HIV-associated neurocognitive disorder in Australia: a case of a high-functioning and optimally treated cohort and implications for international neuroHIV research

Abstract The Australian HIV-infected (HIV+) population is largely comprised of high-functioning men who have sex with men (MSM). Like other English-speaking countries, Australia mostly relies on US neuropsychological normative standards to detect and determine the prevalence of neurological disorders. Whether the US neuropsychological (NP) normative standards are appropriate in Australian HIV+ MSM has not been established. Ninety virally suppressed HIV+ and 49 HIV-uninfected (HIV−) men (respectively 86 and 85 % self-reported MSM; mean age 54 and 56 years, mean premorbid verbal IQ estimate 110 and 111) undertook standard NP testing. The raw neuropsychological data were transformed using the following: (1) US standards as uncorrected scaled scores and demographically corrected T scores (US norms); and (2) z scores (without demographic corrections) derived from Australian comparison group scaled scores (local norms). To determine HIV-associated neurocognitive disorder prevalence, we used a standard definition of impairment based upon a battery-wide summary score: the global deficit score (GDS). Impairment classification (GDS≥0.5) based on the local norms was best at discriminating between the two groups (HIV− = 14.3 % vs. HIV+ = 53.3 %; p<0.0001). This definition was significantly associated with age. Impairment classification based on the US norms yielded much lower impairment rate regardless of the HIV status (HIV−=4.1 % vs. HIV+=14.7 %; p= 0.05), but was associated with historical AIDS, and not age. Both types of summary scores were associated with reduced independence in activities of daily living (p≤ 0.03). Accurate neuropsychological classifications of high (or low) functioning individuals may need country-specific norms that correct for performancebased (e.g., reading) estimates of premorbid cognition in addition to the traditional demographic factors

Syntactic comprehension deficits across the FTD-ALS continuum

To establish the frequency, severity, relationship to bulbar symptoms, and neural correlates of syntactic comprehension deficits across the frontotemporal dementia–amyotrophic lateral sclerosis (FTD-ALS) disease spectrum. In total, 85 participants were included in the study; 20 amyotrophic lateral sclerosis (ALS), 15 FTD-ALS, 27 progressive nonfluent aphasia (PNFA), and 23 controls. Syntactic comprehension was evaluated in ALS, FTD-ALS, PNFA, and controls using the Test for Reception of Grammar. Voxel-based morphometry examined neuroanatomical correlates of performance. Syntactic comprehension deficits were detected in 25% of ALS (p = 0.011), 92.9% of FTD-ALS (p < 0.001), and 81.5% of PNFA (p < 0.001) patients. FTD-ALS was disproportionately impaired compared to PNFA. Impaired Test for Reception of Grammar performance was frequent in ALS with early bulbar involvement but did not correlate with bulbar impairment overall. Left peri-insular atrophy correlated with syntactic comprehension deficits. Syntactic comprehension deficits are frequent in FTD-ALS, more severe than in PNFA, and related to left peri-insular atrophy. A significant minority of ALS patients are impaired, but the relationship between bulbar symptoms and syntactic impairment is not understood

Preservation of episodic memory in semantic dementia:The importance of regions beyond the medial temporal lobes

Episodic memory impairment represents one of the hallmark clinical features of patients with Alzheimer's disease (AD) attributable to the degeneration of medial temporal and parietal regions of the brain. In contrast, a somewhat paradoxical profile of relatively intact episodic memory, particularly for non-verbal material, is observed in semantic dementia (SD), despite marked atrophy of the hippocampus. This retrospective study investigated the neural substrates of episodic memory retrieval in 20 patients with a diagnosis of SD and 21 disease-matched cases of AD and compared their performance to that of 35 age- and education-matched healthy older Controls. Participants completed the Rey Complex Figure and the memory subscale of the Addenbrooke's Cognitive Examination-Revised as indices of visual and verbal episodic recall, respectively. Relative to Controls, AD patients showed compromised memory performance on both visual and verbal memory tasks. In contrast, memory deficits in SD were modality-specific occurring exclusively on the verbal task. Controlling for semantic processing ameliorated these deficits in SD, while memory impairments persisted in AD. Voxel-based morphometry analyses revealed significant overlap in the neural correlates of verbal episodic memory in AD and SD with predominantly anteromedial regions, including the bilateral hippocampus, strongly implicated. Controlling for semantic processing negated this effect in SD, however, a distributed network of frontal, medial temporal, and parietal regions was implicated in AD. Our study corroborates the view that episodic memory deficits in SD arise very largely as a consequence of the conceptual loading of traditional tasks. We propose that the functional integrity of frontal and parietal regions enables new learning to occur in SD in the face of significant hippocampal and anteromedial temporal lobe pathology, underscoring the inherent complexity of the episodic memory circuitry

Scene construction impairments in Alzheimer's disease – A unique role for the posterior cingulate cortex

Episodic memory dysfunction represents one of the most prominent and characteristic clinical features of patients with Alzheimer's disease (AD), attributable to the degeneration of medial temporal and posterior parietal regions of the brain. Recent studies have demonstrated marked impairments in the ability to envisage personally relevant events in the future in AD. It remains unclear, however, whether AD patients can imagine fictitious scenes free from temporal constraints, a process that is proposed to rely fundamentally upon the integrity of the hippocampus. The objective of the present study was to investigate the capacity for atemporal scene construction, and its associated neural substrates, in AD. Fourteen AD patients were tested on the scene construction task and their performance was contrasted with 14 age- and education-matched healthy older Control participants. Scene construction performance was strikingly compromised in the AD group, with significant impairments evident for provision of contextual details, spatial coherence, and the overall richness of the imagined experience. Voxel-based morphometry analyses based on structural MRI revealed significant associations between scene construction capacity and atrophy in posterior parietal and lateral temporal brain structures in AD. In contrast, scene construction performance in Controls was related to integrity of frontal, parietal, and medial temporal structures, including the parahippocampal gyrus and posterior hippocampus. The posterior cingulate cortex (PCC) emerged as the common region implicated for scene construction performance across participant groups. Our study highlights the importance of regions specialised for spatial and contextual processing for the construction of atemporal scenes. Damage to these regions in AD compromises the ability to construct novel scenes, leading to the recapitulation of content from previously experienced events

Validity of Cognitive Screens for HIV-Associated Neurocognitive Disorder: A Systematic Review and an Informed Screen Selection Guide

Various screening tools have been proposed to identify HIV-Associated Neurocognitive Disorder (HAND). However, there has been no systematic review of their strengths and weaknesses in detecting HAND when compared to gold standard neuropsychological testing. Thirty-five studies assessing HAND screens that were conducted in the era of combination antiretroviral therapy were retrieved using standard search procedures. Of those, 19 (54 %) compared their screen to standard neuropsychological testing. Studies were characterised by a wide variation in criterion validity primarily due to non-standard definition of neurocognitive impairment, and to the demographic and clinical heterogeneity of samples. Assessment of construct validity was lacking, and longitudinal useability was not established. To address these limitations, the current review proposed a summary of the most sensitive and specific studies (>70 %), as well as providing explicit caution regarding their weaknesses, and recommendations for their use in HIV primary care settings. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11904-013-0176-6) contains supplementary material, which is available to authorized users

Differentiating between right-lateralised semantic dementia and behavioural-variant frontotemporal dementia : an examination of clinical characteristics and emotion processing

Background and purpose: Right-lateralised semantic dementia (right SD) and behavioural-variant frontotemporal dementia (bvFTD) appear clinically similar, despite different patterns of underlying brain changes. This study aimed to elucidate distinguishing clinical and cognitive features in right SD versus bvFTD, emphasising emotion processing and its associated neural correlates. Methods: 12 patients with right SD and 19 patients with bvFTD were recruited. Clinical features were documented. All patients were assessed on standardised neuropsychological tests and a facial emotion processing battery. Performance was compared to 20 age-matched and education-matched controls. Grey matter intensity was related to emotion processing performance using whole-brain voxel-based morphometry analysis. Results: Patients with right SD exhibited disproportionate language dysfunction, prosopagnosia and a suggestion of increased obsessive personality/behavioural changes versus patients with bvFTD. In contrast, patients with bvFTD demonstrated pronounced deficits in attention/working memory, increased apathy and greater executive dysfunction, compared to patients with right SD. Decreased empathy, disinhibition and diet changes were common to both dementia subtypes. Emotion processing deficits were present in both FTD syndromes but were associated with divergent patterns of brain atrophy. In right SD, emotion processing dysfunction was associated with predominantly right medial and lateral temporal integrity, compared to mainly left temporal, inferior frontal and orbitofrontal and right frontal gyrus integrity in bvFTD. Conclusions: This study demonstrates comparable deficits in facial emotion processing in right SD and bvFTD, in keeping with their similar clinical profiles. These deficits are attributable to divergent neural substrates in each patient group, namely, right lateralised regions in right SD, versus predominantly left lateralised regions in bvFTD.7 page(s

'Language of the past' - exploring past tense disruption during autobiographical narration in neurodegenerative disorders

Compromised retrieval of autobiographical memory (ABM) is well established in neurodegenerative disorders. The recounting of autobiographical events is inextricably linked to linguistic knowledge, yet no study to date has investigated whether tense use during autobiographical narration is disrupted in dementia syndromes. This study investigated the incidence of correct past tense use during ABM narration in patients with Alzheimer's disease (AD, n = 10) and semantic dementia (SD, n = 10) in comparison with healthy older Controls (n = 10). Autobiographical narratives were analysed for episodic content (internal/external) and classified according to tense use (past/present). Across both patient groups, use of the past tense was significantly compromised relative to Controls, with increased levels of off-target present tense verbs observed. Voxel-based morphometry analyses based on structural MRI revealed differential associations between past tense use and regions of grey matter intensity in the brain. Bilateral temporal cortices were implicated in the SD group, whereas frontal, lateral, and medial temporal regions including the right hippocampus emerged in AD. This preliminary study provides the first demonstration of the disruption of specific linguistic constructs during autobiographical narration in AD and SD. Future studies are warranted to clarify at what point in the disease trajectory such deficits in tense use emerge, and whether these deficits are a product or contributing factor in memory disruption in these syndromes.22 page(s

A Screening strategy for HIV-associated neurocognitive disorders that accurately identifies patients requiring neurological review

Background. Human immunodeficiency virus (HIV)–associated neurocognitive disorders (HAND) are not routinely assessed due to the lack of an adequate screening strategy. We aimed to develop a clinically relevant screening procedure for symptomatic HAND, validated against a gold standard neuropsychological (NP) test battery. Methods. Representative HIV-infected (HIV+) and demographically matched HIV-uninfected (HIV−) participants in an observational study completed a standard evaluation for mood, drug and/or alcohol use, and activities of daily living and a newly designed 20-minute computerized CogState battery that assessed 5 cognitive domains. A subset completed standard NP assessment for 8 cognitive domains. HAND definition on screening and gold standard NP was determined using demographically corrected z scores and the global deficit score (≥ 0.5), applying the Frascati criteria. Participants were blinded to screening results, and the NP examiner was blinded to screening and HIV status. Results. A total of 254 HIV+ participants were enrolled—mean age, 48.9 ± 10.2 years; median nadir CD4, 270 cells/mL; tertiary educated, 54%; and HIV− controls, 72. HIV+ HAND screening prevalence was 30.7% (HIV-associated dementia, 3.2%; mild neurocognitive disorder, 12.6%; and asymptomatic neurocognitive disorder, 15.0%; HIV− group: 13.9%; P = .004). Of the 75 participants who completed the NP battery, the HAND rate in the HIV+ group was 50.9% vs 43.4% by screening (P > .50). HAND screening vs gold standard NP sensitivity was 76% and specificity was 71%. Clinically relevant HIV-associated dementia and mild neurocognitive disorder sensitivity was 100% and specificity was 98% (positive predictive value 0.92). Conclusions. Symptomatic HAND warranting neurological review was accurately predicted using a CogState-based screening procedure.7 page(s