David F. Tang-Wai

A comparison of the mini mental state exam to the Montreal cognitive assessment in identifying cognitive deficits in Parkinson's disease.

Dementia is an important and increasingly recognized problem in Parkinsons disease (PD). The mini‐mental state examination (MMSE) often fails to detect early cognitive decline. The Montreal cognitive assessment (MoCA) is a brief tool developed to detect mild cognitive impairment that assesses a broader range of domains frequently affected in PD. The scores on the MMSE and the MoCA were compared in 88 patients with PD. A pronounced ceiling effect was observed with the MMSE but not with the MoCA. The range and standard deviation of scores was larger with the MoCA(7–30, 4.26) than with the MMSE(16–30, 2.55). The percentage of subjects scoring below a cutoff of 26/30 (used by others to detect mild cognitive impairment) was higher on the MoCA (32%) than on the MMSE (11%)(P < 0.000002). Compared to the MMSE, the MoCA may be a more sensitive tool to identify early cognitive impairment in PD.

Imaging correlates of posterior cortical atrophy

The aim of this study was to compare patterns of cerebral atrophy on MRI, and neurochemistry on magnetic resonance spectroscopy (MRS), in patients with posterior cortical atrophy (PCA) and typical Alzheimers disease (AD). Voxel-based morphometry was used to assess grey matter atrophy in 38 patients with PCA, 38 patients with typical AD, and 38 controls. Clinical data was assessed in all PCA patients. Single voxel (1)H MRS located in the posterior cingulate was analyzed in a subset of patients with PCA, typical AD, and control subjects. PCA showed a pattern of atrophy affecting occipital, parietal and posterior temporal lobes, compared to controls. The pattern was bilateral, but more severe on the right. Patients with PCA showed greater atrophy in the right visual association cortex than patients with typical AD, whereas those with AD showed greater atrophy in the left hippocampus than those with PCA. (1)H MRS suggested loss of neuronal integrity and glial activation in subjects with PCA and typical AD. The differing patterns of atrophy on MRI suggest that PCA should be considered a distinct entity from typical AD.

Increased Cerebral Metabolism After 1 Year of Deep Brain Stimulation in Alzheimer Disease

BACKGROUNDnThe importance of developing unique, neural circuitry-based treatments for the cognitive and neuropsychiatric symptoms of Alzheimer disease (AD) was the impetus for a phase I study of deep brain stimulation (DBS) in patients with AD that targeted the fornix.nnnOBJECTIVEnTo test the hypotheses that DBS would increase cerebral glucose metabolism in cortical and hippocampal circuits and that increased metabolism would be correlated with better clinical outcomes.nnnDESIGNnOpen-label trial.nnnSETTINGnAcademic medical center.nnnPATIENTSnA total of 5 patients with mild, probable AD (1 woman and 4 men, with a mean [SD] age of 62.6 [4.2] years).nnnINTERVENTIONnDeep brain stimulation of the fornix.nnnMAIN OUTCOME MEASURESnAll patients underwent clinical follow-up and high-resolution positron emission tomography studies of cerebral glucose metabolism after 1 year of DBS.nnnRESULTSnFunctional connectivity analyses revealed that 1 year of DBS increased cerebral glucose metabolism in 2 orthogonal networks: a frontal-temporal-parietal-striatal-thalamic network and a frontal-temporal-parietal-occipital-hippocampal network. In similar cortical regions, higher baseline metabolism prior to DBS and increased metabolism after 1 year of DBS were correlated with better outcomes in global cognition, memory, and quality of life.nnnCONCLUSIONSnIncreased connectivity after 1 year of DBS is observed, which is in contrast to the decreased connectivity observed over the course of AD. The persistent cortical metabolic increases after 1 year of DBS were associated with better clinical outcomes in this patient sample and are greater in magnitude and more extensive in the effects on cortical circuitry compared with the effects reported for pharmacotherapy over 1 year in AD.

Abnormal network connectivity in frontotemporal dementia: Evidence for prefrontal isolation

INTRODUCTIONnDegraded social function, disinhibition, and stereotypy are defining characteristics of frontotemporal dementia (FTD), manifesting in both the behavioral variant of frontotemporal dementia (bvFTD) and semantic dementia (SD) subtypes. Recent neuroimaging research also associates FTD with alterations in the brains intrinsic connectivity networks. The present study explored the relationship between neural network connectivity and specific behavioral symptoms in FTD.nnnMETHODSnResting-state functional magnetic resonance imaging was employed to investigate neural network changes in bvFTD and SD. We used independent components analysis (ICA) to examine changes in frontolimbic network connectivity, as well as several metrics of local network strength, such as the fractional amplitude of low-frequency fluctuations, regional homogeneity, and seed-based functional connectivity. For each analysis, we compared each FTD subgroup to healthy controls, characterizing general and subtype-unique network changes. The relationship between abnormal connectivity in FTD and behavior disturbances was explored.nnnRESULTSnAcross multiple analytic approaches, both bvFTD and SD were associated with disrupted frontolimbic connectivity and elevated local connectivity within the prefrontal cortex. Even after controlling for structural atrophy, prefrontal hyperconnectivity was robustly associated with apathy scores. Frontolimbic disconnection was associated with lower disinhibition scores, suggesting that abnormal frontolimbic connectivity contributes to positive symptoms in dementia. Unique to bvFTD, stereotypy was associated with elevated default network connectivity in the right angular gyrus. The behavioral variant was also associated with marginally higher apathy scores and a more diffuse pattern of prefrontal hyperconnectivity than SD.nnnCONCLUSIONSnThe present findings support a theory of FTD as a disorder of frontolimbic disconnection leading to unconstrained prefrontal connectivity. Prefrontal hyperconnectivity may represent a compensatory response to the absence of affective feedback during the planning and execution of behavior. Increased reliance upon prefrontal processes in isolation from subcortical structures appears to be maladaptive and may drive behavioral withdrawal that is commonly observed in later phases of neurodegeneration.

Measuring mild cognitive impairment in patients with Parkinson's disease.

We examined the frequency of Parkinson disease with mild cognitive impairment (PD‐MCI) and its subtypes and the accuracy of 3 cognitive scales for detecting PD‐MCI using the new criteria for PD‐MCI proposed by the Movement Disorders Society. Nondemented patients with Parkinsons disease completed a clinical visit with the 3 screening tests followed 1 to 3 weeks later by neuropsychological testing. Of 139 patients, 46 met Level 2 Task Force criteria for PD‐MCI when impaired performance was based on comparisons with normative scores. Forty‐two patients (93%) had multi‐domain MCI. At the lowest cutoff levels that provided at least 80% sensitivity, specificity was 44% for the Montreal Cognitive Assessment and 33% for the Scales for Outcomes in Parkinsons Disease‐Cognition. The Mini‐Mental State Examination could not achieve 80% sensitivity at any cutoff score. At the highest cutoff levels that provided specificity of at least 80%, sensitivities were low (≤44%) for all tests. When decline from estimated premorbid levels was considered evidence of cognitive impairment, 110 of 139 patients were classified with PD‐MCI, and 103 (94%) had multi‐domain MCI. We observed dramatic differences in the proportion of patients who had PD‐MCI using the new Level 2 criteria, depending on whether or not decline from premorbid level of intellectual function was considered. Recommendations for methods of operationalizing decline from premorbid levels constitute an unmet need. Among the 3 screening tests examined, none of the instruments provided good combined sensitivity and specificity for PD‐MCI. Other tests recommended by the Task Force Level 1 criteria may represent better choices, and these should be the subject of future research.

A Phase II Study of Fornix Deep Brain Stimulation in Mild Alzheimer's Disease

Background: Deep brain stimulation (DBS) is used to modulate the activity of dysfunctional brain circuits. The safety and efficacy of DBS in dementia is unknown. Objective: To assess DBS of memory circuits as a treatment for patients with mild Alzheimer’s disease (AD). Methods: We evaluated active “on” versus sham “off” bilateral DBS directed at the fornix-a major fiber bundle in the brain’s memory circuit-in a randomized, double-blind trial (ClinicalTrials.gov NCT01608061) in 42 patients with mild AD. We measured cognitive function and cerebral glucose metabolism up to 12 months post-implantation. Results: Surgery and electrical stimulation were safe and well tolerated. There were no significant differences in the primary cognitive outcomes (ADAS-Cog 13, CDR-SB) in the “on” versus “off” stimulation group at 12 months for the whole cohort. Patients receiving stimulation showed increased metabolism at 6 months but this was not significant at 12 months. On post-hoc analysis, there was a significant interaction between age and treatment outcome: in contrast to patientsu200a<65 years old (nu200a=u200a12) whose results trended toward being worse with DBS ON versus OFF, in patients≥65 (nu200a=u200a30) DBS-f ON treatment was associated with a trend toward both benefit on clinical outcomes and a greater increase in cerebral glucose metabolism. Conclusion: DBS for AD was safe and associated with increased cerebral glucose metabolism. There were no differences in cognitive outcomes for participants as a whole, but participants aged≥65 years may have derived benefit while there was possible worsening in patients below age 65 years with stimulation.

Anti-NMDA-Receptor Encephalitis: Case Report and Literature Review of an Under-Recognized Condition

Anti-N-methyl-D-aspartate receptor (anti-NMDA-R) encephalitis is an immune-mediated syndrome that remains under-recognized despite a growing body of literature. This syndrome has been predominantly described in young females with a constellation of symptoms, including personality changes, autonomic dysfunction and neurologic decompensation. It is commonly associated with mature ovarian teratomas. We describe the classic presentation of anti-NMDA-R encephalitis in three dramatically different patients: Case A, a young woman with ovarian teratoma; Case B, the eldest case reported to date; and Case C, a young male with no identifiable tumor. We review the literature summarizing the differential diagnosis, investigative approach, treatment options and challenges inherent to this disorder. We advocate good supportive care, involvement of multiple health disciplines and use of immune-modulating therapies in patient management. These cases underscore the need for increased awareness and high diagnostic suspicion when approaching the patient with suspected viral encephalitis.

Serotonergic Function and Treatment of Behavioral and Psychological Symptoms of Frontotemporal Dementia

OBJECTIVESnThe purposes of this study were first, to evaluate the effectiveness of citalopram in treating behavioral disturbances in frontotemporal dementia (FTD) subjects and second, to determine whether an association exists between serotonergic function, as determined by a neuroendocrine challenge, and treatment response.nnnDESIGNnSingle-dose citalopram (30 mg per os) challenge followed by a 6-week open-label study.nnnSETTINGnOutpatients referred to memory clinics.nnnPARTICIPANTSnFifteen patients suffering from FTD with severe behavioral and psychological symptoms of dementia.nnnINTERVENTIONnFollowing citalopram challenge, all patients were treated with citalopram titrated to a target dose of 40 mg once daily.nnnMEASUREMENTSnBehavioral disturbances, using the Neuropsychiatric Inventory (NPI) (primary outcome) and Frontal Behavioural Inventory (secondary outcome), were assessed. Change in prolactin concentration following citalopram challenge was used as an index of central serotonergic response.nnnRESULTSnCitalopram treatment was effective in treating behavioral symptoms, with significant decreases in NPI total score (F[2, 28] = 6.644, p = 0.004), disinhibition (F[2, 28] = 4.030, p = 0.029), irritability (F[2, 28] = 7.497, p = 0.003) and depression (F[2, 28] = 3.467, p = 0.045) scores over the 6 weeks. Significant improvement in Frontal Behavioural Inventory scores suggested that citalopram was also effective in the treatment ofbehaviors specific to FTD. A lower change score in concentration of prolactin was significantly positively correlated with greater improvement in the total NPI score from baseline to endpoint (r = 0.687, p = 0.005). A blunted response to a citalopram challenge, implying a dysfunctional serotonergic system, predicted a more positive treatment outcome.nnnCONCLUSIONSnThe results suggest that despite the endogenous serotonin deficiency of FTD, citalopram treatment may be effective in targeting the behavioral disturbances characteristic of FTD.

Whole-brain white matter disruption in semantic and nonfluent variants of primary progressive aphasia

Semantic (svPPA) and nonfluent (nfPPA) variants of primary progressive aphasia are associated with distinct patterns of cortical atrophy and underlying pathology. Little is known, however, about their contrasting spread of white matter disruption and how this relates to grey matter (GM) loss. We undertook a structural MRI study to investigate this relationship. We used diffusion tensor imaging, tract‐based spatial statistics, and voxel‐based morphometry to examine fractional anisotropy (FA) and directional diffusivities in nine patients with svPPA and nine patients with nfPPA, and compared them to 16 matched controls after accounting for global GM atrophy. Significant differences in topography of white matter changes were found, with more ventral involvement in svPPA patients and more widespread frontal involvement in nfPPA individuals. However, each group had both ventral and dorsal tract changes, and both showed spread of diffusion abnormalities beyond sites of local atrophy. There was a clear dissociation in sensitivity of diffusion tensor imaging measures between groups. SvPPA patients showed widespread changes in FA and radial diffusivity, whereas changes in axial diffusivity were more restricted and proximal to sites of GM atrophy. NfPPA patients showed isolated changes in FA, but widespread axial and radial diffusivity changes. These findings reveal the extent of white matter disruption in these variants of PPA after accounting for GM loss. Further, they suggest that differences in the relative sensitivity of diffusion metrics may reflect differences in the nature of underlying white matter pathology in these two subtypes. Hum Brain Mapp, 2013.

What are we seeing? Is posterior cortical atrophy just Alzheimer disease?

Posterior cortical atrophy (PCA) is a dementing syndrome that presents with signs and symptoms of cortical visual dysfunction.1 The clinical features of PCA reflect dysfunction of both the ventral/occipito-temporal visual processing pathway causing apperceptive visual agnosia, alexia, and prosopagnosia and dorsal/occipito-parietal pathway causing Balint syndrome (simultanagnosia, optic ataxia and ocular apraxia), transcortical sensory aphasia, apraxia, and some or all of the elements of Gerstmann syndrome (agraphia, acalculia, finger agnosia, right-left disorientation).2,3 Frontal lobe functions and memory are relatively preserved until later in the course of the disease.nnIn this issue of Neurology , McMonagle et al.4 describe the cognitive profile of 19 patients with PCA and compare this to the profile of 11 patients with typical amnestic Alzheimer disease …