- Email: [email protected]
Pathology and hippocampal atrophy in Alzheimer's disease
Comment
is promising, fine-tuning of these models and extension of current efforts are key. Although these endeavours are expensive, they are vital in our development of disease-modifying therapies and in the ultimate treatment of Parkinson’s disease.
2 3 4 5
Cornelis Blauwendraat, Sara Bandrés-Ciga, *Andrew B Singleton Laboratory of Neurogenetics, National Institute on Aging (CB, SB-C, ABS), and Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke (CB), National Institutes of Health, Bethesda, MD 20892, USA [email protected] We declare no competing interests. Our work is supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, which is part of the US Department of Health and Human Services (project number ZO1 AG000949). 1
6 7 8 9
Nalls MA, Keller MF, Hernandez DG, et al. Baseline genetic associations in the Parkinson’s Progression Markers Initiative (PPMI). Mov Disord 2016; 31: 79–85. Parkinson Progression Marker Initiative. The Parkinson Progression Marker Initiative (PPMI). Prog Neurobiol 2011; 95: 629–35. Ravina B, Tanner C, Dieuliis D, et al. A longitudinal program for biomarker development in Parkinson’s disease: a feasibility study. Mov Disord 2009; 24: 2081–90. Goetz CG, Tilley BC, Shaftman SR, et al. Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord 2008; 23: 2129–70. Kim M, Kim J, Lee S-H, Park H. Imaging genetics approach to Parkinson’s disease and its correlation with clinical score. Sci Rep 2017; 7: 46700. Ravina B, Marek K, Eberly S, et al. Dopamine transporter imaging is associated with long-term outcomes in Parkinson’s disease. Mov Disord 2012; 27: 1392–97. Davis MY, Johnson CO, Leverenz JB, et al. Association of GBA mutations and the E326K polymorphism with motor and cognitive progression in Parkinson disease. JAMA Neurol 2016; 73: 1217–24. Nalls MA, McLean CY, Rick J, et al. Diagnosis of Parkinson’s disease on the basis of clinical and genetic classification: a population-based modelling study. Lancet Neurol 2015; 14: 1002–09.
Latourelle JC, Beste MT, Hadzi TC, et al. Large-scale identification of clinical and genetic predictors of motor progression in patients with newly diagnosed Parkinson’s disease: a longitudinal cohort study and validation. Lancet Neurol 2017; published online Sept 25. http://dx.doi.org/10.1016/ S1474-4422(17)30328-9.
Pathology and hippocampal atrophy in Alzheimer’s disease See Articles page 917
862
Over time, reduced hippocampal volume results in an amnestic syndrome, a core feature of Alzheimer’s disease.1 Damage to the hippocampus is incorporated into the pathological criteria for Alzheimer’s disease, with two regionally separable pathological features required: at least some neurofibrillary tangles in the hippocampus, and β-amyloid deposition and moderate neuritic infiltrate in association cortices.2 The severity of hippocampal tangle formation at clinical onset can be very variable (from some neurons to nearly all neurons involved). Many studies have shown that it is the severity of neuron loss in the hippocampus, rather than the preceding deposition of tau protein, that is most closely associated with the progressive hippocampal atrophy that accompanies Alzheimer’s disease. The assumption has been that this degenerative process is driven by the redistribution of intracellular tau itself, its interactions at neuronal terminals and dendrites with the β-amyloid protein, or both. Mechanistic studies certainly support the concept of such a pathogenic interaction between these two proteins.3 In parallel with refining the diagnostic criteria for Alzheimer’s disease,2 findings of cohort and population-based autopsy studies have shown that
a relatively high proportion of the elderly population (aged 80 years or older) have cerebral age-related TAR DNA binding protein 43 (TDP-43) deposition and hippocampal sclerosis.4 The clinical phenotype of this pathology mimics Alzheimer’s disease through different pathogenic mechanisms. Importantly, TDP43 protein deposition does not usually form amyloid, distinguishing this pathology from that observed for tau and β-amyloid deposition.5 In addition, the deposition of TDP-43 is usually associated with substantial, focal rapid neuronal death, potentially due to the disruption of its essential RNA binding and transport processes, and its prion-like domains.6 In The Lancet Neurology, the study by Keith Josephs and colleagues7 tackles the concept of the pathology responsible for the variable rates of hippocampal atrophy in Alzheimer’s disease. It has been noted that there are four main patterns of atrophy over time in Alzheimer’s disease—59% of patients have typical progressive hippocampal and cortical atrophy, 19% have progressive hippocampal atrophy only, 12% have progressive cortical atrophy only, and 10% have no atrophy in either region over time.8 These patterns are consistent with those identified previously by Whitwell and colleagues using www.thelancet.com/neurology Vol 16 November 2017
imaging at presentation in relation to pathological observations at death.9 In their study,9 71% of 177 patients were classified as typical, 19% as having limbic predominant pathology, and 11% with hippocampal sparing. These studies8,9 alone identify variable rates of regional brain atrophy relating to variable pathological outcomes in patients with Alzheimer’s disease. The new study by Josephs and colleagues7 addresses the effect of additional cellular pathologies, a very common problem in Alzheimer’s disease that has often been overlooked in previous studies; this oversight is potentially responsible for current failure rates in clinical trials. Josephs and colleagues have previously shown that TDP-43 deposition in patients with Alzheimer’s disease occurs in older-onset patients who perform worse on a number of cognitive scores and have smaller hippocampi.10 Other studies have subsequently confirmed that TDP-43 pathology is very common in Alzheimer’s disease, and it independently increases the likelihood of a clinical diagnosis of Alzheimer’s disease.11 Josephs and colleagues have also shown that the distribution of TDP-43 deposition in Alzheimer’s disease follows a characteristic pattern that differs from its deposition in both frontotemporal dementia and amyotrophic lateral sclerosis, but is similar to cerebral age-related TDP-43 with sclerosis in that it concentrates instead in the temporal lobe.12,13 In this study7 of a larger longitudinally followed cohort of autopsied participants from the Mayo Clinic’s ageing and Alzheimer’s disease studies, Josephs and colleagues7 provide further evidence that the additional TDP-43 pathology in the hippocampus is associated with significantly greater atrophy rates than that observed with the deposition of the tau protein alone (4·39% vs 3·11% annual decrease, respectively). Recent colocalisation studies show that 25% of TDP-43 inclusions occur in hippocampal neurons containing tau-immunoreactive tangles,14 suggesting a potential secondary mechanism. Data in this study by Josephs and colleagues7 could suggest that such aggregation of pathologies in the hippocampus cause more substantial degeneration and atrophy over time, and that targeting such an additional mechanism is required. Interestingly, in patients with dementia with Lewy bodies who have both tau and α-synuclein deposition, there is reduced hippocampal atrophy.15 Together these data suggest that the deposition of these functionally diverse neuronal proteins in www.thelancet.com/neurology Vol 16 November 2017
Living Art Enterprises/Science Photo Library
Comment
the hippocampus have considerably different levels of neurotoxicity. This difference in toxicity might be reflected in the microglial changes known to relate to hippocampal atrophy in these disorders.16 It will be important to map these pathological changes on to the different patterns of atrophy previously identified in the population of patients with Alzheimer’s disease and to determine whether those with TDP-43 deposition in the hippocampus have limbic predominant atrophy, while those with α-synuclein deposition have hippocampal sparing. Regardless, the data presented in the study by Jospehs and colleagues7 shows that the TDP-43 pathology is associated with increased neurodegeneration through an additional neurotoxic mechanism that warrants therapeutic focus. Glenda Halliday Brain and Mind Centre, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia [email protected] GH receives research support from the National Health and Medical Research Council of Australia (#1037747; #1079679; #1095927; #1103757), the Motor Neurone Disease Research Institute of Australia, the Michael J Fox Foundation, Shake-it-up Australia, and the MSA Coalition. 1 2
3
Dubois B, Feldman HH, Jacova C, et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol 2014; 13: 614–29. Montine TJ, Phelps CH, Beach TG, et al. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathol 2012; 123: 1–11. Nisbet RM, Polanco JC, Ittner LM, Gotz J. Tau aggregation and its interplay with amyloid-beta. Acta Neuropathol 2015; 129: 207–20.
863
Comment
4
Brenowitz WD, Monsell SE, Schmitt FA, Kukull WA, Nelson PT. Hippocampal sclerosis of aging is a key Alzheimer’s disease mimic: clinical-pathologic correlations and comparisons with both alzheimer’s disease and non-tauopathic frontotemporal lobar degeneration. J Alzheimers Dis 2014; 39: 691–702. 5 Neumann M, Kwong LK, Sampathu DM, Trojanowski JQ, Lee VM. TDP-43 proteinopathy in frontotemporal lobar degeneration and amyotrophic lateral sclerosis: protein misfolding diseases without amyloidosis. Arch Neurol 2007; 64: 1388–94. 6 Guo L, Shorter J. Biology and Pathobiology of TDP-43 and Emergent Therapeutic Strategies. Cold Spring Harb Perspect Med 2017; 7: 9. 7 Josephs KA, Dickson DW, Tosakulwong N, et al. Rates of hippocampal atrophy and post-mortem TDP-43 in Alzheimer’s disease: a longitudinal retrospective study. Lancet Neurol 2017; 16: 917–24. 8 Byun MS, Kim SE, Park J, et al. Heterogeneity of regional brain atrophy patterns associated with distinct progression rates in Alzheimer’s disease. PLoS One 2015; 10: e0142756. 9 Whitwell JL, Dickson DW, Murray ME, et al. Neuroimaging correlates of pathologically defined subtypes of Alzheimer’s disease: a case-control study. Lancet Neurol 2012; 11: 868–77. 10 Josephs KA, Whitwell JL, Knopman DS, et al. Abnormal TDP-43 immunoreactivity in AD modifies clinicopathologic and radiologic phenotype. Neurology 2008; 70: 1850–57.
11 12 13 14 15 16
James BD, Wilson RS, Boyle PA, Trojanowski JQ, Bennett DA, Schneider JA. TDP-43 stage, mixed pathologies, and clinical Alzheimer’s-type dementia. Brain 2016; 139: 2983–93. Hu WT, Josephs KA, Knopman DS, et al. Temporal lobar predominance of TDP-43 neuronal cytoplasmic inclusions in Alzheimer disease. Acta Neuropathol 2008; 116: 215–20. Josephs KA, Murray ME, Whitwell JL, et al. Updated TDP-43 in Alzheimer’s disease staging scheme. Acta Neuropathol 2016; 131: 571–85. Smith VD, Bachstetter AD, Ighodaro E, et al. Overlapping but distinct TDP-43 and tau pathologic patterns in aged hippocampi. Brain Pathol 2017; published online March 24. DOI:10.1111/bpa.12505. Mak E, Su L, Williams GB, et al. Differential Atrophy of Hippocampal Subfields: A Comparative Study of Dementia with Lewy Bodies and Alzheimer Disease. Am J Geriatr Psychiatry 2016; 24: 136–43. Bachstetter AD, Van Eldik LJ, Schmitt FA, et al. Disease-related microglia heterogeneity in the hippocampus of Alzheimer’s disease, dementia with Lewy bodies, and hippocampal sclerosis of aging. Acta Neuropathol Commun 2015; 3: 32.
PML risk and natalizumab: the elephant in the room Published Online September 29, 2017 http://dx.doi.org/10.1016/ S1474-4422(17)30335-6 See Articles page 925
864
Natalizumab is one of the most effective therapies currently available for relapsing-remitting multiple sclerosis.1 With the exception of rare hypersensitivity reactions, monthly intravenous infusions are well tolerated and, for most patients, treatment is not associated with an increase in infections.2 But, for unknown reasons, progressive multifocal leukoencephalopathy (PML), an opportunistic, disabling, and life-threatening disease caused by the John Cunningham virus (JCV), is associated with natalizumab treatment.3 Although PML is a known complication of immunosuppressive treatments, the incidence of PML in people treated with natalizumab is higher than in those treated with other immunosuppressants. This increased risk of PML is thought to be a class effect of α4β1 integrin antibodies and is not limited to patients with multiple sclerosis; PML has also been reported in natalizumab-treated patients with Crohn’s disease and patients given efalizumab for psoriasis.4,5 Notably, blocking of other integrin receptors such as α4β7 integrin does not seem to be associated with an increased risk of PML.6 Establishing the risk of PML and weighing this risk against expected benefits has become a necessary part of multiple sclerosis treatment algorithms.7 Teams at Biogen, the manufacturer of natalizumab, have made a great effort to quantify and stratify the risk of PML associated with natalizumab, using
data from a comprehensive case documentation system, observations from the initial controlled trials and their extensions, and large observational studies initiated after market authorisation of natalizumab. They proposed risk calculations and key risk stratifiers (positivity for anti-JCV antibodies, previous immunosuppression, and natalizumab treatment duration), which were accepted with some relief by clinicians, patients, and regulators as reasonably practical guidance for patient management. By establishing, assessing, and making available a standardised test that allows JCV antibody quantification (anti-JCV antibody index), researchers at Biogen provided evidence that within the group of antibody-positive patients, low index values (<0·9) were associated with a much lower risk than high values, but notably only in patients without previous immunosuppressant use.8 As more data have become available, and in response to criticisms that the methods underestimated the true risk,9,10 Pei-Ran Ho and colleagues11 present an update in The Lancet Neurology with more robust estimates that rely less on assumptions. They calculated risks using pooled patient-level data from four large observational studies with 37 249 patients, including 156 with confirmed PML. Crucially for everyday practice, they provide an estimate of the cumulative risk for patients on natalizumab treatment according to their treatment www.thelancet.com/neurology Vol 16 November 2017
is promising, fine-tuning of these models and extension of current efforts are key. Although these endeavours are expensive, they are vital in our development of disease-modifying therapies and in the ultimate treatment of Parkinson’s disease.
2 3 4 5
Cornelis Blauwendraat, Sara Bandrés-Ciga, *Andrew B Singleton Laboratory of Neurogenetics, National Institute on Aging (CB, SB-C, ABS), and Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke (CB), National Institutes of Health, Bethesda, MD 20892, USA [email protected] We declare no competing interests. Our work is supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, which is part of the US Department of Health and Human Services (project number ZO1 AG000949). 1
6 7 8 9
Nalls MA, Keller MF, Hernandez DG, et al. Baseline genetic associations in the Parkinson’s Progression Markers Initiative (PPMI). Mov Disord 2016; 31: 79–85. Parkinson Progression Marker Initiative. The Parkinson Progression Marker Initiative (PPMI). Prog Neurobiol 2011; 95: 629–35. Ravina B, Tanner C, Dieuliis D, et al. A longitudinal program for biomarker development in Parkinson’s disease: a feasibility study. Mov Disord 2009; 24: 2081–90. Goetz CG, Tilley BC, Shaftman SR, et al. Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord 2008; 23: 2129–70. Kim M, Kim J, Lee S-H, Park H. Imaging genetics approach to Parkinson’s disease and its correlation with clinical score. Sci Rep 2017; 7: 46700. Ravina B, Marek K, Eberly S, et al. Dopamine transporter imaging is associated with long-term outcomes in Parkinson’s disease. Mov Disord 2012; 27: 1392–97. Davis MY, Johnson CO, Leverenz JB, et al. Association of GBA mutations and the E326K polymorphism with motor and cognitive progression in Parkinson disease. JAMA Neurol 2016; 73: 1217–24. Nalls MA, McLean CY, Rick J, et al. Diagnosis of Parkinson’s disease on the basis of clinical and genetic classification: a population-based modelling study. Lancet Neurol 2015; 14: 1002–09.
Latourelle JC, Beste MT, Hadzi TC, et al. Large-scale identification of clinical and genetic predictors of motor progression in patients with newly diagnosed Parkinson’s disease: a longitudinal cohort study and validation. Lancet Neurol 2017; published online Sept 25. http://dx.doi.org/10.1016/ S1474-4422(17)30328-9.
Pathology and hippocampal atrophy in Alzheimer’s disease See Articles page 917
862
Over time, reduced hippocampal volume results in an amnestic syndrome, a core feature of Alzheimer’s disease.1 Damage to the hippocampus is incorporated into the pathological criteria for Alzheimer’s disease, with two regionally separable pathological features required: at least some neurofibrillary tangles in the hippocampus, and β-amyloid deposition and moderate neuritic infiltrate in association cortices.2 The severity of hippocampal tangle formation at clinical onset can be very variable (from some neurons to nearly all neurons involved). Many studies have shown that it is the severity of neuron loss in the hippocampus, rather than the preceding deposition of tau protein, that is most closely associated with the progressive hippocampal atrophy that accompanies Alzheimer’s disease. The assumption has been that this degenerative process is driven by the redistribution of intracellular tau itself, its interactions at neuronal terminals and dendrites with the β-amyloid protein, or both. Mechanistic studies certainly support the concept of such a pathogenic interaction between these two proteins.3 In parallel with refining the diagnostic criteria for Alzheimer’s disease,2 findings of cohort and population-based autopsy studies have shown that
a relatively high proportion of the elderly population (aged 80 years or older) have cerebral age-related TAR DNA binding protein 43 (TDP-43) deposition and hippocampal sclerosis.4 The clinical phenotype of this pathology mimics Alzheimer’s disease through different pathogenic mechanisms. Importantly, TDP43 protein deposition does not usually form amyloid, distinguishing this pathology from that observed for tau and β-amyloid deposition.5 In addition, the deposition of TDP-43 is usually associated with substantial, focal rapid neuronal death, potentially due to the disruption of its essential RNA binding and transport processes, and its prion-like domains.6 In The Lancet Neurology, the study by Keith Josephs and colleagues7 tackles the concept of the pathology responsible for the variable rates of hippocampal atrophy in Alzheimer’s disease. It has been noted that there are four main patterns of atrophy over time in Alzheimer’s disease—59% of patients have typical progressive hippocampal and cortical atrophy, 19% have progressive hippocampal atrophy only, 12% have progressive cortical atrophy only, and 10% have no atrophy in either region over time.8 These patterns are consistent with those identified previously by Whitwell and colleagues using www.thelancet.com/neurology Vol 16 November 2017
imaging at presentation in relation to pathological observations at death.9 In their study,9 71% of 177 patients were classified as typical, 19% as having limbic predominant pathology, and 11% with hippocampal sparing. These studies8,9 alone identify variable rates of regional brain atrophy relating to variable pathological outcomes in patients with Alzheimer’s disease. The new study by Josephs and colleagues7 addresses the effect of additional cellular pathologies, a very common problem in Alzheimer’s disease that has often been overlooked in previous studies; this oversight is potentially responsible for current failure rates in clinical trials. Josephs and colleagues have previously shown that TDP-43 deposition in patients with Alzheimer’s disease occurs in older-onset patients who perform worse on a number of cognitive scores and have smaller hippocampi.10 Other studies have subsequently confirmed that TDP-43 pathology is very common in Alzheimer’s disease, and it independently increases the likelihood of a clinical diagnosis of Alzheimer’s disease.11 Josephs and colleagues have also shown that the distribution of TDP-43 deposition in Alzheimer’s disease follows a characteristic pattern that differs from its deposition in both frontotemporal dementia and amyotrophic lateral sclerosis, but is similar to cerebral age-related TDP-43 with sclerosis in that it concentrates instead in the temporal lobe.12,13 In this study7 of a larger longitudinally followed cohort of autopsied participants from the Mayo Clinic’s ageing and Alzheimer’s disease studies, Josephs and colleagues7 provide further evidence that the additional TDP-43 pathology in the hippocampus is associated with significantly greater atrophy rates than that observed with the deposition of the tau protein alone (4·39% vs 3·11% annual decrease, respectively). Recent colocalisation studies show that 25% of TDP-43 inclusions occur in hippocampal neurons containing tau-immunoreactive tangles,14 suggesting a potential secondary mechanism. Data in this study by Josephs and colleagues7 could suggest that such aggregation of pathologies in the hippocampus cause more substantial degeneration and atrophy over time, and that targeting such an additional mechanism is required. Interestingly, in patients with dementia with Lewy bodies who have both tau and α-synuclein deposition, there is reduced hippocampal atrophy.15 Together these data suggest that the deposition of these functionally diverse neuronal proteins in www.thelancet.com/neurology Vol 16 November 2017
Living Art Enterprises/Science Photo Library
Comment
the hippocampus have considerably different levels of neurotoxicity. This difference in toxicity might be reflected in the microglial changes known to relate to hippocampal atrophy in these disorders.16 It will be important to map these pathological changes on to the different patterns of atrophy previously identified in the population of patients with Alzheimer’s disease and to determine whether those with TDP-43 deposition in the hippocampus have limbic predominant atrophy, while those with α-synuclein deposition have hippocampal sparing. Regardless, the data presented in the study by Jospehs and colleagues7 shows that the TDP-43 pathology is associated with increased neurodegeneration through an additional neurotoxic mechanism that warrants therapeutic focus. Glenda Halliday Brain and Mind Centre, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia [email protected] GH receives research support from the National Health and Medical Research Council of Australia (#1037747; #1079679; #1095927; #1103757), the Motor Neurone Disease Research Institute of Australia, the Michael J Fox Foundation, Shake-it-up Australia, and the MSA Coalition. 1 2
3
Dubois B, Feldman HH, Jacova C, et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol 2014; 13: 614–29. Montine TJ, Phelps CH, Beach TG, et al. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathol 2012; 123: 1–11. Nisbet RM, Polanco JC, Ittner LM, Gotz J. Tau aggregation and its interplay with amyloid-beta. Acta Neuropathol 2015; 129: 207–20.
863
Comment
4
Brenowitz WD, Monsell SE, Schmitt FA, Kukull WA, Nelson PT. Hippocampal sclerosis of aging is a key Alzheimer’s disease mimic: clinical-pathologic correlations and comparisons with both alzheimer’s disease and non-tauopathic frontotemporal lobar degeneration. J Alzheimers Dis 2014; 39: 691–702. 5 Neumann M, Kwong LK, Sampathu DM, Trojanowski JQ, Lee VM. TDP-43 proteinopathy in frontotemporal lobar degeneration and amyotrophic lateral sclerosis: protein misfolding diseases without amyloidosis. Arch Neurol 2007; 64: 1388–94. 6 Guo L, Shorter J. Biology and Pathobiology of TDP-43 and Emergent Therapeutic Strategies. Cold Spring Harb Perspect Med 2017; 7: 9. 7 Josephs KA, Dickson DW, Tosakulwong N, et al. Rates of hippocampal atrophy and post-mortem TDP-43 in Alzheimer’s disease: a longitudinal retrospective study. Lancet Neurol 2017; 16: 917–24. 8 Byun MS, Kim SE, Park J, et al. Heterogeneity of regional brain atrophy patterns associated with distinct progression rates in Alzheimer’s disease. PLoS One 2015; 10: e0142756. 9 Whitwell JL, Dickson DW, Murray ME, et al. Neuroimaging correlates of pathologically defined subtypes of Alzheimer’s disease: a case-control study. Lancet Neurol 2012; 11: 868–77. 10 Josephs KA, Whitwell JL, Knopman DS, et al. Abnormal TDP-43 immunoreactivity in AD modifies clinicopathologic and radiologic phenotype. Neurology 2008; 70: 1850–57.
11 12 13 14 15 16
James BD, Wilson RS, Boyle PA, Trojanowski JQ, Bennett DA, Schneider JA. TDP-43 stage, mixed pathologies, and clinical Alzheimer’s-type dementia. Brain 2016; 139: 2983–93. Hu WT, Josephs KA, Knopman DS, et al. Temporal lobar predominance of TDP-43 neuronal cytoplasmic inclusions in Alzheimer disease. Acta Neuropathol 2008; 116: 215–20. Josephs KA, Murray ME, Whitwell JL, et al. Updated TDP-43 in Alzheimer’s disease staging scheme. Acta Neuropathol 2016; 131: 571–85. Smith VD, Bachstetter AD, Ighodaro E, et al. Overlapping but distinct TDP-43 and tau pathologic patterns in aged hippocampi. Brain Pathol 2017; published online March 24. DOI:10.1111/bpa.12505. Mak E, Su L, Williams GB, et al. Differential Atrophy of Hippocampal Subfields: A Comparative Study of Dementia with Lewy Bodies and Alzheimer Disease. Am J Geriatr Psychiatry 2016; 24: 136–43. Bachstetter AD, Van Eldik LJ, Schmitt FA, et al. Disease-related microglia heterogeneity in the hippocampus of Alzheimer’s disease, dementia with Lewy bodies, and hippocampal sclerosis of aging. Acta Neuropathol Commun 2015; 3: 32.
PML risk and natalizumab: the elephant in the room Published Online September 29, 2017 http://dx.doi.org/10.1016/ S1474-4422(17)30335-6 See Articles page 925
864
Natalizumab is one of the most effective therapies currently available for relapsing-remitting multiple sclerosis.1 With the exception of rare hypersensitivity reactions, monthly intravenous infusions are well tolerated and, for most patients, treatment is not associated with an increase in infections.2 But, for unknown reasons, progressive multifocal leukoencephalopathy (PML), an opportunistic, disabling, and life-threatening disease caused by the John Cunningham virus (JCV), is associated with natalizumab treatment.3 Although PML is a known complication of immunosuppressive treatments, the incidence of PML in people treated with natalizumab is higher than in those treated with other immunosuppressants. This increased risk of PML is thought to be a class effect of α4β1 integrin antibodies and is not limited to patients with multiple sclerosis; PML has also been reported in natalizumab-treated patients with Crohn’s disease and patients given efalizumab for psoriasis.4,5 Notably, blocking of other integrin receptors such as α4β7 integrin does not seem to be associated with an increased risk of PML.6 Establishing the risk of PML and weighing this risk against expected benefits has become a necessary part of multiple sclerosis treatment algorithms.7 Teams at Biogen, the manufacturer of natalizumab, have made a great effort to quantify and stratify the risk of PML associated with natalizumab, using
data from a comprehensive case documentation system, observations from the initial controlled trials and their extensions, and large observational studies initiated after market authorisation of natalizumab. They proposed risk calculations and key risk stratifiers (positivity for anti-JCV antibodies, previous immunosuppression, and natalizumab treatment duration), which were accepted with some relief by clinicians, patients, and regulators as reasonably practical guidance for patient management. By establishing, assessing, and making available a standardised test that allows JCV antibody quantification (anti-JCV antibody index), researchers at Biogen provided evidence that within the group of antibody-positive patients, low index values (<0·9) were associated with a much lower risk than high values, but notably only in patients without previous immunosuppressant use.8 As more data have become available, and in response to criticisms that the methods underestimated the true risk,9,10 Pei-Ran Ho and colleagues11 present an update in The Lancet Neurology with more robust estimates that rely less on assumptions. They calculated risks using pooled patient-level data from four large observational studies with 37 249 patients, including 156 with confirmed PML. Crucially for everyday practice, they provide an estimate of the cumulative risk for patients on natalizumab treatment according to their treatment www.thelancet.com/neurology Vol 16 November 2017