B. F. Boeve

Diagnosis and management of dementia with Lewy bodies Third report of the DLB consortium

The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in ∼50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Classification of primary progressive aphasia and its variants

This article provides a classification of primary progressive aphasia (PPA) and its 3 main variants to improve the uniformity of case reporting and the reliability of research results. Criteria for the 3 variants of PPA—nonfluent/agrammatic, semantic, and logopenic—were developed by an international group of PPA investigators who convened on 3 occasions to operationalize earlier published clinical descriptions for PPA subtypes. Patients are first diagnosed with PPA and are then divided into clinical variants based on specific speech and language features characteristic of each subtype. Classification can then be further specified as “imaging-supported” if the expected pattern of atrophy is found and “with definite pathology” if pathologic or genetic data are available. The working recommendations are presented in lists of features, and suggested assessment tasks are also provided. These recommendations have been widely agreed upon by a large group of experts and should be used to ensure consistency of PPA classification in future studies. Future collaborations will collect prospective data to identify relationships between each of these syndromes and specific biomarkers for a more detailed understanding of clinicopathologic correlations.

Usefulness of MRI measures of entorhinal cortex versus hippocampus in AD

Objective: MRI-based measurements of hippocampal atrophy are a sensitive indicator of the early pathologic degeneration of the medial temporal lobe in AD. However, AD pathology appears first in the transentorhinal/entorhinal cortex, not the hippocampus. The authors tested the hypothesis that MRI-based measurements of the entorhinal cortex are more sensitive than measurements of hippocampal volume in discriminating among three clinical groups; controls, patients with a mild cognitive impairment (MCI), and patients with mild probable AD. Methods: The authors studied 30 controls, 30 patients with MCI, and 30 patients with AD who were matched among clinical groups on age, gender, and education. All underwent a standardized MRI protocol from which the authors made measurements of hippocampal volume, entorhinal cortex volume, and the cumulative length of the medial border of the entorhinal cortex. Results: Pairwise intergroup differences (p < 0.01) were found for all MRI measurements with the exception of the cumulative length of the entorhinal cortex, which did not differentiate controls from MCI patients. Whereas the hippocampal and entorhinal cortex volume measurements provided slightly better intergroup discrimination than the entorhinal distance measurement, overall differences in discriminating ability among the three MRI measurements were minor. Conclusions: Despite the theoretical rationale for the superiority of entorhinal measurements in early AD, the authors found MRI measurements of the hippocampus and entorhinal cortex were approximately equivalent at intergroup discrimination. Measurements of the hippocampus may be preferable because MRI depiction of the boundaries of the entorhinal cortex can be obscured by anatomic ambiguity, image artifact, or both.

Potentially reversible autoimmune limbic encephalitis with neuronal potassium channel antibody

Objectives: To describe the clinical features and coexisting serum autoantibodies in seven patients with encephalitis associated with autoantibodies to α-dendrotoxin-sensitive voltage-gated potassium channels (VGKCs), and to compare this disorder with other autoimmune encephalopathies. Methods: Clinical information was obtained from a retrospective review of medical records and telephone interviews. All autoantibody testing was performed in a single laboratory. Results: The seven patients were examined for subacute cognitive and behavioral changes. Seizures, usually temporal-onset complex partial type, were documented in six patients, and all seven patients had EEG abnormalities. None had symptoms or signs of neuromuscular hyperexcitability. One described hypersalivation. Four patients had additional autoantibody markers of neurologic autoimmunity (muscle acetylcholine receptor, striational, P/Q-type calcium channel, or GAD65), and two had thyroperoxidase antibodies. Two patients had a history of cancer: one had active prostate adenocarcinoma, and the second had a remote history of tongue carcinoma. Cranial MRI demonstrated mesial temporal lobe abnormalities in all patients. One patient improved spontaneously, and six were treated with IV methylprednisolone. Three improved remarkably with treatment. At follow-up evaluation, one had no cognitive deficits, four had mild persistent short-term memory dysfunction, and two had persistent disabling behavioral deficits. Conclusions: Voltage-gated potassium channel antibodies are a valuable serologic marker of a potentially reversible autoimmune encephalopathy. The neurologic manifestations of this disorder are indistinguishable from paraneoplastic limbic encephalitis but are distinct from Morvan syndrome and Hashimoto encephalopathy.

Synucleinopathy pathology and REM sleep behavior disorder plus dementia or parkinsonism

Objective: To determine if synucleinopathy pathology is related to REM sleep behavior disorder (RBD) plus dementia or parkinsonism. Methods: The clinical and neuropathologic findings were analyzed on all autopsied cases evaluated at Mayo Clinic Rochester from January 1990 to April 2002 who were diagnosed with RBD and a neurodegenerative disorder. Ubiquitin and/or α-synuclein immunocytochemistry was used in all cases. The clinical and neuropathologic diagnoses were based on published criteria. Results: Fifteen cases were identified (14 men). All had clear histories of dream enactment behavior, and 10 had RBD confirmed by polysomnography. RBD preceded dementia or parkinsonism in 10 (66.7%) patients by a median of 10 (range 2 to 29) years. The clinical diagnoses included dementia with Lewy bodies (DLB) (n = 6); multiple-system atrophy (MSA) (n = 2); combined DLB, AD, and vascular dementia (n = 1); dementia (n = 1); dementia with parkinsonism (n = 1); PD (n = 1); PD with dementia (n = 1); dementia/parkinsonism/motor neuron disease (n = 1); and AD/Binswanger’s disease (n = 1). The neuropathologic diagnoses were Lewy body disease (LBD) in 12 (neocortical in 11 and limbic in 1) and MSA in 3. Three also had argyrophilic grain pathology. In the LBD cases, concomitant AD pathology was present in six (one also with Binswanger’s pathology, and one also with multiple subcortical infarcts). Conclusion: In the setting of degenerative dementia or parkinsonism, RBD often reflects an underlying synucleinopathy.

Clinicopathologic correlations in 172 cases of rapid eye movement sleep behavior disorder with or without a coexisting neurologic disorder.

OBJECTIVE To determine the pathologic substrates in patients with rapid eye movement (REM) sleep behavior disorder (RBD) with or without a coexisting neurologic disorder. METHODS The clinical and neuropathologic findings were analyzed on all autopsied cases from one of the collaborating sites in North America and Europe, were evaluated from January 1990 to March 2012, and were diagnosed with polysomnogram (PSG)-proven or probable RBD with or without a coexisting neurologic disorder. The clinical and neuropathologic diagnoses were based on published criteria. RESULTS 172 cases were identified, of whom 143 (83%) were men. The mean±SD age of onset in years for the core features were as follows - RBD, 62±14 (range, 20-93), cognitive impairment (n=147); 69±10 (range, 22-90), parkinsonism (n=151); 68±9 (range, 20-92), and autonomic dysfunction (n=42); 62±12 (range, 23-81). Death age was 75±9 years (range, 24-96). Eighty-two (48%) had RBD confirmed by PSG, 64 (37%) had a classic history of recurrent dream enactment behavior, and 26 (15%) screened positive for RBD by questionnaire. RBD preceded the onset of cognitive impairment, parkinsonism, or autonomic dysfunction in 87 (51%) patients by 10±12 (range, 1-61) years. The primary clinical diagnoses among those with a coexisting neurologic disorder were dementia with Lewy bodies (n=97), Parkinsons disease with or without mild cognitive impairment or dementia (n=32), multiple system atrophy (MSA) (n=19), Alzheimers disease (AD)(n=9) and other various disorders including secondary narcolepsy (n=2) and neurodegeneration with brain iron accumulation-type 1 (NBAI-1) (n=1). The neuropathologic diagnoses were Lewy body disease (LBD)(n=77, including 1 case with a duplication in the gene encoding α-synuclein), combined LBD and AD (n=59), MSA (n=19), AD (n=6), progressive supranulear palsy (PSP) (n=2), other mixed neurodegenerative pathologies (n=6), NBIA-1/LBD/tauopathy (n=1), and hypothalamic structural lesions (n=2). Among the neurodegenerative disorders associated with RBD (n=170), 160 (94%) were synucleinopathies. The RBD-synucleinopathy association was particularly high when RBD preceded the onset of other neurodegenerative syndrome features. CONCLUSIONS In this large series of PSG-confirmed and probable RBD cases that underwent autopsy, the strong association of RBD with the synucleinopathies was further substantiated and a wider spectrum of disorders which can underlie RBD now are more apparent.

Autonomic dysfunction in dementia with Lewy bodies

Objective: To assess autonomic function in patients with dementia with Lewy bodies (DLB). Methods: The authors compared data from 20 DLB patients evaluated from 1995 to 2000 to 20 age-matched multiple system atrophy (MSA) and Parkinson disease (PD) patients evaluated from 1999 to 2002. Analysis of variance, Fisher exact test, and Student t-test were applied to compare disease characteristics, autonomic symptoms, and function tests on the Composite Autonomic Scoring Scale (CASS) and Thermoregulatory Sweat Test (TST). Results: In DLB, mean age at onset of autonomic symptoms was 70.3 ± 8.9 years. Orthostatic symptoms were common and orthostatic hypotension occurred in 10/20 DLB, 17/20 MSA, and 1/20 PD patients (p = 0.023, 0.003). CASS-sudomotor for DLB, MSA, and PD were 1.6 ± 1.2, 2.5 ± 0.7, and 0.9 ± 0.8 (p < 0.00001). CASS-cardiovagal were 1.4 ± 0.9, 2.1 ± 0.8, and 0.7 ± 0.6 (p < 0.00001). CASS-adrenergic function were 2.4 ± 1.2, 3.5 ± 0.9, and 0.5 ± 0.6 (p < 0.00001). Total CASS were 5.2 ± 2.0, 8.1 ± 1.3, and 2.2 ± 1.2 (p < 0.00001). The most common pattern of TST in DLB was distal anhidrosis. Mean duration of follow-up was 3.0 ± 1.8 years. Six patients needed medication to maintain blood pressure and five had good response. Conclusions: Autonomic dysfunction is frequent in dementia with Lewy bodies and the severity is intermediate between that of multiple system atrophy and Parkinson disease.

Frequency of tau mutations in three series of non‐Alzheimer's degenerative dementia

Splice‐site and missense mutations have been identified in tau associated with frontotemporal dementia with parkinsonism linked to chromosome 17. In this study we assessed the genetic contribution of tau mutations to three patient series with non‐Alzheimers (non‐AD) degenerative dementia. The groups included (1) a community‐based dementia series from Minnesota, MN; (2) a referral series with clinicopathological tauopathy; and (3) a pathologically confirmed familial frontotemporal dementia series from Manchester, UK. Comparing the three clinical series: in the stringently diagnosed Manchester frontotemporal dementia series, tau mutations were present in 13.6% of cases (three splice‐site mutations); in the clinicopathological referral series that used more general inclusion criteria, 3 cases with P301L mutations were observed, which represents a lower mutation frequency of 3.6% (9.4% in familial cases); in contrast, tau mutations were not detected in the Minnesota community‐based dementia series, suggesting the occurrence of these mutations in dementia generally is rare (<0.2%). These data identify the prevalence of mutations in three different clinical settings and indicate that this figure is sensitive to the diagnostic criteria used in each patient series. Ann Neurol 1999;46:243–248

Effect of APOE ε4 Status on Intrinsic Network Connectivity in Cognitively Normal Elderly Subjects

OBJECTIVE To examine default mode and salience network functional connectivity as a function of APOE ε4 status in a group of cognitively normal age-, sex-, and education-matched older adults. DESIGN Case-control study. SUBJECTS Fifty-six cognitively normal APOE ε4 carriers and 56 age-, sex- and education-matched cognitively normal APOE ε4 noncarriers. MAIN OUTCOME MEASURE Alterations in in-phase default mode and salience network connectivity in APOE ε4 carriers compared with APOE ε4 noncarriers ranging from 63 to 91 years of age. RESULTS A posterior cingulate seed revealed decreased in-phase connectivity in regions of the posterior default mode network that included the left inferior parietal lobe, left middle temporal gyrus, and bilateral anterior temporal lobes in the ε4 carriers relative to APOE ε4 noncarriers. An anterior cingulate seed showed greater in-phase connectivity in the salience network including the cingulate gyrus, medial prefrontal cortex, bilateral insular cortex, striatum, and thalamus in APOE ε4 carriers vs noncarriers. There were no groupwise differences in brain anatomy. CONCLUSIONS The observation of functional alterations in default mode and salience network connectivity in the absence of structural changes between APOE ε4 carriers and noncarriers suggests that alterations in connectivity may have the potential to serve as an early biomarker.

TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers

Objectives: To determine whether TMEM106B single nucleotide polymorphisms (SNPs) are associated with frontotemporal lobar degeneration (FTLD) in patients with and without mutations in progranulin (GRN) and to determine whether TMEM106B modulates GRN expression. Methods: We performed a case-control study of 3 SNPs in TMEM106B in 482 patients with clinical and 80 patients with pathologic FTLD–TAR DNA-binding protein 43 without GRN mutations, 78 patients with FTLD with GRN mutations, and 822 controls. Association analysis of TMEM106B with GRN plasma levels was performed in 1,013 controls and TMEM106B and GRN mRNA expression levels were correlated in peripheral blood samples from 33 patients with FTLD and 150 controls. Results: In our complete FTLD patient cohort, nominal significance was identified for 2 TMEM106B SNPs (top SNP rs1990622, pallelic = 0.036). However, the most significant association with risk of FTLD was observed in the subgroup of GRN mutation carriers compared to controls (corrected pallelic = 0.0009), where there was a highly significant decrease in the frequency of homozygote carriers of the minor alleles of all TMEM106B SNPs (top SNP rs1990622, CC genotype frequency 2.6% vs 19.1%, corrected precessive = 0.009). We further identified a significant association of TMEM106B SNPs with plasma GRN levels in controls (top SNP rs1990622, corrected p = 0.002) and in peripheral blood samples a highly significant correlation was observed between TMEM106B and GRN mRNA expression in patients with FTLD (r = −0.63, p = 7.7 × 10−5) and controls (r = −0.49, p = 2.2 × 10−10). Conclusions: In our study, TMEM106B SNPs significantly reduced the disease penetrance in patients with GRN mutations, potentially by modulating GRN levels. These findings hold promise for the development of future protective therapies for FTLD.