Normal pressure hydrocephalus (NPH) is characterized by pathologically enlarged ventricles without elevated cerebrospinal fluid (CSF) pressure along with a triad of clinical symptoms including gait disturbances, urinary incontinence, and cognitive impairment. NPH is evaluated with lumbar drain trials (LDTs) where CSF is removed over several days to determine if patients would benefit from ventricular shunting. Candidate selection and success for these surgeries remains challenging because other diseases such as Alzheimer’s disease (AD) share common features with NPH in cognitive impairment and enlarged ventricles. Prior research has found that 20%-40% of presumed NPH cases have AD pathology as determined by brain biopsy or autopsy. CSF biomarkers of AD can be altered in NPH and are not always conclusive, complicating the interpretation of results when formulating diagnoses and prognoses. Studies to refine the analyses of AD CSF biomarkers in NPH are needed. We aimed to examine the frequency of CSF biomarker results among patients presenting for NPH evaluations with LDTs.

62 patients presented for LDTs upon physician recommendations. CSF specimens were sent to Mayo Clinic Laboratories for Alzheimer Disease Evaluation (ADEVL) that utilizes Elecsys (Lenexa, KS) CSF electrochemiluminescence immunoassays (Roche Diagnostics, Basel, Switzerland) to measure levels of amyloid-beta 42 (Aβ42), total tau (t-tau), and phosphorylatedtau (p-tau), and p-tau:Aβ42 ratio. Results were classified based on interpretation through the Amyloid/Tau/Neurodegeneration (ATN) framework1: 1) AD - biomarker profile consistent with AD pathologic change, 2) non-AD profile - biomarker levels normal or inconsistent with AD pathologic change, or 3) indeterminate - biomarkers were incongruous with only one or two abnormal levels of Aβ42, t-tau, p-tau, or ptau: Aβ42. Indeterminate cases may represent altered protein levels due to CSF dynamics or AD-related pathologic change. In reviewing recent research on CSF dynamics and AD biomarkers in NPH2 a p-tau threshold of 15 pg/mL was derived and implemented such that cases with Aß42 <=1026 pg/mL and p-tau <15 pg/mL were designated as suspected non-AD, and those with Aß42 <=1026 pg/mL and p-tau >15 pg/mL were designated suspected AD.

Of the 62 LDT cases, 12 (19.35%) were classified as AD, 31 (50%) were indeterminate and 22 (35.48%) were non-AD. Of the 31 indeterminate cases, 21 (33.87% of the overall sample) were suspected non-AD and 7 (11.29% of the full sample) were categorized as suspected AD.

Our findings show that 20%-30% of patients presenting for LDT showed evidence for AD-type pathologic change, consistent with prior reports of AD pathology in cases of possible NPH. Half of all LDT cases had indeterminate AD CSF biomarker results, the interpretations of which were confounded by the potential alterations of CSF biomarkers levels due to NPH independent of AD. Our findings emphasize the need to establish better approaches to interpreting CSF AD biomarkers in evaluating NPH. Future research should examine the discriminative utility of CSF AD biomarkers and the selected p-tau threshold in indeterminate cases for predicting response to LDT and shunting.

Central nervous system (CNS) infections with the dematiaceous fungus Cladophialophora bantiana (C. bantiana) are extremely rare, with approximately 120 confirmed cases reported as of 2016. C. bantiana is a highly neurotropic and thermotolerant fungus found in soil worldwide. The mode of entry into the CNS remains unknown, but inhalation of fungal spores or subcutaneous trauma have been suggested. Entry of fungal spores can cause cerebral phaeohyphomycosis with the main clinical manifestation of a brain abscess. Symptoms are non-specific and can include headache, fever, hemiparesis, aphasia, visual disturbances, and confusion. C. bantiana cerebral phaeohyphomycosis occurs in both immunocompetent and immunocompromised individuals, with a slightly higher prevalence in immunocompetent males for unknown reasons. Diagnosis is often delayed due to its nonspecific presentation and prevalence in individuals without pre-existing immunological disease. Prognosis is poor, with mortality rates of approximately 70% despite aggressive treatment. Treatment is not standardized but may include several anti-fungal agents and surgical intervention. Case reports documenting the variability seen with cerebral phaeohyphomycosis by C. bantiana can provide valuable insight into this emerging disease. C. bantiana’s neurotropic propensity also warrants cognitive investigation of the disease; however, there are currently limited descriptions of cognitive findings in published case reports of C. bantiana CNS infections.

Here, we describe a case of a 35-year-old immunocompetent, college educated male with a CNS C. bantiana infection, presumably following a fall while biking in Costa Rica. First symptoms included left sided facial palsy, headache, and hand weakness, prompting extensive diagnostic workup, with diagnosis of C. bantiana infection confirmed 8 months after symptom onset. Initial treatment included anti-fungal agents and steroids, but his course of infection was complicated by infectious vasculitis with posterior circulation infarcts and obstructive hydrocephalus requiring ventriculoperitoneal shunt placement two years following the fungal infection diagnosis. The most recent brain MRI revealed encephalomalacia in global periventricular areas, two small masses, likely representing small fungal phlegmons, and enhancing lesions in the upper cervical spinal canal.

The patient reported cognitive changes following the infarcts and shunt placement including difficulties with spatial navigation, following directions, and articulating thoughts. Memory concerns and lapses in judgment were also reported. Results from a neuropsychological evaluation revealed high average baseline intellectual abilities with decrements in visuospatial processing, processing speed, executive functioning, and aspects of memory stemming from his executive dysfunction. At the time, his cognitive profile suggested parietal and frontosubcortical systems disruption meeting criteria for mild cognitive impairment. Two years later, the patient reported continuing cognitive difficulties prompting a follow-up neuropsychological evaluation. Results were similar to his first evaluation, revealing deficits in aspects of visuospatial processing, decreased verbal and visual learning, bradyphrenia and processing speed deficits, and difficulties with visual planning and organization. Minimal anxiety and depression, but increased apathy and executive dysfunction were endorsed on self-report measures.

This case report highlights neurological sequela resulting from CNS infection with C. bantiana, -with a course complicated by subsequent strokes, hydrocephalus, and cognitive impairment-, and contributes additional insight into the relatively limited existing reports of an extremely rare but emerging disease.

Cognitive impairment and apathy are well-documented features of idiopathic normal pressure hydrocephalus (iNPH). However, research examining other neuropsychiatric manifestations of iNPH is scant, and it is unknown whether the neuropsychiatric presentation differs for iNPH patients with comorbid Alzheimer’s disease (AD) versus iNPH without AD. This study aims to advance our understanding of neuropsychiatric syndromes associated with iNPH.

Fifty patients from Butler Hospital’s Normal Pressure Hydrocephalus Clinic met inclusion criteria. Caregiver ratings on the Frontal Systems Behavior Scale (FrSBe) were examined to appraise changes in apathy, executive dysfunction, and disinhibition. Patients also completed cognitive tests of global cognition, psychomotor speed, and executive functioning. AD biomarker status was determined by either amyloid-beta (Aβ) positron emission tomography (PET) imaging or cerebrospinal fluid (CSF) total tau to Aβ-42 ratio.

Results revealed clinically significant elevations on the FrSBe’s apathy and executive dysfunction scales and modest correlations among these scales and cognitive measures. Of the 44 patients with available neuroimaging or CSF draw data, 14 presented with comorbid AD. Relative to the iNPH-only group, the iNPH + AD group showed a larger increase from pre-illness to current informant ratings on the executive dysfunction scale, but not the apathy or disinhibition scales.

These results replicate and extend prior research by identifying apathy and executive dysfunction as prominent neuropsychiatric symptoms of iNPH and suggest comorbid AD exacerbates dysexecutive behaviors. Future research is warranted to examine the effects of comorbid AD pathology in response to shunt surgery for iNPH, neuropsychiatric symptom changes, and resultant caregiver burden.