There is a substantial body of evidence that individuals with long-standing HIV infection
experience accelerated neurological aging and prospective lifespan studies that
incorporate neuropsychological and imaging outcomes are needed. Elevated risks of
cerebrovascular disease are evident throughout the life course of persons living with
HIV. Stroke risks are clearly increased in the first few months after antiretroviral
initiation. Autopsy studies of adults with HIV 24-48 years of age showed all have
vascular changes, specifically lymphocytic perivascular infiltration, thickening of
arterial and arteriolar walls, widened perivascular space, hypertrophy of the vascular
muscle layers and perivascular amyloid deposition. Even when excluding individuals with a
history of stroke, cerebrovascular disease risk factors are associated with decreased
cognitive capacity in persons with HIV. Basal ganglia enhancement on MRI indicative of
decreased regional cerebral blood flow and blood brain barrier breakdown is associated
with HIV dementia.
HIV-associated neurocognitive disorder is another manifestation of accelerated aging.
Using diffusion tensor imaging and data from healthy controls to calculate an "brain age
gaps" in individuals with HIV infection, the "brain age gap", is associated with plasma
viral load and cognitive function. In an autopsy study comparing HIV+ persons age 36-60
years with age-matched controls, HIV showed increased amyloid beta immunostaining. The
accumulation of these proteins may be one possible mechanisms of accelerated aging in
HIV. Some have proposed that BBB breakdown secondary to vascular dysfunction may
contribute to this deposition. Distal sensory polyneuropathy (DSPN), a common
neurological comorbidity in HIV that also increases in frequency with age in HIV negative
individuals. Despite extensive diagnostic evaluations, ~40% of people with a DSPN will
have no clear underlying cause identified. DSPN is more common and complex in African
population with additional underlying etiologies being medication toxicities and
nutritional deficiencies.In the RAAZ study, investigators identified a high prevalence of
DSPN among HIV infected individuals prior to ART initiation which is associated with low
body mass index and food insecurity. More recent neuropathy studies have shown that
folate deficiency may play a role in DSPN in Zambia with HIV+ individuals being
especially susceptible. Epilepsy incidence shows a bimodal age distribution with the
increased incidence of seizures and epilepsy in the elderly attributed to the increase of
age-related and aging-related epileptogenic conditions. While the overall prevalence of
epilepsy can be expected to increase with advanced age in HIV, identifying risk factors
for this among persons for epilepsy among those with controlled systemic disease may
offer important insights into the pathophysiology.
HIV-associated accelerated aging of the nervous system is thought to be related to
ongoing low grade inflammation in the setting of treated HIV. Poor CNS penetration of
some antiretroviral therapies (ARVs) has also been proposed as one problem contributing
to neurological morbidity in systemically controlled HIV. ARV neurotoxicity is also
important. Multiple studies have highlighted both the short and long term neurotoxicity
of efavirenz. Darunavir and ritonavir may increase the risk of aging-related cerebral
degeneration. Heneka 2020 proposed that COVID survivors may be at increased risk of
neurological disorders due to direct negative effects of SARS-CoV-2, acceleration of
pre-existing problems or de novo induction of neurodegenerative process. Poor complex
motor performance in persons with HIV is associated with higher inflammatory burden. A
recent report from Ghana found stroke admissions and mortality rates have increased since
SARS-CoV-2's arrival.
In the SNAP Study, the investigators will utilize the existing consortia of neuro-HIV
rural study sites to enroll 150 HIV+ adults >45 years of age stable on ARVs for at least
7 years and an age, gender, and community-matched comparison group of HIV+ adults stable
on ARVs for 1-2 years. These individuals will undergo annual assessments for 6 years to
evaluate their general and neurological health and the aging process that evolves during
the 6 years of assessments.
Understanding whether or not PLWH experience accelerated aging of the nervous system will
provide critical insights for health services planning as antiretroviral therapies allow
PLWH to live into middle and late years. Identifying risk factors for specific neurologic
aging issues will guide clinical care and screening and may inform regarding the
pathophysiological mechanisms involved including the possibility that some therapies
contribute to the long-term neurotoxicity of the condition.