and spoke model of semantic memory and argue against the notion of an anterior temporal lobe semantic hub.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cortex.2019.04.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838679PMC
November 2019

Cognitive rehabilitation, self-management, psychotherapeutic and caregiver support interventions in progressive neurodegenerative conditions: A scoping review.

NeuroRehabilitation 2018 ;43(4):443-471

PenCLAHRC, University of Exeter Medical School, Exeter, UK.

Background: Despite its potentially significant impact, cognitive disability may be overlooked in a number of progressive neurodegenerative conditions, as other difficulties dominate the clinical picture.

Objective: We examined the extent, nature and range of the research evidence relating to cognitive rehabilitation, self-management, psychotherapeutic and caregiver support interventions in Parkinsonian disorders, multiple sclerosis (MS), frontotemporal dementias (FTD), motor neuron disease and Huntington's disease.

Methods: Scoping review based on searches of MEDLINE and CINAHL up to 15 March 2016.

Results: We included 140 eligible papers. Over half of the studies, and almost all the randomised controlled trials, related to MS, while a number of single case studies described interventions for people with FTD. CR interventions addressed functional ability, communication and interaction, behaviour or memory. The majority of psychotherapy interventions involved cognitive behavioural therapy for depression or anxiety. Self-management interventions were mainly available for people with MS. There were few reports of interventions specific to caregivers. Numerous methodological challenges were identified.

Conclusions: The limited range of studies for all conditions except MS suggests a need firstly to synthesise systematically the available evidence across conditions and secondly to develop well-designed studies to provide evidence about the effectiveness of CR and other psychological interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/NRE-172353DOI Listing
February 2019

Prevalence of amyloid-β pathology in distinct variants of primary progressive aphasia.

Ann Neurol 2018 11;84(5):729-740

University of Toulouse, INSERM, Toulouse Neuroimaging Center, Toulouse, France.

Objective: To estimate the prevalence of amyloid positivity, defined by positron emission tomography (PET)/cerebrospinal fluid (CSF) biomarkers and/or neuropathological examination, in primary progressive aphasia (PPA) variants.

Methods: We conducted a meta-analysis with individual participant data from 1,251 patients diagnosed with PPA (including logopenic [lvPPA, n = 443], nonfluent [nfvPPA, n = 333], semantic [svPPA, n = 401], and mixed/unclassifiable [n = 74] variants of PPA) from 36 centers, with a measure of amyloid-β pathology (CSF [n = 600], PET [n = 366], and/or autopsy [n = 378]) available. The estimated prevalence of amyloid positivity according to PPA variant, age, and apolipoprotein E (ApoE) ε4 status was determined using generalized estimating equation models.

Results: Amyloid-β positivity was more prevalent in lvPPA (86%) than in nfvPPA (20%) or svPPA (16%; p < 0.001). Prevalence of amyloid-β positivity increased with age in nfvPPA (from 10% at age 50 years to 27% at age 80 years, p < 0.01) and svPPA (from 6% at age 50 years to 32% at age 80 years, p < 0.001), but not in lvPPA (p = 0.94). Across PPA variants, ApoE ε4 carriers were more often amyloid-β positive (58.0%) than noncarriers (35.0%, p < 0.001). Autopsy data revealed Alzheimer disease pathology as the most common pathologic diagnosis in lvPPA (76%), frontotemporal lobar degeneration-TDP-43 in svPPA (80%), and frontotemporal lobar degeneration-TDP-43/tau in nfvPPA (64%).

Interpretation: This study shows that the current PPA classification system helps to predict underlying pathology across different cohorts and clinical settings, and suggests that age and ApoE genotype should be considered when interpreting amyloid-β biomarkers in PPA patients. Ann Neurol 2018;84:737-748.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354051PMC
November 2018

Empathy in Frontotemporal Dementia.

Authors:
Julie S Snowden

Cogn Behav Neurol 2018 06;31(2):111

Cerebral Function Unit Greater Manchester Neuroscience Centre Salford Royal Foundation Trust Salford, Greater Manchester United Kingdom.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/WNN.0000000000000156DOI Listing
June 2018

Patterns and severity of vascular amyloid in Alzheimer's disease associated with duplications and missense mutations in APP gene, Down syndrome and sporadic Alzheimer's disease.

Acta Neuropathol 2018 10 16;136(4):569-587. Epub 2018 May 16.

Institute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespigny Park, London, UK.

In this study, we have compared the severity of amyloid plaque formation and cerebral amyloid angiopathy (CAA), and the subtype pattern of CAA pathology itself, between APP genetic causes of AD (APPdup, APP mutations), older individuals with Down syndrome (DS) showing the pathology of Alzheimer's disease (AD) and individuals with sporadic (early and late onset) AD (sEOAD and sLOAD, respectively). The aim of this was to elucidate important group differences and to provide mechanistic insights related to clinical and neuropathological phenotypes. Since lipid and cholesterol metabolism is implicated in AD as well as vascular disease, we additionally aimed to explore the role of APOE genotype in CAA severity and subtypes. Plaque formation was greater in DS and missense APP mutations than in APPdup, sEOAD and sLOAD cases. Conversely, CAA was more severe in APPdup and missense APP mutations, and in DS, compared to sEOAD and sLOAD. When stratified by CAA subtype from 1 to 4, there were no differences in plaque scores between the groups, though in patients with APPdup, APP mutations and sEOAD, types 2 and 3 CAA were more common than type 1. Conversely, in DS, sLOAD and controls, type 1 CAA was more common than types 2 and 3. APOE ε4 allele frequency was greater in sEOAD and sLOAD compared to APPdup, missense APP mutations, DS and controls, and varied between each of the CAA phenotypes with APOE ε4 homozygosity being more commonly associated with type 3 CAA than types 1 and 2 CAA in sLOAD and sEOAD. The differing patterns in CAA within individuals of each group could be a reflection of variations in the efficiency of perivascular drainage, this being less effective in types 2 and 3 CAA leading to a greater burden of CAA in parenchymal arteries and capillaries. Alternatively, as suggested by immunostaining using carboxy-terminal specific antibodies, it may relate to the relative tissue burdens of the two major forms of Aβ, with higher levels of Aβ promoting a more 'aggressive' form of CAA, and higher levels of Aβ favouring a greater plaque burden. Possession of APOE ε4 allele, especially ε4 homozygosity, favours development of CAA generally, and as type 3 particularly, in sEOAD and sLOAD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-018-1866-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132946PMC
October 2018

Lysosomes, autophagosomes and Alzheimer pathology in dementia with Lewy body disease.

Neuropathology 2018 May 10. Epub 2018 May 10.

Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Salford Royal Hospital, Salford, UK.

A failure of protein degradation may underpin Lewy body disease (LBD) where α-synuclein is assimilated into the pathognomic Lewy bodies and Lewy neurites. We investigated histological alterations in lysosomes and autophagosomes in the substantia nigra (SN) and cingulate gyrus (CG) in 34 patients with LBD employing antibodies against phosphorylated α-synuclein and lysosomal (lysosomal associated membrane proteins 1 and 2 (LAMP-1 and LAMP-2), cathepsin D (CTSD)) and autophagosomal (microtubule-associated protein light chain 3α (LC3A)) proteins. Immunostained sections were qualitatively and semi-quantitatively assessed for the appearance, distribution and intensity of staining. Four LBD patients had mutations in GBA1. There was significantly less LAMP-1, LAMP-2 and CTSD immunostaining in neurons of the SN in LBD cases compared to control cases and marginally less LAMP-1 in patients with GBA1 mutations compared to those without. Loss of LAMP-1 and CTSD immunoreactivity correlated with cell loss from the SN. There were no changes in LC3A immunoreactivity in the SN, nor any major changes in the CG, or glial cell activity in the SN and CG, for any of the markers. A proportion of amyloid plaques in both the LBD and control cases was immunoreactive for LAMP-1 and LAMP-2, but not CTSD or LC3A proteins. These immunohisochemical features were seen in glial cells, which were negative for amyloid-β. Alterations in lysosomal structure or function, but not macroautophagy, may underpin the pathogenesis of LBD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/neup.12472DOI Listing
May 2018

Scores Obtained from a Simple Cognitive Test of Visuospatial Episodic Memory Performed Decades before Death Are Associated with the Ultimate Presence of Alzheimer Disease Pathology.

Dement Geriatr Cogn Disord 2018 25;45(1-2):79-90. Epub 2018 Apr 25.

Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Neuroscience and Experimental Psychology, University of Manchester, Salford Royal Hospital, Salford, United Kingdom.

Background: Community- or population-based longitudinal studies of cognitive ability with a brain donation end point offer an opportunity to examine relationships between pathology and cognitive state prior to death. Discriminating the earliest signs of dementing disorders, such as Alzheimer disease (AD), is necessary to undertake early interventions and treatments.

Methods: The neuropathological profile of brains donated from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age, including CERAD (Consortium to Establish a Registry for Alzheimer's Disease) and Braak stage, was assessed by immunohistochemistry. Cognitive test scores collected 20 years prior to death were correlated with the extent of AD pathology present at death.

Results: Baseline scores from the Memory Circle test had the ability to distinguish between individuals who developed substantial AD pathology and those with no, or low, AD pathology. Predicted test scores at the age of 65 years also discriminated between these pathology groups. The addition of APOE genotype further improved the discriminatory ability of the model.

Conclusions: The results raise the possibility of identifying individuals at future risk of the neuropathological changes associated with AD over 20 years before death using a simple cognitive test. This work may facilitate early interventions, therapeutics and treatments for AD by identifying at-risk and minimally affected (in pathological terms) individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000486827DOI Listing
October 2018

Association between semantic dementia and progressive supranuclear palsy.

J Neurol Neurosurg Psychiatry 2019 01 16;90(1):115-117. Epub 2018 Apr 16.

Division of Neuroscience and Experimental Psychology, School of Biological Sciences, University of Manchester, Manchester, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jnnp-2017-317839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327859PMC
January 2019

Neuropsychological differentiation of progressive aphasic disorders.

J Neuropsychol 2019 06 8;13(2):214-239. Epub 2018 Feb 8.

Manchester Academic Health Sciences Centre, Cerebral Function Unit, Greater Manchester Neuroscience Centre, Salford Royal NHS Foundation Trust, UK.

The differentiation of subtypes of primary progressive aphasia (PPA) remains challenging. We aimed to identify optimum neuropsychological measures for characterizing PPA, to examine the relationship between behavioural change and subtypes of PPA and to determine whether characteristic profiles of language, working memory, and behavioural changes occur in PPA. Forty-seven patients with PPA and multi-domain Alzheimer's disease (AD) together with 19 age-matched controls underwent a large battery of working memory and language tests. We found that simple tasks of sentence ordering, narrative production, and buccofacial praxis were particularly useful in differentiating non-fluent/agrammatic variant PPA (nfvPPA) from other PPA subtypes, whereas a test of single word comprehension was useful in detecting semantic dementia (SD). No individual tests were discriminating for logopenic variant PPA (lvPPA) relative to nfvPPA. LvPPA and multidomain AD exhibited similar language profiles. A principal components analysis revealed that characteristic PPA profiles extended beyond the realms of language, in particular, the presence of apraxia in nfvPPA, behavioural changes in SD, and working memory deficits in lvPPA. These findings suggest that not all tests are equally discriminatory for PPA and highlight the importance of a test profile in differentiating PPA. These results also support the view that lvPPA is a focal form of AD and emphasize the difficulties classifying lvPPA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jnp.12149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618014PMC
June 2019

The Neuropsychology of Huntington's Disease.

Authors:
Julie S Snowden

Arch Clin Neuropsychol 2017 Nov;32(7):876-887

Greater Manchester Neuroscience Centre, Salford Royal NHS Trust, Salford, UK.

Huntington's disease is an inherited, degenerative brain disease, characterized by involuntary movements, cognitive disorder and neuropsychiatric change. Men and women are affected equally. Symptoms emerge at around 40 years, although there is wide variation. A rare juvenile form has onset in childhood or adolescence. The evolution of disease is insidious and structural and functional brain changes may be present more than a decade before symptoms and signs become manifest. The earliest site of pathology is the striatum and neuroimaging measures of striatal change correlate with neurological and cognitive markers of disease. Chorea and other aspects of the movement disorder are the most visible aspect of the disease. However, non-motor features have greatest affect on functional independence and quality of life, so require recognition and management. The evidence-base for non-pharmacological treatments in Huntington's disease is currently limited, but recent intervention studies are encouraging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/arclin/acx086DOI Listing
November 2017

Semantic dementia and the left and right temporal lobes.

Cortex 2018 10 31;107:188-203. Epub 2017 Aug 31.

Cerebral Function Unit, Greater Manchester Neuroscience Centre, Salford Royal NHS Foundation Trust, Salford, UK.

Semantic dementia, a circumscribed disorder of semantic knowledge, provides a unique model for understanding the neural basis for semantic representation. The study addressed areas of contention: the relative roles of the left and right temporal lobe, the contribution of anterior versus posterior temporal cortex and the status of the anterior temporal lobes as amodal hub. Naming and word comprehension was examined in 41 semantic dementia patients, 31 with left-predominant and 10 right-predominant atrophy. In keeping with expectation, naming and comprehension were significantly poorer in left-predominant patients. Structural magnetic resonance image analysis, using a visual rating scale, showed strong inverse correlations between naming scores and severity of both left anterior and posterior temporal lobe atrophy. By contrast, comprehension performance was more strongly correlated with left posterior temporal atrophy. Analysis of naming errors revealed a correlation between anterior temporal atrophy and associative/functional descriptive responses, implying availability of semantic information. By contrast, 'don't know' responses, indicative of loss of semantic knowledge, were linked to left posterior temporal lobe atrophy. Semantic errors, the hallmark of semantic dementia, were linked to right hemisphere atrophy, especially the right posterior temporal lobe. Matched visual-verbal tasks (famous face and name identification, Pyramids and Palm trees pictures and words, animal knowledge from 3-D models and animal names) administered to nine patients elicited variable correspondence between performance on nonverbal and verbal versions of the task. Marked performance dissociations were demonstrated in some patients: poorer understanding of names/words in left-predominant patients and of faces/pictures/models in right-predominant cases. The findings are compatible with the notion of the anterior temporal lobes as areas of convergence, but are less easily accommodated within the framework of amodal conceptual representation. The data, which reconcile some apparent contradictions in the literature, are discussed in the light of the nature and distribution of degenerative change in semantic dementia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cortex.2017.08.024DOI Listing
October 2018

Differential diagnosis of Alzheimer's disease using spectrochemical analysis of blood.

Proc Natl Acad Sci U S A 2017 09 5;114(38):E7929-E7938. Epub 2017 Sep 5.

School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, United Kingdom;

The progressive aging of the world's population makes a higher prevalence of neurodegenerative diseases inevitable. The necessity for an accurate, but at the same time, inexpensive and minimally invasive, diagnostic test is urgently required, not only to confirm the presence of the disease but also to discriminate between different types of dementia to provide the appropriate management and treatment. In this study, attenuated total reflection FTIR (ATR-FTIR) spectroscopy combined with chemometric techniques were used to analyze blood plasma samples from our cohort. Blood samples are easily collected by conventional venepuncture, permitting repeated measurements from the same individuals to monitor their progression throughout the years or evaluate any tested drugs. We included 549 individuals: 347 with various neurodegenerative diseases and 202 age-matched healthy individuals. Alzheimer's disease (AD; = 164) was identified with 70% sensitivity and specificity, which after the incorporation of apolipoprotein ε4 genotype ( ε4) information, increased to 86% when individuals carried one or two alleles of ε4, and to 72% sensitivity and 77% specificity when individuals did not carry ε4 alleles. Early AD cases ( = 14) were identified with 80% sensitivity and 74% specificity. Segregation of AD from dementia with Lewy bodies (DLB; = 34) was achieved with 90% sensitivity and specificity. Other neurodegenerative diseases, such as frontotemporal dementia (FTD; = 30), Parkinson's disease (PD; = 32), and progressive supranuclear palsy (PSP; = 31), were included in our cohort for diagnostic purposes. Our method allows for both rapid and robust diagnosis of neurodegeneration and segregation between different dementias.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1701517114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617251PMC
September 2017

Metabolic regional and network changes in Alzheimer's disease subtypes.

J Cereb Blood Flow Metab 2018 10 4;38(10):1796-1806. Epub 2017 Jul 4.

2 Division of Neuroscience and Experimental Psychology, University of Manchester, Manchester, UK.

Clinical variants of Alzheimer's disease (AD) include the common amnestic subtype as well as subtypes characterised by leading visual processing impairments or by multimodal neurocognitive deficits. We investigated regional metabolic patterns and networks between AD subtypes. The study comprised 9 age-matched controls and 25 patients with mild to moderate AD. Methods included clinical and neuropsychological assessment, high-resolution FDG PET and T1-weighted 3D MR imaging with PET-MR coregistration, grey matter segmentation, atlas-based regions-of-interest, linear mixed effects and regional correlation analysis. Regional metabolic patterns differed significantly between groups, but significant hypometabolism in the posterior cingulate cortex (PCC) was common to all subtypes. The most distinctive regional abnormality was occipital hypometabolism in the visual subtype. In controls, two large clusters of positive regional metabolic correlations were observed. The most pronounced breakdown of the normal correlation pattern was found in amnestic patients who, in contrast, showed the least regional focal metabolic deficits. The normal positive correlation between PCC and hippocampus was lost in all subtypes. In conclusion, PCC hypometabolism and metabolic correlation breakdown between PCC and hippocampus are the common functional core of all AD subtypes. Network alterations exceed focal regional impairment and are most prominent in the amnestic subtype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0271678X17718436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168902PMC
October 2018

Heterogeneous ribonuclear protein E2 (hnRNP E2) is associated with TDP-43-immunoreactive neurites in Semantic Dementia but not with other TDP-43 pathological subtypes of Frontotemporal Lobar Degeneration.

Acta Neuropathol Commun 2017 06 30;5(1):54. Epub 2017 Jun 30.

Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Salford Royal Hospital, M6 8HD, Salford, UK.

Frontotemporal Lobar Degeneration (FTLD) encompasses certain related neurodegenerative disorders which alter personality and cognition. Heterogeneous ribonuclear proteins (hnRNPs) maintain RNA metabolism and changes in their function may underpin the pathogenesis of FTLD. Immunostaining for hnRNP E2 was performed on sections of frontal and temporal cortex with hippocampus from 80 patients with FTLD, stratified by pathology into FTLD-tau and FTLD-TDP type A, B and C subtypes, and by genetics into patients with C9orf72 expansions, MAPT or GRN mutations, or those with no known mutation, and on 10 healthy controls. Semi-quantitative analysis assessed hnRNP staining in frontal and temporal cortex, and in dentate gyrus (DG) of hippocampus, in the different pathology and genetic groups. We find that hnRNP E2 immunostaining detects the TDP-43 positive dystrophic neurites (DN) within frontal and temporal cortex, and the neuronal cytoplasmic inclusions (NCI) seen in DG granule cells, characteristic of patients with Semantic Dementia (SD) and type C TDP-43 pathology, but did not detect TDP-43 or tau inclusions in any of the other pathological or genetic variants of FTLD. Double immunofluorescence for hnRNP E2 and TDP-43 showed most TDP-43 immunopositive DN to contain hnRNP E2. Present findings indicate an association between TDP-43 and hnRNP E2 which might underlie the pathogenetic mechanism of this form of FTLD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40478-017-0454-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493127PMC
June 2017

Examining the language and behavioural profile in FTD and ALS-FTD.

J Neurol Neurosurg Psychiatry 2017 08 8;88(8):675-680. Epub 2017 Jun 8.

Manchester Academic Health Sciences Centre, Cerebral Function Unit, Greater Manchester Neuroscience Centre, Salford Royal NHS Foundation Trust, Salford, UK.

Background: A proportion of patients with behavioural variant frontotemporal dementia (bvFTD) develop amyotrophic lateral sclerosis (ALS). It is currently unknown whether the behavioural and cognitive syndrome in bvFTD with ALS (ALS-FTD) is indistinguishable from that of bvFTD alone.

Methods: A retrospective cohort of 241 patients with clinical diagnoses of bvFTD (n=185) or ALS-FTD (n=56) was examined with respect to behavioural, cognitive and neuropsychiatric symptoms. Features were rated as present or absent based on information recorded from clinical interviews and detailed neuropsychological assessment.

Results: A number of behavioural and affective changes were reported more frequently in bvFTD than ALS-FTD: social disinhibition (p<0.001), inertia (p<0.001), loss of sympathy and empathy (p0.008), repetitive behaviours (p<0.001) and dietary changes (p<0.001). Warmth of affect demonstrated in the clinic setting was reported more often in ALS-FTD than bvFTD (p<0.001). Executive impairments occurred equally in both groups. Language impairments were more common in ALS-FTD than bvFTD: agrammatism (p<0.017) and impaired sentence comprehension (p<0.036). Psychotic features were relatively rare and did not distinguish the groups.

Conclusions: Our findings suggest differences between bvFTD and ALS-FTD. In particular, while changes in social behaviour are prominent in bvFTD alone, there may be a comparatively greater degree of language impairment in ALS-FTD. Prospective exploration of the pattern of differences between these groups will be essential. Identification of a distinct neuropsychological phenotype in ALS-FTD may have clinical implications for early diagnosis, disease management and care planning and theoretical implications for our understanding of the relationship between ALS and FTD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jnnp-2017-315667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537548PMC
August 2017

Semantic dementia, progressive non-fluent aphasia and their association with amyotrophic lateral sclerosis.

J Neurol Neurosurg Psychiatry 2017 08 29;88(8):711-712. Epub 2017 May 29.

Cerebral Function Unit, Manchester Academic Health Sciences Centre, Greater Manchester Neuroscience Centre, Salford Royal NHS Foundation Trust, Salford, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jnnp-2016-314912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537533PMC
August 2017

Heterogeneous ribonuclear protein A3 (hnRNP A3) is present in dipeptide repeat protein containing inclusions in Frontotemporal Lobar Degeneration and Motor Neurone disease associated with expansions in C9orf72 gene.

Acta Neuropathol Commun 2017 04 21;5(1):31. Epub 2017 Apr 21.

Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Salford Royal Hospital, Salford, M6 8HD, UK.

Frontotemporal Lobar Degeneration (FTLD) encompasses certain related neurodegenerative disorders which alter behaviour, personality and language. Heterogeneous ribonuclear proteins (hnRNPs) maintain RNA metabolism and changes in their function may underpin the pathogenesis of FTLD. Immunostaining for hnRNP A1, A2/B1 and A3 was performed on sections of temporal cortex with hippocampus from 61 patients with FTLD, stratified by pathological hallmarks into FTLD-tau and FTLD-TDP type A, B and C subtypes, and by genetics into patients with C9orf72 expansions, MAPT or GRN mutations, or those without known mutation. Four patients with Motor Neurone Disease (MND) with C9orf72 expansions and 10 healthy controls were also studied. Semi-quantitative analysis assessed hnRNP staining intensity in dentate gyrus (DG) and CA4 region of hippocampus, and temporal cortex (Tcx) in the different pathological and genetic groups.Immunostaining for hnRNP A1, A2/B1 and A3 revealed no consistent changes in pattern or amount of physiological staining across any of the pathological or genetic groups. No immunostaining of any inclusions resembling TDP-43 immunoreactive neuronal cytoplasmic inclusions or dystrophic neurites, was seen in either Tcx or DG of the hippocampus in any of the FTLD cases investigated for hnRNP A1, A2/B1 and A3. However, immunostaining for hnRNP A3 showed that inclusion bodies, resembling those TDP-43 negative, p62-immunopositive structures containing dipeptide repeat proteins (DPR) were variably observed in hippocampus and cerebellum. The proportion of cases showing hnRNP A3-immunoreactive DPR, and the number of hnRNP A3-positive inclusions within cases, was significantly greater in DG than in cells of CA4 region and cerebellum, but the latter was significantly less in all three regions compared to that detected by p62 immunostaining.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40478-017-0437-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399321PMC
April 2017

Functional neuroanatomical associations of working memory in early-onset Alzheimer's disease.

Int J Geriatr Psychiatry 2018 Jan 16;33(1):176-184. Epub 2017 Mar 16.

Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

Objective: To characterize metabolic correlates of working memory impairment in clinically defined subtypes of early-onset Alzheimer's disease.

Background: Established models of working memory suggest a key role for frontal lobe function, yet the association in Alzheimer's disease between working memory impairment and visuospatial and language symptoms suggests that temporoparietal neocortical dysfunction may be responsible.

Methods: Twenty-four patients with predominantly early-onset Alzheimer's disease were clinically classified into groups with predominantly amnestic, multidomain or visual deficits. Patients underwent neuropsychological evaluation focused on the domains of episodic and working memory, T1-weighted magnetic resonance imaging and brain fluorodeoxyglucose positron emission tomography. Fluorodeoxyglucose positron emission tomography data were analysed by using a region-of-interest approach.

Results: Patients with multidomain and visual presentations performed more poorly on tests of working memory compared with amnestic Alzheimer's disease. Working memory performance correlated with glucose metabolism in left-sided temporoparietal, but not frontal neocortex. Carriers of the apolipoprotein E4 gene showed poorer episodic memory and better working memory performance compared with noncarriers.

Conclusions: Our findings support the hypothesis that working memory changes in early-onset Alzheimer's disease are related to temporoparietal rather than frontal hypometabolism and show dissociation from episodic memory performance. They further support the concept of subtypes of Alzheimer's disease with distinct cognitive profiles due to prominent neocortical dysfunction early in the disease course. Copyright © 2017 John Wiley & Sons, Ltd.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gps.4703DOI Listing
January 2018

Consensus classification of posterior cortical atrophy.

Alzheimers Dement 2017 Aug 2;13(8):870-884. Epub 2017 Mar 2.

Dementia Research Centre, UCL Institute of Neurology, London, UK.

Introduction: A classification framework for posterior cortical atrophy (PCA) is proposed to improve the uniformity of definition of the syndrome in a variety of research settings.

Methods: Consensus statements about PCA were developed through a detailed literature review, the formation of an international multidisciplinary working party which convened on four occasions, and a Web-based quantitative survey regarding symptom frequency and the conceptualization of PCA.

Results: A three-level classification framework for PCA is described comprising both syndrome- and disease-level descriptions. Classification level 1 (PCA) defines the core clinical, cognitive, and neuroimaging features and exclusion criteria of the clinico-radiological syndrome. Classification level 2 (PCA-pure, PCA-plus) establishes whether, in addition to the core PCA syndrome, the core features of any other neurodegenerative syndromes are present. Classification level 3 (PCA attributable to AD [PCA-AD], Lewy body disease [PCA-LBD], corticobasal degeneration [PCA-CBD], prion disease [PCA-prion]) provides a more formal determination of the underlying cause of the PCA syndrome, based on available pathophysiological biomarker evidence. The issue of additional syndrome-level descriptors is discussed in relation to the challenges of defining stages of syndrome severity and characterizing phenotypic heterogeneity within the PCA spectrum.

Discussion: There was strong agreement regarding the definition of the core clinico-radiological syndrome, meaning that the current consensus statement should be regarded as a refinement, development, and extension of previous single-center PCA criteria rather than any wholesale alteration or redescription of the syndrome. The framework and terminology may facilitate the interpretation of research data across studies, be applicable across a broad range of research scenarios (e.g., behavioral interventions, pharmacological trials), and provide a foundation for future collaborative work.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jalz.2017.01.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788455PMC
August 2017

Frontotemporal lobar degeneration: Pathogenesis, pathology and pathways to phenotype.

Brain Pathol 2017 11 2;27(6):723-736. Epub 2017 Mar 2.

Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Medical and Human Sciences, University of Manchester, Salford Royal Hospital, Salford, M6 8HD, UK.

Frontotemporal Lobar Degeneration (FTLD) is a clinically, pathologically and genetically heterogeneous group of disorders that affect principally the frontal and temporal lobes of the brain. There are three major associated clinical syndromes, behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD) and progressive non-fluent aphasia (PNFA); three principal histologies, involving tau, TDP-43 and FUS proteins; and mutations in three major genes, MAPT, GRN and C9orf72, along with several other less common gene mutations. All three clinical syndromes can exist separately or in combination with Amyotrophic Lateral Sclerosis (ALS). SD is exclusively a TDP-43 proteinopathy, and PNFA may be so, with both showing tight clinical, histological and genetic inter-relationships. bvFTD is more of a challenge with overlapping histological and genetic features, involvement of any of the three aggregating proteins, and changes in any of the three major genes. However, when ALS is present, all cases show a clear histological phenotype with TDP-43 aggregated proteins, and familial forms are associated with expansions in C9orf72. TDP-43 and FUS are nuclear carrier proteins involved in the regulation of RNA metabolism, whereas tau protein - the product of MAPT - is responsible for the assembly/disassembly of microtubules, which are vital for intracellular transport. Mutations in TDP-43 and FUS genes are linked to clinical ALS rather than FTLD (with or without ALS), suggesting that clinical ALS may be a disorder of RNA metabolism. Conversely, the protein products of GRN and C9orf72, along with those of the other minor genes, appear to form part of the cellular protein degradation machinery. It is possible therefore that FTLD is a reflection of dysfunction within lysosomal/proteasomal systems resulting in failure to remove potentially neurotoxic (TDP-43 and tau) aggregates, which ultimately overwhelm capacity to function. Spread of aggregates along distinct pathways may account for the different clinical phenotypes, and patterns of progression of disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bpa.12486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8029341PMC
November 2017

Co-Occurrence of Language and Behavioural Change in Frontotemporal Lobar Degeneration.

Dement Geriatr Cogn Dis Extra 2016 May-Aug;6(2):205-13. Epub 2016 Jun 1.

Manchester Academic Health Sciences Centre, Cerebral Function Unit, Greater Manchester Neuroscience Centre, Salford Royal NHS Foundation Trust, Salford, Manchester, UK; Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, UK.

Background/objectives: We aimed to evaluate the co-occurrence of language and behavioural impairment in patients with frontotemporal lobar degeneration (FTLD) spectrum pathology.

Methods: Eighty-one dementia patients with pathological confirmation of FTLD were identified. Anonymized clinical records from patients' first assessment were rated for language and behavioural features from frontotemporal dementia consensus criteria, primary progressive aphasia (PPA) criteria and 1998 FTLD criteria.

Results: Over 90% of patients with FTLD pathology exhibited a combination of at least one behavioural and one language feature. Changes in language, in particular, were commonly accompanied by behavioural change. Notably, the majority of patients who displayed language features characteristic of semantic variant PPA exhibited 'early perseverative, stereotyped or compulsive/ritualistic behaviour'. Moreover, 'executive/generation deficits with relative sparing of memory and visuospatial functions' occurred in most patients with core features of non-fluent variant PPA.

Conclusion: Behavioural and language symptoms frequently co-occur in patients with FTLD pathology. Current classifications, which separate behavioural and language syndromes, do not reflect this co-occurrence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000444848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913762PMC
June 2016

Pathological tau deposition in Motor Neurone Disease and frontotemporal lobar degeneration associated with TDP-43 proteinopathy.

Acta Neuropathol Commun 2016 Mar 31;4:33. Epub 2016 Mar 31.

Clinical and Cognitive Sciences Research Group, Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Salford Royal Hospital, Salford, M6 8HD, UK.

It has been suggested that patients with motor neurone disease (MND) and those with MND combined with behavioural variant frontotemporal dementia (bvFTD) (ie FTD + MND) or with FTD alone might exist on a continuum based on commonalities of neuropathology and/or genetic risk. Moreover, it has been reported that both a neuronal and a glial cell tauopathy can accompany the TDP-43 proteinopathy in patients with motor neurone disease (MND) with cognitive changes, and that the tauopathy may be fundamental to disease pathogenesis and clinical phenotype. In the present study, we sought to substantiate these latter findings, and test this concept of a pathological continuum, in a consecutive series of 41 patients with MND, 16 with FTD + MND and 23 with FTD without MND. Paraffin sections of frontal, entorhinal, temporal and occipital cortex and hippocampus were immunostained for tau pathology using anti-tau antibodies, AT8, pThr(175) and pThr(217), and for amyloid β protein (Aβ) using 4G8 antibody. Twenty four (59 %) patients with MND, 7 (44 %) patients with FTD + MND and 10 (43 %) patients with FTD showed 'significant' tau pathology (ie more than just an isolated neurofibrillary tangle or a few neuropil threads in one or more brain regions examined). In most instances, this bore the histological characteristics of an Alzheimer's disease process involving entorhinal cortex, hippocampus, temporal cortex, frontal cortex and occipital cortex in decreasing frequency, accompanied by a deposition of Aβ up to Thal phase 3, though 2 patients with MND, and 1 with FTD did show tau pathology beyond Braak stage III. Four other patients with MND showed novel neuronal tau pathology, within the frontal cortex alone, specifically detected by pThr(175) antibody, which was characterised by a fine granular or more clumped aggregation of tau without neurofibrillary tangles or neuropil threads. However, none of these 4 patients had clinically evident cognitive disorder, and this type of tau pathology was not seen in any of the FTD + MND or FTD patients. Finally, two patients, one with MND and one with FTD, showed a tau pathology consistent with Argyrophilic Grain Disease (AGD). Western blotting and use of 3- and 4-repeat tau antibodies confirmed the histological interpretation of Alzheimer's disease type pathology in all instances except for those patients with accompanying AGD where a banding pattern on western blot, and immunohistochemistry, confirmed 4-repeat tauopathy. In all 3 patient groups, amyloid pathology was more likely to be present in patients dying after 65 years of age, and in the presence of APOE ε4 allele. We conclude that tau pathological changes are equally common amongst patients with MND, FTD + MND and FTD though, in most instances, these are limited in extent. In patients with MND, when cognitive impairment is present this is most likely due to an accompanying/evolving (coincidental) Alzheimer's disease process or, as in a single case, Dementia with Lewy bodies, within the cerebral cortex rather than as a result of TDP-43 proteinopathy. Conversely, in FTD and FTD + MND dementia is more likely to be associated with TDP-43 proteinopathy than tau. Hence, present study shows no progression in severity of (tau) pathology from MND through FTD + MND to FTD, and does not support the concept of these conditions forming a continuum of clinical or pathological change.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40478-016-0301-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4818389PMC
March 2016

Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease.

Alzheimers Dement 2016 08 15;12(8):862-71. Epub 2016 Mar 15.

Centre des Maladies Cognitives et Comportementales, IM2A, ICM, Paris 6 University, France.

Introduction: The genetics underlying posterior cortical atrophy (PCA), typically a rare variant of Alzheimer's disease (AD), remain uncertain.

Methods: We genotyped 302 PCA patients from 11 centers, calculated risk at 24 loci for AD/DLB and performed an exploratory genome-wide association study.

Results: We confirm that variation in/near APOE/TOMM40 (P = 6 × 10(-14)) alters PCA risk, but with smaller effect than for typical AD (PCA: odds ratio [OR] = 2.03, typical AD: OR = 2.83, P = .0007). We found evidence for risk in/near CR1 (P = 7 × 10(-4)), ABCA7 (P = .02) and BIN1 (P = .04). ORs at variants near INPP5D and NME8 did not overlap between PCA and typical AD. Exploratory genome-wide association studies confirmed APOE and identified three novel loci: rs76854344 near CNTNAP5 (P = 8 × 10(-10) OR = 1.9 [1.5-2.3]); rs72907046 near FAM46A (P = 1 × 10(-9) OR = 3.2 [2.1-4.9]); and rs2525776 near SEMA3C (P = 1 × 10(-8), OR = 3.3 [2.1-5.1]).

Discussion: We provide evidence for genetic risk factors specifically related to PCA. We identify three candidate loci that, if replicated, may provide insights into selective vulnerability and phenotypic diversity in AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jalz.2016.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4982482PMC
August 2016

Distinct clinical and pathological phenotypes in frontotemporal dementia associated with MAPT, PGRN and C9orf72 mutations.

Amyotroph Lateral Scler Frontotemporal Degener 2015 16;16(7-8):497-505. Epub 2015 Oct 16.

b Institute of Brain, Behaviour and Mental Health, Faculty of Human and Medical Sciences, University of Manchester , Manchester , UK.

Our objective was to compare the clinical and pathological characteristics of frontotemporal dementia patients with MAPT, GRN and C9orf72 gene mutations. We carried out a cross-sectional comparative study of 74 gene-positive patients (15 MAPT, 17 GRN and 42 C9orf72). Thirty had post mortem pathological data permitting clinico-pathological correlation. MAPT patients were younger than other groups, and showed more frequent behavioural disinhibition, repetitive and stereotyped behaviours, semantic impairment and temporal predominance of atrophy. GRN patients were older at death and more likely to present with non-fluent aphasia. C9orf72 patients alone showed a co-occurrence of ALS. They showed more psychotic symptoms and irrational behaviour, yet were more often reported clinically as socially appropriate and warm. They showed less dietary change than other groups. C9orf72 patients with and without ALS differed only in frequency of psychosis. Greater clinical overlap was observed between GRN and C9orf72 compared to MAPT cases. MAPT cases had tau and GRN and C9orf72, with one exception, TDP-43 pathology. Non-fluent aphasia was linked to TDP subtype A in both GRN and C9orf72 cases and ALS with subtype B. In conclusion, the findings reinforce clinical heterogeneity in FTD and strengthen evidence that genotype influences clinical presentation. Clinical features may inform targeted genetic testing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/21678421.2015.1074700DOI Listing
August 2016

Left hand dystonia as a recurring feature of a family carrying C9ORF72 mutation.

J Neurol Neurosurg Psychiatry 2016 07 17;87(7):793-5. Epub 2015 Jul 17.

Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jnnp-2015-311311DOI Listing
July 2016
-->