Dissociable contributions of precuneus and cerebellum to subjective and objective neuropathy in HIV

Abstract

Neuropathy, typically diagnosed by the presence of either symptoms or signs of peripheral nerve dysfunction, remains a frequently reported complication in the antiretroviral (ART)-treated HIV population. This study was conducted in 109 healthy controls and 57 HIV-infected individuals to investigate CNS regions associated with neuropathy.

An index of objective neuropathy was computed based on 4 measures: deep tendon ankle reflex, vibration sense (great toes), position sense (great toes), and 2-point discrimination (feet). Subjective neuropathy (self-report of pain, aching, or burning; pins and needles; or numbness in legs or feet) was also evaluated. Structural MRI data were available for 126/166 cases.

The HIV relative to the healthy control group was impaired on all 4 signs of neuropathy. Within the HIV group, an objective neuropathy index of 1 (bilateral impairment on 1 measure) or 2 (bilateral impairment on at least 2/4 measures) was associated with older age and a smaller volume of the cerebellar vermis. Moderate to severe symptoms of neuropathy were associated with more depressive symptoms, reduced quality of life, and a smaller volume of the parietal precuneus.

This study is consistent with the recent contention that ART-treated HIV-related neuropathy has a CNS component. Distinguishing subjective symptoms from objective signs of neuropathy allowed for a dissociation between the precuneus, a brain region involved in conscious information processing and the vermis, involved in fine tuning of limb movements.

GRAPHICAL ABSTRACT:

In HIV patients, objective signs of neuropathy correlated with smaller cerebellar vermis (red) volumes whereas subjective symptoms of neuropathy were associated with smaller precuneus (blue) volumes.

INTRODUCTION

Peripheral sensory neuropathy is a persisting and prevalent (15-65%)(Ghosh et al. 2012) HIV-associated disturbance in the post-ART era, which may contribute to gait and balance deficits (Ducic et al. 2004), reduced quality of life (Pandya et al. 2005), and increased morbidity and mortality. Contributing factors to HIV-related peripheral neuropathy include older age (e.g., Chen et al. 2013; Saylor et al. 2017), ART toxicity (Adoukonou et al. 2017; Benevides et al. 2017), substance abuse (Morgello et al. 2004), and alcoholism (Chopra and Tiwari 2012).

Excluding the gold standards of invasive nerve biopsy or costly and complex nerve conduction studies (e.g., Asad et al. 2010; Feng et al. 2009; Nelson et al. 2006; Perkins et al. 2001; Ruhdorfer et al. 2015; Sommer 2018), clinical guidelines for the diagnosis of peripheral neuropathies require “the presence of symptoms and/or signs of peripheral nerve dysfunction” (Boulton 1998). Symptoms described can include burning or deep aching pain, stabbing sensations, or numbness, commonly experienced in the lower limbs and feet. Objective neurological signs of neuropathy can include decreased or absent ankle reflexes, decreased distal vibratory sensation, reduced pain or temperature sensation, and muscle weakness (e.g., Cornblath et al. 1999; Kaku and Simpson 2014). Combinations of more than one objective test have an 87% sensitivity for detecting neuropathy in diabetes (Boulton 1998).

Pain is the most distressing symptom of peripheral neuropathy and is often the main reason patients seek medical attention (cf., Tesfaye et al. 2013). Neuropathic pain intensity, however, is not fully explained by the extent of damage to peripheral nerve fibers (Aziz-Donnelly and Harrison 2017; Cherry et al. 2003). Although long-considered a disease of the peripheral nervous system, there is now increasing evidence for Central Nervous System (CNS) involvement in peripheral neuropathy (Keltner et al. 2017; Keltner et al. 2014; Pfefferbaum et al. 2009; Selvarajah et al. 2011; Tesfaye et al. 2016). Several neuroimaging studies in chronic diabetes have incidentally reported CNS correlates of neuropathy (e.g., de Bresser et al. 2010; Frokjaer et al. 2013; Lunetta et al. 1994; Manor et al. 2012). Diabetes with relative to without neuropathy has been associated with gray matter volume loss in somatosensory cortex, supramarginal gyrus, and cingulate gyrus (Selvarajah et al. 2014). Indeed, volume loss of the cingulate cortex, implicated in affective processing of pain (Absinta et al. 2012; Buckalew et al. 2008; Coppieters et al. 2017), is smaller in patients with chronic neuropathic pain (Sugimine et al. 2016) and small-fiber neuropathy (Hsieh et al. 2015). Similarly, the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) group reported that more intense symptoms of distal neuropathic pain in HIV are associated with a smaller posterior cingulate volume (Keltner et al. 2017). Together, the extant literature suggests that symptomatic neuropathic pain is associated with compromised integrity of the cingulate cortex.

Involvement of the thalamus in nociception has long been hypothesized based on loss of pain and temperature sensation observed in those with lesions of the thalamus (Dejerine and Roussy 1906; Garcin and Lapresle 1954; Head and Holmes 1911; Schuster 1937). Recently, performance on 2-point discrimination in healthy controls was associated with volume of the thalamus (Schmidt-Wilcke et al. 2018).

The current study aimed to determine CNS regions associated with objective and subjective peripheral neuropathy. A neuropathy index was based on 4 objective signs of bilateral lower limb impairment including perception of vibration (great toes), deep tendon ankle reflexes, position sense (great toes), and 2-point discrimination (feet). Subjective symptoms of neuropathy were considered independently. It was hypothesized that a greater incidence of objective signs would be associated with smaller thalamic volume, whereas greater intensity of subjective symptoms would be associated with a smaller posterior cingulate volume.

MATERIALS AND METHODS

Participants

The Institutional Review Boards of Stanford University and SRI International approved this study. Written informed consent was obtained from all participants in accordance with the Declaration of Helsinki by the signing of consent documents in the presence of staff after staff ensured that each participant understood the information provided and appreciated the reasonably foreseeable consequences of study participation. This study sample included 109 controls (45 women, 64 men, 51.7±14.3 years) and 59 participants with HIV infection (HIV: 17 women, 40 men, 53.3±6.9 years).

HIV patients, with a Karnofsky score (Karnofsky 1949) over 90 at study entry, were referred from local outpatient and treatment centers, or recruited during presentations in clinics by project staff and by distribution of flyers at community events. Comparison participants were recruited from the local community by referrals and flyers. All participants were screened using the Structured Clinical Interview for DSM-IV (SCID) (First et al. 1998), structured health questionnaires, and a semi-structured timeline follow-back interview to quantify lifetime alcohol consumption (Skinner and Sheu 1982). Upon initial assessment, subjects were excluded if they had a significant history of medical (e.g., epilepsy, stroke, multiple sclerosis, uncontrolled diabetes, or loss of consciousness > 30 minutes), psychiatric (i.e., schizophrenia or bipolar I disorder), neurological disorders (e.g., neurodegenerative disease), or recent (i.e., past 3 months) alcohol or substance dependence. Modified from the guidelines of an initial report (Antinori et al. 2007), a standardized score for HIV-related qualify of life was based on responses to the Brief Health and Functioning (Bozzette et al. 1995) and Activities of Daily Living questionnaires (Pfeffer et al. 1982) and Global Assessment of Functioning (i.e., GAF) (Endicott et al. 1976).

Evaluation of Peripheral Neuropathy

Four trained and calibrated laboratory personnel (2 PhDs (among them NMZ), 1 RN, and 1 MA with medical training) conducted the examination. Self-report (i.e., subjective) of neuropathy was recorded after questioning participants regarding the bilateral severity (from 1 – 10) of a) pain, aching, or burning; b) pins and needles; or c) numbness in legs or feet and scored as follows: 0 = absence of symptoms, 1 = mild symptoms (1-3), 2= moderate to severe symptoms (4-10).

The four objective signs of lower limb neuropathy evaluated included:

1. perception of vibration (right or left great toe) normal = 0, impaired = 1: perception of vibration <10 seconds

2. deep tendon ankle reflexe (right or left ankle) normal = 0, impaired = 1: absent or hypoactive ankle reflex

3. position sense (right or left great toe) normal = 0, impaired = 1: one or more errors during evaluation

4. 2-point discrimination (right or left soles of feet): a 3-point aesthesiometer was used to determine minimal distance detected between 2 points (e.g., Corkin et al. 1970; Periyasamy et al. 2008). Raw scores were transformed to age-corrected Z-scores. normal = 0, impaired = 1: ≥2 standard deviations from Z-scored control mean.

The peripheral neuropathy (PN) index was tallied as follows: participants were given a score of zero if they were not impaired or had only unilateral impairment on any one of the 4 measures; a score of 1 was assigned for bilateral impairment on any 1 of the 4 measures; and a score of 2 was given for bilateral impairment on at least 2 of the 4 measures.

Quantitative Ataxia Testing

Standing balance was assessed using an ataxia battery (stand heel to toe, walk 10 steps on line, balance on one leg) in eyes open and eyes closed conditions. Age-corrected Z scores were summed for the eyes open and closed conditions separately (Sullivan et al. 2000).

Laboratory Measures

Blood samples (~40cc) were collected and analyzed by Quest Diagnostics for complete blood count with differential, comprehensive metabolic panel including liver enzymes), HIV and hepatitis C virus (HCV) screening.

MRI Acquisition and Analysis

Image Acquisition

MRI data of the brain were acquired on a 3 Tesla GE whole body MR system (General Electric Healthcare, Waukesha, WI) using an 8-channel phased-array head coil. Regional brain volume analyses were based on axial, T1-weighted, Inversion-Recovery Prepared SPGR images (TR=6.55/5.92 ms, TE=1.56/1.93 ms, TI=300ms, matrix = 256×256, thick=1.25 mm, skip=0 mm, 124 slices, field of view (FOV)=24cm). Routine phantom data were used to evaluate spatial fidelity. Drift was corrected by adjusting scanner calibration parameters when necessary to maintain spatial stability within manufacturer guidelines. Imaging data were available for 52 of the 57 HIV subjects.

Image Processing

MRI data were processed using an in-house pipeline (Pfefferbaum et al. 2018). Preprocessing of T1-weighted MRI data involved noise removal (Coupe et al. 2008) and segmentation of brain masks. To generate brain tissue segmentations (gray matter, white matter, and cerebrospinal fluid), average intensity maps were rigidly aligned via ANTS (Avants et al. 2008) before segmentation via Atropos (Avants et al. 2011). Brain tissue was parcellated into regions defined by the SRI24 atlas (Rohlfing et al. 2010) by non-rigidly registering the atlas to the average intensity map via ANTS (Avants et al. 2008). Gray matter volume was quantified for 23 bilateral supratentortial, 5 bilateral infratentorial (including 3 cerebellar regions, vermis, and pons), and 7 bilateral subcortical regions (amygdala, caudate, putamen, pallidum thalamus, parahippocampus, and hippocampus); volumes of corpus callosum, third and lateral ventricles were also quantified (resulting in 38 quantified regions). All brain volumes assessed were corrected for age and supratentorial brain volume corrected (Pfefferbaum et al. 2018).

Statistical Analysis

All statistics were performed using JMP Pro 13.2.0 (SAS Institute Inc. 2016). Two-group differences in the 4 objective measures, the PN index, and subjective neuropathy were assessed using Chi-square tests. Group differences in ataxia measures were evaluated by t-test. Relationships between subjective and objective neuropathy measures with demographic, HIV-related, laboratory, or brain volumes variables were assessed using a 3-group (e.g., NP index score of 0, 1, or 2; subjective symptom score of 0, 1, or 2) analysis of variance (ANOVAs). A nominal logistic regression was conducted to determine the percent of neuropathy (subjective and objective) explained by significantly associated variables. Finally, a data-driven approach including scores on the 4 objective tests, the PN index, subjective neuropathy, and variables associated with the latter two measures were entered into a JMP-based cluster analysis.

RESULTS

Study Participants

Table 1 presents demographic data demonstrating that uninfected-control and HIV-infected participants were matched with respect to age, sex, handedness, body mass index (BMI), systolic and diastolic blood pressure, and heart rate. The HIV relative to the control group had a higher percentage of African-Americans, lower education and socioeconomic status (SES) (Hollingshead 1975), a higher percentage of smokers and individuals with diabetes, more depressive symptoms [as assessed with the Beck Depression Inventory-II (BDI-II) (Beck et al. (1996))], and lower scores on the Dementia Rating Scale (DRS) (Mattis 1998). In addition to traditional indices (length of infection, current and nadir CD4 count, and viral load) and antiretroviral (ART) status, HIV-related variables included evidence for AIDS (i.e., an AIDS-defining illness such as candidiasis or Kaposi’s sarcoma or a CD4 prior nadir <200cells/μL), Global Assessment of Functioning (i.e., GAF) (Endicott et al. 1976), the Veterans Aging Cohort Study (VACS) index, (Tate et al. 2013), and laboratory assessment of HCV infection (Center For Disease Control and Prevention 2017).

Table 1.

Characteristics of the 2 groups: mean±SD / frequency count

	Control (n=109)	HIV (n=57)	p-value*
Demographics
N (men/women)	64/45	40/17	0.15
Age (years)	51.7±14.3	53.3±6.9	0.44
Handedness (Right/Left or Both)	97/12	52/5	0.22
Ethnicity♩ (Caucasian/African American/Asian/Other)	53/29/23/4	24/30/1/2	0.0005
Body Mass Index (BMI)	26.5±4.8	25.3±4.4	0.13
Systolic Blood Pressure	128.1±19.6	123.8±15.3	0.17
Diastolic Blood Pressure	77.8±12.3	75.8±10.8	0.32
Heart Rate	65.8±10.9	69.3±14.8	0.10
Education (years)	15.7±2.5	13.5±2.6	<0.0001
Socioeconomic Status# (SES)	29.1±14.6	40.7±15..2	<0.0001
Smoker (never/past or current)	93/9	34/20	<0.0001
Nicotine (daily)	1.0±2.9	2.8±5.1	0.07
Lifetime Alcohol (kg)	33.6±56.7	76.3±78.8	<0.0001
Diabetes (yes/no)	2/59	6/34	0.03
Beck Depression Index (BDI)	3.3±4.2	10.8±8.7	<0.0001
Dementia Rating Scale (DRS, total raw score)	139.5±3.0	135.7±5.2	<0.0001
HIV-Related Variables
Global Assessment of Functioning (GAF)	84.3±6.1	71.7±10.7	<0.0001
VACS Index	14.1±13.4	31.1±17.5	<0.0001
Hepatitis C Virus (HCV, positive/negative)	3/106	21/36	<0.0001
HIV onset age (years)	-	36.6±8.6	na
HIV duration (years)	-	16.7±7.8	na
Viral Load (log copies/mL)	-	2.1±1.1	na
CD4 cell count (100/mm3)	-	569.6±267.0	na
CD4 cell count nadir (100/mm3)	-	195.3±178.8	na
AIDS-defining event (yes/no)	-	30/27	na
ART (yes/no)	-	50/7	na
Nucleoside Reverse Transcriptase Inhibitors (NRTI, 0/1/2)	-	9/38/10	na
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI, 0/1	-	43/14	na
Protease Inhibitors (PI, 0/1/2)	-	29/11/17	na
Fusion Inhibitors (FI, 0/1)	-	49/8	na

t-tests used on continueous variables; X² used on nominal variables (e.g., handedness)

^♩self-defined: Other = Multiracial or Unknown

^#lower score = higher status

Neuropathy Measures

The HIV group had more impairments indicative of objective neuropathy than the control group (Figure 1a): perception of vibration (χ²=6.5, p=.04) [HIV group: normal=37, 6-10s=15, <5s=4; no feeling=1]; deep tendon ankle reflex (χ²=9.9, p=.007) [HIV group: normal=30, absent=1, hyperactive=1, hypoactive=15, could not detect=10]; position sense (χ²=8.6, p=.01) [HIV group: normal=48, 1 error=3, 2+ errors=6] and 2-point discrimination (χ²=7.5, p=.02). The PN index clearly distinguished the 2 groups (χ²=19.1, p<.0001) (Figure 1b).

Fig 1.

a) Each graph presents percent of total group (control or HIV) with no, unilateral, or bilateral impairments on measures of perception of vibration, tendon reflex, position sense, or 2-point discrimination. b) Graph of percent of total group (control or HIV) with a PI Index of 0=no impairment or only unilateral impairment, 1= bilateral impairment on a single measure of the 4, 2=bilateral impairment on 2 or more of the 4 measures. c) Graph of percent of total group (control or HIV) with 0=no symptoms, 1=mild symptoms, 2=moderate to severe symptoms of bilateral neuropathy.

The HIV-group reported a greater frequency of symptoms of subjective neuropathy (χ²=24.2 p<.0001) [HIV group: normal=39, mild pain=5 (all described as numbness), moderate to severe pain=13 (3 described as pain, aching or burning; 10 as numbness] (Figure 1c).

Relationships

Between Subjective Symptoms and Objective Signs

A total of 18 HIV participants reported symptoms of neuropathy (5 mild, 13 moderate to severe). Regardless of intensity, 3 described their symptoms as “pain, aching or burning” and 15 reported “numbness.” All 3 individuals who reported “pain, aching or burning” had at least 1 bilateral sign of objective neuropathy. Of those who reported numbness, 7 had no objective signs of neuropathy and 8 had at least 1 bilateral sign of objective neuropathy. However, there was no relationship between the subjective neuropathy score and the PN index (p=.66) or any of its components (i.e., perception of vibration (p=.53), deep tendon ankle reflex (p=.21), position sense (p=.47), 2-point discrimination (p=.41)).

PN index

Within the HIV group, a PN index score of 1 or 2 was associated with older age (F(57)=5.1, p=.009; score 0<1=2) (Figure 2a). The index was not related to presence of diabetes, number of depressive symptoms, smoking status, or lifetime quantity of alcohol consumed. Furthermore, the index was not influenced by HIV-related variables including ART medication class (i.e., NRTI, NNRTI, PI, FII) or related to any laboratory blood measures, including presence of HCV.

Fig 2.

Association between the PN Index and a) age (years) and b) volume of the cerebellar vermis (cc). Mean and standard deviation indicated. Inset shows anterior, sagittal, and inferior views of the brain with the cerebellar vermis pictured in blue.

Within the HIV group, those with a PN index of 1 or 2 had a smaller volume of the cerebellar vermis (F(52)=5.4, p=.008; score 0<1=2) (Figure 2b), but not with the volume of any of the other regions quantified.

A model including age and cerebellar vermis volume was significant (χ²=17.6, p=.002), explained 16% of the variance of the PN index, and was driven by both age (p=.03) and vermis volume (p=.02).

Subjective Neuropathy

Within the HIV group, moderate to severe subjective neuropathy was nominally associated with higher BDI-II scores (F(57)=2.6, p=.08; score 0<2) (Figure 3a) and significantly with poorer quality of life (F(52)=3.8, p=03; score 0=1<2) (Figure 3b) and a lower CD4 prior nadir (F(46)=4.0, p=.03; score 0=1<2)) (Figure 3c). Subjective neuropathy was not associated with lifetime alcohol consumed or days since last drink, but those who reported moderate to severe symptoms had significantly higher γ-glutamyl transferase (GGT) levels (F(55)=4.9, p=.01; score 0=1<2) (Figure 3d).

Fig 3.

Associations between subjective neuropathy scores and a) BDI-II scores, b) quality of life scores, c) CD4 prior nadir (cells/mm³), d) GGT levels (U/L), and e) precuneus volume (cc). Mean and standard deviation indicated. Inset shows anterior, sagittal, and inferior views of the brain with the precuneus pictured in blue.

Those with moderate to severe subjective neuropathy had a smaller volume of parietal precuneus (F(52)=4.2, p=.02; score 0=1>2) (Figure 3e), but not with the volume of any other region quantified, including cingulate (midposterior) volume (F(52)=.54, p=.60) and total cortical volume (F(52)=1.2, p=.30).

A model including BDI-II-derived depressive symptoms, quality of life, CD4 prior nadir, GGT, and parietal precuneus volume was significant (χ²=43.4, p<.0001), explained 65.2% of the variance in subjective neuropathy, and was driven by all 5 associated variables (each p<.0002).

Postural Stability

The HIV group performed worse than the control group on both the eyes open (t(154)=15.1, p=.0001) and closed (t(154)=12.6, p=.0005) quantitative ataxia conditions (Figure 4a). The PN index was not associated with either of the ataxia measures. Mild to severe subjective neuropathy was associated with worse performance on ataxia with eyes closed (F(53)=38, p=.03; score 0>2) (Figure 4b) but not open (p=.22).

Fig 4.

a) Performance on ataxia with eyes open and closed by group (control and HIV). b) relationship between subjective neuropathy scores and ataxia with eyes closed.

Cluster Analysis

Variables including the 4 objective measures, the PN index, subjective neuropathy, and associates of the latter two measures including age, CD4 prior nadir, GGT levels, BDI-II scores, quality of life scores, ataxia with eyes closed, and volumes of the precuneus and vermis were entered into a JMP-based cluster analysis. This data-driven approach assigned the 14 variables into 4 clusters: cluster 1 explained 16% of the overall variance and included the PN index, perception of vibration, tendon reflex, and age; cluster 2 explained 13% of the total variance and included depressive symptoms, quality of life, GGT, and precuneus volume; cluster 3 explained 12% of the variance and included subjective neuropathy, ataxia with eyes closed, and CD4 prior nadir; cluster 4, explaining 10% of the variance included 2-point discrimination, position sense, and vermis volume.

DISCUSSION

As was expected, the HIV relative to the control group had a greater intensity of subjective symptoms of neuropathy, a higher incidence of objective neuropathy, and evidence for postural instability based on quantitative ataxia results. A clear relation between subjective and objective neuropathy scores was not forthcoming (cf., Cherry et al. 2005; McArthur 1998) and therefore supported their independence. A higher incidence of objective neuropathy was associated with older age and volume of the cerebellar vermis. A greater intensity of subjective symptoms of neuropathy was associated with more depressive symptoms, reduced quality of life, a low CD4 prior nadir, GGT levels, and precuneus volume. Moderate to severe subjective neuropathy was also associated with worse performance on ataxia with eyes closed.

Unlike previous reports, the current study did not find significant contributions of HCV (but see Cherry et al. 2010; Mapoure et al. 2018), ART (Cherry et al. 2009; but see Lee et al. 2015), or diabetes (Evans et al. 2011) to either objective signs or self-report of symptoms of neuropathy. An association of the PN index with older age, however, was notable (Chen et al. 2013; Saylor et al. 2017) and expected as the incidence of neuropathy is higher, even in healthy aging (Brouwer et al. 2015). This finding highlights challenges facing an aging HIV population (Nookala et al. 2017).

Although no studies to date have implicated the vermis in the pathophysiology of frequently studied neuropathies (e.g., alcoholic, diabetic, HIV- associated), several disorders with symptoms and signs of neuropathy are associated with smaller volume of the cerebellar vermis. A syndrome referred to as CANVAS features ataxia, vestibular areflexia, and neuropathy and includes cerebellar atrophy involving anterior and dorsal vermis (Szmulewicz et al. 2011a; Szmulewicz et al. 2011b; Taki et al. 2018). Similarly, ARCAS, an autosomal recessive ataxia, includes signs of distal sensorimotor neuropathy and atrophy of the superior vermis (Prodi et al. 2013; Vermeer et al. 2008; Vermeer et al. 1993). A case study of 3 incidents of infection with the human T-lymphocyte virus reported peripheral neuropathy of the lower limbs and atrophy of the superior vermis (Castillo et al. 2000). Whether the vermis is principally involved in HIV-related peripheral neuropathy will require further investigation. Loss of pain and temperature sensation following thalamic lesions has led to the hypothesis that the thalamus is involved in nociception (Dejerine and Roussy 1906; Garcin and Lapresle 1954; Head and Holmes 1911; Schuster 1937). Furthermore, performance on 2-point discrimination of the index fingers in healthy controls has recently been found to be associated with volume of the thalamus (Schmidt-Wilcke et al. 2018). The current study did not find a relationship between the PN index and thalamic volume; the volume of the total thalamus, however, was smaller in the combined group (i.e., unilateral+bilateral) of those with position sense impairment (χ²=4.3 p=.04). Future studies focused on high-resolution imaging and segmentation of thalamic subregions (cf., Tourdias et al. 2014) may provide evidence for involvement of specific thalamic nuclei in objective neuropathy.

Comporting with the literature, this study identified relationships between HIV-related neuropathic pain and depressive symptoms (Ellis et al. 2010; Robinson-Papp et al. 2010) and poor quality of life (Keltner et al. 2012). A relation between low CD4 prior nadir and neuropathic pain symptoms was not expected in the post-ART era (cf., Childs et al. 1999), but suggests that low CD4 counts increase the risk for HIV-associated neuropathy. While direct measures of heavy alcohol use (i.e., total lifetime alcohol consumed and recency of drinking) were not related (Bauer et al. 2005; Benevides et al. 2017), GGT levels, often used as an indirect biomarker of recent alcohol consumption (Andresen-Streichert et al. 2018), were higher in those with moderate to severe subjective neuropathy relative to those without neuropathy. The relationship between GGT and neuropathy, however, may not be mediated by alcohol: GGT has been associated with limited joint mobility and neuropathic pain symptoms in diabetics, independent of alcohol consumption, BMI, and metabolic control of diabetes (Arkkila et al. 2001). The relation between GGT and symptomatic neuropathy has also been shown in diabetic She Chinese (Lin et al. 2011) and Korean (Cho 2010) populations. Rather than as a marker for recent alcohol consumption, GGT has been hypothesized to serve as an index of oxidative stress (Lee et al. 2004; Lim et al. 2004) in the etiology of neuropathy (El Boghdady and Badr 2012) and thus may reflect an underlying mechanisms in HIV-related peripheral neuropathy.

This study reports a nominal association between subjective symptoms of neuropathy and postural instability. Although a review of studies focused on the association between peripheral neuropathy and gait and balance deficits in people living with HIV found no significant associations (Berner et al. 2017), peripheral neuropathy is related to joint kinematic impairment in diabetics (Mustapa et al. 2016).

Here although specifically tested, volume of the posterior cingulate was not associated with symptoms of neuropathy (cf., Hellmuth et al. 2016; Keltner et al. 2017; Keltner et al. 2014; Pfefferbaum et al. 2009). Instead, a relation was identified between subjective neuropathy and volume of the precuneus, which participates in reflective self-awareness (Kjaer et al. 2002; Lou et al. 2004) as has been suggested by a number of imaging studies (Cavanna and Trimble 2006; Fiset et al. 1999; Lou et al. 2005). Although distinct regions, the posterior cingulate and the precuneus have the highest level of metabolism in the brain (Gusnard et al. 2001; Laureys 2004), and are together considered pivotal for conscious information processing (Vogt and Laureys 2005).

One limitation of the current study is that despite a reasonable sample size, many relations were evaluated. We would argue, however, that these relations were considered in the context of nominal regressions, which demonstrated, after accounting for significant associations, persisting relations between neuropathy measures and brain volumes. Furthermore, the results of the cluster analysis provide data-driven support for dissociable functions of the vermis and precuneus: whereas the vermis clustered with performance on position sense and 2point discrimination, precuneus was associated with more depressive symptoms, poor quality of life, and high levels of GGT.

A more general limitation of this study is a lack of consensus regarding diagnosis of HIV-related neuropathy. For example, although the CHARTER studies describe objective measures to diagnose HIV-associated sensory neuropathy, their studies on CNS associations appear to rely on self-report of subjective symptoms (Keltner et al. 2017; Keltner et al. 2014).

In conclusion, this study provides support for a CNS substrate of peripheral neuropathy. Specifically, objective signs of neuropathy were associated with smaller volumes of cerebellar vermis, whereas subjective symptoms of neuropathy were associated with smaller volumes of the precuneus. Although these central substrates of neuropathy remain to be confirmed, the current study contributes to a growing body of literature showing CNS changes relevant to both signs and symptoms of neuropathy.