We performed a clinicopathological study to assess the burden of small vessel disease (SVD) type of pathological changes in elderly demented subjects, who had clinical evidence of autonomic dysfunction, either carotid sinus hypersensitivity or orthostatic hypotension or both or had exhibited unexpected repeated falls. Clinical and neuropathological diagnoses in 112 demented subjects comprised dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), Alzheimer's disease (AD), Mixed dementia (mostly AD‐DLB) and vascular dementia (VaD). Of these, 12 DLB subjects had no recorded unexpected falls in life and therefore no evidence of concomitant autonomic dysfunction. A further 17 subjects were assessed as aging controls without significant pathology or signs of autonomic dysfunction. We quantified brain vascular pathological changes and determined severities of neurodegenerative lesions including α‐synuclein pathology. We found moderate‐severe vascular changes and high‐vascular pathology scores ( P < 0.01) in all neurodegenerative dementias and as expected in VaD compared to similar age controls. Arteriolosclerosis, perivascular spacing and microinfarcts were frequent in the basal ganglia and frontal white matter (WM) across all dementias, whereas small infarcts (<5 mm) were restricted to VaD. In a sub‐set of demented subjects, we found that vascular pathology scores were correlated with WM hyperintensity volumes determined by MRI in life ( P < 0.02). Sclerotic index values were increased by ~50% in both the WM and neocortex in all dementias compared to similar age controls. We found no evidence for increased α‐synuclein deposition in subjects with autonomic dysfunction. Our findings suggest greater SVD pathological changes occur in the elderly diagnosed with neurodegenerative dementias including DLB and who develop autonomic dysfunction. SVD changes may not necessarily manifest in clinically overt symptoms but they likely confound motor or cognitive dysfunction. We propose dysautonomia promotes chronic cerebral hypoperfusion to impact upon aging‐related neurodegenerative disorders and characterize their end‐stage clinical syndromes.

Our hypothesis is that changes in gene and protein expression are crucial to the development of late-onset Alzheimer&rsquo;s disease. Previously we examined how DNA alleles control downstream expression of RNA transcripts and how those relationships are changed in late-onset Alzheimer&rsquo;s disease. We have now examined how proteins are incorporated into networks in two separate series and evaluated our outputs in two different cell lines. Our pipeline included the following steps: (i) predicting expression quantitative trait loci; (ii) determining differential expression; (iii) analysing networks of transcript and peptide relationships; and (iv) validating effects in two separate cell lines. We performed all our analysis in two separate brain series to validate effects. Our two series included 345 samples in the first set (177 controls, 168 cases; age range 65&ndash;105; 58&percnt; female; KRONOSII cohort) and 409 samples in the replicate set (153 controls, 141 cases, 115 mild cognitive impairment; age range 66&ndash;107; 63&percnt; female; RUSH cohort). Our top target is heat shock protein family A member 2 (HSPA2), which was identified as a key driver in our two datasets. HSPA2 was validated in two cell lines, with overexpression driving further elevation of amyloid-&beta;40 and amyloid-&beta;42 levels in APP mutant cells, as well as significant elevation of microtubule associated protein tau and phosphorylated-tau in a modified neuroglioma line. This work further demonstrates that studying changes in gene and protein expression is crucial to understanding late onset disease and further nominates HSPA2 as a specific key regulator of late-onset Alzheimer&rsquo;s disease processes.10.1093/brain/awy215_video1awy215media15824729224001.

The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.

AimsFrontotemporal lobar degeneration (FTLD) and motor neurone disease are linked by the possession of a hexanucleotide repeat expansion in C9ORF72, and both show neuronal cytoplasmic inclusions within cerebellar and hippocampal neurones which are TDP-43 negative but immunoreactive for p62 and dipeptide repeat proteins (DPR), these being generated by a non-ATG RAN translation of the expanded region of the gene.MethodsTwenty-two cases of FTLD from Newcastle were analysed for an expansion in C9ORF72 by repeat primed PCR and Southern blot. Detailed case note analysis was performed, and blinded retrospective clinical impressions were achieved by review of clinical histories. Sections from all major brain regions were immunostained for TDP-43, p62 and DPR. The extent of TDP-43 and DPR pathology in expansion bearers was compared with that in 13 other previously identified cases from the Manchester Brain Bank with established disease.ResultsThree Newcastle patients bearing an expansion in C9ORF72 were identified. These three patients died prematurely, two from bronchopneumonia within 10 months and 3 years of onset, and one from myocardial infarction 3 years after onset. In all three, DPR were plentiful throughout all cerebral cortical regions, hippocampus and cerebellum, but TDP-43 pathological changes were sparse. The severity of DPR pathological changes in these three patients was similar to that in the Manchester series, although the extent of TDP-43 pathology was significantly less.ConclusionWidespread accumulation of DPR within nerve cells may occur much earlier than that of TDP-43 in patients with FTLD bearing expansion in C9ORF72.

Objective: To investigate whether an increasing load of β-amyloid and/or neuritic plaques influences the phenotype, and thus the clinical diagnostic accuracy, of dementia with Lewy bodies (DLB). Methods: A series of 64 subjects with autopsy-proven DLB was studied. Last diagnosis before death was used to determine the clinical diagnostic accuracy of DLB in relation to Lewy body distribution and extent of Alzheimer β-amyloid and/or neuritic pathology. DLB pathologic diagnosis was made according to consensus criteria, using α-synuclein immunostaining for Lewy body identification. β-Amyloid immunostaining was used for quantifying β-amyloid deposits. The Consortium to Establish a Registry for Alzheimer's Disease criteria and Braak stage were applied for semiquantitative grading of neuritic plaque and neurofibrillary tangle pathology. Results: Overall clinical diagnostic accuracy for the entire DLB cohort was high (80%), reflecting the high prevalence of core clinical features (fluctuations [81%], parkinsonism [77%], visual hallucinations [70%]). Lower frequencies of core clinical features of DLB, resulting in lower accuracy of its clinical diagnosis, were associated with decreasing Lewy body distribution (p < 0.0001) and with increasing neuritic plaque pathology (p = 0.035), but not with the number of β-amyloid plaque deposits. Conclusions: The likelihood of occurrence of the DLB clinical syndrome is positively related to the extent of Lewy body pathology and negatively related to the severity of Alzheimer neuritic pathology, while β-amyloid load has no effect.

Y. S. Davidson, A. C. Robinson, Q. Hu, M. Mishra, A. Baborie, E. Jaros, R. H. Perry, N. J. Cairns, A. Richardson, A. Gerhard, D. Neary, J. S. Snowden, E. H. Bigio and D. M. A. Mann (2013) Neuropathology and Applied Neurobiology39, 157–165

The objective of this study was to determine the neuropathological correlates of regional medial temporal lobe volume measures on magnetic resonance imaging (MRI) in subjects with Lewy body dementia (LBD). Twenty-three autopsy-confirmed LBD cases with an MRI scan close to death (mean 1.5 years) were studied. MRI-based volumetric measures were calculated for total intracranial volume, hippocampus, entorhinal cortex, and amygdala. Quantitative neuropathological analysis of plaques, tangles, and Lewy bodies were carried out in the same regions. Spearman's rho was used to examine correlations between MRI volumes and neuropathology measures and linear regression to assess the relationship between neuropathology and MRI volumes. A significant inverse correlation was observed between normalized amygdala volume and percent area of Lewy bodies in the amygdala (r = −0.461, p = 0.035). There were no other significant correlations between regional MRI volume and measures of neuropathology. Lewy body, but not Alzheimer's disease (AD) pathology was associated with reduced amygdala volume in pathologically-verified LBD cases but neither Lewy body nor Alzheimer's disease pathology was associated with volume loss in the hippocampus or entorhinal cortex, suggesting other neuropathological factors account for atrophy in these structures in LBD.

Objective: Most pathologic studies indicate that significant vascular changes are found in the majority of elderly persons, either alone or in association with neurodegenerative processes such as Alzheimer disease (AD) or dementia with Lewy bodies (DLB). Cumulative burden of cerebrovascular lesions can explain cognitive decline described as vascular cognitive impairment, but because there is a lack of consensus in the best way to quantify vascular pathology, the relationship between cognitive decline and cerebrovascular disease remains uncertain. We developed a rating scheme for cerebrovascular lesions using postmortem brains from patients with dementia from 2 European tertiary care memory clinics.Methods: A total of 135 brains with a neuropathologic diagnosis of vascular dementia (VaD) (n = 26), AD + VaD (n = 39), DLB + VaD (n = 21), AD + DLB + VaD (n = 9), AD (n = 19), and DLB (n = 21) were investigated in this study. Cerebrovascular lesions were rated on large sections from the hippocampus, the temporal lobe, the frontal lobe, and basal ganglia.Results: In patients with dementia, vessel wall modifications such as arteriolosclerosis or amyloid angiopathy are the most common and presumably the earliest changes. Modifications in perivascular spaces and myelin loss are the next most common. Lacunar or regional infarcts may occur as a consequence of an independent process or in the final phase of small vessel diseases.Conclusion: A staging system based on this conceptual model of cerebrovascular pathology could enable the neuropathologic quantification of the cerebrovascular burden in dementia. Further studies are needed to determine whether this system can be used in large-scale studies to understand clinical-cerebrovascular pathologic correlations. Neurology (R) 2012;78:1043-1050

Neurogenesis occurs in the subventricular zone and the sub-granular layer of the hippocampus and is thought to take place in 5 stages, including proliferation, differentiation, migration, targeting, and integration phases, respectively. In Alzheimer's disease (AD) both increased and decreased neurogenesis has been reported and cholinergic activity is assumed to be involved in neurogenesis. The aim of this study was to systematically assess different phases of neurogenesis and their relation to AD and cholinergic pathology.We investigated post-mortem brain tissue from 20 AD patients and 21 non-demented controls that was neuropathologically characterized according to standardized criteria. Hippocampal sections were stained with antibodies against neurogenic markers Musashi-1, nestin, PSA-NCAM, doublecortin, and β-III-tubulin as well as ChAT (choline-acetyltransferase). Using image analysis immunoreactivity was assessed in the subventricular zone, the sub-granular layer, and the granule cell layer by determining the integrated optical density.In the sub-granular layer and the granule cell layer Musashi-1 and ChAT immunoreactivities were significantly lower in AD and decreased with increasing Braak stages. Conversely, immunorreactivities of both nestin and PSA-NCAM were significantly higher in AD and increased with increasing Braak stages while no changes were seen for doublecortin and β-III-tubulin, except for significantly higher doublecortin levels in the granule cell layer of AD cases. Of note, Musashi-1 immunoreactivity significantly correlated with ChAT immuonoreactivity across different Braak stages. In the subventricular zone only nestin immunoreactivity was significantly higher in AD and significantly increased with increasing Braak stages, while no significant differences were seen for all other markers.Our finding of a reduction of ChAT and Musashi-1 levels in AD is compatible with the assumption that cholinergic pathology per se has a detrimental influence on neurogenesis. We conclude that neurogenic abnormalities in AD differ between phases and areas of neurogenesis and stages of AD; while hippocampal stem cells (Musashi-1) decrease, proliferation (nestin) increases and differentiation/migration phase as well as axonal/dendritic targeting (doublecortin and β-III-tubulin) remains virtually unchanged. This suggests an attenuation of stem cells together with compensatory increased proliferation that, however, does not result in an increased number of migratory neuroblasts and differentiated neurons in AD.

Neuropathology and Applied NeurobiologyVolume 38, Issue 5 p. 505-508 Atheromatous disease in small intracerebral vessels, microinfarcts and dementia R. N. Kalaria, R. N. Kalaria Centre for Brain Ageing and Vitality, Institute for Ageing and Health, Newcastle University, Campus for Ageing & VitalitySearch for more papers by this authorR. H. Perry, R. H. Perry Centre for Brain Ageing and Vitality, Institute for Ageing and Health, Newcastle University, Campus for Ageing & VitalitySearch for more papers by this authorJ. O'Brien, J. O'Brien Centre for Brain Ageing and Vitality, Institute for Ageing and Health, Newcastle University, Campus for Ageing & VitalitySearch for more papers by this authorE. Jaros, E. Jaros Centre for Brain Ageing and Vitality, Institute for Ageing and Health, Newcastle University, Campus for Ageing & Vitality Neuropathology/Cellular Pathology, Royal Victoria Infirmary, Newcastle upon Tyne, UKSearch for more papers by this author R. N. Kalaria, R. N. Kalaria Centre for Brain Ageing and Vitality, Institute for Ageing and Health, Newcastle University, Campus for Ageing & VitalitySearch for more papers by this authorR. H. Perry, R. H. Perry Centre for Brain Ageing and Vitality, Institute for Ageing and Health, Newcastle University, Campus for Ageing & VitalitySearch for more papers by this authorJ. O'Brien, J. O'Brien Centre for Brain Ageing and Vitality, Institute for Ageing and Health, Newcastle University, Campus for Ageing & VitalitySearch for more papers by this authorE. Jaros, E. Jaros Centre for Brain Ageing and Vitality, Institute for Ageing and Health, Newcastle University, Campus for Ageing & Vitality Neuropathology/Cellular Pathology, Royal Victoria Infirmary, Newcastle upon Tyne, UKSearch for more papers by this author First published: 29 February 2012 https://doi.org/10.1111/j.1365-2990.2012.01264.xCitations: 17Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume38, Issue5August 2012Pages 505-508 RelatedInformation

Neuropathology and Applied NeurobiologyVolume 38, Issue 1 p. 101-104 Frontotemporal lobar degeneration in a very young patient is associated with fused in sarcoma (FUS) pathological changes A. Baborie, A. Baborie Department of Neuropathology, Walton Centre for Neurology and Neurosurgery, LiverpoolSearch for more papers by this authorE. Jaros, E. Jaros Neuropathology/Cellular Pathology, Royal Victoria Infirmary Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Hospitals NHS Foundation TrustSearch for more papers by this authorT. D. Griffiths, T. D. Griffiths Cognitive Neurology Clinic, Newcastle General Hospital and Newcastle University, Newcastle upon TyneSearch for more papers by this authorP. Momeni, P. Momeni Department of Internal Medicine 4C101/4C160/4C127, Texas Tech University Health Sciences Center, Lubbock, TX, USASearch for more papers by this authorR. Perry, R. Perry Institute for Ageing and Health, Newcastle University, Campus for Ageing and VitalitySearch for more papers by this authorD. M. A. Mann, D. M. A. Mann Neurodegeneration and Mental Health Research Group, Greater Manchester Neurosciences Centre, University of Manchester, Salford, UKSearch for more papers by this author A. Baborie, A. Baborie Department of Neuropathology, Walton Centre for Neurology and Neurosurgery, LiverpoolSearch for more papers by this authorE. Jaros, E. Jaros Neuropathology/Cellular Pathology, Royal Victoria Infirmary Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Hospitals NHS Foundation TrustSearch for more papers by this authorT. D. Griffiths, T. D. Griffiths Cognitive Neurology Clinic, Newcastle General Hospital and Newcastle University, Newcastle upon TyneSearch for more papers by this authorP. Momeni, P. Momeni Department of Internal Medicine 4C101/4C160/4C127, Texas Tech University Health Sciences Center, Lubbock, TX, USASearch for more papers by this authorR. Perry, R. Perry Institute for Ageing and Health, Newcastle University, Campus for Ageing and VitalitySearch for more papers by this authorD. M. A. Mann, D. M. A. Mann Neurodegeneration and Mental Health Research Group, Greater Manchester Neurosciences Centre, University of Manchester, Salford, UKSearch for more papers by this author First published: 05 July 2011 https://doi.org/10.1111/j.1365-2990.2011.01209.xCitations: 3Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1 Stone J, Griffiths TD, Rastogi S, Perry RH, Cleland PG. Non-Picks frontotemporal dementia imitating schizophrenia in a 22-year-old man. J Neurol 2003; 250: 369–70 2 Mackenzie IR, Baborie A, Pickering-Brown S, Du Plessis D, Jaros E, Perry RH, Neary D, Snowden JS, Mann DM. Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype. Acta Neuropathol (Berl) 2006; 112: 539–49 3 Blatt GJ, Rosene DL. Organization of direct hippocampal efferent projections to the cerebral cortex of the rhesus monkey: projections from CA1, prosubiculum, and subiculum to the temporal lobe. J Comp Neurol 1998; 392: 92–114 4 Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J, Kovacs GG, Ghetti B, Halliday G, Holm IE, Ince PG, Kamphorst W, Revesz T, Rozemuller AJ, Kumar-Singh S, Akiyama H, Baborie A, Spina S, Dickson DW, Trojanowski JQ, Mann DM. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol (Berl) 2010; 119: 1–4 5 Mackenzie IRA, Foti D, Woulfe J, Hurwitz TA. Atypical frontotemporal lobar degeneration with ubiquitin-positive, TDP-43-negative neuronal inclusions. Brain 2008; 131: 1282–93 6 Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, Mackenzie IR. A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 2009; 132: 2922–31 7 Urwin H, Josephs KA, Rohrer JD, Mackenzie IR, Neumann M, Authier A, Seelaar H, Van Swieten JC, Brown JM, Johannsen P, Nielsen JE, Holm IE, FReJA Consortium, Dickson DW, Rademakers R, Graff-Radford NR, Parisi JE, Petersen RC, Hatanpaa KJ, White CL 3rd, Weiner MF, Geser F, Van Deerlin VM, Trojanowski JQ, Miller BL, Seeley WW, van der Zee J, Kumar-Singh S, Engelborghs S, De Deyn PP, Van Broeckhoven C, Bigio EH, Deng HX, Halliday GM, Kril JJ, Munoz DG, Mann DM, Pickering-Brown SM, Doodeman V, Adamson G, Ghazi-Noori S, Fisher EM, Holton JL, Revesz T, Rossor MN, Collinge J, Mead S, Isaacs AM. FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration. Acta Neuropathol (Berl) 2010; 120: 33–41 8 Seelaar H, Klijnsma KY, de Koning I, van der Lugt A, Chiu WZ, Azmani A, Rozemuller AJ, van Swieten JC. Frequency of ubiquitin and FUS-positive, TDP-43-negative frontotemporal lobar degeneration. J Neurol 2010; 257: 747–53 9 Menon R, Baborie A, Jaros E, Mann DM, Ray PS, Larner AJ. What's in a name? Neuronal intermediate filament inclusion disease (NIFID), frontotemporal lobar degeneration-intermediate filament (FTLD-IF) or frontotemporal lobar degeneration-fused in sarcoma (FTLD-FUS)? J Neurol Neurosurg Psychiatry 2010. Online First: 8 November 2010. doi: 10.1136/jnnp.2010.220947 10 Baborie A, Griffiths TD, Jaros E, McKeith IG, Burn DJ, Richardson A, Ferrari R, Moreno J, Momeni P, Duplessis D, Pal P, Rollinson S, Pickering-Brown S, Thompson JC, Neary D, Snowden JS, Perry R, Mann DM. Pathological correlates of frontotemporal lobar degeneration in the elderly. Acta Neuropathol (Berl) 2010; 121: 365–71 11 Huey ED, Putnam KT, Grafman J. A systematic review of neurotransmitter deficits and treatments in frontotemporal dementia. Neurology 2006; 66: 17–22 12 Cairns NJ, Grossman M, Arnold SE, Burn DJ, Jaros E, Perry RH, Duyckaerts C, Stankoff B, Pillon B, Skullerud K, Cruz-Sanchez FF, Bigio EH, Mackenzie IR, Gearing M, Juncos JL, Glass JD, Yokoo H, Nakazato Y, Mosaheb S, Thorpe JR, Uryu K, Lee VM, Trojanowski JQ. Clinical and neuropathologic variation in neuronal intermediate filament inclusion disease. Neurology 2004; 63: 1376–84 13 Dormann D, Rodde R, Edbauer D, Bentmann E, Fischer I, Hruscha A, Than ME, Mackenzie IR, Capell A, Schmid B, Neumann M, Haass C. ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. EMBO J 2010; 29: 2841–57 Citing Literature Volume38, Issue1February 2012Pages 101-104 ReferencesRelatedInformation

Objective The purpose of this study was to investigate the neuropathological substrates underlying in vivo hippocampal atrophy on magnetic resonance imaging (MRI) in autopsy confirmed neurodegenerative dementia cases.Methods Thirty-one neuropathologically verified cases (23 with Lewy body dementia (LBD) and eight with Alzheimer's disease (AD)) were included who had undergone an MRI scan close to death (mean 1.5 years). Manual volumetric measurements were undertaken for the hippocampus, entorhinal cortex and amygdala on MRI, along with quantitative neuropathological analysis of plaque, tangle and Lewy body pathology in the same regions. The relationship between neuropathology and MRI volumes was assessed using correlations and linear regression.Results Hippocampal and amygdala volumes were significantly smaller in cases with AD than with LBD, but there was no difference in entorhinal cortex volume. Analysing all cases together, a significant positive correlation was observed between normalised hippocampal volume and percent area of Lewy bodies in the hippocampus (r=0.449, p=0.017) but not with tangles (r=0.059, p=0.766) or plaques (r=-0.361, p=0.119). There were no other significant correlations between regional MRI volume and measures of neuropathology. Regression analysis showed that overall diagnosis of AD rather than burden of individual pathological changes was the most significant predictor of hippocampal volume loss in autopsy confirmed cases.Conclusion Our results suggest that (i) hippocampal and amygdala but not entorhinal cortex, volumes differ between AD and LBD and (ii) factors other than current markers of neurodegenerative pathological change are responsible for atrophy of medial temporal lobe structures in AD and LBD. Copyright (c) 2012 John Wiley & Sons, Ltd.

A. Ekonomou, M. Johnson, R. H. Perry, E. K. Perry, R. N. Kalaria, S. L. Minger and C. G. Ballard (2012) Neuropathology and Applied Neurobiology38, 344–353Increased neural progenitors in individuals with cerebral small vessel diseaseAims: Recent work has highlighted a significant increase of neural stem/progenitor cells after stroke in humans. In this study, we examined neurogenesis in small vessel disease, a key concurrent pathology in Alzheimer's disease. Methods: We assayed autopsy tissue from 13 vascular dementia patients with small vessel disease and 12 age‐matched subjects without cerebrovascular pathology, undertaking immunohistochemistry in the affected brain area and the subventricular zone with a well‐characterized battery of antibodies to detect neural stem cells/progenitors and immature neurones, as well as choline acetyltransferase immunoreactivity. Results: We showed significant increases ranging from 33% to 92% (P < 0.05) in neural progenitor cells around the areas of microvascular pathology and in the subventricular zone in patients with small vessel disease compared to individuals without cerebrovascular changes, even in patients with severe cerebrovascular disease, as defined by neuropathological assessment. Some of the progenitor cells give rise to immature neurones in the affected areas. These alterations were associated with vascular changes, but were unrelated to the cholinergic deficit observed in the cortex and subventricular zone in these patients, in contrast to other dementias examined such as dementia with Lewy bodies. Conclusions: This study provides evidence for neurogenesis in small vessel disease and may have important implications for the development of new therapies for neurodegenerative diseases.

Objective To determine whether cases of frontotemporal lobar degeneration (FTLD) do exist in elderly individuals and have clinical and neuropathological features distinct from those with presenile onset. Design Retrospective matched cohort study. Setting Regional Neuroscience Centre, North East England. Patients We compared clinicopathological features of 11 cases of FTLD in elderly individuals with 19 cases of presenile-onset FTLD. Results Retrospective case note analysis showed that most elderly patients with FTLD had behavioral features consistent with orbitofrontal and basofrontal involvement, similar to presenile-onset FTLD, though symptomatic memory loss was present in 91% (10 of 11) of elderly patients with FTLD compared with only 36% (7 of 19) of patients with presenile-onset FTLD. Neuropathologically, the group of elderly patients with FTLD comprised 7 with FTLD–TDP-43, 1 with ubiquitin-positive FTLD, 2 with FTLD-tau/Pick disease, and 1 with FTLD-tau/neurofibrillary tangle–predominant dementia with TDP-43, a composition similar to presenile-onset FTLD. However, hippocampal sclerosis was more common in elderly patients with FTLD than patients with presenile-onset FTLD (82% vs 37%) and more severe in elderly patients with FTLD (P < .05). By contrast, severe atrophy of the frontal and temporal lobes was less common in elderly patients with FTLD (frontal: 45%; temporal: 27%) than patients with presenile-onset FTLD (frontal: 63%; temporal: 78%). Elderly patients with FTLD represented 3.2% of all elderly patients with dementia autopsied at Newcastle General Hospital. Conclusions Frontotemporal lobar degeneration in elderly patients does exist as a separate entity from presenile-onset FTLD. Its main features include (1) clinically frequent memory loss and behavioral change predominating over language and semantic dysfunction and (2) neuropathologically prominent hippocampal sclerosis but less pronounced cortical lobar atrophy. Clinically, FTLD in elderly patients is underrecognized and should be considered in the elderly subjects presenting with an “atypical Alzheimer disease” phenotype.

In 2006, two papers were published, each describing pathological heterogeneity in cases of frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions (FTLD-U) [7, 11]. In both studies, large series of cases were evaluated and the investigators felt that they could recognize three distinct histological patterns, based on the morphology and anatomical distribution of ubiquitin immunoreactive neuronal inclusions. The findings of Sampathu et al. were further supported by differential labelling of the pathology, using a panel of novel monoclonal antibodies; whereas, Mackenzie et al. found relatively specific clinicopathological correlations. Most importantly, the pathological features that defined the subtypes in these two studies were almost identical, providing powerful validation of the results. However, because the studies were conducted simultaneously and independently, the numbering of the subtypes, used in the respective papers, did not match (Table 1). Table 1 Proposed new classification system for FTLD-TDP pathology, compared with existing systems Shortly thereafter, further work by one of the two groups led to the identification of the transactive response DNA-binding protein with Mr 43 kD (TDP-43) as the ubiquitinated pathological protein in most cases of FTLD-U as well as the majority of sporadic amyotrophic lateral sclerosis (ALS) and some familial ALS [10]. It was subsequently confirmed that most FTLD-U cases had TDP-43 pathology and that the same pathological patterns could be recognized based on the results of TDP-43 immunohistochemistry (IHC) [1, 2]. By this time, a fourth FTLD-U subtype had been described, specifically associated with the familial syndrome of inclusion body myopathy with Paget’s disease of bone and frontotemporal dementia (IBMPFD) caused by mutations in the valosin-containing protein (VCP) gene [4], and this was also shown to have TDP-43 pathology [9]. As a result, cases of FTLD with TDP-43 pathology are now designated as FTLD-TDP and the term FTLD-U is no longer recommended [8]. The two classification systems for FTLD-U/FTLD-TDP have now gained wide acceptance and have repeatedly been validated by the discovery of additional clinical, genetic and pathological correlations. However, the continued use of two discordant numbering systems proves to be an ongoing source of confusion within the field. Previous attempts, by other groups of authors, to promote one classification over the other have not been successful. To resolve this issue, the principal authors of the original two papers are now proposing a new classification for FTLD-TDP pathology, the sole purpose of which is to provide a single harmonized system that replaces the two currently in use. In developing this new classification, the following principles were adhered to: (1) different pathological subtypes are designated by letters to help distinguish this from the pre-existing number-based systems, (2) the order of subtypes should not exactly match either of the previous systems to avoid any apparent bias, and (3) the order of the subtypes should be based on their relative frequency, with “A” being the most common. The result is summarized in Table 1. Type A is equivalent to type 1 of Mackenzie et al. and type 3 of Sampathu et al., being characterized by numerous short dystrophic neurites (DN) and crescentic or oval neuronal cytoplasmic inclusions (NCI), concentrated primarily in neocortical layer 2. Moderate numbers of lentiform neuronal intranuclear inclusions (NII) are also a common but inconsistent feature of this subtype. Type B matches Mackenzie et al. type 3 and Sampathu et al. type 2, with moderate numbers of NCI, throughout all cortical layers, but very few DN. Type C is the same as Mackenzie et al. type 2 and Sampathu et al. type 1, having a predominance of elongated DN in upper cortical layers, with very few NCI. Finally, Type D refers to the pathology associated with IBMPFD caused by VCP mutations, characterized by numerous short DN and frequent lentiform NII. Based on the results of more recent studies, there are a number of other modifications that we could have considered incorporating into this new system. Additional pathological subtypes could be added; for instance, to describe the TDP-43 pathology that is found in the mesial temporal lobe in a high proportion of cases of Alzheimer’s disease and most other common neurodegenerative conditions [3]. The pathological criteria for each of the subtypes could be expanded to include characteristic findings in subcortical regions [5, 6]. The description of the pathological features could be modified to take into account the greater sensitivity and specificity of TDP-43 IHC, which may demonstrate additional findings, not recognized with the ubiquitin immunostaining techniques upon which the original classifications were based (such as neuronal “pre-inclusions”) [2]. Although these and other recent findings represent important advances in our understanding of FTLD-TDP, most have not yet been broadly replicated or completely defined. Therefore, in order to make the transition to a new classification as simple and widely acceptable as possible and, most importantly, to allow for direct translation with the currently existing systems, we are not proposing any other significant changes, beyond the coding of the subtypes. In summary, we believed that adoption of a single harmonized system for the classification of FTLD-TDP neuropathology would greatly improve communication within the rapidly advancing field of FTLD diagnosis and research. Future attempts to resolve any outstanding issues related to the practical implementation and interpretation of FTLD pathological classification should also benefit. As indicated by their inclusion as co-authors on this paper, this proposal has received the unanimous support of all of the neuropathologists involved in the original two studies [7, 11].

Neuronal intermediate filament inclusion disease (NIFID), a rare form of frontotemporal lobar degeneration (FTLD), is characterized neuropathologically by focal atrophy of the frontal and temporal lobes, neuronal loss, gliosis, and neuronal cytoplasmic inclusions (NCI) containing epitopes of ubiquitin and neuronal intermediate filament (IF) proteins. Recently, the ‘fused in sarcoma’ (FUS) protein (encoded by the FUS gene) has been shown to be a component of the inclusions of NIFID. To further characterize FUS proteinopathy in NIFID, we studied the spatial patterns of the FUS-immunoreactive NCI in frontal and temporal cortex of 10 cases. In the cerebral cortex, sectors CA1/2 of the hippocampus, and the dentate gyrus (DG), the FUS-immunoreactive NCI were frequently clustered and the clusters were regularly distributed parallel to the tissue boundary. In a proportion of cortical gyri, cluster size of the NCI approximated to those of the columns of cells was associated with the cortico-cortical projections. There were no significant differences in the frequency of different types of spatial patterns with disease duration or disease stage. Clusters of NCI in the upper and lower cortex were significantly larger using FUS compared with phosphorylated, neurofilament heavy polypeptide (NEFH) or α-internexin (INA) immunohistochemistry (IHC). We concluded: (1) FUS-immunoreactive NCI exhibit similar spatial patterns to analogous inclusions in the tauopathies and synucleinopathies, (2) clusters of FUS-immunoreactive NCI are larger than those revealed by NEFH or ΙΝΑ, and (3) the spatial patterns of the FUS-immunoreactive NCI suggest the degeneration of the cortico-cortical projections in NIFID.

Frontotemporal lobar degeneration (FTLD) is clinically, pathologically and genetically heterogeneous. Recent descriptions of a pathological sub-type that is ubiquitin positive, TDP-43 negative and immunostains positive for the Fused in Sarcoma protein (FUS) raises the question whether it is associated with a distinct clinical phenotype identifiable on clinical grounds, and whether mutations in the Fused in Sarcoma gene (FUS) might also be associated with FTLD. Examination of a pathological series of 118 cases of FTLD from two centres, showing tau-negative, ubiquitin-positive pathology, revealed FUS pathology in five patients, four classified as atypical FTLD with ubiquitin inclusions (aFTLD-U), and one as neuronal intermediate filament inclusion disease (NIFID). The aFTLD-U cases had youthful onset (22–46 years), an absence of strong family history, a behavioural syndrome consistent with frontotemporal dementia (FTD) and severe caudate atrophy. Their cognitive/behavioural profile was distinct, characterised by prominent obsessionality, repetitive behaviours and rituals, social withdrawal and lack of engagement, hyperorality with pica, and marked stimulus-bound behaviour including utilisation behaviour. They conformed to the rare behavioural sub-type of FTD identified previously by us as the “stereotypic” form, and linked to striatal pathology. Cognitive evaluation revealed executive deficits in keeping with subcortical-frontal dysfunction, but no cortical deficits in language, perceptuospatial skills or praxis. The patient with NIFID was older and exhibited aphasia and dyspraxia. No patient had clinical evidence of motor neurone disease during life, or a mutation in the FUS gene. In the complementary clinical study of 312 patients with clinical syndromes of FTLD, genetic analysis revealed a 6 bp deletion in FUS in 3 patients, of questionable significance. One presented a prototypical picture of FTD, another expressive language disorder, and the third semantic dementia. None showed the early onset age or distinctive ‘stereotypic’ picture of patients with aFTLD-U. We conclude that aFTLD-U is associated with a distinct clinical form of frontotemporal dementia, potentially allowing identification of such patients in life with a high degree of precision. Whether mutations in the FUS gene cause some cases of FTLD remains unresolved.