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Case Report: HIV, alzheimers, dementia - An individual with human immunodeficiency virus, dementia, and central nervous system amyloid deposition
 
 
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"Diagnosis of dementia in older HIV-infected individuals is on the rise. HIV-infected adults over 55 comprise the fastest growing age group in the HIV-positive population....finding suggests that some older HIV-positive patients with dementia may be misdiagnosed with HIV-associated neurocognitive disorders (HAND) when they may be developing AD.....some patients experience HAND and AD - a new type of mixed dementia....According to the most recent CDC HIV Surveillance Report with data through 2013, 53,000 people in the U.S. living with HIV are 65 and older, the age when Alzheimer's disease risk begins to escalate. That number is expected to double in less than 10 years and doesn't include those who have not been diagnosed. Worldwide, more than 37 million people are living with HIV."
 
from Jules: Federal officials and advocates have NOT addressed the needs adequately for aging HIV+ patients, this includes The White House & HHS, although the White House held a few aging meetings no firm special plan has been discussed to address the needs for patients, as well HHS marginalizes this problem, services & special attention is needed, by 2020 over 30% of HIV+ in the USA will be over 60. Its not just the federal govt ignoring this but advocates & activists as well have not dedicated time to understanding or advocating for attention. As well, HIV researchers and care leadership has been dismissing these issues. I know because I have tried for the past few years to raise attention for some of the key issues related to HIV + Aging including specialized services needed but I have made NO headway with The White House, advocates nor HHS officials.
 
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First Diagnosed Case of Alzheimer's Disease in HIV-Positive Individual Reported
 
WASHINGTON (April 15, 2016) - Georgetown University researchers are reporting the first case of Alzheimer's disease diagnosed in an HIV-positive individual. The finding in a 71-year-old man triggers a realization about HIV survivors now reaching the age when Alzheimer's risk begins to escalate.
 
Published online in the open access journal Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, neurologist R. Scott Turner, MD, PhD, (pictured) diagnosed the patient after a PET scan showed deposition of amyloid in the brain. Until this point, Turner says, clinicians thought that individuals with HIV may not develop AD because HIV-related inflammation in the brain may prevent amyloid clumps from forming.
 
"This patient may be a sentinel case that disputes what we thought we knew about dementia in HIV-positive individuals," says Turner, who leads the Memory Disorders Program at Georgetown University Medical Center.
 
In addition, Turner says the finding suggests that some older HIV-positive patients with dementia may be misdiagnosed with HIV-associated neurocognitive disorders (HAND) when they may be developing AD. It also may be possible that some patients experience HAND and AD - a new type of mixed dementia, Turner says. "Chronic HIV infection and amyloid deposition with aging may represent a "double-hit" to the brain that results in progressive dementia."
 
"While it may be challenging to diagnose the cause of dementia in an HIV-positive patient, the diagnosis matters because HAND and AD are treated differently," he says. "For Alzheimer's disease, we now have four FDA-approved drugs and more effective treatments are on the way. For HAND, we prescribe anti-retroviral drugs that have a better chance of penetrating the brain. So getting a correct diagnosis is important, and a critical first step in advancing the field."
 
HAND will develop in 30-50 percent of individuals with long-term HIV infections. But HAND symptoms are identical to those with AD, Turner says. He adds, "The medical community assumes that dementia with HIV is caused by HAND. Physicians haven't considered Alzheimer's, so it's possible that a number of older HIV-positive individuals may be misdiagnosed."
 
Published studies to date point to only five individuals with HAND who have undergone amyloid PET imaging, and all were negative; however, the oldest of these patients was 67, Turner says.
 
Diagnosis of dementia in older HIV-infected individuals is on the rise. HIV-infected adults over 55 comprise the fastest growing age group in the HIV-positive population. According to the most recent CDC HIV Surveillance Report with data through 2013, 53,000 people in the U.S. living with HIV are 65 and older, the age when Alzheimer's disease risk begins to escalate. That number is expected to double in less than 10 years and doesn't include those who have not been diagnosed. Worldwide, more than 37 million people are living with HIV.
 
"This case report reveals important new insights into the specific issue of HIV-related neurological impairment," says Jeffrey Crowley, MPH, program director of the National HIV/AIDS Initiative at the O'Neill Institute for National and Global Health Law at Georgetown Law. Crowley is former director of the White House Office of National AIDS Policy and senior advisor on disability policy. "This finding must lead to additional population-based studies, as well as timely clinical and programmatic interventions to better support individuals with HIV who are facing neurological decline."
 
This work was supported, in part, by a grant from the Alzheimer's Drug Discovery Foundation. Piramal, Inc., manufacturer of florbetaben (NeuraCeq) used to identify amyloid, covered the cost of the amyloid PET scan. (Amyloid PET scans, which cost about $4,000, are not covered by Medicare).
 
Co-authors on the report include Georgetown researchers Melanie Chadwick, NP; Wesley A. Horton; Gary Simon, MD, PhD; Xiong Jiang, PhD; and Giuseppe Esposito, MD.
 
"This case report suggests that progressive dementia in older HIV+ individuals may be due to HAND, AD, or both. We propose that the individual described here may have a mixed dementia-HAND and probable AD, but dementia due to either diagnosis alone cannot be excluded. This case suggests that CNS HIV infection does not preclude Aβ/amyloid deposition.
 
.......It is currently unknown whether chronic HIV infection and/or treatment are risk factors for Alzheimer's disease (AD). As an increasing fraction of the HIV+ populace advances into the geriatric age range, clinicians will be challenged to differentiate HAND from other dementias of aging, including AD.....The subject is a 71 year-old man with a 14-year history of HIV infection.....His physical and neurologic examination was remarkable only for cognitive impairment.....This sentinel case raises new questions regarding diagnosis, pathogenesis, and treatment of dementia in older HIV+ subjects that require further studies.
 
This case report suggests that progressive dementia in older HIV+ individuals may be due to HAND, AD, or both. We propose that the individual described here may have a mixed dementia-HAND and probable AD, but dementia due to either diagnosis alone cannot be excluded. This case suggests that CNS HIV infection does not preclude Aβ/amyloid deposition. In fact, chronic HIV infection may be a risk factor for AD because of neuroinflammation, accelerated CNS aging, and reduced cognitive reserve-thus constituting a "double-hit." In support of this notion, Cysique et al. [13] report that CSF biomarker profiles of HIV+ individuals suggest a 10x higher risk for AD compared with age-matched uninfected subjects. Although CNS HIV infection may be the primary etiology of HAND, a role for cART is also possible because of adverse effects of chronic treatment. Consistent with this notion, Caniglia et al. [14] report that cART regimens with a high CNS penetration effectiveness score increase the risk of HIV dementia. Antiretroviral medications disrupt microglial phagocytosis of β-amyloid and increase its production by neurons in vitro [15]. In contrast, Lan et al. [16] suggest that cART inhibits Aβ clearance in macrophages and Aβ production in neurons, but these effects do not significantly alter CNS Aβ accumulation in a mouse model. Clearly, the potential interactions of HAND and AD pathologies leading to dementia, including a possible role of cART, require further research."
 
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An individual with human immunodeficiency virus, dementia, and central nervous system amyloid deposition
 
April 14 2016
 
Raymond Scott Turnera,*, Melanie Chadwicka, Wesley A. Hortona, Gary L. Simonb, Xiong Jiangc, Giuseppe Espositod aDepartment of Neurology, Georgetown University, Washington, DC, USA bDepartment of Infectious Diseases, George Washington University, Washington, DC, USA cDepartment of Neuroscience, Georgetown University, Washington, DC, USA dDepartment of Radiology, Georgetown University, Washington, DC, USA
 
Abstract
 
Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) is found in 30%-50% of individuals with HIV infection. To date, no HIV+ individual has been reported to have a positive amyloid PET scan.
 
We report a 71-year-old HIV+ individual with HAND. Clinical and neuropsychologic evaluations confirmed a progressive mild dementia.
 
A routine brain MRI was normal for age. [18F]Fluorodeoxyglucose-PET revealed mild hypermetabolism in bilateral basal ganglia and hypometabolism of bilateral parietal cortex including the posterior cingulate/precuneus. Resting state functional MRI revealed altered connectivity as found with individuals with mild AD. CSF examination revealed a low Aβ42/tau index but a low phospho-tau. An amyloid PET/CT with [18F]florbetaben revealed pronounced cortical radiotracer deposition.
 
This case report suggests that progressive dementia in older HIV+ individuals may be due to HAND, AD, or both. HIV infection does not preclude CNS Aβ/amyloid deposition. Amyloid PET imaging may be of value in distinguishing HAND from AD pathologies.
 
1. Introduction
 
More than 36.9 million individuals worldwide are infected with human immunodeficiency virus (HIV) in 2014 [1]. HIV infection has largely changed from a fatal illness to a chronic manageable condition since the introduction of combination antiretroviral treatment (cART) in 1996. HIV-infected adults older than 55 years comprise the fastest growing age group in the HIV+ population [2]. HIV-associated neurocognitive disorder (HAND) occurs in 30%-50% of HIV+ individuals treated with cART [3]. The etiology of HAND remains unclear but may be due to viral infection and inflammation accelerating CNS aging [4] and decreasing cognitive reserve. It is currently unknown whether chronic HIV infection and/or treatment are risk factors for Alzheimer's disease (AD). As an increasing fraction of the HIV+ populace advances into the geriatric age range, clinicians will be challenged to differentiate HAND from other dementias of aging, including AD.
 
Putative biomarkers of AD pathology, including cerebrospinal fluid (CSF) proteomics-Aβ/amyloid, tau, phospho-tau, and others, and amyloid PET neuroimaging are supportive of a clinical diagnosis of AD pathology [5] in HIV-uninfected individuals. Only one case of HAND and biomarker-supported AD has been reported-with abnormal [18F]fluorodeoxyglucose-PET and CSF proteomics [6]. However, a review of CSF AD biomarkers in subjects with HAND reveals low amyloid levels in both diagnoses, increased phospho-tau in AD, and inconsistent tau levels in HAND [7]. To date, no HIV+ individual has been reported to have a positive amyloid PET scan. In fact, Ances et al. [8] suggest that HAND is not associated with increased CNS fibrillar amyloid as detected by amyloid PET imaging because all five subjects examined were negative, but the oldest was 67 years old. Given the aging HIV+ populace, we report the sentinel case of a possible new emerging epidemic of HAND/AD.
 
2. Methods and results
 
2.1. Case study

 
The subject is a 71 year-old man with a 14-year history of HIV infection diagnosed after presenting with flu-like symptoms and a viral pneumonia. He was subsequently treated with cART. He and his wife noted mild short-term memory problems for 5 years with insidious onset and a more noticeable decline in the last 3 years. His symptoms manifested by comprehension difficulty, forgetting recent conversations, and difficulty with multitasking. Functionally, he stated that he took longer to complete projects and sometimes made mistakes. He could no longer work as an attorney. His spouse stated that he had trouble learning new skills such as using his cellular telephone. As calculations became more challenging, his spouse assumed household financial management. He currently shops independently but requires a list. He performs personal care and basic activities of daily living with minimal or no assistance. He describes his mood as fearful of his cognitive disorder. He remains socially active, exercises daily, and enjoys weekly religious services. He denies aggression, anxiety, agitation, hallucinations, delusions, paranoia, and suicidal ideation. He has a long-standing history of sleep problems. His spouse also reports frequent (2-3 times a week) episodes of violent movements and screaming while dreaming. The patient reports these events as acting out his dreams. His spouse also reports occasional jerks of his extremities during sleep. Review of clinical records indicates a stable HIV infection with consistent compliance with cART (most recently abacavir, lamivudine, darunavir, and ritonavir). He also takes atorvastatin for hypercholesterolemia. There is no history of CNS infection or injury, stroke, transient ischemic attack, or alcohol or drug abuse. He had one episode of loss of consciousness with a minor head injury secondary to syncope in 2002. His mother died at age 89 years with probable AD; his father died at age 71 years with parkinsonism and dementia.
 
His physical and neurologic examination was remarkable only for cognitive impairment. His Mini-Mental State Examination [9] score was 22/30, and Montreal Cognitive Assessment [10] score was 20/30. He recalled zero of five words on delayed recall. He had difficulty with repetition and gave concrete answers to similarities. He named only seven words beginning with F in 1 minute. His paragraph recall was 5/25 immediately and 2/25 after 30 minutes. He underwent two neuropsychological evaluations 27 months apart-both consistent with dementia-which revealed interval decline of working memory and verbal fluency (Table 1). His laboratory workup revealed a chronic subnormal CD4 T cell count (∼300-350/μL), depressed CD4/CD8 ratio (0.75), and nondetectable plasma HIV RNA (<20 copies/μL); all other blood tests were normal. A polysomnogram revealed no significant sleep disordered breathing with minimal periodic limb movements unassociated with arousals and sleep fragmentation.
 
A routine brain MRI revealed atrophy and white matter changes consistent with age. [18F]fluorodeoxyglucose-PET revealed mild hypermetabolism in bilateral basal ganglia (consistent with HAND [11]) and marked hypometabolism of parietal cortex including the posterior cingulate/precuneus (consistent with AD; Fig. 1A). Likewise, resting state functional MRI (fMRI) revealed altered connectivity as found in individuals with MCI/AD using the posterior cingulate cortex as a seed region (Fig. 1B and C). CSF examination revealed 0 cells, normal glucose (59 mg/dL), elevated protein (118 mg/dL), a low Aβ42/tau index (consistent with AD), and a low phospho-tau (indeterminate for AD). More specifically, analysis of CSF proteomics revealed Aβ42 237 pg/mL, total tau 285 pg/mL, phospho-tau 49 pg/mL, and an amyloid/tau index of 0.41 (Athena Diagnostics, Worcester, MA, USA). An amyloid PET/CT with [18F]florbetaben (NEURACEQ; Piramal Imaging, Matran, Switzerland) revealed pronounced radiotracer deposition in the frontal, temporal, and parietal lobes bilaterally including the posterior cingulate/precuneus consistent with AD (Fig. 1D). His APOE genotype was not determined. He was prescribed a cholinesterase inhibitor for dementia due to AD. Enrollment in treatment trials of AD was precluded by HIV infection.
 
3. Discussion
 
This case report suggests that progressive dementia in older HIV+ individuals may be due to HAND, AD, or both. We propose that the individual described here may have a mixed dementia-HAND and probable AD, but dementia due to either diagnosis alone cannot be excluded. This case suggests that CNS HIV infection does not preclude Aβ/amyloid deposition. In fact, chronic HIV infection may be a risk factor for AD because of neuroinflammation, accelerated CNS aging, and reduced cognitive reserve-thus constituting a "double-hit." In support of this notion, Cysique et al. [13] report that CSF biomarker profiles of HIV+ individuals suggest a 10x higher risk for AD compared with age-matched uninfected subjects. Although CNS HIV infection may be the primary etiology of HAND, a role for cART is also possible because of adverse effects of chronic treatment. Consistent with this notion, Caniglia et al. [14] report that cART regimens with a high CNS penetration effectiveness score increase the risk of HIV dementia. Antiretroviral medications disrupt microglial phagocytosis of β-amyloid and increase its production by neurons in vitro [15]. In contrast, Lan et al. [16] suggest that cART inhibits Aβ clearance in macrophages and Aβ production in neurons, but these effects do not significantly alter CNS Aβ accumulation in a mouse model. Clearly, the potential interactions of HAND and AD pathologies leading to dementia, including a possible role of cART, require further research.
 
Cognitive decline in HAND may be mediated in part by CNS Aβ/amyloid accumulation [17]. Although pathologic studies of brain show that HIV increases intracellular and possibly extracellular Aβ42, Ortega and Ances [18] suggest that HIV+ individuals are not at increased risk for AD. Amyloid PET neuroimaging will be useful to distinguish putative neuropathologies of HAND-either HIV associated, amyloid associated, or both. However, to date, only five individuals with HAND have undergone amyloid PET imaging-all were negative, but the oldest subject was 67 years old [8]. Longitudinal studies of older HIV-infected versus uninfected cohorts are now needed to further define the potential interactions of HIV with AD-clinically, pathologically, and effects on prognostic, diagnostic, and theragnostic biomarkers, including fMRI.
 
Older individuals with HAND may be included in the target population of a new study designed to determine the clinical utility of amyloid imaging in subjects with dementia of uncertain etiology (IDEAS, or Imaging Dementia-Evidence for Amyloid Scanning, clinicaltrials.gov #NCT02420756). Furthermore, the optimal cART regimen for HAND remains unclear; some investigators propose a regimen with a high CNS penetration effectiveness to improve efficacy. The safety and efficacy of Food and Drug Administration-approved medications for dementia due to AD in subjects with coexisting HAND is unclear because HIV infection is invariably exclusionary in MCI and AD trials. Antiamyloid and other therapies for MCI and AD now under development may also be effective for older HIV+ individuals. This sentinel case raises new questions regarding diagnosis, pathogenesis, and treatment of dementia in older HIV+ subjects that require further studies.

 
 
 
 
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