Cognitive Profile and Markers of Alzheimer Disease–Type Pathology in Patients With Lewy Body Dementias

Objective To determine whether patients with Lewy body dementia (LBD) with likely Alzheimer disease (AD)–type copathology are more impaired on confrontation naming than those without likely AD-type copathology. Methods We selected 57 patients with LBD (dementia with Lewy bodies [DLB], n = 38; Parkinson disease dementia [PDD], n = 19) with available AD CSF biomarkers and neuropsychological data. CSF β-amyloid1-42 (Aβ42), phosphorylated-tau (p-tau), and total-tau (t-tau) concentrations were measured. We used an autopsy-validated CSF cut point (t-tau:Aβ42 ratio > 0.3, n = 43), or autopsy data when available (n = 14), to categorize patients as having LBD with (LBD + AD, n = 26) and without (LBD − AD, n = 31) likely AD-type copathology. Analysis of covariance tested between-group comparisons across biologically defined groups (LBD + AD, LBD − AD) and clinical phenotypes (DLB, PDD) on confrontation naming (30-item Boston Naming Test [BNT]), executive abilities (letter fluency [LF], reverse digit span [RDS]), and global cognition (Mini-Mental State Examination [MMSE]), with adjustment for age at dementia onset, time from dementia onset to test date, and time from CSF to test date. Spearman correlation related cognitive performance to CSF analytes. Results Patients with LBD + AD performed worse on BNT than patients with LBD − AD (F = 4.80, p = 0.03); both groups performed similarly on LF, RDS, and MMSE (all p > 0.1). Clinically defined PDD and DLB groups did not differ in performance on any of these measures (all p > 0.05). A correlation across all patients showed that BNT score was negatively associated with CSF t-tau (ρ = −0.28, p < 0.05) and p-tau (ρ = −0.26, p = 0.05) but not Aβ42 (p > 0.1). Conclusion Markers of AD-type copathology are implicated in impaired language performance in LBD. Biologically based classification of LBD may be advantageous over clinically defined syndromes to elucidate clinical heterogeneity.

[1]  J. Trojanowski,et al.  Tau pathology associates with in vivo cortical thinning in Lewy body disorders , 2020, Annals of clinical and translational neurology.

[2]  Alzheimer's Disease Neuroimaging Initiative,et al.  Multimodal in vivo and postmortem assessments of tau in Lewy body disorders , 2020, Neurobiology of Aging.

[3]  J. Kulisevsky,et al.  The combined effect of amyloid-β and tau biomarkers on brain atrophy in dementia with Lewy bodies , 2020, NeuroImage: Clinical.

[4]  J. Filoteo,et al.  Cognitive decline profiles differ in Parkinson disease dementia and dementia with Lewy bodies , 2020, Neurology.

[5]  D. Irwin,et al.  Pathological Influences on Clinical Heterogeneity in Lewy Body Diseases , 2020, Movement disorders : official journal of the Movement Disorder Society.

[6]  M. Onofrj,et al.  CSF tau proteins correlate with an atypical clinical presentation in dementia with Lewy bodies , 2019, Journal of Neurology, Neurosurgery, and Psychiatry.

[7]  C. Jack,et al.  Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report , 2019, Brain : a journal of neurology.

[8]  J. Trojanowski,et al.  Cognitive and Pathological Influences of Tau Pathology in Lewy Body Disorders , 2018, Annals of neurology.

[9]  D. Irwin,et al.  The Contribution of Tau, Amyloid-Beta and Alpha-Synuclein Pathology to Dementia in Lewy Body Disorders , 2018, Journal of Alzheimer's disease & Parkinsonism.

[10]  Mário João Fartaria,et al.  Episodic memory decline in Parkinson’ s disease: relation with white matter hyperintense lesions and influence of quantification method , 2018, Brain Imaging and Behavior.

[11]  John L. Robinson,et al.  Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated , 2018, Brain : a journal of neurology.

[12]  C. Jack,et al.  NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease , 2018, Alzheimer's & Dementia.

[13]  J. Trojanowski,et al.  CSF tau and β-amyloid predict cerebral synucleinopathy in autopsied Lewy body disorders , 2018, Neurology.

[14]  J. Graff‐Radford,et al.  The limbic and neocortical contribution of α-synuclein, tau, and amyloid β to disease duration in dementia with Lewy bodies , 2018, Alzheimer's & Dementia.

[15]  T. Uchihara,et al.  Reader response: Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB consortium , 2018, Neurology.

[16]  C. DeCarli,et al.  Impact of multiple pathologies on the threshold for clinically overt dementia , 2017, Acta Neuropathologica.

[17]  M. Grossman,et al.  Narrative Organization Deficit in Lewy Body Disorders Is Related to Alzheimer Pathology , 2017, Front. Neurosci..

[18]  T. Montine,et al.  Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis , 2017, The Lancet Neurology.

[19]  David T. Jones,et al.  AV‐1451 tau and β‐amyloid positron emission tomography imaging in dementia with Lewy bodies , 2016, Annals of neurology.

[20]  Keith A. Johnson,et al.  Tau Positron Emission Tomographic Imaging in the Lewy Body Diseases. , 2016, JAMA neurology.

[21]  W. M. van der Flier,et al.  Concomitant AD pathology affects clinical manifestation and survival in dementia with Lewy bodies , 2016, Journal of Neurology, Neurosurgery & Psychiatry.

[22]  D. Galasko,et al.  Phenotypic differences based on staging of Alzheimer's neuropathology in autopsy-confirmed dementia with Lewy bodies. , 2016, Parkinsonism & related disorders.

[23]  C. Mariani,et al.  Survival and dementia in GBA‐associated Parkinson's disease: The mutation matters , 2016, Annals of neurology.

[24]  A. Singleton,et al.  Arguing against the proposed definition changes of PD , 2016, Movement disorders : official journal of the Movement Disorder Society.

[25]  Lilah M. Besser,et al.  Results From the NACC Uniform Data Set Neuropsychological Battery Crosswalk Study , 2016, Alzheimer disease and associated disorders.

[26]  G. Deuschl,et al.  MDS clinical diagnostic criteria for Parkinson's disease , 2015, Movement disorders : official journal of the Movement Disorder Society.

[27]  Clifford R. Jack,et al.  Pattern of brain atrophy rates in autopsy-confirmed dementia with Lewy bodies , 2015, Neurobiology of Aging.

[28]  Murray Grossman,et al.  A platform for discovery: The University of Pennsylvania Integrated Neurodegenerative Disease Biobank , 2014, Alzheimer's & Dementia.

[29]  R. Barker,et al.  The spectrum of cognitive impairment in Lewy body diseases , 2014, Movement disorders : official journal of the Movement Disorder Society.

[30]  Susan M Resnick,et al.  Changes in Brain Function Occur Years before the Onset of Cognitive Impairment , 2013, The Journal of Neuroscience.

[31]  T. Montine,et al.  Neuropsychologic assessment in collaborative Parkinson’s disease research: A proposal from the National Institute of Neurological Disorders and Stroke Morris K. Udall Centers of Excellence for Parkinson’s Disease Research at the University of Pennsylvania and the University of Washington , 2013, Alzheimer's & Dementia.

[32]  Leslie M. Shaw,et al.  Longitudinal change in CSF Tau and Aβ biomarkers for up to 48 months in ADNI , 2013, Acta Neuropathologica.

[33]  Bruce L. Miller,et al.  Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS , 2011, Neuron.

[34]  J. Trojanowski,et al.  CSF amyloid β 1-42 predicts cognitive decline in Parkinson disease , 2010, Neurology.

[35]  Loraine K. Obler,et al.  Bilateral brain regions associated with naming in older adults , 2010, Brain and Language.

[36]  C. Christine,et al.  Cognitive and Neuropsychiatric Profile of the Synucleinopathies: Parkinson Disease, Dementia With Lewy Bodies, and Multiple System Atrophy , 2009, Alzheimer disease and associated disorders.

[37]  R. Petersen,et al.  Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects , 2009, Annals of neurology.

[38]  Keith A. Johnson,et al.  Imaging amyloid deposition in Lewy body diseases , 2008, Neurology.

[39]  A. Tröster.  Neuropsychological Characteristics of Dementia with Lewy Bodies and Parkinson’s Disease with Dementia: Differentiation, Early Detection, and Implications for “Mild Cognitive Impairment” and Biomarkers , 2008, Neuropsychology Review.

[40]  K. Jellinger,et al.  Prevalence and impact of vascular and Alzheimer pathologies in Lewy body disease , 2008, Acta Neuropathologica.

[41]  E B Larson,et al.  Cognitive differences in dementia patients with autopsy-verified AD, Lewy body pathology, or both , 2005, Neurology.

[42]  A. Tröster,et al.  Lexical, semantic, and action verbal fluency in Parkinson's disease with and without dementia. , 1999, Journal of clinical and experimental neuropsychology.

[43]  A. Hossain,et al.  A comparative study on detection of influential observations in linear regression , 1991 .

[44]  R. Iman,et al.  Rank Transformations as a Bridge between Parametric and Nonparametric Statistics , 1981 .

[45]  S. Folstein,et al.  "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. , 1975, Journal of psychiatric research.

[46]  Keith A. Johnson,et al.  Alzheimer's Disease Biomarkers and Future Decline in Cognitive Normal Older Adults. , 2017, Journal of Alzheimer's disease : JAD.

[47]  T. Montine,et al.  Cerebrospinal fluid biomarkers and cognitive performance in non-demented patients with Parkinson's disease. , 2011, Parkinsonism & related disorders.

[48]  Charles Duyckaerts,et al.  National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach , 2011, Acta Neuropathologica.