**6. Cognitive impairment after shunt surgery**

On the other hand, other studies have demonstrated that patients with iNPH can be impaired in broader cognitive domains; the definition of fronto-subcortical dementia has therefore to be considered reductive, given that the cognitive deficits observed in iNPH can extend beyond executive function, attention, working memory, and episodic memory to visuoperceptual and

Saito et al. [64] evaluated 32 iNPH patients, 32 AD patients and 30 healthy elderly controls, using an extensive and comprehensive neuropsychological battery to investigate all the different cognitive domains: language, memory, executive functions, visuospatial and visuoperceptual abilities, attention, and mental processing speed. Their results suggested that iNPH is associated with impairment in various aspects of cognition involving both frontal-executive and posterior-cortical functions, such as visuoperceptual and visuospatial abilities. In particular, defective performances were found on the visual discrimination and visual counting tasks; visuoperceptual and visuospatial abilities in iNPH patients were more severe than in those with AD, whereas the degree of memory impairment was comparable to that in AD

The main involvement of visuospatial functions was observed also by Bugalho et al. [65]; 17 iNPH patients have been compared with 14 healthy controls and the authors suggested that visuospatial deficits, and not executive dysfunction, could be an early sign of cognitive dete-

Some studies, instead, focused on the nature of the memory deficit in order to identify a specific pattern. Walchenbach et al. [63] analyzed 51 iNPH patients, administering the MMSE and neuropsychological tests assessing both cortical (language, visuoperceptual skills and praxis, and memory functions) and fronto-subcortical functions (mental speed, concept shifting, and abstract reasoning). They suggested that the pattern of memory deficit in iNPH is of the frontal lobe type, in which recall is disproportionately affected with respect to recognition, while in patients with AD recall and recognition are both impaired. Ogino et al. [46] observed memory impairment in iNPH, but they found that impairment of executive functions was more severe, while impairment of memory and orientation was milder in patients with iNPH than in those with AD. On the contrary, Saito et al. [64] found that both recognition and recall were impaired in a similar fashion both in iNPH and AD groups, thus suggesting that memory

Therefore the data of the literature seem to confirm a wide range of cognitive decline in iNPH patients and according to Devito et al. [66] we can conclude that: "in some cases it may be qualitatively similar to normal aging, in others it may manifest as progressive dementia with

However, there is no general agreement on the neuropsychological instruments to be used in assessing cognitive deficits. Bugalho et al. [65] employed a cognitive assessment protocol focused on various cognitive domains (global cognitive function, verbal memory, impulse control, verbal fluency, working memory, attention, visuospatial reasoning, and visuoconstructive abilities) and also on mood and hand dexterity. Devito et al. [66] in a not recent but very interesting paper have reviewed possible application of clinical neuropsychology and

rioration in iNPH patients regardless of the severity of global cognitive dysfunctions.

impairment in iNPH is not exclusively ascribable to frontal lobe dysfunction.

gait disturbance, clinically similar to Alzheimer's or Parkinson's disease".

visuospatial functions [26, 56, 62, 63].

54 Hydrocephalus: Water on the Brain

patients.

iNPH is considered a potentially reversible dementia and as described above the treatment of choice is ventriculo-peritoneal or atrial shunt device placement. When considering the global outcome, there is a general agreement about the fact that short-term results are more likely to be influenced by shunt-associated risks, while long-term results are more influenced by other factors, such as concomitant neurodegenerative and cerebrovascular diseases; the one-year post-shunt period can be considered a determinant of long-term results of the treatment [68].

Shunt surgery can help to reduce cognitive impairment, especially if it is performed during the early stage of deterioration, as it will be more detailed below; if the pressure is not relieved quickly by a shunt patients with severe iNPH will in fact develop overall cognitive impairment [9, 50]. This deterioration is only partially reversible as reported by Andrèn et al. [69], who described the effects of waiting for at least 6 months before surgery and compared the outcome with that seen in patients who waited for less than 3 months. The patients of the first group significantly deteriorated; both groups ameliorated at the same size after surgery, but since the symptoms of the patients of the first group had worsened while waiting, their final outcome was significantly poorer.

Indeed, most studies report an improvement after surgery, but there is no general agreement neither about cognitive functions are more likely to be restored after shunt placement nor about possible indicators with a predictive value.

outcome. However, no cognitive evaluation was performed; the patients were evaluated using only a specific scale for iNPH and a Comorbidity Index to account for additional dis-

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In some studies the response to shunt has been related to the presence/absence of findings consistent with Alzheimer pathology on cortical biopsy or CSF sampling, but the results are contradictory. Golomb et al. [75] at a mean post-shunt follow-up of 4.3 months, found a small but significant improvement in tests of attention and processing speed only in patients with a cortical biopsy negative for Alzheimer pathology. These data were confirmed by Savolainen et al. [76], who studied 51 patients under 75 years of age with possible iNPH; 25 of these patients underwent shunt surgery. One year after shunt placement, 72% of the patients showed a good recovery in activities of daily living, 58% experienced improved urinary incontinence, and 57% walked better; the positive effects of the shunt were still present at 5 years. However, no change on neuropsychological test performances was found, leading the authors to conclude that neuropsychological evaluation, and the MMSE in particular, is of little value in diagnosing iNPH. Eight patients with shunt and nine without shunt died in the course of the five-year follow-up. The patients with a positive biopsy for Alzheimer pathology had worsened more than those with a negative biopsy after 1 year, but mortality was not

On the contrary, Pyykko et al. [77] did not find any differences in CSF Aβ levels or tau biomarkers between shunt-responding and non-responding iNPH patients, the latter, however, were older; no identification of a cognitive profile was identified as no formal neuropsychological evaluation was performed in order to better define the response to shunt placement. The same results have been obtained by Yasar et al. [78] the presence of AD pathology in 26% of the population with iNPH did not significantly influence the clinical response to shunt

Some studies have focused on the caregiver, interpreting a change of caregiver burden as an indirect sign of clinical/cognitive modification. A decrease in caregiver burden was reported by Kazui et al. [79] in the caregivers of 81 iNPH patients 1 year after the patients underwent the shunt procedure; the improvement of cognitive impairment was identified as the major factor contributing to the reduced caregiver burden, even though a formal neuropsychologi-

Petersen et al. [80] evaluated the impact of shunt surgery on social function and health-related quality of life in 37 patients 6 months after the procedures; non cognitive evaluation was performed. Twenty-four (65%) showed a clinical improvement, while in 31(86%) quality of life returned almost within normal range as a consequence of their greater independence. Despite these good results, the caregiver burden was reduced only in caregivers to male patients.

In order to better understand the mechanisms underlying iNPH, some authors looked for correlations between cognitive changes and metabolic functioning in specific cerebral regions. Calcagni et al. [81] performed F-FDG PET/CT scanning 3 days before and 1 week after shunt placement in a small group of iNPH patients. After surgery the global glucose rate significantly increased in all patients, while the ventricular size did not change. Clinical status and

eases, which could influence the clinical presentation and outcome.

increased in these patients.

cal evaluation was not performed.

surgery.

Iddon et al. [50], as already mentioned, studied 11 patients (5 demented and 6 non-demented); the demented patients showed a significant improvement after shunt surgery, whereas in the not demented patients who presented frontal deficits no improvement could be detected. The same authors suggested that even successful shunt surgery may not alleviate all aspects of cognitive impairment.

Thomas et al. [70] reported that verbal memory and psychomotor speed appear to be the functions more likely to respond to shunt surgery; 22 (53.2%) out of 42 patients at least 3 months after surgery showed an overall cognitive improvement (defined as a four-point improvement on MMSE or an improvement by 1 standard deviation in 50% of the neuropsychological tests) and a significant improvement in tests of verbal memory and psychomotor speed. However, in patients who, at baseline, presented impairment of both verbal memory and visuoconstructive functions, the cognitive improvement was less pronounced; on this basis the authors suggested that baseline cognitive scores may distinguish patients responsive to surgery, that is, the greater the impairment the smaller the recovery. Other studies report an improvement of memory, frontal lobe, and visuoconstructive functions at 6 months [71] and 1 year [62] after shunt surgery; in the paper by Mataró et al. [71] a concomitant significant increase in the global corpus callosum size on MRI was also reported.

In a series of 47 consecutive patients, Hellstrom et al. [72] reported that most of the wide range cognitive functions are typically affected in iNPH improved at 3 months after shunt placement; contrary to the study by Mataró et al. [71] the more severe functional deficits showed the greatest improvements, although they were not completely restored to the levels present in healthy controls.

Saito et al. [64] found that frontal functions (assessed using the TMT and FAB) were improved at 1 year after the shunt procedure in 26 out of 32 patients; the authors excluded that the improvement observed could be ascribed to a possible practice effect. Actually, this is an important question which can occur when patients are evaluated after a short interval of time.

Other studies have followed the patients for a longer period, identifying as outcomes the evolution toward dementia and the survival. Koivisto et al. [73] in a study with a median followup of 4.8 years, found an increased risk of dementia and cognitive decline even in patients who had initially responded to the shunt. At the end of the follow-up period, 117/146 (80%) had cognitive decline and 67/146 (46%) clinical dementia, mainly AD and vascular dementia. In a multivariate analysis, memory deficit as a first symptom emerged as a predictor of dementia. Interestingly, eight (5%) patients who at baseline had the full triad of symptoms presented dementia without any other signs of neurodegenerative or vascular disease.

Golz et al. [74] followed up 147 patients for 6 years after surgery through yearly examinations; 69 died during the follow-up, 61 reached the six-year assessment. Of these 61 patients, 59% had an excellent outcome, 15% satisfactory benefit, and 26% unsatisfactory results. The authors concluded that shunt surgery can be considered a safe procedure with a favorable outcome. However, no cognitive evaluation was performed; the patients were evaluated using only a specific scale for iNPH and a Comorbidity Index to account for additional diseases, which could influence the clinical presentation and outcome.

Indeed, most studies report an improvement after surgery, but there is no general agreement neither about cognitive functions are more likely to be restored after shunt placement nor

Iddon et al. [50], as already mentioned, studied 11 patients (5 demented and 6 non-demented); the demented patients showed a significant improvement after shunt surgery, whereas in the not demented patients who presented frontal deficits no improvement could be detected. The same authors suggested that even successful shunt surgery may not alleviate all aspects of

Thomas et al. [70] reported that verbal memory and psychomotor speed appear to be the functions more likely to respond to shunt surgery; 22 (53.2%) out of 42 patients at least 3 months after surgery showed an overall cognitive improvement (defined as a four-point improvement on MMSE or an improvement by 1 standard deviation in 50% of the neuropsychological tests) and a significant improvement in tests of verbal memory and psychomotor speed. However, in patients who, at baseline, presented impairment of both verbal memory and visuoconstructive functions, the cognitive improvement was less pronounced; on this basis the authors suggested that baseline cognitive scores may distinguish patients responsive to surgery, that is, the greater the impairment the smaller the recovery. Other studies report an improvement of memory, frontal lobe, and visuoconstructive functions at 6 months [71] and 1 year [62] after shunt surgery; in the paper by Mataró et al. [71] a concomitant significant

In a series of 47 consecutive patients, Hellstrom et al. [72] reported that most of the wide range cognitive functions are typically affected in iNPH improved at 3 months after shunt placement; contrary to the study by Mataró et al. [71] the more severe functional deficits showed the greatest improvements, although they were not completely restored to the levels present

Saito et al. [64] found that frontal functions (assessed using the TMT and FAB) were improved at 1 year after the shunt procedure in 26 out of 32 patients; the authors excluded that the improvement observed could be ascribed to a possible practice effect. Actually, this is an important question which can occur when patients are evaluated after a short interval of time. Other studies have followed the patients for a longer period, identifying as outcomes the evolution toward dementia and the survival. Koivisto et al. [73] in a study with a median followup of 4.8 years, found an increased risk of dementia and cognitive decline even in patients who had initially responded to the shunt. At the end of the follow-up period, 117/146 (80%) had cognitive decline and 67/146 (46%) clinical dementia, mainly AD and vascular dementia. In a multivariate analysis, memory deficit as a first symptom emerged as a predictor of dementia. Interestingly, eight (5%) patients who at baseline had the full triad of symptoms presented dementia without any other signs of neurodegenerative or vascular disease.

Golz et al. [74] followed up 147 patients for 6 years after surgery through yearly examinations; 69 died during the follow-up, 61 reached the six-year assessment. Of these 61 patients, 59% had an excellent outcome, 15% satisfactory benefit, and 26% unsatisfactory results. The authors concluded that shunt surgery can be considered a safe procedure with a favorable

increase in the global corpus callosum size on MRI was also reported.

about possible indicators with a predictive value.

cognitive impairment.

56 Hydrocephalus: Water on the Brain

in healthy controls.

In some studies the response to shunt has been related to the presence/absence of findings consistent with Alzheimer pathology on cortical biopsy or CSF sampling, but the results are contradictory. Golomb et al. [75] at a mean post-shunt follow-up of 4.3 months, found a small but significant improvement in tests of attention and processing speed only in patients with a cortical biopsy negative for Alzheimer pathology. These data were confirmed by Savolainen et al. [76], who studied 51 patients under 75 years of age with possible iNPH; 25 of these patients underwent shunt surgery. One year after shunt placement, 72% of the patients showed a good recovery in activities of daily living, 58% experienced improved urinary incontinence, and 57% walked better; the positive effects of the shunt were still present at 5 years. However, no change on neuropsychological test performances was found, leading the authors to conclude that neuropsychological evaluation, and the MMSE in particular, is of little value in diagnosing iNPH. Eight patients with shunt and nine without shunt died in the course of the five-year follow-up. The patients with a positive biopsy for Alzheimer pathology had worsened more than those with a negative biopsy after 1 year, but mortality was not increased in these patients.

On the contrary, Pyykko et al. [77] did not find any differences in CSF Aβ levels or tau biomarkers between shunt-responding and non-responding iNPH patients, the latter, however, were older; no identification of a cognitive profile was identified as no formal neuropsychological evaluation was performed in order to better define the response to shunt placement.

The same results have been obtained by Yasar et al. [78] the presence of AD pathology in 26% of the population with iNPH did not significantly influence the clinical response to shunt surgery.

Some studies have focused on the caregiver, interpreting a change of caregiver burden as an indirect sign of clinical/cognitive modification. A decrease in caregiver burden was reported by Kazui et al. [79] in the caregivers of 81 iNPH patients 1 year after the patients underwent the shunt procedure; the improvement of cognitive impairment was identified as the major factor contributing to the reduced caregiver burden, even though a formal neuropsychological evaluation was not performed.

Petersen et al. [80] evaluated the impact of shunt surgery on social function and health-related quality of life in 37 patients 6 months after the procedures; non cognitive evaluation was performed. Twenty-four (65%) showed a clinical improvement, while in 31(86%) quality of life returned almost within normal range as a consequence of their greater independence. Despite these good results, the caregiver burden was reduced only in caregivers to male patients.

In order to better understand the mechanisms underlying iNPH, some authors looked for correlations between cognitive changes and metabolic functioning in specific cerebral regions. Calcagni et al. [81] performed F-FDG PET/CT scanning 3 days before and 1 week after shunt placement in a small group of iNPH patients. After surgery the global glucose rate significantly increased in all patients, while the ventricular size did not change. Clinical status and independence in daily life was measured using scales evaluating activities of daily living, gait, urinary incontinence, cognition (the modified Rankin scale, the Krauss scale, the Larsson categorization system, the Stein-Langfitt scale); a relationship between functional data and clinical assessment was found only after surgery, not before, while changes both in FDG uptake and in global cognitive functioning measured by MMSE were reported in 3 out of 19 subjects. A further study by the same authors [82] confirmed these data. In an earlier study, Dumarey et al. [83] observed an improvement of regional blood flow in the bilateral dorsolateral frontal and left mesiotemporal cortex in patients who had previously seen to be clinical responders to the spinal tap test. All these data show that functional changes occur early than morphological ones and seem to suggest a prompt metabolic response by neuronal cells possibly related to neuronal plasticity. As yet, however, functional imaging does not seem to provide prognostic information making it possible to identify patients who will benefit from surgery.

On the contrary, the degree of Alzheimer pathology is reported to be important in predicting the response to surgery in the study by Hamilton et al. [85]; out of 37 patients 12 showed a negative biopsy, the remaining 25 subjects showed a high percentage (above 60%) not only of neuritic plaques but also of neurofibrillary tangles, which indicates the presence of tau pathology. Patients with moderate-to-severe Aβ and tau pathology showed more severe baseline cognitive impairment and poorer performance postoperatively on NPH symptom severity scales and measures of cognition, while patients with mild Alzheimer pathology responded well to shunting. The authors suggest that some patients may be relatively unimpaired by the presence of cortical Alzheimer pathology; the different results obtained in respect to previous

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Leinonen et al. [86] evaluated the predictive value of brain biopsy for the long-term outcome of iNPH in 468 patients with possible iNPH; the presence of beta-amyloid was detected in 197 (42%) patients, and together with tau pathology in 44 cases (9%), but it did not affect the

On the other hand, Alzheimer pathology as neuritic plaques can be present also in the brain of normal healthy individuals [87]; therefore, in order to ameliorate the differentiation of diagnosis, also CSF biological markers have been investigated. The specific combination of both low CSF beta-amyloid (Aβ)-42 and elevated CSF phosphorylated tau (P-tau) in fact is considered the biological signature of Alzheimer's disease, where low Aβ levels reflect amyloid

In 2007, Kapaki et al. [89] studied 85 patients subdivided in 67 with AD and 18 with iNPH, and 72 healthy controls. Aβ-42 levels were significantly decreased in both diseases as compared with controls, while P-tau levels were significantly increased only in Alzheimer's patients; therefore the authors concluded that P-tau may be a useful marker in the differentiation of

In the same year Agren-Wilsson et al. [90] studied 62 iNPH patients, 26 patients with subcortical vascular encephalopathy and 23 healthy controls. The CSF concentration of neurofilament light protein was elevated in iNPH and vascular encephalopathy compared with the controls, levels of total tau (T-tau), P-tau, and Aβ-42 were lower in iNPH compared with vascular encephalopathy and controls; all markers except Aβ-42 were significantly elevated after shunt surgery. These results lead the authors to conclude that not a specific marker but the combined pattern of more markers can distinguish iNPH from vascular patients and controls.

Lower CSF levels of both T-tau and P-tau and amyloid precursor protein have been reported also by Jeppsson et al. [91] in 28 iNPH patients compared with 20 healthy controls, while neurofilament light protein was elevated. After surgery there was an increase; these data have been interpreted as due to a reduced periventricular metabolism and axonal degeneration

Kang et al. [92] found lower CSF Aβ-42 levels and lower P-tau levels in 35 iNPH patients in respect to the control reference values; tau levels correlated with gait disturbance and CSF P-tau/Aβ ratios were significantly higher in patients who did not respond to shunt surgery.

deposition and high tau levels indicate a prevalent non specific neuronal damage [88].

studies are explained by the different methods employed.

survival.

iNPH from Alzheimer's disease.

rather than to a major cortical damage.
